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Authored By: Nina Meins

At the age of 32, I was an active, working wife and mother until deep vein thrombosis (DVT) changed my life. I never had issues with blood clots, in fact, I knew nothing about them.  I had taken birth control pill for 14 years, which I previously stopped to become pregnant with my first child.  The first pregnancy progressed with no complications.  My second pregnancy would prove that anyone’s life can change in an instant.  Not only did my life get turned upside down, but my husband, children, and immediate family and friends felt the effects of my health problems.

It was May 2006 and I was pregnant with my second child.  At the start of the pregnancy, nothing seemed abnormal – I had no complications or major health problems.  However, at 31 weeks, the pregnancy began to get complicated when I was hospitalized with pre-term labor.  The two week hospitalization was followed by strict orders for complete bed rest for the remainder of my pregnancy. At the end of week 36, I went back to the hospital with labor contractions.  Having delivered my first child via c-section, there was no question that this delivery was to following the same course.   I ended up delivering my son the night of May 16^th.  He was a month early, but healthy as a horse.

The second morning after my delivery, I was examined by my doctor and given the clearance to become mobile.  Anxiously, I followed the doctor’s orders.

It was at that point that I noticed my left leg was swollen and heavy – from toe to hip.  An ultrasound was performed, revealing a massive DVT.  I was immediately transferred from the Women’s Hospital to a general hospital where the medical staff was more familiar with treating DVT.  The hospital staff decided to treat me with a low molecular weight heparin rather then a Heparin drip, even though an IV was in place. I was also started on Coumadin.

Less than 24 hours after starting the anticoagulant therapy, I developed chest pain.  I was put on oxygen.  The next morning the hospital staff talked about releasing me. My INR was far from an optimal range, I was still on oxygen, and no one seemed to understand why!  Finally, the staff decided to send me for a CT scan of my lungs.  The test revealed that a pulmonary embolism (PE) was responsible for my shortness of breath.  As a result, I remained in the hospital for another three days until my INR was in the appropriate range.

At this point, I was having a hard time understanding what was happening.  My family and I did not know what questions to ask.  I had an infant to think about as well as my three-year old daughter and husband.  I was trying to nurse or pump milk while I was receiving oxygen.   The thought of dying never crossed my mind because I was focused on my baby.

Three months later, I saw a specialist.  On my first a new blood clot was found in my leg. When the specialist looked at my old hospital charts he learned that I had been diagnosed with two different clotting disorders during my previous hospitalization.  With this new information in hand, and the new clot in my leg, it was decided that an IVC filter would be appropriate.

I now see a vascular doctor at the University of Arkansas for Medical Sciences in Little Rock.  He placed three venous stents in my abdomen in April 2008.  In the process, he learned that my original clot, which is now calcified, extends from mid-thigh to my navel and that the main vein is completely damaged.  The venous stents help the blood flow back to my heart easing my shortness of breath caused by the lack of oxygen.

This experience has taught me to listen to your body, ask questions, (regardless if you think they are stupid or not), and get second, even third, opinions.  I now understand my purpose in this life. I know understand that my strengthening patient advocacy is one of my purposes in life.  Raising awareness about DVT/PE symptoms and risk factors is widely needed for healthcare profession and patients, as well as for the general public.

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Authored By: Behnood Bikdeli, MD^1,2 and Babak Sharif-Kashani, MD¹

1- Cardiovascular Department, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Masih-Daneshvari Hospital, Shahid Beheshti University MC
2- Cardiovascular Research Center, Modarres Hospital,  Shahid Beheshti University MC, Tehran, Iran

Introduction and Epidemiology:

Historically, Avicenna, the great Persian physician, philosopher and scientist  described several issues concerning deep vein thrombosis (DVT) almost 1000 years ago in his  book “Ghanoon” (the Canon of Medicine), which was a major reference book for biomedical sciences in Europe until the 17^th century. [1] Hundreds of years of research and experience have brought us a much clearer understanding of venous thromboembolism (VTE), nevertheless, he had correctly described varicose veins and parts of the clinical picture of DVT, and had indicated the association of both conditions with old age. The major recommended treatment for lower extremity venous thrombosis at that time was open surgical thrombectomy. Although we could not find clear description of pulmonary embolism in his Canon of Medicine, he had cautioned that “…care should be taken while cleaning the veins from the obstructing material or the particles might migrate to the upper organs…”. Remarkably, he had also recommended leg elevation and compression bandage for varicose veins. [2]

In the current era, nationwide epidemiologic studies on VTE are missing in Iran, even though the figures are expected not to be far from that of the Western society. So far, the NRITLD (write out abbreviation first time used) DVT registry is the largest prospective registry of objectively-confirmed DVT patients [3], however, since the NRITLD is a referral tertiary care center, extrapolation of the findings of that registry to all Iranian VTE patients is limited. The NRITLD DVT registry has so far provided promising data. In terms of risk factors and presenting signs and symptoms, no marked differences were present between the data from the European and North American registries and that of our registry. Our registry also has focused on some newer issues,  namely suggesting that significant differences do exist about clinical outcomes and coexisting conditions, based on thrombus sidedness. Patients with right-sided DVT were shown to have a higher rate of pulmonary embolism, embolic burden score, and massive pulmonary embolism. Moreover, right-sided DVT was significantly more common in cancer patients. [3] Further details are beyond the scope of this manuscript but such findings are now under investigation in collaboration with other international investigators. The few existing studies in Iran suggest that predisposing factors to VTE are similar in Iran and the Western society. Interestingly, injection drug use has been commonly found in patients with lower extremity DVT. [3,4]  Moreover, tuberculosis (TB), which is not so common as before, is still a major health problem in some parts of Iran. Since TB can affect all  three parts of the Virchow’s triad, at NRITLD, a referral center for tuberculosis in the Middle East, we evaluated the coexistence of TB and VTE. Our reported number of 46 cases, is up to now the largest ever reported in the literature. [5] More detailed assessment of this coexistence is now under investigation at our center.

Even though large case-control studies evaluating the three common genetic predisposing factors to VTE (i.e. factor V mutations, prothrombin G20210A mutant variants, and methylenetetrahydrofolate reductase gene mutations) are missing and the results of the available studies are limited by small number of enrolled patients or methodological problems, there is a general agreement that such mutations, particularly Leiden V mutation, occur more commonly in Iranian VTE patients, compared to healthy controls. [6-8]

Prophylaxis:

Until recently, thromboprophylaxis was infrequently considered at Iranian hospitals, mainly because of the disbelief that the Iranian people were not susceptible to VTE. A report from a university hospital in Tehran during the 1990s confirmed that none of the 210 patients with diagnosed symptomatic VTE had received thromboprophylaxis. [9] Other studies suggested that thromboprophylaxis appropriateness was likewise very low at several departments. [10]

In the past few years, however, several attempts have been made to enhance the physicians’ knowledge and awareness of the significance of VTE, particularly for hospitalized patients in Iran. Much progress has been made in the last ten years to introduce computerized systems in Iranian healthcare facilities. However, even today now, there are no hospitals or medical centers with fully electronic medical records in Iran. Therefore, using electronic alerts systems for VTE prevention [11] are not feasible at Iranian hospitals. Accordingly, to improve VTE prophylaxis state and thromboprophylaxis appropriateness, we devised a study using sticker reminders that were pasted on the patients’ files. Compared to the time period before intervention, our intervention effectively lead to improved thromboprophylaxis appropriateness (from 70.4% to 78.1%, P=0.03), reduced prophylaxis underutilization, and reduced thromboprophylaxis initiation delay in at-risk patients (P=0.03, and P=0.01 correspondingly) while it did not lead to increased risk of major bleeding or other major adverse events. [12] In a separate study, we also evaluated the different types of pharmacological and non-pharmacological prophylaxis options and thromboprophylaxis appropriateness, as well as local and systemic complications due to thromboprophylaxis at hospitalized patients at Masih-Daneshvari Hospital, NRITLD, prospectively (AssessMent of ProphylAxis for VenouS ThromboembolIsm in Hospitalized patients: The MASIH Study). The findings of this study will be published soon.

Mechanical prophylaxis is infrequently used at Iranian hospitals. While it is partly due to lack of the required equipment (e.g. paucity of intermittent pneumatic compression devices) and lack of knowledge of responsible physicians plays a major role. For several physicians in Iran “thromboprophylaxis” is almost synonymous to “pharmacological prophylaxis”[13] . Cardiac surgeons are exceptions, they commonly recommend compression stockings postoperatively.

A separate analysis of data from the MASIH (type out abbreviation first time used) study showed that the effects of our intervention of pasting sticker reminders did not extend far beyond the intervention period and prophylaxis appropriateness showed a declining trend in the MASIH study, compared to the post-intervention period after pasting sticker reminders for VTE prophylaxis. This issue needs further investigation but suggests that sticker reminders should be used continuously to keep the thrmboprophylaxis appropriateness close to the desired standards.

Currently, in order to raise the staff awareness for VTE prophylaxis assessment in hospitalized patients, we utilize a group of VTE nurses who check the clinical files of all the hospitalized patients right after admission, and every ten days if the duration of stay of the patients  will be beyond 10 days, or every time the patient’s condition changes dramatically (e.g. need for unforeseen surgical procedure).

Based on our experience, we have found three major categories of problems concerning inappropriate VTE prophylaxis:

1)    Lack of proper knowledge of VTE prophylaxis among healthcare providers (risk assessment, evaluation of contraindications, and deciding the proper prophylaxis strategies)
2)    Neglect of the healthcare providers because of excessive workload or lack of desired experience
3)    Lack of determination and/or overly-conservative decisions to abstain scientifically-unproven risks or to exaggerate the scientifically-proven risks (mainly bleeding)

The first problem could be tackled using several educational strategies including (but not limited to) more comprehensive discussion of VTE at medical schools’ core curricula, and CME programs for healthcare providers. The second obstacle could be dealt with in two different ways, one is to reduce the physicians’ workload so that each physician provides a higher standard of care for a lesser number of patients. Since this is less practical in many settings because of economical limitations, the alternative could be providing various reminder systems to inform the responsible physicians from the risk level of their patients. The last issue is very difficult to resolve, but perhaps could be improved by case presentation sessions in which clear evidence about the risks and benefits of thromboprophylaxis would be thoroughly reviewed. An audit system can monitor how the above steps will be undertaken. Recently, a series of adapted recommendations were developed for VTE prophylaxis, but their widespread use was limited. [14]

Diagnosis:

Several pretest clinical prediction models, especially the Wells models for diagnosis of DVT and PE [15,16] are used or over-used at several medical centers in Iran, particularly at academic hospitals. However, some studies,  with retrospective design and certain methodological limitations, suggested that diagnostic accuracy of the Wells and Geneva clinical prediction rules are moderately lower in Iranian patients. [16,17] In those studies, Wells criteria could correctly predict the likelihood of pulmonary embolism in almost two thirds of PE patients, while one-third of cases with symptomatic objectively-confirmed PE were designated as “unlikely” to have PE, by the aforementioned criteria. The modified Geneva score showed lower false-negative rates, although not as good as that of the derivation set. [17-19] Those studies, however, mostly enrolled hospitalized patients (rather than those with initial evaluation at the emergency room), in whom the d-dimer levels were already expected to be higher than normal. Accordingly, solo reliance on the clinical prediction rules, to supplant rather than as a supplement to clinical decision making, was not feasible.

In the prospective NRITLD DVT registry, PE Wells score could not predict the occurrence of PE (P=0.50), or massive PE (P=0.81).  In addition, there was no association between the embolic burden score and PE Wells score, either. Interestingly, the DVT Wells scores were inversely associated with subsequent diagnosis of PE (P=0.001). [3]

Even though multidetector computed tomography machines are currently available at some medical centers in Iran, the standard para-clinical diagnostic procedures for assessment of VTE include lower limb ultrasonography, single-detector computed tomography pulmonary angiography, and less frequently ventilation/perfusion scanning. Although lack of widespread availability of multidetector CT scans may lead into missing patients with subsegmental PE, evidence exists that adverse outcomes of this problem are negligible and serial ultrasonography could be useful for at-risk patients with negative results for PE with single-detector scans. [20,21] Transthoracic echocardiography is routinely performed for those with suspected massive-PE, or patients with suspected PE who have major underlying cardiorespiratory problems. Recently, digital photoplethysmography (DPPG) has been used as a simple diagnostic tool for DVT at our center with appreciable sensitivity, although the ideal clinical setting for its use needs further investigation. [22,23]

Treatment:

In February 2008, guidelines for VTE management for primary care physicians in Iran were developed in collaboration with the World Health Organization (WHO). [24]

No national practice guidelines or protocols for VTE treatment for specialists exists in Iran, and the majority of current practice is based on the American College of Chest Physicians (ACCP) recommendations [25], with adjustments based on the availability/ functionality of recommended statements at the local settings.

