Chemistry:Heparin

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Short description: Anticoagulant
Heparin
Heparin General Structure V.1.svg
Clinical data
Pronunciation/ˈhɛpərɪn/ HEP-ər-in
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous therapy, subcutaneous injection
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityErratic
MetabolismLiver
Elimination half-life1.5 hours
ExcretionUrine[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC12H19NO20S3
Molar mass593.45 g·mol−1
 ☒N☑Y (what is this?)  (verify)

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan.[2][3] Since heparins depend on the activity of antithrombin, they are considered anticoagulants.[4] Specifically it is also used in the treatment of heart attacks and unstable angina.[2] It is given intravenously or by injection under the skin.[2] Other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines.[3][5]

Common side effects include bleeding, pain at the injection site, and low blood platelets.[2] Serious side effects include heparin-induced thrombocytopenia.[2] Greater care is needed in those with poor kidney function.[2]

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).[6][7][8]

Heparin appears to be relatively safe for use during pregnancy and breastfeeding.[9] Heparin is produced by basophils and mast cells in all mammals.[10]

The discovery of heparin was announced in 1916.[11] It is on the World Health Organization's List of Essential Medicines.[12] A fractionated version of heparin, known as low molecular weight heparin, is also available.[13]

History

Heparin was discovered by Jay McLean and William Henry Howell in 1916, although it did not enter clinical trials until 1935.[14] It was originally isolated from dog liver cells, hence its name (ἧπαρ 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.[15] In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. 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.[16][17] 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.

In the 1930s, several researchers were investigating heparin. Erik Jorpes at Karolinska Institutet published his research on the structure of heparin in 1935,[18] which made it possible for the Swedish company Vitrum AB to launch the first heparin product for intravenous use in 1936. 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. The first human trials of heparin began in May 1935, and, by 1937, it was clear that Connaught's heparin was safe, easily available, and effective as a blood anticoagulant. Prior to 1933, heparin was available in small amounts, was extremely expensive and toxic, and, as a consequence, of no medical value.[19]

Heparin production experienced a break in the 1990s. 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 2020, 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.[20]

Medical use

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. While heparin itself does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation for the following conditions:[21]

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,[22][23] but no evidence indicates any one is more effective than the other in preventing mortality.[24]

In angiography, 2 to 5 units/mL of unfractionated heparin saline flush is used to prevent the clotting of blood in guidewires, sheaths, and catheters, thus preventing thrombus from dislodging from these devices into the circulatory system .[25][26]

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.[27]

Adverse effects

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.[28] 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.[29]

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.[21]

As with many drugs, overdoses of heparin can be fatal. In September 2006, heparin received worldwide publicity when three prematurely born infants died after they were mistakenly given overdoses of heparin at an Indianapolis hospital.[30]

Contraindications

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.[31]

Antidote to heparin

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).[32] It may be used in those who overdose on heparin or to reverse heparin's effect when it is no longer needed.[33]

Physiological function

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.[34] 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.[35]

Evolutionary conservation

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

  1. Turkey[36]
  2. Whale[37]
  3. Dromedary camel[38]
  4. Mouse[39]
  5. Humans[40]
  6. Lobster[41]
  7. Fresh water mussel[42]
  8. Clam[43]
  9. Shrimp[44]
  10. Mangrove crab[45]
  11. Sand dollar[45]
  12. Atlantic salmon[46][47]
  13. Zebra fish[48]

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

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.[49]

Mechanism of action

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.[50] 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 1000-fold due to the binding of heparin.[51] 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.[35] 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.[52] 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%.[53]

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

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,[54] whereas LMWH has a half-life of four to five hours.[55] 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.[56]

Natural degradation or clearance

Unfractionated heparin has a half-life of about one to two hours after infusion,[54] 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.[57]

Chemistry

Heparin structure

Ball-and-stick model of heparin

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.[58] 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.[59] 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.[60]

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.

