Low molecular weight heparin

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Low molecular weight heparin
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Nadroparin in prefilled syringe
Pharmacokinetic data
Bioavailability 100%
Chemical and physical data
Molar mass 4-6 kDa

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. [1] They are used in the prevention of blood clots and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial infarction.

Contents

Heparin is a naturally occurring polysaccharide that inhibits coagulation, the process that leads to thrombosis. Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of varying molecular weights, from 5000 to over 40,000 Daltons, make up polydisperse pharmaceutical-grade heparin. [2] LMWHs, in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin.

Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis. However, the effects of natural, or unfractionated heparin are more unpredictable than LMWH. [3]

Medical uses

Because it can be given subcutaneously and does not require APTT monitoring, LMWH permits outpatient treatment of conditions such as deep vein thrombosis or pulmonary embolism that previously mandated inpatient hospitalization for unfractionated heparin administration.

Because LMWH has more predictable pharmacokinetics and anticoagulant effect, LMWH is recommended over unfractionated heparin for patients with massive pulmonary embolism, [4] and for initial treatment of deep vein thrombosis. [5] As compared to placebo or no intervention, prophylactic treatment of hospitalized medical patients using LMWH and similar anticoagulants reduces the risk of venous thromboembolism, notably pulmonary embolism. [6] [7]

More recently these agents have been evaluated as anticoagulants in acute coronary syndrome (ACS) managed by percutaneous intervention (PCI). [8] [9]

The use of LMWH needs to be monitored closely in patients at extremes of weight or in-patients with renal dysfunction. An anti-factor Xa activity may be useful for monitoring anticoagulation. Given its renal clearance, LMWH may not be feasible in patients that have end-stage renal disease. LMWH can also be used to maintain the patency of cannulae and shunts in dialysis patients.

Patients with cancer are at higher risk of venous thromboembolism and LMWHs are used to reduce this risk. [10] The CLOT study, published in 2003, showed that, in patients with malignancy and acute venous thromboembolism, dalteparin was more effective than warfarin in reducing the risk of recurrent embolic events. [11] Use of LMWH in cancer patients for at least the first 3 to 6 months of long-term treatment is recommended in numerous guidelines and is now regarded as a standard of care. [10]

Contraindications

The use of LMWHs should be avoided in patients with known allergies to LMWHs, heparin, sulfites or benzyl alcohol, in patients with active major bleeding, or patients with a history of heparin-induced low blood platelet count (also known as heparin-induced thrombocytopenia or HIT). High treatment doses are contraindicated in acute bleedings such as cerebral or gastrointestinal haemorrhage. LMWHs are more dependent on renal function for their excretion than unfractionated heparin so their biological half-life may be prolonged in patients with kidney failure and therefore their use in the setting of creatinine clearance rate (CrCl) <30 mL/min may need to be avoided. [12] Apart from using unfractionated heparin instead, it may be possible to reduce the dose and/or monitor the anti-Xa activity to guide treatment. [13]


The most common side-effects include bleeding, which could be severe or even fatal, allergic reactions, injection site reactions, and increases in liver enzyme tests, usually without symptoms. [14] The use of heparin and LMWHs can sometimes be complicated by a decrease in platelet count, a complication known as Heparin Induced Thrombocytopenia.13 Two forms have been described: a clinically benign, non-immune and reversible form (Type I) and a rare, more serious immune-mediated form or Type II. HIT Type II is caused by the formation of auto antibodies that recognize complexes between heparin and platelet factor 4 (PF4) and is therefore associated with a substantial risk of thrombotic complications. The incidence is difficult to estimate but may reach up to 5% of patients treated with UFH or about 1% with LMWH. [14]

Antidote

In clinical situations in which the antithrombotic effect of LMWHs needs to be neutralized, protamine is used to neutralize heparin by binding to it. [9] Studies in animals and in vitro studies have demonstrated that protamine neutralizes the antithrombin activity of LMWHs, normalizing the aPTT and thrombin time. However, protamine appears to only partially neutralize the anti-factor Xa activity of LMWH. Because the molecular weight of heparin impacts its interaction with protamine, it is likely that the lack of complete neutralization of anti-factor Xa is due to a reduced protamine binding to the LMWHs moieties in the preparation. Protamine is a medicine that requires a high level of caution when used.