Unfractionated heparin is the mainstay of VTE treatment in Iran, and the most commonly used treatment plan is 80U/kg as bolus, followed by heparin infusion with adjustments according to the Raschke’s nomogram. [26] Enoxaparin sodium (ClexaneÒ) was first launched in Iran in 2001 and is also used widely although home treatment for acute VTE is rarely performed in Iran. Whereas drugs such as rivaroxaban, apixaban, bivalirudin, hirudin, fondaparinux, and idraparinux are not available in Iran, dabigatran is available at a few major cities, although without insurance coverage. For patients with proven or suspected heparin-induced thrombocytopenia (HIT), danaparoid is the only choice, which is just available at a few institutions at major medical centers.

Open surgical thrombectomy has been performed with excellent results at experienced centers for patients with massive PE or severe chronic thromboembolic pulmonary hypertension (CTEPH) [27-29], however, percutaneous mechanical thrombectomy (PMT) is not an available option in Iran. Interventional cardiologists perform several procedures in Iran, however, PMT is not included in their list, or the educational curriculum of interventional cardiology fellows in Iran. Similarly, catheter-directed thrombolysis for lower extremity DVT is extremely rare.

Public Awareness

In general, public awareness about venous thromboembolism is low in Iran. Several websites with the native (Farsi) language provide a wide array of information about manifestations, complications, diagnosis, treatment, and prevention of VTE, however, web access is almost limited to educated people in Iran. Whereas there is substantial contribution to awareness programs about coronary artery disease and stroke using various media, this is not the case with VTE. Nevertheless, attempts have been made to inform passengers of overseas flights to observe the safety precautions for VTE prevention

Summary

In summary, much progress has been made in prevention, diagnosis, and treatment of venous thromboembolic disease in Iran. However, it is still a long way away from the  North American standards. In this evolutionary process, academic centers such as NRITLD have provided substantial contribution.

Acknowledgements

The authors would like to thank Ilene Sussman PhD for her administrative support, Mansoor Keshavarz, MD, PhD from the Department of Physiology and Faculty of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran for his helpful comments, and Behin Pourmirza MD from the Sanofi-Aventis group for providing information about enoxaparin sodium launch in Iran and the Consensus-Based VTE Prophylaxis Protocol in Iran.

References:

1)     Ohio State University Website: http://hcs.osu.edu/hort/history/023.html, accessed on July, 17, 2010.

2)     Avicenna’s Canon of Medicine, Translated by Abdorrahman Sharafkandi, 5th Edition, Soroush Publications, 2008: pp 415-418.

3)     Bikdeli B, Sharif-Kashani B, Chitsaz E, Bikdeli B, Chitsazan M, Kermani-Randjbar S, Behzadnia N, Yazdani S, Saliminejad L, Masjedi MR. Dexter DVT versus Sinister DVT: Which is the More Sinister?  Findings from the NRITLD DVT Registry. Semin Thromb Hemost, In Press.

4)     Masoomi M, Ramezani MA, Shahriari S, Shahesmaeeli A, Mirzaeepour F. Is opium addiction a risk factor for deep vein thrombosis? A case-control study. Blood Coagul Fibrinolysis. 2010; 21: 109-12.

5)     Sharif-Kashani B, Bikdeli B, Moradi A, Tabarsi P, Chitsaz E, Shemirani S, et al. Coexisting venous thromboembolism in patients with tuberculosis. Thromb Res. 2010; 125: 478-80.

6)     Rahimi Z, Mozafari H, Shahriari-Ahmadi A, Alimogaddam K, Ghavamzadeh A, Aznab M, Mansouri K, Rezaei M, Parsian A. Deep venous thrombosis and thrombophilic mutations in western Iran: association with factor V Leiden. Blood Coagul Fibrinolysis. 2010; 21: 385-8.

7)     Chegeni R, Kazemi B, Hajifathali A, Pourfathollah A, Lari GR. Factor V mutations in Iranian patients with activated protein C resistance and venous thrombosis. Thromb Res. 2007; 119: 189-93.

8)     Soheili ZS, Samiei SH, Kavari M, Ataei Z, Moghaddasi MH, Ahmadi A, Shashaani T. Prevalence of G20210A and MTHFR mitation in Iranian patients with venous thromboembolism disorder. Abstract. haematologica reports 2005; 1(issue 9):October 2005.

9)     Safavi E, Zahedpour Anaraki MR, Firooz Bakhsh Sh, Nikparvar Fard M. The Study of Diagnosed Venous Thromboembolism. Tanaffos: Journal of Respiratory Diseae, Thoracic Surgery, Intensive Care and Tuberculosis. 2003; 5: 15-22.

10)   Heidar Nezhad H, Zendeh Del N, Kolahi S, Pirzeh A, Eslam Panah S. Practice of deep vein thrombosis prophylaxis in teaching hospitals of Tabriz . Tanaffos: Journal of Respiratory Disease, Thoracic Surgery, Intensive Care and Tuberculosis. 2003; 6(2): 31-37.

11)   Kucher N, Koo S, Quiroz R, Cooper JM, Paterno MD, Soukonnikov B, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005; 352: 969-77.

12)   Sharif-Kashani B, Raeissi S, Bikdeli B, Shahabi P, Behzadnia N, et al. Sticker Reminders Improve Thromboprophylaxis Appropriateness in Hospitalized Patients. Thromb Res, In Press.

13)   Bikdeli B, Sharif-Kashani B, Raessi S, Shahabi P, Ehteshami-Afshar S, Masjedi MR. Chest Physicians’ Knowledge of Appropriate Thromboprophylaxis: Findings from the PROMOTE Study. 21st International Congress on Thrombosis, Milan, July 2010.

14)   Attarian H, Fahimi H, Fazel I, et al. Adapted Consensus-Based VTE Prophylaxis Protocol in Iran. 2007.

15)   Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep vein thrombosis in clinical management. Lancet 1997; 350: 1795-98.

16)   Wells PS, Anderson Dr, Rodger M, et al. “Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.” Thromb Haemost 2000; 83: 416-20.

17)   Malekmohammad M, Adimi P, Seyedi SR, Sharif-Kashani B. Assessment of Wells Criteria in Patients with Pulmonary Embolism. Tanaffos 2008; 7: 50-53.

18)   Jamaati HR, Hashemian MR, Malekmohammad M, Bagheri-Moghadam A, Kahkouee S, Miri M, Radmand G, Masjedi MR. Predictive Accuracy of Revised Geneva Score in the Diagnosis of Pulmonary Embolism. Tanaffos 2009; 8: 7-13.

19)   Le Gal G, Rodger MA. Clinical prediction rules for diagnosis of venous Thromboembolism. In: Van Beek E, Büller HR, Oudkerk M. Deep Vein Thrombosis and Pulmonary Embolism, Wiley-Blackwell, 2009.

20)   van Strijen MJ, de Monyé W, Schiereck J, Kieft GJ, Prins MH, Huisman MV, et al. Single-detector helical computed tomography as the primary diagnostic test in suspected pulmonary embolism: a multicenter clinical management study of 510 patients. Ann Intern Med 2003; 138: 307- 14.

21)   Carrier M, Righini M, Wells PS, Perrier A, Anderson DR, Rodger MA, et al. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost. 2010,  Epub ahea of print.

22)   Sharif-Kashani B, Behzadnia N, Shahabi P. Comparing results of digital photoplethysmography in two groups of chronic obstructive pulmonary disease patients with and without high pulmonary artery pressure. Phlebology. 2008; 23: 125-9.

23)   Sharif-Kashani B, Behzadnia N, Shahabi P, Sadr M. Screening for deep vein thrombosis in asymptomatic high-risk patients: a comparison between digital photoplethysmography and venous ultrasonography. Angiology. 2009; 60: 301-7.

24)     Bikdeli B, Sharif-Kashani B, Nouhi F, Masjedi MR, Hassantash SA, Dabbagh A, et al. Adapted Clinical Practice Guidelines on Venous Thromboembolic Diseases for Iranian General Practitioners, a Collaborative Project of the World Health Organization and Iranian Ministry of Health and Medical Education under the Health Sector Reform Project (HSR), MOHME Publications, 2008.

25)   Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133: 381S–453S.

26)   Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med. 1993 Nov 1;119(9):874-81.

27)   Mirhosseini SM,  Ahmadi ZH, Ahmadi SH, Arab M, Sharif-Kashani B, Bikdeli B. Pulmonary thromboembolectomy: Solving the Problem of Undissolved Clots. The Sixth International Congress of Iranian Society of Cardiac Surgeons in Collaboration with STS, Tehran, October 2009.

28)   Zarrabi K, Mollazadeh R, Ostovan MA, Abdi Ardekani AR. Retrograde pulmonary embolectomy in 11 patients. Ann Thorac Surg. 2008; 85: 1471-2.

29)   Amirghofran AA, Emami Nia A, Javan R. Surgical embolectomy in acute massive pulmonary embolism. Asian Cardiovasc Thorac Ann. 2007; 15: 149-53.

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Authored by Paul D. Stein, M.D Department of Internal Medicine and Research and Advanced Studies Program, Michigan State and Fadi Matta, MD University College of Osteopathic Medicine, East Lansing, Michigan

ABSTRACT

Background:  Methods for preventing venous stasis include graduated compression stockings and ankle exercise in the form of repetitive dorsiflexion and plantar flexion.  We measured the effects of graduated compression stockings and ankle exercise on venous blood velocity.

Methods:  Time averaged peak blood velocity in the popliteal vein of 25 men aged 23-39 years was measured while supine and sitting, at rest and with ankle exercise, with and without graduated compression stockings.

Results:   Popliteal vein blood velocity was lower when sitting than when lying supine.  Blood velocity increased with ankle exercise.  Graduated compression stockings had no effect at rest and stockings did not augment blood velocity with ankle exercise.

Conclusion:  Ankle exercise may be useful for decreasing venous stasis.  In healthy young men, graduated compression stockings had no effect, but these data on compression stockings may not apply to hospitalized patients, many of whom have venous insufficiency.

Prevention of venous stasis is one of the methods by which the incidence of deep venous thrombosis presumably can be reduced.  Mechanical methods for preventing venous stasis include graduated compression stockings, intermittent pneumatic compression devices and the venous foot pump (1).  These interventions have been shown to reduce the risk of deep venous thrombosis after general surgery (2), neurosurgery (2), elective hip arthroplasty (3), total knee arthroplasty (4,5), and surgery for hip fracture (6).

Randomized controlled trials of graduated compression stockings have demonstrated a 64% reduction in the relative risk of venous thrombosis in general surgical patients and 57% relative risk reduction following total hip replacement compared to no treatment (7).  Meta-analysis showed that after moderate risk surgery, graduated compression stockings resulted in a significant risk reduction of venous thromboembolism (8). Cochrane review showed that there was an overall effect favoring treatment with graduated compression stockings, comparing stockings to no stockings and comparing stockings plus another method to that method alone (9).    Graduated compression stockings, however, have not uniformly been shown to be effective.   Some showed no benefit in the prevention of deep venous thrombosis after stroke (10) or in elderly patients (11).