  • IdoA(2S)-GlcNS(6S)*
  • Error creating thumbnail: convert: no images defined `/tmp/transform_de0f534d810c.png' @ error/convert.c/ConvertImageCommand/3229. Error code: 1
    IdoA(2S)-GlcNS
  • IdoA-GlcNS(6S)
  • GlcA-GlcNAc
  • GlcA-GlcNS
  • IdoA-GlcNS

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.[61]

Three-dimensional structure

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.[62] 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.[63] 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.[64]

Two different structures of heparin

In the image above:

  • 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

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

The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum).[65] 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.[66] 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.[67][68]

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)
UA(2S)-GlcNS(6S)

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.[69][70] 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

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.[71]

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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

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.[72][73]

Other functions

  • Blood specimen test tubes, vacutainers, and capillary tubes that use the lithium salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops. Heparin has the advantage over EDTA of not affecting levels of most ions. However, the concentration of ionized calcium may be decreased if the concentration of heparin in the blood specimen is too high.[74] Heparin can interfere with some immunoassays, however. As lithium heparin is usually used, a person's lithium levels cannot be obtained from these tubes; for this purpose, royal-blue-topped (and dark green-topped) vacutainers containing sodium heparin are used.
  • Heparin-coated blood oxygenators are available for use in heart-lung machines. Among other things, these specialized oxygenators are thought to improve overall biocompatibility and host homeostasis by providing characteristics similar to those of native endothelium.
  • The DNA binding sites on RNA polymerase can be occupied by heparin, preventing the polymerase from binding to promoter DNA. This property is exploited in a range of molecular biological assays.
  • Common diagnostic procedures require PCR amplification of a patient's DNA, which is easily extracted from white blood cells treated with heparin. This poses a potential problem, since heparin may be extracted along with the DNA, and it has been found to interfere with the PCR reaction at levels as low as 0.002 U in a 50 μL reaction mixture.[75]
  • Heparin has been used as a chromatography resin, acting as both an affinity ligand and an ion exchanger.[76][77][78] Its polyanionic structure can mimic nucleic acids like DNA and RNA, making it useful for purification of nucleic acid-binding proteins including DNA and RNA polymerases and transcription factors.[79] Heparin's specific affinity for VSV-G,[80] a viral envelope glycoprotein often used to pseudotype retroviral and lentiviral vectors for gene therapy, allows it to be used for downstream purification of viral vectors.[81][82]
  • Heparin is being trialed in a nasal spray form as prophylaxis against COVID-19 infection.[83] Furthermore, its reported from trials that due to anti-viral, anti-inflammatory and its anti-clotting effects its inhalation could improve at a 70% rate on patients that were actively struck by a COVID-19 infection.[84]

Society and culture

Contamination recalls

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.[85]

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. S. marcescens can lead to life-threatening injuries and/or death.[86]

2008 recall due to adulteration in drug from China

Main page: Chemistry:2008 Chinese heparin adulteration

In March 2008, major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.[87][88] According to the FDA, the adulterated heparin killed nearly 80 people in the United States.[89] 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.[90]

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

In 2006, Petr Zelenka, a nurse in the Czech Republic, deliberately administered large doses to patients, killing seven, and attempting to kill ten others.[91]

Overdose issues

In 2007, 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.[92] 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.,[93][94] and settled with the hospital for $750,000.[95] 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.[96]

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. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling.[97] (As of July 2008), the exact cause of the twins' death was under investigation.[98][99]

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. The exact circumstances surrounding her death are still under investigation.[100]

Production

Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestines or bovine (cattle) lungs.[101] Advances to produce heparin synthetically have been made in 2003 and 2008.[102] In 2011, a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported.[103]

Research

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.[104][105]

