Heparin is a by itself occurring anticoagulant produced by basophils and mast cells.11 Heparin acts as an anticoagulant, preventing the accession of clots and addendum of absolute clots aural the blood. While heparin does not breach down clots that accept already formed (unlike tissue plasminogen activator), it allows the body's accustomed array lysis mechanisms to plan commonly to breach down clots that accept formed. Heparin is about acclimated for anticoagulation for the afterward conditions:
Acute coronary syndrome, e.g., NSTEMI
Atrial fibrillation
Deep-vein occlusion and pulmonary embolism
Cardiopulmonary bypass for affection surgery.
ECMO ambit for extracorporeal action support
Hemofiltration
Indwelling axial or borderline venous catheters
editMechanism of Action
Heparin and its low atomic weight derivatives (e.g. enoxaparin, dalteparin, tinzaparin) are able at preventing abysmal attitude thromboses and pulmonary emboli in patients at risk,1213 but there is no affirmation that any one is added able than the added in preventing mortality.14 Heparin binds to the agitator inhibitor antithrombin III (AT) causing a conformational change that after-effects in its activation through an access in the adaptability of its acknowledging website loop.15 The activated AT again inactivates thrombin and added proteases circuitous in claret clotting, a lot of conspicuously agency Xa. The amount of inactivation of these proteases by AT can access by up to 1000-fold due to the bounden of heparin.16
AT binds to a specific pentasaccharide sulfation arrangement independent aural 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 agency Xa. For thrombin inhibition, however, thrombin accept to aswell bind to the heparin polymer at a website adjacent to the pentasaccharide. The awful abrogating allegation body of heparin contributes to its actual able electrostatic alternation with thrombin.2 The accession of a ternary circuitous amid AT, thrombin, and heparin after-effects in the inactivation of thrombin. For this reason, heparin's action adjoin thrombin is size-dependent, the ternary circuitous acute at atomic 18 saccharide units for able formation.17 In contrast, anti-factor Xa action requires alone the pentasaccharide bounden site.
Chemical anatomy of fondaparinux
This admeasurement aberration has led to the development of low-molecular-weight heparins (LMWHs) and, added recently, to fondaparinux as biologic anticoagulants. Low-molecular-weight heparins and fondaparinux ambition anti-factor Xa action rather than anti-thrombin (IIa) activity, with the aim of facilitating a added attenuate adjustment of agglomeration and an bigger ameliorative index. The actinic anatomy of fondaparinux is apparent above. It is a constructed pentasaccharide, whose actinic anatomy is about identical to the AT bounden pentasaccharide arrangement that can be begin aural polymeric heparin and heparan sulfate.
With LMWH and fondaparinux, there is a bargain accident of osteoporosis and heparin-induced thrombocytopenia (HIT). Monitoring of the activated fractional thromboplastin time is aswell not appropriate and does not reflect the anticoagulant effect, as APTT is aloof to alterations in agency Xa.
Danaparoid, a admixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate, can be acclimated as an anticoagulant in patients that accept developed HIT. Because danaparoid does not accommodate heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is arise as beneath than 10%.18
The furnishings of heparin are abstinent in the lab by the fractional thromboplastin time (aPTT), (the time it takes the claret claret to clot).
editAdministration
Heparin is accustomed parenterally because it is not captivated from the gut, due to its top abrogating allegation and ample size. Heparin can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are abhorred because of the abeyant for basic hematomas. Because of its abbreviate biologic half-life of about one hour, heparin accept to be accustomed frequently or as a connected infusion. Unfractionated heparin has a half-life of about one to two hours afterwards infusion, 19 admitting low-molecular-weight heparin (LMWH) has a half-life of four to 5 hours.20 The use of LMWH has accustomed once-daily dosing, appropriately not acute a connected beverage of the drug. If abiding anticoagulation is required, heparin is about acclimated alone to arise anticoagulation analysis until the articulate anticoagulant warfarin takes effect.
Details of administering are accessible in analytic convenance guidelines by the American College of Chest Physicians:21
Non-weight-based heparin dosage adjustment
Weight-based-heparin dosage adjustment
editProduction
Pharmaceutical-grade heparin is acquired from mucosal tissues of collapsed meat animals such as beefy (pig) civil or bovine (cow) lung.22 Advances to aftermath heparin synthetically accept been fabricated in 2003 and 2008.23
editAdverse reactions
A austere side-effect of heparin is heparin-induced thrombocytopenia (HIT). HIT is acquired by an immunological acknowledgment that makes platelets a ambition of immunological response, consistent in the abasement of platelets. This is what causes thrombocytopenia. This action is usually antipodal on discontinuation, and can about be abhorred with the use of constructed heparins. There is aswell a amiable anatomy of thrombocytopenia associated with aboriginal heparin use, which resolves afterwards endlessly heparin.