Review of randomized trials shows that the incidence of asymptomatic deep venous thrombosis in long distance air travelers who wore stockings was 10% that of non-wearers (12).  Randomized trials also showed less edema in travelers who wore compression stockings compared with those who did not (12).  A prominent cause of deep venous thrombosis during airline travel would appear to be venous stasis. Venous blood velocity and/or flow decrease while sitting (13,14), although activation of coagulation may also play a role (15).  A marker of activated coagulation, thrombin-antithrombin complex, has been shown to increase after air travel (15).   Elastic compression in the supine reverse Trandelenburg position has been show to increase systemic plasma levels of tissue factor pathway inhibitor (TFPI) (16).  Compression stockings may also cause improved tissue oxygenation through decreased venous pooling (17).

Another benefit of graduated compression stockings is reduction of the prevalence of post-thrombotic syndrome (18).   Based on 5 randomized trials of patients with deep venous thrombosis comparing treatment with venous compression to controls, mild to moderate post-thrombotic syndrome occurred in 22% treated with venous compression stockings or elastic bandages compared with 37% in patients with deep venous thrombosis who did not receive either (18).  Severe post-thrombotic syndrome occurred in 5% of those treated with graduated compression stockings or elastic bandages compared with 12% with deep venous thrombosis who did not receive venous compression.

Ankle exercise in the form of repetitive dorsiflexion and plantar flexion is another option for reducing venous stasis.  Early and frequent ambulation of hospitalized patients at risk of venous thromboembolism is an important principle of patient care (1).  Previous investigators have shown that ankle exercise increases venous blood velocity while supine (19-21).  It has also been shown that periodic foot exercise performed against resistance enhanced popliteal blood velocity and volume flow when measured some minutes later with the subject sitting but not exercising (14).

Recognizing the potential beneficial effects of graduated compression stockings and of ankle exercise, in the prevention of venous stasis, we assessed their effects on venous blood velocity.  Unanswered questions included the effects of sitting on blood velocity and the extent to which blood velocity was increased in the sitting position, as well as in the supine position, with compression stockings.  We further assessed whether ankle exercise was effective in increasing blood velocity (22) and whether compression stockings further enhanced the effects of ankle exercise on blood velocity (23).

We evaluated 20 healthy men aged 20-33 years at rest and during ankle exercise (22) and repeated the investigations with ankle exercise with and without graduated compression stockings in 25 healthy men, aged 23-39 years (23).  Some men volunteered for both investigations.  Time-averaged peak velocity was measured in the popliteal vein with Doppler ultrasonography.  Thigh-length new fitted graduated compression stockings were used (23).  A hole was cut in the stocking to permit measurement of blood velocity in the popliteal vein.

The following observations were made (22,23)(Figures 1,2):

• When sitting at rest, venous blood velocity decreased, compared with blood velocity in the supine position at rest.
• Ankle exercise nearly tripled venous blood velocity when supine.
• Ankle exercise tripled venous blood velocity when sitting, but blood velocity remained lower than with ankle exercise when supine.
• Graduated compression stockings did not increase venous blood velocity while resting quietly in a supine position.
• Graduated compression stockings did not increase venous blood velocity while resting quietly in a sitting position.
• Graduated compression stockings did not augment venous blood velocity with ankle exercise in a supine position.
• Graduated compression stockings did not augment venous blood velocity with ankle exercise in a sitting position.

It is important to emphasize that these data were obtained in healthy volunteers.  Ankle exercise increased blood velocity and, therefore, would reduce stasis.   The fact that ankle exercise increased blood velocity while sitting, as well as when supine, suggests that ankle exercise may be useful in reducing the prevalence of deep venous thrombosis in travelers.

The beneficial effects of graduated compression stockings on the prevention of deep venous thrombosis are not explained by our data.   We showed no augmentation of blood velocity with graduated compression stockings while supine or sitting, at rest or during exercise. Others, using venous ultrasound, also showed no increased blood velocity with compression stockings (24-26).   Some, however, using older methods, showed increased blood velocity with venous compression (27-29).

Our studies were in healthy young men.  Venous insufficiency of the deep veins occurs in 9% of adults (30) and 21% of men>50 years and 12% of women >50 years (31).  It is reasonable to assume that graduated compression stockings would be more effective in patients with venous insufficiency.   Regarding the effects of graduated compression stockings on the prevention of post-thrombotic syndrome, we can assume that patients with deep venous thrombosis have damaged venous valves.   Therefore, compression would assist venous flow in such patients.

REFERENCES:

1. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:381S-453S.
2. Urbankova J, Quiroz R, Kucher N, et al. Intermittent pneumatic compression and deep vein thrombosis prevention. A meta-analysis in postoperative patients. Thromb Haemost. 2005; 94:1181-1185.
3. Freedman KB, Brookenthal KR, Fitzgerald RH Jr, et al. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am. 2000; 82:929-938.
4. Westrich GH, Haas SB, Mosca P, et al. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone Joint Surg Br. 2000;82:795-800
5. Blanchard J, Meuwly JY, Leyvraz PF, et al. Prevention of deep-vein thrombosis after total knee replacement. Randomised comparison between a low-molecular-weight heparin (nadroparin) and mechanical prophylaxis with a foot-pump system. J Bone Joint Surg Br. 1999; 81:654-659.
6. Handoll HH, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database Syst Rev. 2002;(4): CD000305.
7. Agu O, Hamilton G, Baker D.  Graduated compression stockings in the prevention of venous thromboembolism. Br J Surg. 1999 ;86:992-1004
8. Wells PS, Lensing AW, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis. Arch Intern Med. 1994; 154 : 67-72.
9. Sachdeva A, Dalton M, Amaragiri SV, Lees T. Elastic compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev 2010;7:CD001484.
10. Dennis M, Sandercock PA, Reid J, et al. CLOTS Trials Collaboration, Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet. 2009; 373:1958-1965.
11. Labarere J, Bosson JL, Sevestre MA, et al; Association pour la Promotion de l’Angiologie Hospitalière. Graduated compression stocking thromboprophylaxis for elderly inpatients: a propensity analysis. J Gen Intern Med. 2006 ;21:1282-1287.
12. Clarke M, Hopewell S, Juszczak E, et al.  Compression stockings for preventing deep vein thrombosis in airline passengers.  Cochrane Database Syst Rev. 2006:CD004002.
13. Delis KT, Knaggs AL, Sonecha TN, et al. Lower limb venous haemodynamic impairment on dependency: quantification and implications for the “economy class” position. Thromb Haemost. 2004; 91:941-950.
14. Hitos K, Cannon M, Cannon S, et al. Effect of leg exercises on popliteal venous blood flow during prolonged immobility of seated subjects: implications for prevention of travel-related deep vein thrombosis. J Thromb Haemost. 2007; 5:1890-1895
15. Schreijer AJ, Cannegieter SC, Meijers JC, et al. Activation of coagulation system during air travel: a crossover study. Lancet 2006;367:832-838.
16. Arcelus JI, Caprini JA, Hoffman KN, et al. Modifications of plasma levels of tissue factor pathway inhibitor and endothelin-1 induced by a reverse Trendelenburg position: influence of elastic compression–preliminary results. J Vasc Surg 1995;22:568-572.
17. Agu O, Baker D, Seifalian AM. Effect of graduated compression stockings on limb oxygenation and venous function during exercise in patients with venous insufficiency. Vascular 2004;12:69-76.
18. Musani M, Matta F, Yaekoub AY, et al. Venous Compression in the Prevention of Post-Thrombotic Syndrome. Am J Med (In press)
19. Yang D, Vandongen YK, Stacey MC. Effect of exercise on calf muscle pump function in patients with chronic venous disease. Br J Surg. 1999; 86:338-341.
20. McNally MA, Cooke EA, Mollan RA. The effect of active movement of the foot on venous blood flow after total hip replacement. J Bone Joint Surg Am. 1997; 79:1198-1201.
21. Kwon OY, Jung DY, Kim Y, et al. Effects of ankle exercise combined with deep breathing on blood flow velocity in the femoral vein. Aust J Physiother. 2003; 49:253-258.
22. Stein PD, Yaekoub AY, Ahsan ST, et al. Ankle Exercise and Venous Blood Velocity. Thromb Haemost 2009; 101:1100-110
23. Stein PD, Matta F, Yaekoub AY, et al. Effect of Compression Stockings on Venous Blood Velocity. Thromb Haemost 2010; 103: 138–144
24. Macklon NS, Greer IA. Technical note: compression stockings and posture: a comparative study of their effects on the proximal deep veins of the leg at rest. Br J Radiol. 1995;68:515-518.
25. Mayberry JC, Moneta GL, DeFrang RD, Porter JM. The influence of elastic compression stockings on deep venous hemodynamics. J Vasc Surg. 1991 ;13:91-99.
26. Keith SL, McLaughlin DJ, Anderson FA Jr, et al. Do graduated compression stockings and pneumatic boots have an additive effect on the peak velocity of venous blood flow? Arch Surg. 1992; 127:727-730
27. Spiro M, Roberts VC, Richards JB. Effect of externally applied pressure on femoral vein blood flow. Br Med J. 1970 ;1:719-723
28. Meyerowitz BR, Nelson R. Measurement of the velocity of blood in lower limb veins with and without compression. Surgery 1964; 56:481-48
29. Stanton JR, Freis ED, Wilkins RW. The acceleration of linear flow in the deep veins of the lower extremity of man by local compression. J Clin Invest 1949; 28:553-558
30. Criqui MH, Jamosmos M, Fronek A, et al. Chronic venous disease in an ethnically diverse population: the San Diego Population Study. Am J Epidemiol 2003; 158:448-456
31. Ruckley CV, Evans CJ, Allan PL, et al. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg 2002; 36:520-525

LEGENDS:

Figure 1.

Time averaged peak blood velocity in the popliteal vein while supine and sitting at rest, with and without graded compression stockings (GCS). There was no statistically significant difference between blood velocity with and without GCS. Data are from Stein et al (23).

Figure 2.

Time averaged peak blood velocity in the popliteal vein while supine and sitting at rest and during ankle exercise, with and without graded compression stockings (GCS).  There was no statistically significant difference between blood velocity with and without GCS.  Data are from Stein et al (23).

BY: Lori B. Hornsby, PharmD, BCPS, Assistant Clinical Professor
Department of Pharmacy Practice
Auburn University Harrison School of Pharmacy
Ambulatory Clinical Pharmacist

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*Financial disclosures: none declared

Introduction

In 1856 Virchow described changes in the composition of blood that were later termed a hypercoagulable state.   This was identified as one of the primary factors responsible for thrombosis formation. Today the term “thrombophilia” is used to describe disorders that affect normal hemostasis, shifting the balance toward thrombus formation. Thrombophilia may be inherited or acquired. Inherited thrombophilia includes factor V Leiden, prothrombin G20210A mutation, deficiencies in natural anticoagulants (protein C, -S, and antithrombin), hyperhomocysteinemia, and elevations in factors VIII, IX, and XI. Acquired disorders include antiphospholipid antibodies as well as certain causes of activated protein C deficiency and hyperhomocysteinemia.  Inherited thrombophilias are independent risk factors for venous thromboembolism although their role in arterial events is not as well established.  Antiphospholipid antibodies have been shown to increase the risk of both venous and arterial events as well as pregnancy related complications. Thrombophilia status does not affect the treatment of VTE in non-pregnant individuals. Although often conducted in clinical practice, the utility of routine thrombophilia screening has been questioned. The incidence, mechanisms, and implications of each disorder will be discussed in the article below in addition to considerations for treatment and screening for the various thrombophilia.

eDiscussion Points:

1. Is there clinical utility in screening individuals with a history of VTE for thrombophilia?
2. Is there a role for thrombophilia screening in other settings (i.e. in family members of those with known thrombophilia or in women prior to oral contraceptive use)?