Disease states sensitive to heparin Heparin's effect in experimental models Clinical status
Acquired immunodeficiency syndrome Reduces the ability of human immunodeficiency virus types 1 and 2 to adsorb to cultured T4 cells.[106] –
Adult respiratory distress syndrome Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models Controlled clinical trials
Allergic encephalomyelitis Effective in animal models –
Allergic rhinitis Effects as for adult respiratory distress syndrome, although no specific nasal model has been tested Controlled clinical trial
Arthritis Inhibits cell accumulation, collagen destruction and angiogenesis Anecdotal report
Asthma As for adult respiratory distress syndrome, however, it has also been shown to improve lung function in experimental models Controlled clinical trials
Cancer Inhibits tumour growth, metastasis and angiogenesis, and increases survival time in animal models Several anecdotal reports
Delayed-type hypersensitivity reactions Effective in animal models –
Inflammatory bowel disease Inhibits inflammatory cell transport in general, no specific model tested Controlled clinical trials
Interstitial cystitis Effective in a human experimental model of interstitial cystitis Related molecule now used clinically
Transplant rejection Prolongs allograft survival in animal models –
– 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.[104]

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

  1. ↑ "Heparin". 2012-02-10. http://online.lexi.com. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Heparin Sodium". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/heparin-sodium.html. 
  3. ↑ 3.0 3.1 "Heparin (Mucous) Injection BP – Summary of Product Characteristics". September 2016. https://www.medicines.org.uk/emc/medicine/8308. 
  4. ↑ "Anticoagulants: A Review of the Pharmacology, Dosing, and Complications". Current Emergency and Hospital Medicine Reports 1 (2): 83–97. June 2013. doi:10.1007/s40138-013-0014-6. PMID 23687625. 
  5. ↑ Clinical Laboratory Medicine. Lippincott Williams & Wilkins. 2002. p. 662. ISBN 9780683307511. https://books.google.com/books?id=3PJVLH1NmQAC&pg=PA662. 
  6. ↑ "AstraZeneca COVID-19-Vakzine Umgang mit dem Risiko von Gerinnungskomplikationen". https://www.dgho.de/publikationen/stellungnahmen/gute-aerztliche-praxis/coronavirus/astrazeneca-vakzine-gerinnungsstoerungen-20210330.pdf. 
  7. ↑ "Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination". The New England Journal of Medicine 384 (22): 2092–2101. June 2021. doi:10.1056/NEJMoa2104840. PMID 33835769. 
  8. ↑ Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination. The Ontario COVID-19 Science Advisory Table. 2021-03-26. doi:10.47326/ocsat.2021.02.17.1.0. https://covid19-sciencetable.ca/wp-content/uploads/2021/03/Science-Brief_AstraZeneca_General_20210326_published.pdf. 
  9. ↑ "Heparin Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/heparin.html. 
  10. ↑ Textbook of Medical Physiology. Elsevier Saunders. 2006. p. 464. ISBN 978-0-7216-0240-0. 
  11. ↑ Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. 2013. p. 189. ISBN 9781118354469. https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA189. 
  12. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  13. ↑ Fisher's Contact Dermatitis. PMPH-USA. 2008. p. 142. ISBN 9781550093780. https://books.google.com/books?id=dQBAzfyCeQ8C&pg=PA142. 
  14. ↑ "Heparin used as an anticoagulant". AnimalResearch.info. http://animalresearch.info/en/medical-advances/145/heparin-used-as-an-anticoagulant/. 
  15. ↑ "The discovery of heparin". Circulation 19 (1): 75–8. January 1959. doi:10.1161/01.CIR.19.1.75. PMID 13619023. 
