By Rohil Badkundri, Aditya Bhave, Atharva Athalye, Rohan Rege, Varun Rangnekar, The GTF Group, Atlanta, GA


We were inspired to write this research article on the subject of heparin following my presentation at Loyola University’s Heparin Centennial Symposium on October 28, 2016. Heparin is, simply termed, an anticoagulant. It is used extensively to treat conditions such as deep-vein Thrombosis and Pulmonary Embolism, as well as during surgical procedures. For these reasons, Heparin has maintained a very strong position in the medical world for the past 100 years.


Heparin was first discovered, accidentally, by Jay McLean over a hundred years ago. McLean was assisting scientist William Howell in the investigation of pro-coagulant preparations as a second-year medical student at Johns Hopkins University .

McLean isolated a fat-soluble anticoagulant in canine liver tissue in 1916. In 1918, Howell called the anticoagulant heparin, based on the Greek word for liver, “hepar.” McLean’s findings most probably influenced the work of Howell and team, which eventually led to the polysaccharide being discovered.

Mc Lean

Chemical Structure

The chemical formula of Heparin is C12H19NO20S3. The molar mass ranges from 12,000 to 15,000 grams/mole. In essence, Heparin is a heterogeneous mixture of polysaccharides linked by glycosidic linkages. The chemical structure is given below:

Heparin Molecule

Mechanism of Action

The molecular basis for the anticoagulant action of heparin lies in its ability to bind to and enhance the inhibitory activity of the plasma protein antithrombin against several serine proteases of the coagulation system, most importantly factors IIa (thrombin), Xa and IXa. In fact, Heparin augments the anticoagulant potential of antithrombin by a thousand fold.


Heparin is used widely in medicine as an anticoagulant. It treats clot disorders such as pulmonary embolism, myocardial infarction, deep vein thrombosis, and stroke, by preventing the clot from growing larger and allowing body mechanisms to naturally break down the clot. In terms of surgical procedures, Heparin is used to prevent formation of blood clots, so that the physicians can perform the needed procedures. Examples of surgical procedures that make use of Heparin include open-heart surgery, bypass surgery, kidney dialysis, and blood transfusions.


There are 2 main formulations used commonly in medicine:

a. Unfractionated Heparin (UFH)

UFH was the original Heparin discovered in 1916. Being unfractionated, UFH is found in various size fragments with different molecular weights. UFH is the most potent form of Heparin, and is the form used most in surgery. It is administered intravenously. However, being the most potent form also means  the most risky        in terms of side effects such as alopecia, HIT, and bleeding.

b. Low Molecular Weight Heparin (LMWH)

LMWH was developed in 1993. It works similarly to Heparin, in that it produces its primary anticoagulant effect by activating antithrombin. It is derived from UFH through chemical or enzymatic depolymerization to yield fragments approximately one third the size of heparin. Similar to UFH, LMWH is heterogeneous with respect to molecular size and anticoagulant activity. However, unlike UFH, LMWH generally has much smaller fragments. Depolymerization of UFH into lower-molecular-weight fragments results in several changes in its properties, all due to reduced binding of LMWH to proteins or cells.

Let us look at the Expectations from an Ideal Injectable Anticoagulant:

1. Should have a wide therapeutic margin

2. Should have no interaction with foods and drugs

3. Should be devoid of adverse effects such as bleeding, alopecia, osteoporosis, or HIT

4. There should be no need for routine blood monitoring

5. The anticoagulant effect should be predictable

6. Anticoagulant effects can be easily reversed

Advantages of LMWH

LMWH is less potent compared to unfractionated heparin, making it safer to use.

LMWH has a more predictable effect

Less Pharmacokinetic Limitations

More predictable anticoagulant effect due to less binding to plasma proteins

Does not require monitoring

Has a lower incidence of HIT (discussed later in this article)

Can be administered subcutaneously

Has a longer half life.


Some side effects of Heparin include: bleeding and easy bruising, pain, redness, warmth, irritation, or skin changes at the injection site, itching, and bluish-colored skin. More serious side effects include osteoporosis (result of long-term Heparin treatment), alopecia, and Heparin-induced thrombocytopenia (HIT). HIT causes a deficiency of platelets in the blood. Heparin binds to platelets, causing activation and release of platelet factor 4. Heparin then complexes PF4 and stimulates the formation of antibodies that cause the very serious condition known as heparin-induced thrombocytopenia (HIT). Below is an image of gangrene in a patient caused by HIT.


Antidote of Heparin

Heparin has a short half-life of about 6 hours, so simply stopping the administration of heparin may be enough to reverse some adverse effects without needing the antidote for heparin. However, if an antidote is needed, protamine sulfate, a compound derived from purified fish sperm, can neutralize Heparin.

Have we reached our target ideal, yet?


Requisites UFH LMWH Ideal
Effective anticoagulant x x xx
No drug Interaction x x xx
No food Interaction x x xx
No need for routine blood monitoring x xx
Wide margin of safety x xx
Predictable Effect x xx
Effects can be easily antagonized by an antidote X x xx
Can be given in various doses X x xx


As can be seen through this table, we have not yet reached our target goal, which needs lot more work in this area.

International Heparin Centennial Symposium held at Loyola University on October 28, 2016.

This event was held to honor and celebrate the 100 years of Heparin, arranged by Jawed Fareed, PhD, Professor of Pharmacology and Pathology, and Head of the Thrombosis and Hemostasis Laboratory at Loyola University and his staff.

