heparin heparin heparin, also known as unfractionated heparin (ufh), is a medication and naturally occurring glycosaminoglycan. since heparins depend on the activity of antithrombin, they are considered anticoagulants. specifically it is also used in the treatment of heart attacks and unstable angina. it is given intravenously or by injection under the skin. other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines. heparinclinical datapronunciation/ˈhɛpərɪn/ hep-ər-in ahfs/drugs.commonographlicense data us dailymed: heparin routes ofadministrationintravenous therapy, subcutaneous injectionatc codeb01ab01 (who) c05ba03 (who) s01xa14 (who)legal statuslegal status us: ℞-only in general: ℞ (prescription only) pharmacokinetic databioavailabilityerraticmetabolismliverelimination half-life1.5 hoursexcretionurineidentifiers iupac name see heparin structure cas number9005-49-6 ysodium: 9041-08-1 ypubchem cid22833565iuphar/bps4214drugbankdb01109 nchemspider17216115 yuniit2410km04achemblchembl526514 ycomptox dashboard (epa)dtxsid20872761 dtxsid301010914, dtxsid20872761 echa infocard100.029.698 chemical and physical dataformulac12h19no20s3molar mass593.45 g·mol−1 inchi inchi=1s/c26h41no34s4/c1-4(28)27-7-9(30)8(29)6(2-52-63(43,44)45)53-24(7)56-15-10(31)11(32)25(58-19(15)21(36)37)55-13-5(3-62(40,41)42)14(60-64(46,47)48)26(59-22(13)38)57-16-12(33)17(61-65(49,50)51)23(39)54-18(16)20(34)35/h5-19,22-26,29-33,38-39h,2-3h2,1h3,(h,27,28)(h,34,35)(h,36,37)(h,40,41,42)(h,43,44,45)(h,46,47,48)(h,49,50,51)/t5-,6+,7+,8+,9+,10+,11+,12-,13-,14+,15-,16-,17+,18+,19-,22-,23?,24+,25+,26-/m0/s1 ykey:zfgmdibridkwmy-pastxaensa-n y ny (what is this?) (verify) common side effects include bleeding, pain at the injection site, and low blood platelets. serious side effects include heparin-induced thrombocytopenia. greater care is needed in those with poor kidney function. 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). heparin appears to be relatively safe for use during pregnancy and breastfeeding. heparin is produced by basophils and mast cells in all mammals. the discovery of heparin was announced in 1916. it is on the world health organization's list of essential medicines. a fractionated version of heparin, known as low molecular weight heparin, is also available. history heparin was discovered by jay mclean and william henry howell in 1916, although it did not enter clinical trials until 1935. 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. 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. 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, 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. 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. 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: acute coronary syndrome, e.g., nstemi atrial fibrillation deep-vein thrombosis and pulmonary embolism (both prevention and treatment) other thrombotic states and conditions cardiopulmonary bypass for heart surgery ecmo circuit for extracorporeal life support hemofiltration indwelling central or peripheral venous catheters 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, but no evidence indicates any one is more effective than the other in preventing mortality. 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 . 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. 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. 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. 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. 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. 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. 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). it may be used in those who overdose on heparin or to reverse heparin's effect when it is no longer needed. 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. 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. 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: turkey whale dromedary camel mouse humans lobster fresh water mussel clam shrimp mangrove crab sand dollar atlantic salmon zebra fish 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. 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. 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. 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. 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. 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. 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%. 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, whereas lmwh has a half-life of four to five hours. 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