Heparin

Anticoagulant

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Pharmaceutical compound

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan.[3][4] Heparin is a blood anticoagulant that increases the activity of antithrombin.[5] It is used in the treatment of heart attacks and unstable angina.[3] It can be given intravenously or by injection under the skin.[3] Its anticoagulant properties make it useful to prevent blood clotting in blood specimen test tubes and kidney dialysis machines.[4][6]

Common side effects include bleeding, pain at the injection site, and low blood platelets.[3] Serious side effects include heparin-induced thrombocytopenia.[3] Greater care is needed in those with poor kidney function.[3]

Heparin is contraindicated for suspected cases of vaccine-induced pro-thrombotic immune thrombocytopenia (VIPIT) secondary to SARS-CoV-2 vaccination, as heparin may further increase the risk of bleeding in an anti-PF4/heparin complex autoimmune manner, in favor of alternative anticoagulant medications (such as argatroban or danaparoid).[7][8][9]

Heparin appears to be relatively safe for use during pregnancy and breastfeeding.[10] Heparin is produced by basophils and mast cells in all mammals.[11]

The discovery of heparin was announced in .[12] It is on the World Health Organization's List of Essential Medicines.[13] A fractionated version of heparin, known as low molecular weight heparin, is also available.[14]

History

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Heparin was discovered by Jay McLean and William Henry Howell in , although it did not enter clinical trials until .[15] It was originally isolated from dog liver cells, hence its name (&#;παρ hēpar is Greek for 'liver'; hepar + -in).

McLean was a second-year medical student at Johns Hopkins University, and was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue.[16] In , Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. In the early s, Howell isolated a water-soluble polysaccharide anticoagulant, which he also termed 'heparin', although it was different from the previously discovered phosphatide preparations.[17][18] McLean's work as a surgeon probably changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery.

It had at first been accepted that it was Howell who discovered heparin. However in the s, Jay McLean became unhappy that he had not received appropriate recognition for what he saw as his own discovery. Though relatively discreet about his claim and not wanting to upset his former chief, he gave lectures and wrote letters claiming that the discovery was his. This gradually became accepted as fact, and indeed after his death in , his obituary credited him as being the true discoverer of heparin. This was elegantly restated in in a plaque unveiled in Johns Hopkins to commemorate the major contribution (of McLean) to the discovery of heparin in in collaboration with Professor William Henry Howell.[19]

In the s, several researchers were investigating heparin. Erik Jorpes at Karolinska Institutet published his research on the structure of heparin in ,[20] which made it possible for the Swedish company Vitrum AB to launch the first heparin product for intravenous use in . Between and , Connaught Medical Research Laboratories, then a part of the University of Toronto, perfected a technique for producing safe, nontoxic heparin that could be administered to patients, in a saline solution. The first human trials of heparin began in May , and, by , it was clear that Connaught's heparin was safe, easily available, and effective as a blood anticoagulant. Prior to , heparin was available in small amounts, was extremely expensive and toxic, and, as a consequence, of no medical value.[21]

Heparin production experienced a break in the s. Until then, heparin was mainly obtained from cattle tissue, which was a by-product of the meat industry, especially in North America. With the rapid spread of BSE, more and more manufacturers abandoned this source of supply. As a result, global heparin production became increasingly concentrated in China, where the substance was now procured from the expanding industry of breeding and slaughtering hog. The dependence of medical care on the meat industry assumed threatening proportions in the wake of the COVID-19 pandemic. In , several studies demonstrated the efficacy of heparin in mitigating severe disease progression, as its anticoagulant effect counteracted the formation of immunothrombosis. However, the availability of heparin on the world market was decreased, because concurrently a renewed swine flu epidemic had reduced significant portions of the Chinese hog population. The situation was further exacerbated by the fact that mass slaughterhouses around the world became corona hotspots themselves and were forced to close temporarily. In less affluent countries, the resulting heparin shortage also led to worsened health care beyond the treatment of covid, for example through the cancellation of cardiac surgeries.[22]

Medical use

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A vial of heparin sodium for injection

Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. Heparin itself does not break down clots that have already formed, instead it prevents clot formation by inhibiting thrombin and other procoagulant serine proteases. Heparin is generally used for anticoagulation for the following conditions:[23]

Heparin and its low-molecular-weight derivatives (e.g., enoxaparin, dalteparin, tinzaparin) are effective in preventing deep vein thromboses and pulmonary emboli in people at risk,[24][25] but no evidence indicates any one is more effective than the other in preventing mortality.[26]