  16. ↑ "Heparin, an anticoagulant". American Journal of Physiology 63: 434–435. 1922. 
  17. ↑ "History of drugs for thrombotic disease. Discovery, development, and directions for the future". Circulation 89 (1): 432–49. January 1994. doi:10.1161/01.cir.89.1.432. PMID 8281678. 
  18. ↑ "The chemistry of heparin". The Biochemical Journal 29 (8): 1817–30. August 1935. doi:10.1042/bj0291817. PMID 16745848. 
  19. ↑ "Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928–1937". Health Heritage Research Services. http://www.healthheritageresearch.com/Heparin-Conntact9608.html. 
  20. ↑ "How blood met plastics, plant and animal extracts: Material encounters between medicine and industry in the twentieth century". Studies in History and Philosophy of Science 92: 45–55. April 2022. doi:10.1016/j.shpsa.2022.01.007. PMID 35131685. 
  21. ↑ 21.0 21.1 "Heparin". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK538247/. Retrieved 2022-10-31. 
  22. ↑ "Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery". The New England Journal of Medicine 339 (2): 80–5. July 1998. doi:10.1056/NEJM199807093390204. PMID 9654538. 
  23. ↑ "Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer". The New England Journal of Medicine 346 (13): 975–80. March 2002. doi:10.1056/NEJMoa012385. PMID 11919306. 
  24. ↑ "Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures". The Cochrane Database of Systematic Reviews 2021 (4): CD000305. 2002. doi:10.1002/14651858.CD000305. PMID 12519540. 
  25. ↑ "Heparin Flush Use in Transfemoral Cerebral Angiography Survey" (in en). Journal of Radiology Nursing 39 (3): 199–206. September 2020. doi:10.1016/j.jradnu.2020.06.001. 
  26. ↑ "The Use of Heparin during Endovascular Peripheral Arterial Interventions: A Synopsis". Scientifica 2016: 1456298. 2016. doi:10.1155/2016/1456298. PMID 27190678. 
  27. ↑ "Unfractionated heparin for hemodialysis: still the best option". Seminars in Dialysis 23 (5): 510–5. 2010. doi:10.1111/j.1525-139X.2010.00770.x. PMID 21039876. 
  28. ↑ "Heparin induced thrombocytopenia: diagnosis and management update". Postgraduate Medical Journal 83 (983): 575–582. September 2007. doi:10.1136/pgmj.2007.059188. PMID 17823223. 
  29. ↑ "Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution". American Journal of Hematology 56 (1): 12–16. September 1997. doi:10.1002/(sici)1096-8652(199709)56:1<12::aid-ajh3>3.0.co;2-5. PMID 9298861. 
  30. ↑ "3rd Ind. preemie infant dies of overdose". Associated Press. Fox News. 20 September 2006. http://www.foxnews.com/story/0,2933,214729,00.html. 
  31. ↑ Australian Medicines Handbook (2019 (online) ed.). Adelaide: Australian Medicines Handbook Pty Ltd. January 2019. https://amhonline.amh.net.au/. 
  32. ↑ Internal medicine, Jay H. Stein, p. 635
  33. ↑ "Protamine Sulfate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/protamine-sulfate.html. 
  34. ↑ "Heparan sulfates and heparins: similar compounds performing the same functions in vertebrates and invertebrates?". Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas 32 (5): 529–38. May 1999. doi:10.1590/S0100-879X1999000500005. PMID 10412563. 
  35. ↑ 35.0 35.1 Lehninger, Principles of Biochemistry. Freeman. 2004. p. 254. ISBN 978-0-7167-4339-2. https://archive.org/details/lehningerprincip00lehn_0/page/254. 
  36. ↑ "Turkey intestine as a commercial source of heparin? Comparative structural studies of intestinal avian and mammalian glycosaminoglycans". Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology 134 (1): 189–97. January 2003. doi:10.1016/S1096-4959(02)00250-6. PMID 12524047. 
