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.

In the early 1920s, 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.

This was elegantly restated in 1963 in a plaque unveiled at Johns Hopkins to commemorate the major contribution (of McLean) to the discovery of heparin in 1916 in collaboration with Professor William Henry Howell.

Between 1933 and 1936, 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.

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 hogs.

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.

In less affluent countries, the resulting heparin shortage also led to worsened health care beyond the treatment of COVID-19, for example through the cancellation of cardiac surgeries.

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.

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.

[51] 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.

For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.

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.

Under physiological conditions, the ester and amide sulfate groups are deprotonated and attract positively charged counterions to form a heparin salt.

[63] 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.

[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.

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).

The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum).

[74][75] Considering the animal source of pharmaceutical heparin, the number of potential impurities is 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.

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.

[87] In December 2007, 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.

[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".

[98] In July 2008, another set of twins born at Christus Spohn Hospital South, in Corpus Christi, Texas, died after an accidentally administered overdose of the drug.

[100][101] In March 2010, a two-year-old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center.

[102] Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestines or bovine (cattle) lungs.

[105] 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.