In angiography, 2 to 5 units/mL of unfractionated heparin saline flush is used as a locking solution to prevent the clotting of blood in guidewires, sheaths, and catheters, thus preventing thrombus from dislodging from these devices into the circulatory system .[27][28]

Unfractionated heparin is used in hemodialysis. Comparing to low-molecular-weight heparin, unfractionated heparin does not have prolonged anticoagulation action after dialysis, and low cost. However, the short duration of action for heparin would require it to maintain continuous infusion to maintain its action. Meanwhile, unfractionated heparin has higher risk of heparin-induced thrombocytopenia.[29]

Adverse effects

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A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT), caused by an immunological reaction that makes platelets a target of immunological response, resulting in the degradation of platelets, which causes thrombocytopenia.[30] This condition is usually reversed on discontinuation, and in general can be avoided with the use of synthetic heparins. Not all patients with heparin antibodies will develop thrombocytopenia. Also, a benign form of thrombocytopenia is associated with early heparin use, which resolves without stopping heparin. Approximately one-third of patients with diagnosed heparin-induced thrombocytopenia will ultimately develop thrombotic complications.[31]

Two non-hemorrhagic side-effects of heparin treatment are known. The first is elevation of serum aminotransferase levels, which has been reported in as many as 80% of patients receiving heparin. This abnormality is not associated with liver dysfunction, and it disappears after the drug is discontinued. The other complication is hyperkalemia, which occurs in 5 to 10% of patients receiving heparin, and is the result of heparin-induced aldosterone suppression. The hyperkalemia can appear within a few days after the onset of heparin therapy. More rarely, the side-effects alopecia and osteoporosis can occur with chronic use.[23]

As with many drugs, overdoses of heparin can be fatal. In September , heparin received worldwide publicity when three prematurely born infants died after they were mistakenly given overdoses of heparin at an Indianapolis hospital.[32]

Contraindications

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Heparin is contraindicated in those with risk of bleeding (especially in people with uncontrolled blood pressure, liver disease, and stroke), severe liver disease, or severe hypertension.[33]

Antidote to heparin

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Protamine sulfate has been given to counteract the anticoagulant effect of heparin (1 mg per 100 units of heparin that had been given over the past 6 hours).[34] It may be used in those who overdose on heparin or to reverse heparin's effect when it is no longer needed.[35]

Physiological function

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Heparin's normal role in the body is unclear. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials.[36] In addition, it is observed across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system. It is a highly sulfated glycosaminoglycan. It has the highest negative charge density of any known biological molecule.[37]

Evolutionary conservation

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In addition to the bovine and porcine tissue from which pharmaceutical-grade heparin is commonly extracted, it has also been extracted and characterized from:

The biological activity of heparin within species 6&#;11 is unclear and further supports the idea that the main physiological role of heparin is not anticoagulation. These species do not possess any blood coagulation system similar to that present within the species listed 1&#;5. The above list also demonstrates how heparin has been highly evolutionarily conserved, with molecules of a similar structure being produced by a broad range of organisms belonging to many different phyla.[citation needed]

Pharmacology

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In nature, heparin is a polymer of varying chain size. Unfractionated heparin (UFH) as a pharmaceutical is heparin that has not been fractionated to sequester the fraction of molecules with low molecular weight. In contrast, low-molecular-weight heparin (LMWH) has undergone fractionation for the purpose of making its pharmacodynamics more predictable. Often either UFH or LMWH can be used; in some situations one or the other is preferable.[51]

Mechanism of action

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Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop.[52] The activated AT then inactivates thrombin, factor Xa and other proteases. The rate of inactivation of these proteases by AT can increase by up to -fold due to the binding of heparin.[53] Heparin binds to AT via a specific pentasaccharide sulfation sequence contained within the heparin polymer:

GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)

The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin.[37] The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.[54] In contrast, antifactor Xa activity via AT requires only the pentasaccharide-binding site.

This size difference has led to the development of low-molecular-weight heparins (LMWHs) and fondaparinux as anticoagulants. Fondaparinux targets anti-factor Xa activity rather than inhibiting thrombin activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate.

With LMWH and fondaparinux, the risk of osteoporosis and heparin-induced thrombocytopenia (HIT) is reduced. Monitoring of the activated partial thromboplastin time is also not required and does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa.