Precautions

LMWH trials usually excluded individuals with unpredictable pharmacokinetics, and as a result patients with risks such as the severely obese or in advanced stages of kidney failure show decreased benefits due to fractionated heparin's increased half-life. [15] LMWHs should be used with extreme caution in patients undergoing any procedure involving spinal anaesthesia/puncture, in conditions with increased risk of bleeding or in patients with a history of heparin-induced thrombocytopenia.

Pharmacology

Mechanism of action

Coagulation cascade is a normal physiological process which aims at preventing significant blood loss or hemorrhage following vascular injury. Unfortunately, there are times when a blood clot (thrombus) will form when it is not needed. For instance, some high risk conditions such as prolonged immobilization, surgery, or cancer can increase the risk of developing a blood clot which can potentially lead to significant consequences.

The coagulation cascade consists of a series of steps in which a protease cleaves and subsequently activates the next protease in the sequence. [2] Since each protease can activate several molecules of the next protease in the series, this biological cascade is amplified. The final result of these reactions is to convert fibrinogen, a soluble protein, to insoluble threads of fibrin. Together with platelets, the fibrin threads form a stable blood clot.

Antithrombin (AT), a serine protease inhibitor, is the major plasma inhibitor of coagulation proteases. [16] LMWHs inhibit the coagulation process through binding to AT via a pentasaccharide sequence. This binding leads to a conformational change of AT which accelerates its inhibition of activated factor X (factor Xa). Once dissociated, the LMWH is free to bind to another antithrombin molecule and subsequently inhibit more activated factor X. Unlike AT activated by heparin, AT activated by LMWH cannot inhibit thrombin (factor IIa), but can only inhibit clotting factor Xa.

The effects of LMWHs cannot be acceptably measured using the partial thromboplastin time (PTT) or activated clotting time (ACT) tests. [17] Rather, LMWH therapy is monitored by the anti-factor Xa assay, measuring anti-factor Xa activity rather than a clotting time. The methodology of an anti-factor Xa assay is that patient plasma is added to a known amount of excess recombinant factor X and excess antithrombin. If heparin or LMWH is present in the patient plasma, it will bind to antithrombin and form a complex with factor X, inhibiting it from becoming factor Xa. [18] The amount of residual factor Xa is inversely proportional to the amount of heparin/LMWH in the plasma. The amount of residual factor Xa is detected by adding a chromogenic substrate that mimics the natural substrate of factor Xa, making residual factor Xa cleave it, releasing a colored compound that can be detected by a spectrophotometer. [18] Antithrombin deficiencies in the patient do not affect the assay, because excess amounts of antithrombin is provided in the reaction. [18] Results are given in units/mL of antifactor Xa, such that high values indicate high levels of anticoagulation and low values indicate low levels of anticoagulation in the plasma sample. [18]

LMWHs have a potency of greater than 70 units/mg of anti-factor Xa activity and a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5. [19] (see table 1)

LMWHAverage molecular weightRatio anti-Xa/anti-IIa activity
Bemiparin 36008.0
Nadroparin 43003.3
Reviparin 44004.2
Enoxaparin 45003.9
Parnaparin 50002.3
Certoparin 54002.4
Dalteparin 50002.5
Tinzaparin 65001.6

Table 1 Molecular weight (MW) data and anticoagulant activities of currently available LMWH products. Adapted from Gray E et al. 2008. [20]

Manufacturing process

Figure 1: The anhydromannose in IdoA(2S)-anhydromannose can be reduced to an anhydromannitol Reduction fig.png
Figure 1: The anhydromannose in IdoA(2S)-anhydromannose can be reduced to an anhydromannitol

Various methods of heparin depolymerisation are used in the manufacture of low-molecular-weight heparin. [2] These are listed below:

Deaminative cleavage with nitrous acid results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannitol using a suitable reducing agent as shown in figure 1.