Over 120 scientists from all over the world were invited to present various aspects and advances of Heparin. Rohil Badkundri, one of the authors, represented Georgia Thrombosis Forum at the symposium, and presented a poster titled “One hundred years of Heparin”. This poster has now been posted on the website of the International Union of Angiology (see attached).

Summary and Conclusion

Heparin, though 100 years old, is still being widely used.  For the most part, it fits the characteristics of an ideal anticoagulant agent, outlined earlier in this article. Of course, Heparin is still not perfect, and therefore more work is needed to reach the goal of an ideal anticoagulant agent. This defines the role of research in furthering medicine.

Rohil, one of the authors, has taken a challenge. The challenge is to create the ideal anticoagulant. In terms fitting for their trip to Loyola’s symposium, Dr. Laddu described it as “a perfect Heparin”. Rohil has decided to accept the challenge and make it his goal to perfect Heparin starting now and in the future.


Omer Iqbal, MD

Jawed Fareed, PhD

Atul Laddu, MD, PhD, FACC

The authors consulted the following references in preparation of this article.

1.  Discovery of Heparin: The unknown history of heparin’s discovery – Dinis da Gama A., 2008 Jan-Mar

2.  Jay McLean photo:

3.  Heparin Structure:

4.  Formulations and Toxicity of Heparin: Low-Molecular-Weight Heparin: A Review of the Results of Recent Studies of the Treatment of Venous Thromboembolism and Unstable Angina – Jack Hirsh, October, 1998

5.  HIT photo:

6.  Treatment of Toxicity of Heparin:


Report of the International Heparin Centennial Symposium was held at Loyola University Medical Center on October 28, 2016. The event was meant to celebrate and discuss the advancement of Heparin, one hundred years after its discovery. Rohil represented the Georgia Thrombosis Forum at the symposium, and presented a poster titled “One hundred years of Heparin”.

I first got involved with this project after Dr. Laddu informed me of an opportunity to present a poster at Loyola in October. I had visited Loyola in June for High School Scholars Day, so I was familiar with the research, the staff at Loyola University, and campus. Dr. Laddu offered the opportunity to me and a few other GTF members who had also attended High School Scholars Day, but I was the only one able to attend the event. Over the next several weeks, I worked tirelessly under the guidance of Dr. Laddu and my father, to complete GTF’s first major poster.

I presented the poster in front of world-class researchers. The researchers seemed quite interested in my poster and I received many questions, to which I was able to give confident answers. The researchers were impressed with my work and many of them assumed that I was actually a medical student.

Regarding the symposium itself, I found the researcher’s presentations to be extremely interesting. Of the many wonderful presentations, the ones by Dr. Linhardt, Dr. Walenga, and Dr. Petitou particularly fascinated me. Dr. Linhardt’s presentation, “Structural Analysis of Heparins and Bioengineered Heparins”, suggested using CRISPR-cas to insert the Heparin producing gene in bacteria. The Heparin produced would have the advantage of having fewer impurities because bioengineered heparin is more standard than that derived from animals. Dr. Walenga’s talk, “Validation of Sole Anti-Xa Oligosaccharides as Antithrombotic Agents”, discussed identification of antithrombin-binding oligosaccharide sequences within Heparin. Certain variations of these sequences were found to have a high-antithrombin affinity, making the compounds far more efficient in preventing the formation of clots. These oligosaccharide sequences were then isolated and made into Heparin-derived Anti-Xa Oligosaccharides. This science has a bright future, with the hope being to prevent Heparin-induced thrombocytopenia by preventing PF4 (platelet factor 4) from binding to Heparin by inhibiting/removing the binding site altogether. “The Discovery of Pentasaccharides and their Impact on the Development of Newer Therapeutic Agents”, by Dr. Maurice Petitou focused on the structural characterization of the AT binding sequence in Heparin, followed by chemical synthesis of the corresponding pentasaccharide found within Heparin. The synthetic pentasaccharide does not interact with PF4, thus preventing HIT. The final result of the research was a neutralizable synthetic Heparin that inhibits thrombin and Factor Xa without causing Heparin-induced thrombocytopenia (HIT), no risk of contamination, and no risk of shortage, as the compound is synthesized from glucose. The compound was shown to be effective in anticoagulation with the drug Fondaparinux and its derivatives.

As for my personal impression of the event as a whole, I was very impressed with the symposium and quite happy with my presentation. I feel the trip was worth every minute and dollar spent. I learned a great amount from the presentations, gained connections by talking with researchers, and had great success in presenting GTF’s poster. The trip itself was very enjoyable. While we did have some hotel problems, our overall stay was very nice. During the dinner at the Drake Hotel, Dr. Fareed called on me to make some comments on the spot. I had not had any preparation or knowledge beforehand that this was going to happen, so I did miss a couple points that I should have mentioned in my speech, but overall I believe I did well and will do even better next time I am placed in a similar situation.

I would most definitely recommend such an opportunity, or similar opportunities, to other GTF members. The connections, experience, and knowledge gained from this trip are priceless. That being said, this type of opportunity is not for everyone. I would not recommend this type of event to those without a strong background and interest in research. To make the most out of this type of event, one must have a very in-depth knowledge of the topic (in this case Heparin). Not only should you be able to understand and explain well your own material (in this case the poster), but also the material shown by others (in this case the presentations made in the symposium). A knowledge of research also helps you converse with the researchers, make more connections, and overall have a better experience.

At the conclusion of our journey, Dr. Laddu offered me a grand challenge. The challenge was to create the ideal anticoagulant. I readily accepted this big challenge.