Danaparoid, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate can be used as an anticoagulant in patients having developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%.[55]

The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), one of the measures of the time it takes the blood plasma to clot. Partial thromboplastin time should not be confused with prothrombin time, or PT, which measures blood clotting time through a different pathway of the coagulation cascade.

Administration

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Heparin vial for subcutaneous injection

Heparin is given parenterally because it is not absorbed from the gut, due to its high negative charge and large size. It can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are avoided because of the potential for forming hematomas. Because of its short biologic half-life of about one hour, heparin must be given frequently or as a continuous infusion. Unfractionated heparin has a half-life of about one to two hours after infusion,[56] whereas LMWH has a half-life of four to five hours.[57] The use of LMWH has allowed once-daily dosing, thus not requiring a continuous infusion of the drug. If long-term anticoagulation is required, heparin is often used only to commence anticoagulation therapy until an oral anticoagulant e.g. warfarin takes effect.

The American College of Chest Physicians publishes clinical guidelines on heparin dosing.[58]

Natural degradation or clearance

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Unfractionated heparin has a half-life of about one to two hours after infusion,[56] whereas low-molecular-weight heparin's half-life is about four times longer. Lower doses of heparin have a much shorter half-life than larger ones. Heparin binding to macrophage cells is internalized and depolymerized by the macrophages. It also rapidly binds to endothelial cells, which precludes the binding to antithrombin that results in anticoagulant action. For higher doses of heparin, endothelial cell binding will be saturated, such that clearance of heparin from the bloodstream by the kidneys will be a slower process.[59]

Chemistry

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Heparin structure

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Native heparin is a polymer with a molecular weight ranging from 3 to 30 kDa, although the average molecular weight of most commercial heparin preparations is in the range of 12 to 15 kDa.[60] Heparin is a member of the glycosaminoglycan family of carbohydrates (which includes the closely related molecule heparan sulfate) and consists of a variably sulfated repeating disaccharide unit.[61] The main disaccharide units that occur in heparin are shown below. The most common disaccharide unit* (see below) is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S). For example, this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa.[62]

Not shown below are the rare disaccharides containing a 3-O-sulfated glucosamine (GlcNS(3S,6S)) or a free amine group (GlcNH3+). Under physiological conditions, the ester and amide sulfate groups are deprotonated and attract positively charged counterions to form a heparin salt. Heparin is usually administered in this form as an anticoagulant.

GlcA = β-D-glucuronic acid, IdoA = α-L-iduronic acid, IdoA(2S) = 2-O-sulfo-α-L-iduronic acid, GlcNAc = 2-deoxy-2-acetamido-α-D-glucopyranosyl, GlcNS = 2-deoxy-2-sulfamido-α-D-glucopyranosyl, GlcNS(6S) = 2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate

One unit of heparin (the "Howell unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 ml of cat's blood fluid for 24 hours at 0 °C.[63]

Three-dimensional structure

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The three-dimensional structure of heparin is complicated because iduronic acid may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. The conformational equilibrium is influenced by sulfation state of adjacent glucosamine sugars.[64] Nevertheless, the solution structure of a heparin dodecasaccharide composed solely of six GlcNS(6S)-IdoA(2S) repeat units has been determined using a combination of NMR spectroscopy and molecular modeling techniques.[65] Two models were constructed, one in which all IdoA(2S) were in the 2S0 conformation (A and B below), and one in which they are in the 1C4 conformation (C and D below). However, no evidence suggests that changes between these conformations occur in a concerted fashion. These models correspond to the protein data bank code 1HPN.[66]

Two different structures of heparin

In the image above:

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• A = 1HPN (all IdoA(2S) residues in 2S0 conformation) Jmol viewer
• B = van der Waals radius space filling model of A
• C = 1HPN (all IdoA(2S) residues in 1C4 conformation) Jmol viewer
• D = van der Waals radius space filling model of C

In these models, heparin adopts a helical conformation, the rotation of which places clusters of sulfate groups at regular intervals of about 17 angstroms (1.7 nm) on either side of the helical axis.

Depolymerization techniques

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Either chemical or enzymatic depolymerization techniques or a combination of the two underlie the vast majority of analyses carried out on the structure and function of heparin and heparan sulfate (HS).