Factor V Leiden

First described in 1994, factor V Leiden is the most common inherited thrombophilia and accounts for more than 90% of all cases of activated protein C deficiency. (1,2) Heterozygosity for factor V Leiden is found in 5% of Caucasians and 20-40% of individuals with VTE. (3,4) The prevalence in those of African and Asian descent is only 0.05%.(3)  Homozygosity in the general population is rare (0.02%) and found in only 3% of VTE cases.(4)  During normal hemostasis, factor Va is inactivated by protein C via binding to the cleavage site at position 506 of factor V (R506Q). Factor V Leiden results from a point mutation at the cleavage site due to a substitution of glutamine for arginine rendering factor Va resistant to inactivation by protein C. (2) Heterozygosity for factor V Leiden increases the relative risk of VTE by 3-8 fold while homozygosity increases the relative risk by as much as 80-fold.(5)

Prothrombin G20210A Mutation

Prothrombin G20210A mutation also referred to as prothrombin variant, prothrombin mutation, and factor II mutation is the second most common genetic thrombophilia. Identified in 1996, prothrombin mutation is found in 3% of Caucasians, 0.06% of African and Asian descendents, and an estimated 6-18% of all individuals with VTE. (3,6) A point mutation at the 3’untranslated region of the prothrombin gene leads to increased prothrombin levels and ultimately increased activation of thrombin. Heterozygosity for prothrombin mutation increases the relative risk of VTE by 3-fold.(6)  Information is limited for those homozygous for prothrombin mutation.

Anticoagulant Deficiencies

Deficiencies in antithrombin (AT), protein C, and protein S were the first inherited coagulopathies to be described. These disorders are rare, found in 0.5% of the general population and 2-5% of individuals with VTE. (3) Unlike the point mutations responsible for factor V Leiden and  prothrombin mutation, more than 100 underlying mutations have been identified for AT, protein C and protein S deficiencies.(3,7)  These disorders may also be acquired secondary to severe liver disease, vitamin K deficiency, pregnancy, or oral contraceptive use.(5,7)

Antithrombin is a glycoprotein synthesized in the liver and responsible for the inactivation of coagulation factors IIa, Xa, and to a lesser extent factors IXa, XIa, and XIIa. Circulating AT has little activity until bound to heparin or naturally occurring heparin-like substances such as heparin sulphate found on the endothelial surface.(2)  Two types of AT deficiency have been identified. Type I is a quantitative deficiency where both AT activity and antigen levels are decreased. Type II is a qualitative deficiency where AT activity is decreased while antigen levels remain normal. Type II deficiency is further divided into 3 subtypes, differentiated based on the mutation location and the assay used in the diagnosis. This differentiation may have clinical utility in that the VTE risk for those with Type IIb is much lower compared to other subtypes. Heterozygosity is most common as homozygosity usually results in death in utero.(8)  AT deficiency increases the risk of VTE by 25-50 fold.(5)  By age 50, approximately 50% of individuals with AT deficiency have experienced a VTE with the exception of Type IIb with an incidence of only 6%.(8)

Protein C is a vitamin-K dependent glycoprotein synthesized in the liver and activated by the formation of thrombin. In the presence of free protein S, activated protein C proteolytically inactivates both factors Va and VIIIa, two important cofactors involved in thrombin generation. Deficiency of protein C leads to an imbalance in normal hemostasis resulting in an increase in thrombin generation. Deficiencies may be quantitative (Type I) or qualitative (Type II).(3)

Protein S, another vitamin-K dependent glycoprotein, serves as a cofactor essential for protein C activity. Forty-percent of protein S circulates in the free or active form while 60% is bound to C4b-binding protein (C4bBP) and thus inactive. Three types of protein S deficiency have been identified. Type I and Type III are quantitative deficiencies while Type II is a qualitative deficiency.  Both total and free levels are reduced in Type I, while only free levels are affected in Type III. Unlike AT deficiency there does not appear to be any clinical utility in differentiating the type of protein C or S deficiency.(5)  The relative risk of VTE in protein C and protein S deficiencies have been estimated to be between 10-15 and 5-10 respectively. (4,5)

Antiphospholipid Antibodies

Antiphospholipid (aPL) antibodies include lupus anticoagulant, elevated levels of anticardiolipin antibodies, or elevated levels of anti-b₂-glycoprotein I antibodies (b₂GPI) and is the most common cause of acquired thrombophilia. Antiphospholipid syndrome (APS) is an autoimmune disorder diagnosed by both clinical and laboratory criteria. A diagnosis of APS requires one or more episodes of thrombosis, one or more unexplained fetal deaths (>10 weeks gestation), or 3 or more unexplained consecutive miscarriages (<10 weeks gestation) in addition to testing positive for either lupus anticoagulant, medium or high titers of anticardiolipin antibodies (IgG or IgM), or anti-b₂ -glycoprotein I antibodies (IgG or IgM). Due to transient elevations of aPL antibodies, positive findings should be confirmed with repeat testing separated by 12 weeks.(9)  The mechanism by which aPL antibodies induce thrombosis is not fully understood. Irritation of platelet and endothelial cell membranes activating the coagulation cascade has been postulated as well as inhibition of protein C.  Antiphospholipid antibodies are found in 1-5% of young, healthy control subjects and 12-35% of individuals with systemic lupus erythematosus (SLE).(10)  The overall risk for thrombosis in the general population with aPL antibodies has been difficult to determine however 2-10% of individuals with VTE test positive.(4)  More than half of all patients with aPL antibodies and SLE develop APS within 7-20 years, a much higher incidence than those without SLE.(10)

Hyperhomocysteinemia

Hyperhomocysteinemia, either inherited or acquired, results from impairment in the conversion of methionine to cysteine leading to increased levels of the intermediate product homocysteine. Mutations of either methylenetetrahydrofolate reductase (MTHFR) or cystathionine B-synthase in addition to deficiencies in folate, vitamin B₁₂, and vitamin B₆ have been identified as potential causes. The exact mechanism responsible for the increased risk of thrombosis is still under investigation but appears to be multifactorial and may include activation of factor V, inhibition of protein C, impairment of endothelial cell function, and others. (2) Mild hyperhomocysteinemia defined as serum homocysteine levels >15 mmol/L has been found in 5% of the general population and 7% of individuals with VTE.(4)  It has been estimated to increase the risk of VTE by 1.5-2 fold.(11)

Elevated levels of Factors VIII, IX, and XI

Increased levels of coagulation factor VIII, defined as plasma levels >150 IU/dl and found in 11% of the general population and 25% of individuals with VTE, has been shown to increase the incidence of VTE by 5-fold.(4)  Individuals with factor IX levels above the 90^th percentile were found to have a 2-3 fold increased risk of VTE.(12)  Factor XI levels above the 90^th percentile has been suggested to increase the risk of thrombosis by 2-fold.(13)  Underlying genetic variations have yet to be determined but data suggests these elevations in coagulation factors are more than transient elevations associated with the acute event.(4)

Thrombophilia in Pregnancy

Multiple factors affect normal hemostasis during and immediately after pregnancy. Factors shifting the balance toward hypercoagulability include elevations in prothrombin, factors V, VII, VIII, IX, X, XII, and fibrinogen as well as decreased levels of protein S.(2)  These changes are thought to be responsible for the 4-fold increased risk of VTE during pregnancy and 14-fold increase pueroperium.(14)  Approximately 50% of women experiencing a VTE during pregnancy are found to have an underlying thrombophilia.(15)  The risk of VTE during pregnancy appears to be highest for those homozygous for either factor V Leiden or the prothrombin mutation, those heterozygous for both factor V Leiden and prothrombin mutation, and those with AT deficiency.(15-18)  Several thrombophilia have been associated with early fetal loss, most notably aPL antibodies but also factor V Leiden  and prothrombin mutation.(10,16)  The exact mechanisms are not clearly understood but are thought to be multifactorial and ultimately related to poor placental perfusion and placental insufficiency due to thrombus formation.(10)

Thrombophilia and Oral Contraceptive Use

Oral contraceptives have been estimated to increase the risk of VTE by 4-fold in all users.(14)  Multiple mechanisms have been postulated that ultimately alter endothelial function and regulation of coagulation factors.(2)  The risk of VTE with oral contraceptive use is significantly elevated in women with underlying thrombophilia as compared to those without thrombophilia. The incidence may be increased by as much as 40-fold with Factor V Leiden and 60-fold with prothrombin mutation.(19)

Screening and Treatment

Although thrombophilia increases the baseline risk for VTE, the absolute risk is low and must be weighed against the hemorrhagic risks associated with preventative therapy. Therefore treatment of asymptomatic patients and screening the general population or even family members of affected individuals is not recommended.(5)  Some authors suggest a benefit in screening women prior to oral contraceptive use however the cost effectiveness of this approach has been questioned.  The number of women that would need to be screened in order to find those with thrombophilia carrying the highest risk and the number of women unnecessarily denied treatment with oral contraceptives would limit the utility of screening in this setting. (20) Others suggest screening only women with a positive family history of VTE prior to prescribing oral contraceptives, yet this method demonstrated a low sensitivity and predictive value when studied. (19)

Well-designed trials evaluating treatment for prevention of VTE during pregnancy and pregnancy related complications in women with thrombophilia are lacking. Recommendations based on the specific thrombophilia and histories of events are provided in the recent American College of Chest Physicians guidelines. (15) In non-pregnant patients with VTE, the presence of an underlying thrombophilia does not alter the choice of treatment or intensity of therapy.(15, 21,22)  Patients with AT deficiency may theoretically require larger doses of heparin due to heparin activity contingent on binding to AT. Although the clinical significance of this is questionable, higher prophylaxis doses of unfractionated heparin and monitoring anti-Xa levels for low molecular weight heparin in individuals with known AT deficiency may be warranted.  Guidelines for the use of AT replacement are not available but may be considered in situations where the risk of VTE is high and the use of traditional anticoagulants is contraindicated. (8)  Although treatment with vitamin B supplementation may reduce levels of plasma homocysteine in individuals with hyperhomocysteinemia, this approach has failed to show a benefit in prevention and recurrence of VTE. (23,24)

Whether the duration of anticoagulation therapy after an initial VTE should differ in those with an underlying thrombophilia is unclear. The optimal duration is the duration necessary to prevent a recurrence without subjecting the patient to undue risk of treatment. Regardless of thrombophilia status, 25% of individuals will experience a recurrent event within 5 years and 30% within 10 years.(25)  The benefit of anticoagulation therapy in preventing recurrence is well established, however is lost once therapy is discontinued.(26-28)  The benefit of continued therapy must be weighed against the hemorrhagic risk associated with treatment as well as the burden of continuous monitoring. It is therefore desirable to determine which individuals are at highest risk and would benefit most from extended therapy. Clinicians often screen for thrombophilia to guide duration of therapy, a practice that assumes an underlying thrombophilia increases the recurrence risk and would therefore warrant extended durations of or life-long anticoagulation therapy. This practice however has been challenged by multiple studies as well as practice guidelines.  The 8^th consensus conference of the American College of Chest Physicians on antithrombotic therapy for venous thromboembolic disease did not include thrombophilia as a consideration when determining duration of therapy after an initial event.(29)  Although thrombophilia have been identified as risk factors for initial events, their predictability in regard to recurrent thromboembolism is not as clear. With the exception of aPL antibodies most thrombophilia have demonstrated either a weak association or no association with risk of recurrence. (Table 1) (30-41)

APS has reported hazard ratios of 2.5-8.5 and recurrence rates as high as 50-70% without continued anticoagulation therapy and even 3-24% per year while on therapy. Therefore most authorities suggested indefinite therapy in individuals with APS.(25)  Data is significantly limited for rare disorders such as AT, protein C, and protein S deficiencies. While the rate of recurrence may be significant to justify indefinite therapy for those homozygous for factor V Leiden or prothrombin mutation as well as those with combined disorders and deficiencies in natural anticoagulants, the utility of routine testing to find these few individuals is questionable.

It is also important to realize that negative results do not rule out the presence of thrombophilia yet to be identified. In the early 1990s, an underlying thrombophilia was identified in <10% of VTE cases. Over the last decade, since the identification of factor V Leiden and prothrombin mutation, over 50% of individuals with a VTE are found to have a thrombophilia.(42) Realizing that VTE occurrence is usually multifactorial, it leaves to question if thrombus formation is ever truly idiopathic. Rather all individuals with VTE carry  some underlying risk, with less thrombogenic factors requiring an external factor to tip the scale in favor of thrombus formation. This could explain both findings from trials failing to show an increased risk of recurrence with known thrombophilia in addition to the significant rate of recurrence after “idiopathic” events in general.