  37. ↑ "Comparative studies on the structures of highly active and relatively inactive forms of whale heparin". Journal of Biochemistry 90 (1): 241–6. July 1981. doi:10.1093/oxfordjournals.jbchem.a133456. PMID 7287679. 
  38. ↑ "Isolation and characterization of raw heparin from dromedary intestine: evaluation of a new source of pharmaceutical heparin". Comparative Biochemistry and Physiology. Toxicology & Pharmacology 136 (4): 357–65. December 2003. doi:10.1016/j.cca.2003.10.009. PMID 15012907. 
  39. ↑ "Mouse heparin proteoglycan. Synthesis by mast cell-fibroblast monolayers during lymphocyte-dependent mast cell proliferation". The Journal of Biological Chemistry 257 (15): 8661–6. August 1982. doi:10.1016/S0021-9258(18)34179-6. PMID 6807978. 
  40. ↑ "Isolation and characterization of human heparin". Biochemistry 31 (49): 12441–5. December 1992. doi:10.1021/bi00164a020. PMID 1463730. 
  41. ↑ "An unusual heparan sulfate isolated from lobsters (Homarus americanus)". The Journal of Biological Chemistry 257 (16): 9840–4. August 1982. doi:10.1016/S0021-9258(18)34147-4. PMID 6213614. 
  42. ↑ "Glycosaminoglycans in Anodonta californiensis, a Freshwater Mussel". The Biological Bulletin 185 (2): 263–276. October 1993. doi:10.2307/1542006. PMID 27768418. http://www.biolbull.org/cgi/content/abstract/185/2/263. Retrieved 2007-03-22. 
  43. ↑ "Structure and antithrombin-binding properties of heparin isolated from the clams Anomalocardia brasiliana and Tivela mactroides". The Journal of Biological Chemistry 262 (24): 11413–21. August 1987. doi:10.1016/S0021-9258(18)60822-1. PMID 3624220. 
  44. ↑ "Structural features and anticoagulant activities of a novel natural low molecular weight heparin from the shrimp Penaeus brasiliensis". Biochimica et Biophysica Acta (BBA) - General Subjects 1428 (2–3): 273–83. August 1999. doi:10.1016/S0304-4165(99)00087-2. PMID 10434045. 
  45. ↑ 45.0 45.1 "Distribution of sulfated glycosaminoglycans in the animal kingdom: widespread occurrence of heparin-like compounds in invertebrates". Biochimica et Biophysica Acta (BBA) - General Subjects 1475 (3): 287–94. July 2000. doi:10.1016/S0304-4165(00)00079-9. PMID 10913828. 
  46. ↑ "Purification, characterization and in vivo studies of salmon heparin". Thrombosis Research 126 (6): e409-17. December 2010. doi:10.1016/j.thromres.2010.07.004. PMID 20937523. 
  47. ↑ "Disaccharide analysis of chondroitin and heparin from farmed Atlantic salmon". Glycoconjugate Journal 33 (2): 121–3. April 2016. doi:10.1007/s10719-016-9652-8. PMID 26993287. 
  48. ↑ "Structural characterization of glycosaminoglycans from zebrafish in different ages". Glycoconjugate Journal 26 (2): 211–8. February 2009. doi:10.1007/s10719-008-9177-x. PMID 18777207. 
  49. ↑ "The heparins: all a nephrologist should know". Nephrology, Dialysis, Transplantation 20 (10): 2036–42. October 2005. doi:10.1093/ndt/gfi004. PMID 16030035. 
  50. ↑ "Heparin enhances the specificity of antithrombin for thrombin and factor Xa independent of the reactive center loop sequence. Evidence for an exosite determinant of factor Xa specificity in heparin-activated antithrombin". The Journal of Biological Chemistry 276 (18): 14961–71. May 2001. doi:10.1074/jbc.M011550200. PMID 11278930. 
  51. ↑ "Mechanism of the anticoagulant action of heparin". Molecular and Cellular Biochemistry 48 (3): 161–82. October 1982. doi:10.1007/BF00421226. PMID 6757715. 
  52. ↑ "Synthesis of thrombin-inhibiting heparin mimetics without side effects". Nature 398 (6726): 417–22. April 1999. doi:10.1038/18877. PMID 10201371. Bibcode: 1999Natur.398..417P. 
  53. ↑ Shalansky, Karen. DANAPAROID (Orgaran) for Heparin-Induced Thrombocytopenia. Vancouver Hospital & Health Sciences Centre, February 1998 Drug & Therapeutics Newsletter. Retrieved on 8 January 2007.