Enzymatic

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The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum).[67] This bacterium is capable of using either heparin or HS as its sole carbon and nitrogen source. To do so, it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases, and sulfamidases.[68] The lyases have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I (EC 4.2.2.7), II (no EC number assigned) and III (EC 4.2.2.8) and each has distinct substrate specificities as detailed below.[69][70]

Heparinase enzyme Substrate specificity Heparinase I GlcNS(±6S)-IdoA(2S) Heparinase II GlcNS/Ac(±6S)-IdoA(±2S)
GlcNS/Ac(±6S)-GlcA Heparinase III GlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA)

The lyases cleave heparin/HS by a beta elimination mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue.[71][72] The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromophore (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed, as well as providing a convenient method for detecting the fragments produced by enzyme digestion.

Chemical

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Nitrous acid can be used to chemically depolymerize heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions, nitrous acid effects deaminative cleavage of the chain.[73]

IdoA(2S)-aMan: The anhydromannose can be reduced to an anhydromannitol

At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, albeit at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit.

At low pH, deaminative cleavage results in the release of inorganic SO4, and the conversion of GlcNS into anhydromannose (aMan). Low-pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysaccharides such as chondroitin sulfate and dermatan sulfate, chondroitin sulfate and dermatan sulfate not being susceptible to nitrous acid cleavage.

Detection in body fluids

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Current clinical laboratory assays for heparin rely on an indirect measurement of the effect of the drug, rather than on a direct measure of its chemical presence. These include activated partial thromboplastin time (APTT) and antifactor Xa activity. The specimen of choice is usually fresh, nonhemolyzed plasma from blood that has been anticoagulated with citrate, fluoride, or oxalate.[74][75]

Other functions

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Society and culture

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Contamination recalls

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Considering the animal source of pharmaceutical heparin, the numbers of potential impurities are relatively large compared with a wholly synthetic therapeutic agent. The range of possible biological contaminants includes viruses, bacterial endotoxins, transmissible spongiform encephalopathy (TSE) agents, lipids, proteins, and DNA. During the preparation of pharmaceutical-grade heparin from animal tissues, impurities such as solvents, heavy metals, and extraneous cations can be introduced. However, the methods employed to minimize the occurrence and to identify and/or eliminate these contaminants are well established and listed in guidelines and pharmacopoeias. The major challenge in the analysis of heparin impurities is the detection and identification of structurally related impurities. The most prevalent impurity in heparin is dermatan sulfate (DS), also known as chondroitin sulfate B. The building-block of DS is a disaccharide composed of 1,3-linked N-acetyl galactosamine (GalN) and a uronic acid residue, connected via 1,4 linkages to form the polymer. DS is composed of three possible uronic acid (GlcA, IdoA or IdoA2S) and four possible hexosamine (GalNAc, Gal- NAc4S, GalNAc6S, or GalNAc4S6S) building-blocks. The presence of iduronic acid in DS distinguishes it from chrondroitin sulfate A and C and likens it to heparin and HS. DS has a lower negative charge density overall compared to heparin. A common natural contaminant, DS is present at levels of 1&#;7% in heparin API, but has no proven biological activity that influences the anticoagulation effect of heparin.[87]

In December , the US Food and Drug Administration (FDA) recalled a shipment of heparin because of bacterial growth (Serratia marcescens) in several unopened syringes of this product. S. marcescens can lead to life-threatening injuries and/or death.[88]

recall due to adulteration in drug from China

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In March , major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.[89][90] According to the FDA, the adulterated heparin killed nearly 80 people in the United States.[91] The adulterant was identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used for arthritis, which was intended to substitute for actual heparin in potency tests.[92]

According to the New York Times: "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock".

Use in homicide

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In , Petr Zelenka, a nurse in the Czech Republic, deliberately administered large doses to patients, killing seven, and attempting to kill ten others.[93]

Overdose issues

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In , a nurse at Cedars-Sinai Medical Center mistakenly gave the 12-day-old twins of actor Dennis Quaid a dose of heparin that was 1,000 times the recommended dose for infants.[94] The overdose allegedly arose because the labeling and design of the adult and infant versions of the product were similar. The Quaid family subsequently sued the manufacturer, Baxter Healthcare Corp.,[95][96] and settled with the hospital for $750,000.[97] Prior to the Quaid accident, six newborn babies at Methodist Hospital in Indianapolis, Indiana, were given an overdose. Three of the babies died after the mistake.[98]

In July , another set of twins born at Christus Spohn Hospital South, in Corpus Christi, Texas, died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling.[99] As of July  , the exact cause of the twins' death was under investigation.[100][101]

In March , a two-year-old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center. The exact circumstances surrounding her death are still under investigation.[102]