Data suggesting an idiopathic event alone may warrant long-term therapy further questions the clinical utility of thrombophilia screening. (26-28)  If all patients with an unprovoked VTE is a candidate for extended therapy, thrombophilia status would not be a factor in treatment decisions. Because this approach is not always appropriate due to bleeding risk and burden of monitoring, factors to aid clinicians in stratifying patients to determine those that would benefit from indefinite therapy and those who could be treated for shorter durations remains an important subject for continued research.

Although controversial there may be situations where screening is warranted.  In addition, some practitioners will continue to screen patients in search of an explanation.  It is therefore important to ensure evaluations are conducted at the appropriate time and findings are interpreted accurately if testing for thrombophilia is pursued. Screening should not be conducted during the acute event or during anticoagulation therapy as often done. (42) Testing within 3 weeks after an event can give false positive results for all natural anticoagulant deficiencies, as they are transiently decreased during this time. Patients may test false positive for protein C or protein S deficiency while on warfarin therapy and AT deficiency while receiving heparin. (5,42) Testing for AT deficiency while on warfarin may result in false negative results. Due to transient fluctuations, confirmatory testing should be conducted for all conditions other than factor V Leiden and prothrombin mutation. (8)  Information regarding individual assays and interpretation of results are available and warrant review by those conducting thrombophilia screening. (5)

Table 1: Risk of VTE recurrence for specified thrombophilia in comparison to those without thrombophilia

*Systematic Review

FVL=Factor V Leiden; AT=Antithrombin; OR=Odds ratio; RR=Relative risk; HR=Hazards ratio

References

1. Voorberg J, Roelse J, Koopman R, et al. Association of idiopathic venous thromboembolism with single point-mutation at ARg506 of factor V. Lancet 1994;343:1535-6.
2. Martinelli I, Bucciarelli P, Mannucci P. Thrombotic risk factors: Basic pathophysiology. Crit Care Med 2010;38:S3-S9.
3. Seligsohn U, Lubetzky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222-31.
4. Lindhoff-Last E, Luxembourg B. Evidence-based indications for thrombophilia screening. VASA 2008;37:19-30.
5. Walker I, Greaves M, Preston F. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28.
6. Poort S, Rosendaal F, Reitsma P, et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associate with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-703.
7. Middeldorp S, Vlieg A. Does thrombophilia testing help in the clinical management of patients? British Journal of Haematology 143;321-35.
8. Patnaik M, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229-39.
9. Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.
10. Gezer S. Antiphospholipid syndrome. Dis Mon 2003;49:696-741.
11. Oger E, Legal G, Couturaud F, et al. Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case-control study. J Thromb Haemost 2006;4:793-9.
12. van Hylckama Vlieg A, van der Linden I, Bertina R, et al. High levels of factor IX increases the risk of venous thrombosis. Blood 2000;95:3678-82.
13. Meijers J, Tekelenburg W, Bouma B, et al. High levels of coagulatin factor XI as a risk factor for venous thrombosis. N Engl J Med 2000;342:696-701.
14. Rosendaal F. Risk factors for venous thrombotic disease. Thrombosis and Haemostasis 1999;82:610-19.
15. Bates S, Greer I, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8^th ed.) Chest 2008;133:844S-886S.
16. Robertson L, Wu O, Langhorne P, et al. for The Thrombosis Risk and Economic Assessment of Thrombphilia Screening (TREATs) Study: thrombophilia in pregnancy; a systematic review. Br J Haematol 2005;132:171-96.
17. Gerhardt A, Scharf R, Beckman M, et al. Prothrombin and factor V mutations in women with thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374-80.
18. McColl M, Ramsay J, Tait R, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997;8:1183-8.
19. Legnani C, Palareti G, Guazzaloca G, et al. Venous thromboembolism in young women. Role of thrombophilic mutations and oral contraceptive use. Eur Heart J 2002;23:984-90.
20. Vandenbroucke J, van der Meer, F, Helmerhorst F, Rosendaal F. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996;313:1127-30.
21. Kearon C, Julian J, Kovacs M, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood 2008;112:4432-6.
22. Baglin C, Brown K, Luddington R, et al. Risk of recent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors: East Anglian Thrombophilia Study Group. Br J Haematol. 1998;100:764-8.
23. Den Heijer M, Willems H, Blom H, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism. A randomized, placebo-controlled, double-blind trial. Blood 2007;109:139-44.
24. Ray J, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism. Ann Intern Med 2007;146:761-7.
25. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: Risk factors for recurrence. Arterioscler Thromb Vasc Biol 2009;29:298-310.
26. Ridker P, Goldhaber S, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-34.
27. Palareti G, Cosmi B, Legnani C, et al. D-Dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355:1780-9.
28. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-7.
29. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob G E, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Practice Guidelines (8^th edition). Chest 2008; 133:454S-545S.
30. Ho W, Hankey G, Quinlan D, et al. Risk of recurrent venous thromboembolism in patients with common thrombophilia. A systematic review. Arch Intern Med 2006:166:729-36.
31. Marchiori A, Mosena L, Prins M, et al. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007;92:1107-14.
32. Segal J, Brotman D, Necochea A, et al. Predictive value of Factor V Leiden and Prothrombin G20210A in adults wit venoug thromboembolism and in family members of theose with a mutation. A Systematic Review. JAMA 2009;301:2472-85.
33. Christiansen S, Cannegieter, S, Koster T, Vandenbroucke J, Rosendaal F. Thrombophilia, clinical factors, and recurrent thromboembolic events. JAMA 2005;293:2352-61.
34. Prandoni P, Lensing  A, Cogo A, Cuppini S, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7.
35. Miles J, Miletich J, Goldhaber S. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol 2001;37:215-18.
36. DeStefano V, Martinelli I, Mannucci P, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both Factor V Leiden and the G20210A Prothrombin mutation. N Engl J Med 1999;341:801-6.
37. Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism  in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003;362:523-6.
38. Kyrle P, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457-62.
39. Eichinger S, Weltermann A, Mannhalter C, et al. The risk of recurrent venous thromboembolism in heterozygous carriers of Factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med 2002;162:2357-60.
40. DeStefano V, Martinelli I, Mannucci P, et al. The riskof recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation. British Journal of Haematology 2001;113:630-5.
41. Simioni P, Prandoni P, Lensing A, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000;96:3329-33.
42. Favaloro E, McDonald D, Lippi G. Laboratory investigation of thrombophilia: The good, the bad, and the ugly. Semin Thromb Hemost 2009;35:695-710.

Marc Carrier MD MSc*† and Agnes Y Lee MD MSc¶§.

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*Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
† Clinical Epidemiology Program, The Ottawa Health Research Institute, Ottawa, Ontario Canada
¶ Thrombosis Program, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
§ Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Authors have no conflicts of interest to declare.

Occult cancers are frequent in patients with unprovoked venous thromboembolism (VTE) and approximately 10% of patients with unprovoked VTE will be diagnosed with cancer within one year of their thrombotic event. A “limited” occult cancer screening (medical history taking, physical examination, routine laboratory blood tests and a chest-X ray) detects a large proportion of these occult malignancies. A more extensive occult cancer screening strategy (computed tomography, ultrasound, tumor markers, etc) seems to increase the number of cancers detected. However, current evidence does not support improvements in malignancy-related mortality, morbidity or quality of life with an extensive cancer screening strategy. Further clinical trials are required to assess the risks and benefits of a comprehensive screening program in patients with unprovoked VTE.

The association between occult cancers and VTE was first described by Dr Armand Trousseau in 18651. Over time it has become clear that the strongest association exists between occult malignancies and VTE that are unprovoked. Patients who develop an unprovoked VTE have a four-fold higher risk of receiving a diagnosis of cancer within the next few months compared to patients with VTE triggered by known risk factors2-4. Approximately 10% of patients with unprovoked VTE will be diagnosed with cancer within one year of their thrombotic event2;5, with the highest standardized incidence ratio of cancer observed within the first 6 months of VTE diagnosis 6;7. The occult tumor types most commonly presenting with unprovoked VTE are cancers of the ovary, pancreas and liver6;8.
Given that occult cancers are common in patients with unprovoked VTE, it has been suggested that these patients should undergo cancer screening. However, the utility of a search strategy is controversial. There is presently no consensus and, in fact, there is great diversity in experts opinions and clinical practices regarding whether to screen and what type of tests should be included9-12. Proponents of screening argue that identifying these occult cancers are important for several reasons: 1) occult cancers detected at the time of the VTE diagnosis may be at a curable stage, while if detection is delayed this may no longer be the case; 2) earlier detection and treatment of cancer might help to prevent cancer-related complications (e.g. compression syndromes) or reduce the need for aggressive or highly toxic cancer therapies; and 3) treatment of cancer-associated VTE is different from that for VTE not associated with cancer as with low molecular weight heparin is recommended over vitamin K antagonists13 to reduce the risk of recurrent VTE 14 and potentially increase survival in cancer patients15;16.

Limited occult cancer screening

Retrospective studies have suggested that “limited” occult cancer screening (medical history taking, physical examination, routine laboratory blood tests and a chest-X ray) is adequate to detect up to 90% of occult cancers in patients with VTE3;12;17. In a retrospective cohort study of 1389 patients with confirmed VTE (provoked and unprovoked), investigators identified 150 cases with occult cancers, of which 83% were easily detected by a combination of medical history, physical examination and routine blood tests3. Sixty-six (44%) patients had their cancer detected within the next 6 months. In another retrospective cohort study, 16 of 142 patients (12%) with unprovoked VTE were diagnosed with cancer during their hospitalization17. All 16 patients had at least one or more abnormalities on “limited” occult cancer screening. Three patients were diagnosed with cancer during follow-up, two of whom did not have any clinical abnormalities at initial evaluation. Only 3.6% of patients who did not have any abnormal findings on the “limited” occult cancer screening subsequently developed cancer. Based on these two retrospective studies, a “limited” occult cancer screening strategy appears to be a sensible approach to detect a large majority of occult cancers.

Extensive occult cancer screening
Several retrospective and prospective cohort studies have assessed the use of more extensive occult cancer screening programs in patients with unprovoked VTE2. One randomized controlled trial and one prospective cohort study suggest that a more extensive occult cancer screening can increase the rate of detection of cancer18;19. The largest prospective cohort study followed 864 VTE patients (40% unprovoked and 60% provoked) undergoing a two-step screening strategy18. The initial screening step consisted of “limited” occult cancer screening, which included a thorough history and physical examination, blood work (complete blood count, liver and renal function test, sedimentation rate and serum electrophoresis), a urinalysis and a chest X-ray. A total of 167 patients had abnormalities and 34 (20%) of these patients had a confirmed diagnosis of cancer. The remaining 830 patients underwent further investigations including: ultrasonography (U/S) of the abdomen/pelvis and serum tumour markers (carcinoembryonic antigen (CEA), prostate specific antigens (PSA) for men and cancer antigen-125 (CA-125) for women). Fifty four patients (6.5%) had abnormal findings in the second step of the screening and 13 of these (24%) patients subsequently had a confirmed diagnosis of cancer. During the 1-year follow-up, 14 (1.7%) additional cancers were diagnosed. Therefore the first step or “limited” occult cancer screening had a sensitivity of 56% and adding a second step or “more extensive” screening increased the sensitivity to 77%. This study suggests that “limited” occult cancer screening alone is insufficient to detect all occult cancers, and that almost a quarter of cancers remain undetected despite extensive testing. However, the design of this study does not answer the question of whether cancer screening would offer a beneficial effect on the prognosis (mortality, morbidity) of VTE patients. A recently completed prospective centre-controlled cohort study, the Trousseau study, assessed the added value of performing mammography in women and thoracic and abdominal computed tomography (CT) in all patients presenting with idiopathic VTE20. A total of 630 patients were enrolled, of whom 288 underwent basic investigations and 342 had CT +/- mammography performed in addition to basic investigations. The main patient characteristics were similar for both groups. Malignancy was diagnosed at enrolment in 2.4% of those in the basic investigations group and 3.5% in those who also underwent CT +/- mammography. However, there was no difference in the number of cancers subsequently diagnosed (5.3% vs. 3.7%, respectively) or in overall mortality (8.3% vs 7.6%, respectively) during 31 months of follow up.