  54. ↑ 54.0 54.1 "Low molecular weight heparins and heparinoids". The Medical Journal of Australia 177 (7): 379–83. October 2002. doi:10.5694/j.1326-5377.2002.tb04807.x. PMID 12358583. http://www.mja.com.au/public/issues/177_07_071002/eik10205_fm.html. 
  55. ↑ "New anticoagulants for treatment of venous thromboembolism". Circulation 110 (9 Suppl 1): I19-26. August 2004. doi:10.1161/01.CIR.0000140901.04538.ae. PMID 15339877. 
  56. ↑ "Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 188S–203S. September 2004. doi:10.1378/chest.126.3_suppl.188S. PMID 15383472. 
  57. ↑ "Update on heparin: what do we need to know?". Journal of Thrombosis and Thrombolysis 29 (2): 199–207. February 2010. doi:10.1007/s11239-009-0411-6. PMID 19882363. 
  58. ↑ "Chapter 21. Principles of Antithrombotic Therapy". Williams Hematology (7th ed.). 2006. ISBN 978-0-07-143591-8. http://www.accessmedicine.com/content.aspx?aID=2138678. 
  59. ↑ "Synthesis and heparin-like biological activity of amino acid-based polymers". Polymers for Advanced Technologies 11 (8–12): 377–387. 2000. doi:10.1002/1099-1581(200008/12)11:8/12<377::AID-PAT985>3.0.CO;2-D. 
  60. ↑ "Studies on the Conformation of Heparin by1H and13C NMR Spectroscopy". Macromolecules 12 (5): 1001–1007. 1979. doi:10.1021/ma60071a044. ISSN 0024-9297. Bibcode: 1979MaMol..12.1001G. 
  61. ↑ "Online Medical Dictionary". Centre for Cancer Education. 2000. http://cancerweb.ncl.ac.uk/cgi-bin/omd?Howell+unit. 
  62. ↑ "Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences". Carbohydrate Research 195 (2): 157–67. January 1990. doi:10.1016/0008-6215(90)84164-P. PMID 2331699. 
  63. ↑ "N.m.r. and molecular-modelling studies of the solution conformation of heparin". The Biochemical Journal 293 (Pt 3): 849–58. August 1993. doi:10.1042/bj2930849. PMID 8352752. 
  64. ↑ "N.M.R. and molecular-modeling studies of the solution conformation of heparin". http://www.rcsb.org/pdb/files/1hpn.pdb. 
  65. ↑ "Crystal structure of heparinase II from Pedobacter heparinus and its complex with a disaccharide product". The Journal of Biological Chemistry 281 (22): 15525–35. June 2006. doi:10.1074/jbc.M512055200. PMID 16565082. 
  66. ↑ "Heparinase production by Flavobacterium heparinum". Applied and Environmental Microbiology 41 (2): 360–5. February 1981. doi:10.1128/AEM.41.2.360-365.1981. PMID 7235692. Bibcode: 1981ApEnM..41..360G. 
  67. ↑ "Examination of the substrate specificity of heparin and heparan sulfate lyases". Biochemistry 29 (10): 2611–7. March 1990. doi:10.1021/bi00462a026. PMID 2334685. 
  68. ↑ "Specificity studies on the heparin lyases from Flavobacterium heparinum". Biochemistry 32 (32): 8140–5. August 1993. doi:10.1021/bi00083a012. PMID 8347612. 
  69. ↑ "Isolation and characterization of oligosaccharides obtained from heparin by the action of heparinase". Biochemistry 11 (4): 563–8. February 1972. doi:10.1021/bi00754a013. PMID 5062409. 
  70. ↑ "Mapping and quantification of the major oligosaccharide components of heparin". The Biochemical Journal 254 (3): 781–7. September 1988. doi:10.1042/bj2540781. PMID 3196292. 
  71. ↑ "Formation of anhydrosugars in the chemical depolymerization of heparin". Biochemistry 15 (18): 3932–42. September 1976. doi:10.1021/bi00663a005. PMID 9127. 
  72. ↑ "A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during cardiopulmonary bypass: a pilot investigation". Anesthesia and Analgesia 91 (3): 533–8. September 2000. doi:10.1213/00000539-200009000-00006. PMID 10960371. 
  73. ↑ R. Baselt (2008). Disposition of Toxic Drugs and Chemicals in Man (8 ed.). Foster City, CA: Biomedical Publications. pp. 728–729. ISBN 978-0-9626523-7-0. 