Production

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Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestines or bovine (cattle) lungs.[103] Advances to produce heparin synthetically have been made in and .[104] In , a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported.[105]

Research

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As detailed in the table below, the potential is great for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.[106][107]

&#; indicates that no information is available

As a result of heparin's effect on such a wide variety of disease states, a number of drugs are indeed in development whose molecular structures are identical or similar to those found within parts of the polymeric heparin chain.[106]

Drug molecule Effect of new drug compared to heparin Biological activities Heparin tetrasaccharide Nonanticoagulant, nonimmunogenic, orally active Antiallergic Pentosan polysulfate Plant derived, little anticoagulant activity, anti-inflammatory, orally active Anti-inflammatory, antiadhesive, antimetastatic Phosphomannopentanose sulfate Potent inhibitor of heparanase activity Antimetastatic, antiangiogenic, anti-inflammatory Selectively chemically O-desulphated heparin Lacks anticoagulant activity Anti-inflammatory, antiallergic, antiadhesive

References

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Further reading

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You have full access to this article via your institution.

Heparin was the first anticoagulant agent to be discovered and isolated for medical use, and is one of the oldest drugs still to be in widespread clinical use. Indeed, heparin remains on the WHO Model List of Essential Medicines &#; the safest and most effective medicines needed in a health-care system.

Heparin is a naturally occurring glycosaminoglycan produced in the body by basophils and mast cells (image). The substance was identified a centenary ago, although who should be credited with the discovery remains controversial.

In , Jay McLean was a second-year medical student working with the physiologist William Henry Howell at Johns Hopkins Medical School in Baltimore, Maryland, USA. The pair were initially working on cephalin, thought to be a procoagulant substance that neutralized antithrombin and thereby allowed the activation of prothrombin, leading to clotting.

A transmission electron micrograph of an activated mast cell releasing granules containing heparin and histamine.

Credit: Science Photo Library /Alamy Stock Photo

After this work, McLean extracted fat-soluble compounds called phosphatides from dog liver that seemed to have anticoagulant properties in vitro, and which produced excessive bleeding when given to experimental animals. McLean then moved to the University of Pennsylvania and continued his research into cephalins.

Nevertheless, work on anticoagulants continued in the Howell laboratories. In , together with medical student L. Emmett Holt Jr, Howell isolated another fat-soluble anticoagulant, distinct from the one previously isolated by McLean. Howell coined the name 'heparin' for this type of substance (derived from the Greek for 'liver', from which it was first isolated).

In , Howell described an aqueous extraction protocol and, in , refined this protocol and identified a water-soluble polysaccharide anticoagulant, which he also termed 'heparin' (despite being different from the compounds previously isolated in and ).

This water-soluble heparin was commercially produced, but contained impurities that caused adverse effects such as headaches, fevers, and nausea, which limited its medicinal use. Howell retired in , and died in .

In , Charles Best (famous for being a co-discover of insulin with fellow Canadian Sir Frederick Banting) working with graduate student Arthur Charles decided to try to purify heparin further to reduce or eliminate the adverse effects, and to demonstrate its utility in the prevention of thrombus formation. In , Arthur Charles and senior colleague David Scott published a series of three papers outlining a protocol for isolating a crude preparation of heparin from bovine liver, an analysis of extrahepatic tissues in which heparin could be identified, and a protocol for purifying heparin.

heparin infused into the brachial artery resulted in a significantly increased clotting time

In , Best and colleagues published their observations that heparin prevented thrombus formation in dogs whose veins had undergone mechanical or chemical trauma. On 16 April , the purified form of heparin was used in a human for the first time: a saline solution of heparin infused into the brachial artery resulted in a significantly increased clotting time, with no toxic adverse effects.

A Swedish physiologist Erik Jorpes had visited Best in Canada in and then returned to the Karolinska Institute in Stockholm. In , Jorpes published his research into the structure of heparin, which allowed a Swedish company to begin commercial production of heparin for intravenous use. By , Peter Moloney and Edith Taylor had patented a method to produce heparin with a high yield and at a low cost, which established the widespread availability and use of the drug.

Before the s, Howell was widely credited with the discovery of heparin, although Best and many others contributed to its development into a clinically usable product. In , a plaque was unveiled at Johns Hopkins University to commemorate Jay McLean MD (&#;), &#;in recognition of his major contribution to the discovery of heparin in as a second-year medical student in collaboration with Professor William H. Howell&#;.

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