Only one randomized controlled trial has evaluated the effect of extensive screening on patient survival. The SOMIT investigators group randomized patients with negative “limited” occult cancer screening to either a strategy of more extensive testing or to no further testing19. The “limited” occult cancer screening consisted of: clinical history, physical examination, complete blood count, liver function tests, calcium, urinalysis and chest X-ray. The more extensive testing battery included U/S and CT of the abdomen/pelvis, gastroscopy or double-contrast barium swallowing, colonoscopy or sigmoidoscopy followed by barium enema, fecal occult blood, sputum cytology, CEA, CA-125, alpha-fetoprotein (α-FP), PSA and trans-abdominal U/S of prostate for men, Papanilacou smear and mammography for women. Two hundred and one eligible patients with unprovoked VTE and negative “limited” occult cancer screening were included into the study and randomized. A total of 56 patients were diagnosed with cancer. Thirty two (57%) were diagnosed by the “limited” occult cancer screening. Out of the 99 patients undergoing extensive testing, 13 (13%) were diagnosed with cancer. Only one cancer was missed and became symptomatic in the two-year follow-up period. The sensitivity of the extensive occult cancer screening was 93%. Furthermore, more cases with earlier-stage cancers (T1-2,N0) were detected by extensive screening compared to the control group (64% versus 20%, p=0.047). Although there was an absolute risk reduction of malignancy-related mortality of 1.9% in favor of the extensive testing group during the 2-year follow-up period, this difference was not statistically significant. This result may be secondary to the inadequate statistical power from the small sample size (Type II error) or to no true difference in survival between the groups. The SOMIT investigators were only able to recruit 20% of the expected number of patients and the study was conducted in only 5 of the 40 centers approached. The limited recruitment of participants and centers raises concerns about selection bias and the generalizability of these findings. Furthermore, it is uncertain whether extensive screening simply introduces lead-time and length-time biases, as opposed to prolonging survival.

The components of an ideal extensive malignancy screening program are still unknown. A decision analysis using the data from the SOMIT trial reported that “limited” occult cancer screening in combination with a CT abdomen/pelvis had a number needed to screen (NNS) of 1021. In other words, ten patients with unprovoked VTE need to be screened with a “limited” panel and CT abdomen/pelvis to find one case of occult cancer. A “limited” occult cancer screening in combination with U/S of the abdomen alone, U/S of the abdomen and colonoscopy or U/S abdomen and tumour markers have a NNS of 20, 17 and 17, respectively21. Similarly a meta-analysis including 4378 patients from 15 studies demonstrated that extensive occult cancer screening using CT of the abdomen/pelvis statistically significantly increased the proportion of occult cancer detected from 49% to 70%2. However, investigators could not determine complication rates, cost-effectiveness and difference in morbidity and mortality associated with more extensive screening2.

Before performing extensive screening in patients with unprovoked VTE, a number of factors must be considered. These include: 1) morbidity and risks of invasive diagnostic procedures to confirm the presence of malignancy; 2) cost of extensive testing; 3) incidental findings and their associated morbidity; and 4) psychological burden associated with new diagnosis of malignancy or false-positives. Finally, it is important to bear in mind that improvements in cancer outcome not only depend on accurate and timely screening but also on effective cancer treatments. Currently, one clinical trial is assessing the potential benefits of a comprehensive CT of the abdomen/pelvis22.

In conclusion, occult cancers are found in 10% of patients with unprovoked VTE. A “limited” occult cancer screening detects a large proportion of occult cancers in these patients. A more extensive occult cancer screening strategy seems to increase the number of cancers detected. However, current evidence shows that extensive cancer screening strategy does not improve malignancy-related mortality, morbidity or quality of life. Further clinical trials are required to assess the risks and benefits of a comprehensive screening program in patients with unprovoked VTE. In the meantime, patients should be carefully evaluated by history, physical examination, routine blood work and undergo age- and gender-specific cancer screening (e.g. colon cancer screening in patients over 50 years of age). Further follow-up is only required in patients with abnormal findings.

References:

1. Trousseau A. Clinique medicale de l’Hotel-Dieu de Paris. Geneve-Paris-Bruxelles: Alliance Culturelle du Livre. Geneve-Paris-Bruxelles: Alliance Culturelle du Livre . 1963.
2. Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rodger MA. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008; 149(5):323-333.
3. Nordstrom M, Lindblad B, Anderson H, Bergqvist D, Kjellstrom T. Deep venous thrombosis and occult malignancy: an epidemiological study. BMJ 1994; 308(6933):891-894.
4. Otten HM, Prins MH. Venous thromboembolism and occult malignancy. Thromb Res 2001; 102(6):V187-V194.
5. White RH, Chew HK, Zhou H, Parikh-Patel A, Harris D, Harvey D et al. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med 2005; 165(15):1782-1787.
6. Baron JA, Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer. Lancet 1998; 351(9109):1077-1080.
7. Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 338(17):1169-1173.
8. Iodice S, Gandini S, Lohr M, Lowenfels AB, Maisonneuve P. Venous thromboembolic events and organ-specific occult cancers: a review and meta-analysis. J Thromb Haemost 2008; 6(5):781-788.
9. Buller HR, van Doormaal FF, van Sluis GL, Kamphuisen PW. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 5 Suppl 1:246-254.
10. Piccioli A, Prandoni P. Screening for occult cancer in patients with idiopathic venous thromboembolism: yes. J Thromb Haemost 2003; 1(11):2271-2272.
11. Lee AY. Screening for occult cancer in patients with idiopathic venous thromboembolism: no. J Thromb Haemost 2003; 1(11):2273-2274.
12. Lee AY. Thrombosis and cancer: the role of screening for occult cancer and recognizing the underlying biological mechanisms. Hematology Am Soc Hematol Educ Program 2006;438-443.
13. Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25(34):5490-5505.
14. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349(2):146-153.
15. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23(10):2123-2129.
16. Lazo-Langner A, Goss GD, Spaans JN, Rodger MA. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost 2007; 5(4):729-737.
17. Cornuz J, Pearson SD, Creager MA, Cook EF, Goldman L. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep venous thrombosis. Ann Intern Med 1996; 125(10):785-793.
18. Monreal M, Lensing AW, Prins MH, Bonet M, Fernandez-Llamazares J, Muchart J et al. Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism. J Thromb Haemost 2004; 2(6):876-881.
19. Piccioli A, Lensing AW, Prins MH, Falanga A, Scannapieco GL, Ieran M et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004; 2(6):884-889.
20. van Doormaal FF, Otten H. Screening for malignancy in patients with idiopathic venous thromboembolism. The Trousseau Investigators. J Thromb Haemost 7[suppl 1], OC-MO-014. 2009.
21. DI Nisio M, Otten HM, Piccioli A, Lensing AW, Prandoni P, Buller HR et al. Decision analysis for cancer screening in idiopathic venous thromboembolism. J Thromb Haemost 2005; 3(11):2391-2396.
22. Carrier M, Wells PE, Tao H, Rodger MA. Screening for occult malignancy in patients with idiopathic venous thromboembolism: A prospective pilot cohort study using a comprehensive computed tomography of the abdomen/pelvis. J Thromb Haemost 5 Suppl 1[abst.], P-S-556. 2007.

Behnood Bikdeli MD

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ABSTRACT:

Background: Despite the global efforts to control tuberculosis, it remains a common, life-threatening infectious disease. Tuberculosis can lead to hypercoagulability, increased venous stasis, and endothelial dysfunction, thus increasing the susceptibility to venous thromboembolism (VTE). However, few studies have assessed the epidemiology of the association between tuberculosis and VTE. We recently completed a study to address this coexistence.

Methods: Medical records of hospitalized tuberculosis patients at the National Research Institute of Tuberculosis and Lung Disease (NRITLD) from January 2001 to December 2008 were reviewed. Patients with coexisting VTE were selected. Presenting signs and symptoms, and co-morbidities in these patients were studied.

Results: 3293 tuberculosis patients were hospitalized, of whom 46 had coexisting symptomatic VTE (31 males, 15 females, mean age: 53.4 ± 19.6 years; DVT: 26, PE: 13, DVT+PE: 7). Of these 46, 29 had a primary diagnosis of tuberculosis, and symptomatic VTE evolved during hospitalization. None of the 29 patients had received VTE thromboprophylaxis. Of the remaining 17 patients with TB and VTE, 15 were tuberculosis patients undergoing outpatient treatment who were admitted to hospital with a primary diagnosis of VTE. Two other patients were initially hospitalized because of VTE, and coexisting tuberculosis was discovered during hospitalization. Mean hospitalization length was 28.6 ± 14.0 days. Four patients died during hospitalization. Median survival time of the patients was 407 days (95% CI: 269.7- 544.4 days).

Conclusion: VTE is an important co-morbidity of tuberculosis patients. Most of our patients developed in-hospital VTE while they were not receiving thromboprophylaxis. Guidelines to institute VTE prophylaxis in TB patients should be considered. Follow-up for VTE signs and symptoms in TB patients is warranted.

Tuberculosis (TB) is a serious potentially-treatable infectious disease. Even though the epidemiology and at risk population are not identical in the developed and developing countries, it is a major health problem in both settings. ⁽¹⁾ In the early 1940s, it was thought that venous thromboembolism (VTE) is rare in TB patients. ⁽²⁾ However, they are predisposed to venous thromboembolism (VTE) due to several pathophysiologic mechanisms, affecting all three parts of the Virchow’s Triad.^(3-5) Only a few studies have addressed this issue. Therefore, we recently investigated the coexisting venous thromboembolic events among the tuberculosis patients of the National Research Institute of Tuberculosis and Lung Disease (NRITLD), a WHO-collaborating university-affiliated teaching hospital that provides specialized care for TB patients in the Middle East. ⁽⁶⁾

METHODS:

We retrospectively reviewed the medical records of 3293 TB patients hospitalized at NRITLD from January 2001 to December 2008. Patients with coexisting VTE (DVT, PE or both) were selected using the ninth revision of the International Classification of diseases coding system (ICD-9). Gray-scale evaluation of venous compressibility and color Doppler evaluation and computed tomography pulmonary angiography (CTPA) were used to confirm diagnoses of DVT and PE in patients with signs and symptoms suggestive of VTE. TB diagnosis was considered in all patients with positive results for mycobacterium tuberculosis complex in at least one of the following: the smear, culture, biopsy, or body-fluid specimens. Demographic data and co-morbid conditions of the TB-VTE patients were recorded. Also, we tried to contact all of them in January 2009 for follow-up. Those who could not be contacted for survival analysis were considered as “censored” after the last available follow-up visit. Chi square test was used to compare categorical variables.

RESULTS:

46 patients had coexisting diagnosed symptomatic VTE (26 patients with DVT, 13 with PE, and 7 with both DVT and PE). Majority of these 46 were hospitalized TB patients who suffered from in-hospital VTE (n=29). Additional 15 were tuberculosis patients undergoing post-discharge outpatient TB treatment whom were admitted with a primary diagnosis of VTE. Two remaining patients were hospitalized for VTE treatment for which coexisting TB was diagnosed in the course of hospitalization. Hospital stay mean length was 28.7±14.0 days. Background information and co-morbidities are summarized in table1.

From those with in-hospital TB+VTE (n=31, overall), four patients died during the hospital stay. In comparison to a random sample of 420 TB patients without coexisting VTE at our center (who had an in-hospital mortality rate of 3.5%), in-hospital mortality of TB+VTE patients was significantly higher (P=0.02). Four additional patients died during the follow-up. Using the Kaplan-Meier analysis, median survival time was 407 days (95% CI: 269.6- 544.4 days).