  74. ↑ "The use of heparin in preparing samples for blood-gas analysis". Medical Laboratory Observer 39 (10): 16–8, 20; quiz 22–3. October 2007. PMID 18018679. http://www.mlo-online.com/articles/200710/1007cover_story.pdf. Retrieved 2016-04-18. 
  75. ↑ "Effects of heparin on polymerase chain reaction for blood white cells". Journal of Clinical Laboratory Analysis 13 (3): 133–40. 1999. doi:10.1002/(SICI)1098-2825(1999)13:3<133::AID-JCLA8>3.0.CO;2-0. PMID 10323479. 
  76. ↑ "Fractionation of proteins by heparin chromatography". 2D PAGE: Sample Preparation and Fractionation. Methods in Molecular Biology. 424. 2008. pp. 213–21. doi:10.1007/978-1-60327-064-9_18. ISBN 978-1-58829-722-8. https://archive.org/details/2dpagesampleprep00anto/page/213. 
  77. ↑ "Affinity Chromatography". http://www.sigmaaldrich.com/life-science/proteomics/protein-chromatography/affinity-chromatography.html#heparin. 
  78. ↑ "HiTrap Heparin HP". http://www.gelifesciences.com/webapp/wcs/stores/servlet/ProductDisplay?categoryId=11426&catalogId=10101&productId=21154&storeId=11786&langId=-1. 
  79. ↑ "Performing a Separation of DNA binding proteins with GE Healthcare Products Based on Heparin". https://www.sigmaaldrich.com/technical-documents/protocols/biology/affinity-chromatography/separating-dna-binding-proteins-with-heparin.html. 
  80. ↑ "Cell surface heparan sulfate is a receptor for attachment of envelope protein-free retrovirus-like particles and VSV-G pseudotyped MLV-derived retrovirus vectors to target cells". Molecular Therapy 5 (5 Pt 1): 538–46. May 2002. doi:10.1006/mthe.2002.0578. PMID 11991744. 
  81. ↑ "Purification of retrovirus particles using heparin affinity chromatography". Gene Therapy Protocols. Methods in Molecular Biology. 434. 2008. pp. 1–11. doi:10.1007/978-1-60327-248-3_1. ISBN 978-1-60327-247-6. 
  82. ↑ "A novel purification strategy for retrovirus gene therapy vectors using heparin affinity chromatography". Biotechnology and Bioengineering 90 (4): 391–404. May 2005. doi:10.1002/bit.20301. PMID 15812800. 
  83. ↑ "Melbourne researchers trial use of common blood-thinning drug heparin to combat COVID-19". ABC News. 21 December 2021. https://www.abc.net.au/news/2021-12-22/melbourne-researchers-trial-use-of-common-drug-to-combat-covid/100717224. 
  84. ↑ "A 70-year-old drug may be the answer to treating COVID-19". The Australian Financial Review. 19 January 2022. https://www.afr.com/policy/health-and-education/a-70-year-old-drug-may-be-the-answer-to-treating-covid-19-20220119-p59pjt. 
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  86. ↑ "AM2 PAT, Inc. Issues Nationwide Recall of Pre-Filled Heparin Lock Flush Solution USP (5 mL in 12 mL Syringes)" (Press release). US FDA. December 20, 2007. Archived from the original on 2007-12-23.
  87. ↑ CBS News. "Blood-thinning drug under suspicion". http://www.cbsnews.com/stories/2008/03/01/eveningnews/main3896578.shtml. 
  88. ↑ "Information on Heparin" (Press release). US FDA. Archived from the original on 2012-04-15.
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  91. ↑ "Nurse committed murders to "test" doctors". Radio Praha. 2006-05-12. http://www.radio.cz/en/article/85964. 
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  97. ↑ Statement by Dr. Richard Davis, Chief Medical Officer, CHRISTUS Spohn Health System[yes|permanent dead link|dead link}}], July 10, 2008
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  100. ↑ "Nebraska Med. Center Investigates Staff After Girl's Death". KETV Omaha. 2010-03-31. http://www.ketv.com/news/23020944/detail.html. 
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