Figure 2: UA(2S)-GlcNS(6S) UA(2S)-GlcNS(6S).svg
Figure 2: UA(2S)-GlcNS(6S)

Likewise both chemical and enzymatic beta-elimination result in the formation of an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as shown in figure 2.

In addition, low molecular weight heparins can also be chemoenzymatically synthesized from simple disaccharides. [21]

Differences between LMWHs

Comparisons between LMWHs prepared by similar processes vary. For example, a comparison of Dalteparin and Nadroparin suggests they are more similar than products produced by different processes. However, comparison of enoxaparin and tinzaparin shows they are very different from each other with respect to chemical, physical, and biological properties.

As might be expected, products prepared by distinctly different processes are dissimilar in physical, chemical, and biological properties. [2] [16] Hence a slight change in the depolymerisation process could result in substantial variation of the structure or composition of a given LMWH.

Therefore, for every LMWH, a strictly defined depolymerisation procedure is needed to guarantee the sameness of the final LMWH product and the predictability of clinical outcomes. LMWHs, as biological origin products, rely on stringent manufacturing procedures to guarantee the absence of biological or chemical contamination. It is therefore critical to adopt stringent manufacturing practices, through rigorous quality assurance steps, to ensure the highest quality of the produced LMWHs and to guarantee patient safety. These quality assurance steps, to be effective, need to be implemented from the raw material (crude heparin) collection to the final LMWH product.

Due to these identified and potential differences, several organizations, including the United States Food and Drug Administration, the European Medicines Agency, and the World Health Organization, regard LMWHs as individual products that should not be considered as clinically equivalent, as they differ in many crucial aspects such as molecular, structural, physiochemical, and biological properties. [22] [23] [24] According to international guidelines, the choice of an individual LMWH should be based on its proven clinical safety and efficacy for each indication. [14]

Differences from unfractionated heparin

Differences from heparin (i.e. "unfractionated heparin") include:

Generics and biosimilars

When the commercial patent of a LMWH expires, a generic or biosimilar LMWH can then be marketed. The first 'generic' LMWH was approved by the Food and Drug Administration in July 2010. The FDA has used 5 analytical and pharmacological criteria to establish the authenticity of a generic LMWH, without requiring clinical studies in patients. [27]

From a regulatory viewpoint, the FDA considers LMWHs (as well as insulin, glucagon and somatropin) as "generic" drugs, even though they may be sourced from biological material. The European Medicines Agency considers LMWHs as biologicals so their regulatory approval - as biosimilars - is approached differently compared to the FDA. [28] [29]

Related Research Articles

Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, and dialysis equipment. They can also be used as rodenticides.

Venous thrombosis blood clot (thrombus) that forms within a vein

A venous thrombus is a blood clot (thrombus) that forms within a vein. Thrombosis is a term for a blood clot occurring inside a blood vessel. A common type of venous thrombosis is a deep vein thrombosis (DVT), which is a blood clot in the deep veins of the leg. If the thrombus breaks off (embolizes) and flows towards the lungs, it can become a pulmonary embolism (PE), a blood clot in the lungs. This combination is called venous thromboembolism.

Heparin anticoagulant

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. As a medication it is used as an anticoagulant. Specifically it is also used in the treatment of heart attacks and unstable angina. It is given by injection into a vein or under the skin. Other uses include inside test tubes and kidney dialysis machines.

Antiphospholipid syndrome Human disease

Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia. The diagnostic criteria require one clinical event and two antibody blood tests spaced at least three months apart that confirm the presence of either lupus anticoagulant or anti-β2-glycoprotein-I.