DISCUSSION

Our series of cases was one of the largest in the literature regarding the coexistence of VTE and TB. In our series none of the 29 TB patients who suffered from in-hospital VTE, had received thromboprophylaxis. The latest edition of the American College of Chest Physicians Guidelines on Antithrombotic and Thrombolytic Therapy states that “For acutely ill medical patients admitted to hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, we recommend thromboprophylaxis with Low Molecular Weight Heparin (LMWH), Low dose unfractionated heparin (LDUH), or fondaparinux”.⁽⁷⁾

While the majority of hospitalizations for TB patients in North America is due to severe respiratory disease and/ or major debilitating co-morbidities, many TB patients in developing countries are hospitalized only to receive their anti-tuberculous treatment under close monitoring, according to the DOTS strategy. ⁽⁸⁾ Even though co-morbidities in our series were not rare, they were unevenly distributed and almost half of all co-morbidities were found in five patients with several risk factors who suffered from VTE while they were continuing their post-discharge outpatient treatment. Therefore, in summary, the majority of our TB patients with in-hospital VTE, did not have any known coexisting risk factors for VTE and did not present with severe respiratory distress or severe illness before developing VTE events, and hence, had not received thromboprophylaxis.

It should be pointed out that our series of cases included only TB patients with symptomatic proven VTE. Therefore, the incidence rate of VTE in our series is smaller than that reported in many VTE clinical trials focusing on medical patients, such as MEDENOX, PREVENT, and ARTEMIS. ^(9-11) Patients enrolled in those studies were generally older than our patients and had serious cardiorespiratory compromise, or another acute medical problem associated with at least one other coexistent VTE risk factor. In those studies, routine ultrasonography or venography was performed for all patients to detect symptomatic as well as asymptomatic VTE. Despite the fact that the patients in our study were in general much younger, and had a lower rate of coexisting co-morbidities, the rate of symptomatic VTE in our study was quite comparable to that of MEDENOX, PREVENT, and ARTEMIS; i.e. below 1%. We highly believe that we would have found a higher incidence rate of VTE had we used screening for asymptomatic VTE, similar to the above-mentioned three studies.

Accordingly, we believe that VTE merits to be seriously considered as an important VTE risk factor, even when serious respiratory compromise is not present. Therefore, we suggest that VTE prophylaxis should be strongly considered for most hospitalized patients with diagnosed tuberculosis, irrespective of the cardiorespiratory functional status.

Studies specifically focusing the coexistence of VTE and TB are scant in the literature. White et al. reported 46 patients with TB+VTE among 1366 adults treated for tuberculosis, although detailed data about co-morbidities was missing.⁽¹²⁾Ambrosetti et al. reported 5 cases of DVT and two cases of PE from 1237 TB patients in Italy. ⁽⁵⁾ Other studies have reported smaller numbers of cases. Therefore, our series focusing on more than 3000 TB patients is one of the largest in the literature and based on our findings we suggest VTE prophylaxis for most hospitalized TB patients.

We are currently evaluating the significance of coexisting VTE among TB patients, by comparing the TB-VTE group with 500 randomly selected TB patients without coexisting VTE. Future prospective studies can better elucidate the epidemiologic coexistence of TB and VTE and the ideal anticoagulation regimens.

Unresolved debatable questions in this field include:

• Would there be the need for an extended prophylaxis regimen for TB patients?
  In our study, some TB patients (n=15) suffered from symptomatic VTE several weeks after discharge when they were continuing their outpatient TB treatment.

• What would be the ideal anticoagulation regimen for TB patients (prophylactic, and therapeutic)? Thrombocytopenia and hepatic dysfunction are two common problematic conditions which may coexist with TB, especially in those with HIV-associated TB. Both conditions will pose additional difficulties for proper anticoagulation.

Acknowledgements:

I would like to thank Dr Goldhaber for his kind support for preparation of this manuscript and his kind offer to give me the chance to prepare this review for NATF and Dr Sussman for her editorial assistance.

References:

1. WHO. The world health report 2004: changing history. Geneva: World Health Organization; 2004.
2. Zahn DW, Peirce CT. Venous thrombosis and pulmonary embolism in tuberculosis. Am J Med. 1948; 5: 716-28.
3. Robson SC, White NW, Aronson I, Woollgar R, Goodman H, Jacobs P. Acute-phase response and the hypercoagulable state in pulmonary tuberculosis. Br J Haematol 1996;93:943–9.
4. Turken O, Kunter E, Sezer M, et al. Hemostatic changes in active pulmonary tuberculosis. Int J Tuberc Lung Dis 2002; 6: 927–32.
5. Ambrosetti M, Ferrarese M, Codecasa LR, et al. For the AIPO/SMIRA TB Study Group. Incidence of venous thromboembolism in tuberculosis patients. Respiration 2006; 73: 396.
6. Sharif-Kashani B, Bikdeli B, Moradi A, Tabarsi P, Chitsaz E, Shemirani S, et al. Coexisting venous thromboembolism in patients with tuberculosis. Thromb Res. In Press (PMID: 20137804).
7. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous hromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 381S–453S.
8. World Health Organization Stop TB Strategy, accessed on December, 28, 2009. Available at: http://www.who.int/tb/dots/whatisdots/en/index2.html
9. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341:793–800.
10. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004;17(110):874-9.
11. Cohen AT, Davidson BL, Gallus AS, et al. ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332:325-9.
12. White NW. Venous thrombosis and rifampicin. Lancet 1989;192:434–5.

Table1. Background Information and Co-morbidities

Brenda Blackburn, Patient and Advocate

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In June 2008, when I first woke up with a pain in back of my right leg, I assumed it was a pulled muscle. And although I was a bit bewildered by it, I tried not to worry. However, as the days progressed, it became more painful, achy, and tender; walking became increasingly difficult.

The pain initially felt like it was coming from my calf, then behind my knee, and as time passed it seemed to travel down my leg.  In my ignorance, I thought the pain was working itself down and out, so it must be improving.

The pain lasted almost two weeks before I finally went to see a doctor, late one Friday afternoon. I later discovered, I was lucky to have finally sought medical attention before boarding a cross-country plane to Toronto the following Monday morning. Instead of flying, I ended up in the Emergency Room. Not only did I have deep vein thrombosis (DVT) located from above my right knee to my ankle, but while being treated as an outpatient at the hospital, I developed a small pulmonary embolism (PE). I have been told, many times over, that I am lucky to be alive and lucky I did not board that plane.

After completing my warfarin therapy last September, I requested hereditary testing. My father, who passed away from congestive heart failure last year, had a history of both arterial and venous clotting. He was prescribed a lifetime of warfarin use (which we had always attributed it solely to his heart disease). I tested positive for Thrombophilia, specifically Factor V Leiden, which increases the tendency of my blood to clot. It turns out that I inherited this genetic condition from my father, who never knew he had it.

When all of this happened initially, I had never heard of DVT, its risk factors (some of which I had), or its symptoms.  After my diagnosis, other than anticoagulation information, I had no other take-home resources about DVT, so I began to scour the Internet. It was with shock that I realized that every year more people in America die of DVT than breast cancer, AIDS, and motor vehicle accidents combined.  I was also completely surprised by the lack of Canadian resources or organized support. As an adult educator I felt it was my moral responsibility to take responsibility and do something to help.

My mission then became two-fold:

• To raise public awareness and education, so that others may learn the signs and symptoms of DVT and PE.

and

• To be a patient advocate, supporter, and provider of resources.

I promptly contacted the North American Thrombosis Forum (NATF) and was pleased to join as an Advocacy Committee member in September 2008, while attending the Annual Summit.

The next month I started the DVT Support Group of the Lower Mainland, the first known, in-person, support group in Canada.  Membership is for anyone who:

• Has or had DVT and/or PE
• Has a blood disorder (Thrombophilia—such as Factor V Leiden) that may increase the risk of developing a DVT
• Is currently taking anticoagulants
• Would like to raise public awareness
• Has family or friends with VTE or
• Anyone who wants to learn about risk factors, symptoms, and prevention

Our group is small but growing rapidly. We now have 52 members (28 online and 24 offline), with ages ranging from 14 to 90.  They are largely from British Columbia, but we also have a few members from Alberta, Ontario, and the United States. We receive patient referrals from the Anticoagulation Clinic of Burnaby Hospital (where I received my treatment) and from the new Thrombosis Program of Vancouver General Hospital (the Director, Dr. Agnes Lee, who I met through NATF in 2008).  In fact, 18 of our newest members came from the Thrombosis Program’s very successful one-year celebration on March 17, with which our group was proud to be involved.

We provide several benefits for our members:

• A website through www.meetup.com that provides: information, a large number of relevant resource links, a message board, intra-email, an RSVP system and more.  We are also on Twitter, and one of our members has started a DVT Facebook group.
• As “meet-up” organizer I send each new member hard copy resources, kindly provided by or purchased from affiliate organizations in the U.S.
• We hold a free “meet-up” every month with the following format: discussion, questions and answers, news and resources, and periodic guest speakers based on member needs.  Minutes are taken (excluding confidential sharing) and e-mailed to all members, allowing those who are unable to attend to feel included.

While these small steps may sound commonplace to our U.S. neighbors (where great DVT organizations are in place), in Canada it’s a big step, working to seal a large gap that desperately needs to be filled. It’s truly a grassroots start, but great things are often achieved from humble beginnings.

Amir A. Kuperman, MD and Benjamin Brenner, MD from Rambam Medical Center, Haifa, Israel

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Three factors influence the occurrence of thrombosis: blood stasis, endothelial injury and thrombophilia (The Virchow triangle). Thrombophilia is an inherited or acquired predisposition, detected by a set of laboratory tests, which increases the risk for venous thromboembolism (DVT or PE) or pregnancy complications, like: preeclampsia, intra-uterine fetal death, intra-uterine growth restriction and placental abruption [1,2]. Acquired or secondary thrombophilia includes: active cancer, certain chemotherapies, nephrotic syndrome, disseminated intravascular coagulation (DIC), thrombosis thrombocytopenic purisra (TTP), pregnancy and some inflammatory or autoimmune diseases.

As new thrombophilic conditions have been described, it has become evident that many individuals who carry these defects remain asymptomatic. Furthermore, while there is an increase in the number of abnormalities recognized as likely to enhance the risk of thrombosis, detailed laboratory investigations fail to detect any abnormality in at least 50% of patients who present with a history of thrombosis. It should also be stated that not all prospective cohort studies found an association between thrombophilias and obstetric complications, and in fact, most women with thrombophilia have normal pregnancy outcome. This complicates the issue. One of the main problems with thrombophilia screening is its overuse and abuse. Indeed, in real-world setting – testing for inherited thrombophilia is frequently at odds with the recommendations of the College of American Pathologists (CAP) consensus conference [3].

Then, who should be tested for thrombophilia?

Thrombophilia may manifest clinically as one or more of the following: thrombosis at unusual venous circulations (cerebral, splanchnic), warfarin skin necrosis, purpura fulminans, superficial or deep vein thrombosis, pulmonary embolism, recurrent fetal loss and possibly other pregnancy complications [4]. No absolute indications for thrombophilia testing have been determined. Testing for heritable thrombophilia is not indicated in unselected patients presenting with venous thrombosis. Testing selected patients may give an indication of risk of recurrence following completion of anticoagulant therapy, for example those patients presenting with venous thrombosis at an early age (<40) and who are from apparent thrombosis prone families (more than two other symptomatic family members). Analysis of the large MEGA (Multiple Environmental and Genetic Assessment) study showed that testing for inherited thrombophilia did not reduce recurrence of venous thrombosis [5]. Other selected patient groups in whom the results of testing may influence treatment are children with purpura fulminans and pregnant women at risk of venous thrombosis. Other “relative” indications would be populations at increased risk for thrombosis (pregnancy, hormonal therapy, chemotherapy and high-risk surgery), patients with idiopathic thrombosis and patients with recurrent thrombosis.

It has been shown that single or multiple thrombophilic defects are not associated with a higher risk of recurrent VTE during warfarin therapy [6]. There are no clinical studies assessing whether thrombophilia testing following a venous thrombotic event is clinically effective and cost-effective in the management of thrombosis compared with no testing for thrombophilia [7].