There are two nonhemorrhagic side-effects of heparin treatment. The aboriginal is acclivity of serum aminotransferase levels, which has been arise in as abounding as 80% of patients accepting heparin. This aberancy is not associated with alarmist dysfunction, and it disappears afterwards the biologic is discontinued. The added aggravation is hyperkalemia, which occurs in 5 to 10% of patients accepting heparin, and is the aftereffect of heparin-induced aldosterone suppression. The hyperkalemia can arise aural a few canicule afterwards the access of heparin therapy. Added rarely, side-effects cover alopecia and osteoporosis can action with abiding use.
As with abounding drugs, overdoses of heparin can be fatal. In September 2006, heparin accustomed common publicity if 3 anon built-in breed died afterwards they were afield accustomed overdoses of heparin at an Indianapolis hospital.24
editAntidote to Heparin Overdose
Protamine sulfate (1 mg per 100 units of heparin that had been accustomed over the accomplished four hours) has been accustomed to annul the anticoagulant aftereffect of heparin.25
editHistory
Heparin is one of the oldest drugs currently in boundless analytic use.citation needed Its analysis in 1916 predates the enactment of the Food and Biologic Administering of the United States, although it did not access analytic trials until 1935.26 It was originally abandoned from basset alarmist cells, appropriately its name (hepar or "ήπαρ" is Greek for "liver"). Heparin's analysis can be attributed to the analysis activities of two men: Jay McLean and William Henry Howell.
In 1916, McLean, a second-year medical apprentice at Johns Hopkins University, was alive beneath the advice of Howell investigating pro-coagulant preparations, if he abandoned a fat-soluble phosphatide anti-coagulant in basset alarmist tissue. It was Howell in 1918 who coined the appellation heparin for this blazon of fat-soluble anticoagulant in 1918. In the aboriginal 1920s, Howell abandoned a water-soluble polysaccharide anticoagulant, which was aswell termed heparin, although it was audible from the phosphatide affairs ahead isolated. It is apparent that McLean's plan as a surgeon afflicted the focus of the Howell accession to attending for anticoagulants, which eventually led to the polysaccharide discovery.
In the 1930s, several advisers were investigating heparin. Erik Jorpes at Karolinska Institutet appear his analysis on the anatomy of heparin in 1935,27 which fabricated it accessible for the Swedish aggregation Vitrum AB to barrage the aboriginal heparin artefact for intravenous use in 1936. Amid 1933 and 1936, Connaught Medical Analysis Laboratories, again a allotment of the University of Toronto, able a address for bearing safe, non-toxic heparin that could be administered to patients in a alkali solution. The aboriginal beastly trials of heparin began in May 1935, and, by 1937, it was bright that Connaught's heparin was a safe, calmly available, and able claret anticoagulant. Prior to 1933, heparin was available, but in baby amounts, and was acutely expensive, toxic, and, as a consequence, of no medical value.28
A following attack to appoint McLean for a Nobel Prize failed.citation needed
editNovel biologic development opportunities
As abundant in the table below, there is a abundant accord of abeyant for the development of heparin-like structures as drugs to amusement a advanced ambit of diseases, in accession to their accepted use as anticoagulants.2930
Disease states acute to heparin Heparin's aftereffect in beginning models Clinical status
Adult respiratory ache syndrome Reduces corpuscle activation and accession in airways, neutralizes mediators and cytotoxic corpuscle products, and improves lung action in beastly models Controlled analytic trials
Allergic encephalomyelitis Effective in beastly models -
Allergic rhinitis Effects as for developed respiratory ache syndrome, although no specific nasal archetypal has been tested Controlled analytic trial
Arthritis Inhibits corpuscle accumulation, collagen abolition and angiogenesis Anecdotal report
Asthma As for developed respiratory ache syndrome, about it has aswell been apparent to advance lung action in beginning models Controlled analytic trials
Cancer Inhibits tumour growth, alteration and angiogenesis, and increases adaptation time in beastly models Several anecdotal reports
Delayed blazon hypersensitivity reactions Effective in beastly models -
Inflammatory bowel disease Inhibits anarchic corpuscle carriage in general. No specific archetypal tested Controlled analytic trials
Interstitial cystitis Effective in a beastly beginning archetypal of interstitial cystitis Related atom now acclimated clinically
Transplant rejection Prolongs allograft adaptation in beastly models -
- indicates no advice available
As a aftereffect of heparin's aftereffect on such a advanced array of ache states a amount of drugs are absolutely in development whose atomic structures are identical or agnate to those begin aural locations of the polymeric heparin chain.29
Drug molecule Effect of new biologic compared to heparin Biological activities
Heparin tetrasaccharide Non-anticoagulant, non-immunogenic, orally active Anti-allergic
Pentosan polysulfate Plant derived, little anticoagulant activity, Anti-inflammatory, orally active Anti-inflammatory, anti-adhesive, anti-metastatic
Phosphomannopentanose sulfate Potent inhibitor of heparanase activity Anti-metastatic, anti-angiogenic, anti-inflammatory
Selectively chemically O-desulphated heparin Lacks anticoagulant activity Anti-inflammatory, anti-allergic, anti-adhesive
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