Deep vein thrombosis formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein, most commonly in the legs. Symptoms can include pain, swelling, redness, or warmth of the affected area. About half of cases have no symptoms. Complications can include pulmonary embolism, as a result of detachment of a clot, which travels to the lungs, and post-thrombotic syndrome. Together, DVT and pulmonary embolism are known as venous thromboembolism (VTE).

Heparin-induced thrombocytopenia development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant

Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia, due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis because platelets release microparticles that activate thrombin, thereby leading to thrombosis. When thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal antibodies that activate platelets. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.

Protein S deficiency disorder associated with increased risk of venous thrombosis

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor VIIIa. Decreased (antigen) levels or impaired function of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free, only free protein S has activated protein C cofactor activity

Thrombophilia abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels)

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable abnormality, but most of these only develop thrombosis in the presence of an additional risk factor.

Factor X mammalian protein found in Homo sapiens

Factor X, also known by the eponym Stuart–Prower factor, is an enzyme of the coagulation cascade. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

Fondaparinux chemical compound

Fondaparinux is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.

The prothrombinase complex consists of the serine protein, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, to thrombin (Factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can Factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

Dalteparin sodium pharmaceutical drug

Dalteparin is a low molecular weight heparin. It is marketed as Fragmin. Like other low molecular weight heparins, dalteparin is used for prophylaxis or treatment of deep vein thrombosis and pulmonary embolism. It is normally administered by self-injection.

Antithrombin III deficiency is a deficiency of antithrombin III. This deficiency may be inherited or acquired. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism, and repetitive intrauterine fetal death (IUFD). Hereditary antithrombin deficiency results in a state of increased coagulation which may lead to venous thrombosis. Inheritance is usually autosomal dominant, though a few recessive cases have been noted. The disorder was first described by Egeberg in 1965. The causes of acquired antithrombin deficiency are easier to find than the hereditary deficiency.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

Bemiparin sodium pharmaceutical drug

Bemiparin is an antithrombotic and belongs to the group of low molecular weight heparins (LMWH).

Reviparin sodium pharmaceutical drug

Reviparin is an antithrombotic and belongs to the group of low molecular weight heparins (LMWH).

Idraparinux chemical compound

Idraparinux sodium is an anticoagulant medication in development by Sanofi-Aventis.

Direct Xa inhibitor Endogenous factors and drugs that inhibit or block the activity of factor xa

Direct factor Xa inhibitors ('xabans') are a class of anticoagulant drugs which act directly upon factor X in the coagulation cascade, without using antithrombin as a mediator.

Semuloparin is an experimental antithrombotic being developed by Sanofi-Aventis and belongs to the group of low molecular weight heparins (LMWH). It has completed Phase III clinical trials for the prevention of thromboembolism following various kinds of surgery such as hip replacement, as well as for patients undergoing chemotherapy.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

References

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  2. 1 2 3 4 Linhardt RJ, Gunay NS (1999). "Production and chemical processing of low molecular weight heparins". Seminars in Thrombosis and Hemostasis. 25 Suppl 3: 5–16. PMID   10549711.
  3. ↑ Garcia DA, Baglin TP, Weitz JI, et al. (2012). "Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e24S–43S. doi:10.1378/chest.11-2291. PMC   3278070 . PMID   22315264.
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  5. ↑ Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal JB, Bass EB, Weiss KB, Green L, Owens DK (February 2007). "Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians". Annals of Internal Medicine. 146 (3): 204–10. doi:10.7326/0003-4819-146-3-200702060-00149. PMID   17261857.
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  28. ↑ Jeske, Walter (2013). "Update on the safety and bioequivalence of biosimilars – focus on enoxaparin". Drug Healthc. Patient Saf. 5: 133–141. doi:10.2147/DHPS.S28813. PMC   3684140 . PMID   23788840.
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