To date, a limited number of genetic variants have been proven to be independent risk factors for thromboembolism (VTE). These include mutations in the genes encoding the natural anticoagulants antithrombin, protein C and protein S and the clotting factors fibrinogen, prothrombin and factor V. The most widely studied acquired thrombophilias are the antiphospholipid syndromes, characterized by persisting lupus inhibitor activity and/or elevated anticardiolipin levels in association with thrombotic problems or pregnancy morbidity. In some instances, for example, elevated factor VIII, non-factor V Leiden (FVL) activated protein C (APC) resistance or elevated homocysteine levels; the changes are the result of interactions between genetic and environmental factors. Population screening studies have shown that a reduction in antithrombin function may be evident in as many as one in 200–400 individuals. Inherited deficiency of protein C has been estimated to occur in one in 300–500 of the population, but to date the prevalence of protein S deficiency has not been established in a large-scale study of healthy individuals. Estimation of plasma levels of these factors is also dependent on age, sex, lipid levels, estrogen and anticoagulant use. The FVL mutation occurs in 2–7% of Caucasian population and the prothrombin G20210A mutation in around 2%. The prevalence of high concentrations of factor VIIc and hyperhomocysteinaemia depend on the ‘cut-off ’ applied. This also applies to the definition of abnormal APC resistance, occurring in the absence of FVL. Factor VIIIc concentrations exceeding 150 IU/dl have been reported in 11% of the general population and in 25% of subjects with venous thrombosis. High levels of factor VIIIc may occur as part of an acute phase response and higher values are observed in subjects with non-FVL APC resistance and in non-blood group O subjects. Plasma homocysteine levels >18.5 mmol/l are found in 5–10% of European populations and are associated with >2-fold increased risk of VTE. Hence, the overall prevalence of thrombophilic abnormalities is relatively high, in contrast to the adverse events that may be attributed to these conditions. This reflects the requirement for several thrombotic risk factors to be present for a clinical event to occur. Acquired risk factors can often be identified in subjects presenting with VTE. Tissue trauma, including surgery, immobilization, cancer, estrogen use, pregnancy and the puerperium, are prominent participating factors. The attributable risk associated with each of these ranges from 4 to 18%.   The increased risk of venous thromboembolism in patients with thrombophilia is summarized in table 1 [8]. And the increased risk of pregnancy complications in women with thrombophilia is summarized in table 2 [8].

Management of patients could be modified in special situations if thrombophilia is present. For example, patients with systemic lupus erythematosus that have antiphospholipid antibodies are considered candidates to receive primary prophylaxis with low-dose aspirin. Primary prophylaxis for thrombophilia patients is also considered in high-risk situations, like: puerperium, immobilization or major surgery. Avoidable risk factors, like hormonal therapy, can be reconsidered when thrombophilia is diagnosed. After thrombosis has occurred, duration of anticoagulation (secondary prophylaxis) can be extended if severe or combined thrombophilia is present.

We can conclude that large prospective studies should be undertaken to refine the risks, and establish the associations of thrombophilias with VTE. The relative value of a thrombophilia-screening program to other healthcare programs needs to be established.

Beth Waldron, DVT/PE Patient and Public Policy Communications Consultant

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Increasing media coverage of thrombosis is essential towards improving overall public awareness, enhancing policy advocacy and cultivating funding for medical research.  Unfortunately, the media tends to pay very little attention to thrombosis. Studies analyzing health journalism show that the media’s most frequently covered health topics center around the conditions of cancer, heart disease, diabetes, obesity, HIV/AIDS, and autism.[i] So if thrombosis is a common medical condition, why isn’t there more media coverage?

A complex topic with low public awareness

To understand the dearth of coverage, consider first what makes a ‘good story’ from the health journalist perspective.  A ‘good health story’ is one that is timely (i.e., tied to a current event or new breakthrough), one that can be succinctly told, one that is easy for a general audience to understand (i.e. not overly-laden in medical jargon) and one that has a wide-audience appeal.  In several of these areas, thrombosis presents a challenge for journalists trying to craft ‘a good story’.

First, thrombosis is a complex topic lacking widespread public awareness.[ii] To craft a story touching on thrombosis requires a journalist to first step-back and lay a bit of background information for the audience before the main story can move forward. Consider that in a news story on more well-known conditions—such as breast cancer, AIDS or diabetes—a general audience will already know (on the most basic level) what these conditions are when presented with the terms. Therefore, a media story about, for example, breast cancer doesn’t require any explanation at all about ‘what is breast cancer’.  It is presumed an audience has a basic familiarity with breast cancer as a medical condition.

Such is not the case for thrombosis.  Despite it being a common condition, the word ‘thrombosis’ is a term still confined mainly to the medical sphere. Substitute the more lay-friendly term ‘blood clot’ for ‘thrombosis’ and, while it is made easier to for more people to understand, it still does not resonate in the public consciousness with the same intuitive cognition as the term ‘cancer’.  No matter what you call it, the public simply does not have a basic understanding of thrombosis.ii

Therefore, to talk about blood clots in the media means having to provide additional background explanation. Depending on the context of the story, it might require defining differences in deep vein thrombosis and pulmonary embolism. It might also require explaining thrombophilia, blood-thinners, how clots are diagnosed, treated options—-the potential facets are many. What first seems to be a simple story to those of us with an understanding of thrombosis can quickly evolve into having to explain nearly everything to an audience with no intuitive knowledge of clots or clotting disorders.

The task of covering a thrombosis story is further complicated by the fact that the average American adult reads at a seventh-grade level. [iii] For this reason, most health-related material is written at a fifth-grade literacy level to ensure greatest comprehension.  Since thrombosis is a complex topic without intuitive public awareness, it doesn’t lend itself neatly to the simplistic, concise coverage that is the hallmark of a general interest story.

Media in economic decline

The need for simplicity in content is further exacerbated by the fact that both space in the newspaper and time on the airwaves equals money. It is no secret that traditional print and broadcast media is undergoing a transformation brought on by economic uncertainties. Media outlets can no longer afford to spend resources on providing in-depth coverage of a topic to the same degree they once did. The more succinct a story can be, the greater the chances for coverage not only because it is more understandable by the audience, but also because it is more cost-effective than a story that requires more in-depth coverage.

Economic pressures also encourage media outlets to select medical stories that are as ‘ready-made’ as possible.  Since journalists have neither the time nor resources to do extensive in-depth digging for factual information, it is a bonanza when they are handed a fairly complete news story that requires minimal effort to polish.  In this regard, medical conditions, which benefit from the support of large, well-funded advocacy organizations with full-time public relations staff, stand the best chances of providing the media with desirable ‘ready-made’ articles and video clips.

Thrombosis organizations have a comparatively short history of media relations

Recall how often you’ve seen or heard news articles with a connection to cancer or heart disease.   These conditions benefit from the support of several long-standing, well-organized, well-funded advocacy organizations with large staff whose full-time task is to promote public relations and media coverage!

By comparison, nonprofit thrombosis advocacy organizations are truly still in their infancy—most have been founded only within the last decade and have a small staff which must wear many administrative hats; the media relations hat is but one of them. Cultivating media ties and networking with journalists requires an investment of both time and financial resources—a challenge for young nonprofits.

Tips to improve media coverage

I’ve presented why we’ve not seen more thrombosis related articles in the press, but now for the big question: How to increase media coverage of thrombosis?  Thankfully, we are living in the ‘information age’ in which we have a plethora of venues—print, radio, television, Internet—in which to disseminate information. The advent of online publications and social media has profoundly influenced the way in which all health information is conveyed—whether it is online or in traditional print and broadcast media.  While the methods and informal rules of getting media coverage may be in flux depending upon the venue, some fundamental guidelines apply regardless of the media outlet.  If you are trying to gain media coverage for a thrombosis related topic—an event, fundraiser, research study, upcoming conference—here are a few basic tips to increase the chances your message will receive attention by the media.

1. Start with a strategic plan.  Sending out a few random press releases into the void of a media mailing list is unlikely to garner much attention.  Formulate a plan which analyzes ‘who is the desired target audience’, ‘which publications will reach that audience’, and ‘who are the journalists active in that area’.  Don’t underestimate the importance of local and ‘small’ media outlets—they are typically the most receptive to story ideas, especially if a story can be presented as having a strong local connection. Additionally, small outlets can be a backdoor way into reaching a larger audience as many larger media outlets ‘pick stories up’ from the smaller outlets.

2. Look for tie-ins to current events. It is not enough to tell a journalist that thrombosis is an important topic ‘just because it is’.  It may be important, but it also has to have a real-world relevancy.  If there is a way to tie-in your proposed story to an upcoming conference, an upcoming fundraiser, a specific achievement such as new research or new protocols, a local celebrity or well-known community leader who may have recently been affected by thrombosis, a remarkable local patient or volunteer….any ‘hook’ that transforms thrombosis from being ‘an important but detached, flat topic’ to being rated ‘interesting and newsworthy’ by an editor.

3. Write an effective press release. Yes, it reflects old-school public relations, but an effective press release still works wonders!  Make sure your press release includes the ‘who, what, when and where’ in the first paragraph.  Use active verbs and avoid clichés. Limit press releases to one page when possible—reporters don’t have time to sift through more. Include contact information so a journalist can easily follow-up with you for more details.

4. Consider creating a supplemental ‘press kit’ with a ready-to-go article. While the one-page press release is the first step, time-pressed journalists appreciate knowing they can also receive the detailed frame of an article provided upon request—links to articles, additional sources, the contact information of people who can be interviewed, even photographs and video clips—such information all helps make the journalist’s job easier, thereby making it easier for them to cover your story.  Indicate when such supplemental information is available.

5. Address your inquiries to a specific person. While news organizations have a generic email or fax in which they receive story inquiries and press releases, make the extra effort to obtain the name of the health journalist or editor.  Getting your inquiry into the hands of a specific person and not simply a general mailbox—which may be screened by anyone from a non-heath editor to an intern—will increase the likelihood of a personal response.

6. Be polite and say ‘thank you’! It may seem obvious to be polite, but it always surprises me how many people fail to do this simple step. There is opportunity even in rejection. Be nice to your local health journalists now and they’ll remember you down the road.  Most media organizations have only one or two journalists tagged to cover health related news.  Even if a reporter responds negatively to your current inquiry, thank them for their time and try to develop a good rapport for the future.  Odds are good, the next inquiry you send will be to the same person!

7. Ask about Public Service Announcements. Public Service Announcements (PSAs) are announcements of events, services or ‘public good’ type information.  While some print publications run PSA ‘ads’ for filler material, column space tends to be too precious for unpaid advertising.  For this reason, most PSAs can be found on radio, television and most recently, the Internet. Broadcasters often commit a portion of their airtime to free public service spots on behalf of nonprofit organizations or community causes. Call your radio or TV station and ask to speak to the Public Service Director. Find out what kind of spots they run, what rules apply, what their time limits and formats are and to whom and by when should they be submitted.

And most importantly…

8.  Don’t give up!! Acquiring media coverage requires both patience and persistence.  Remember the old adage, ‘if at first you don’t succeed…’.  Well, it’s true! If you don’t at least try, then nothing changes.  For patients, like myself, that simply isn’t an option! Keep at it and GOOD LUCK!

Background information:  Beth Waldron is a public policy communications consultant in North Carolina.  She is also a thrombosis and thrombophila patient who has had DVT and PE and is homozygous for the Factor V Leiden mutation.

[ii] “Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism”, US Department of Health and Human Services, 2008.

[iii] “National Assessment of Adult Literacy ”, National Center for Education Statistics, 2003

Authored by, Aman Khurana, MD, Vascular Medicine Fellow and Suman Rathburn MD, MS, Associate Professor of Medicine and Director of Vascular Medicine Program from the University of Oklahoma Health Sciences Center

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Chronic Venous Insufficiency (CVI) is a common medical condition but often overlooked by the medical community.  Manifestations of CVI are a result of longstanding venous hypertension due to chronic venous obstruction or venous valvular reflux. Most patients present with symptoms of leg heaviness, aching, cramps, itching, tingling, restless leg, swelling, fatigue, pruritus and skin changes. Skin changes in the extremities range from dilated veins (small reticular veins, teleangiectases and varicose veins) to edema, hyperpigmentation, fibrosis and ulceration. Complications include cellulitis and venous ulcers. Treatment is aimed at reducing venous pooling, either with conservative measures initially, or with endovascular interventions if disabling symptoms persist. Compression therapy using short-stretch bandages and then graded compression garments are the mainstay of therapy. Skin and wound care is of paramount importance in preventing more serious complications.