Low-molecular-weight heparin

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Low-molecular-weight heparin
Fraxiparine 0,4ml yellow background.jpg
Nadroparin in prefilled syringe
Pharmacokinetic data
Bioavailability 100%
Chemical and physical data
Molar mass 4-6kDa

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

Contents

Heparin is a naturally occurring polysaccharide that inhibits coagulation, leading 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 polysaccharides. 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. Various methods of fractionation or depolymerization of polymeric heparin obtain these.

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 effects, 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) and 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 with 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 dalteparin was more effective in patients with malignancy and acute venous thromboembolism than warfarin in reducing the risk of recurrent embolic events. [11] The 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 in 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 bleeding such as cerebral or gastrointestinal hemorrhage. LMWHs depend more on renal function for their excretion than unfractionated heparin, so their biological half-life may be prolonged in patients with kidney failure. Therefore, their use in patients with 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. [3]

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. [13] 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 autoantibodies 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. [13]

Antidote

In clinical situations where the antithrombotic effect of LMWHs needs to be neutralized, protamine is used to neutralize heparin by binding to it. [9] Animal and in vitro studies have demonstrated that protamine neutralizes the antithrombin activity of LMWHs, normalizing the aPTT and thrombin time. However, protamine appears only partially to neutralize the anti-factor Xa activity of LMWH. Because the molecular weight of heparin impacts its interaction with protamine, the lack of complete neutralization of anti-factor Xa is likely due to reduced protamine binding to the LMWH 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. 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. [14] LMWHs should be used with extreme caution in patients undergoing any procedure involving spinal anesthesia/puncture, in conditions with increased risk of bleeding or in patients with a history of heparin-induced thrombocytopenia.

Pharmacology

Mechanism of action

The coagulation cascade is a normal physiological process to prevent significant blood loss or hemorrhage following vascular injury. Unfortunately, there are times when a blood clot (thrombus) forms 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 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. [15] LMWHs inhibit the coagulation process by binding to AT via a pentasaccharide sequence. This binding leads to a conformational change of AT, increasing the rate at which it inhibits 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. [16] Instead, 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's plasma, it will bind to antithrombin and form a complex with factor X, inhibiting it from becoming factor Xa. [17] 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 a spectrophotometer can detect. [17] Antithrombin deficiencies in the patient do not affect the assay because excess amounts of antithrombin is provided in the reaction. [17] Results are given in units/mL of anti-factor Xa, such that high values indicate high levels of anticoagulation and low values indicate low levels of anticoagulation in the plasma sample. [17]

LMWHs have a targeted therapeutic window of approximately 0.6–1.2 IU/ml. LMWH has a potency of 70 units/mg of anti-factor Xa activity and a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5. [18] (see Table 1)

LMWHAverage molecular weightRatio anti-Xa/anti-IIa activity
Bemiparin 36009.7
Nadroparin 43003.3
Reviparin 44004.2
Enoxaparin 45003.9
Parnaparin 50002.3
Certoparin 54002.4
Dalteparin 60002.5
Tinzaparin 65001.6

Table 1 Molecular weight (MW) data and anticoagulant activities of currently available LMWH products. Adapted from Gray E et al. 2008. [19]

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

Deaminative cleavage with nitrous acid forms 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, chemical and enzymatic beta-elimination results in 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. [20]

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, a 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] [15] Hence, a slight change in the depolymerization process could result in substantial variation in the structure or composition of a given LMWH.

Therefore, for every LMWH, a strictly defined depolymerization 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 clinically equivalent, as they differ in many crucial aspects such as molecular, structural, physiochemical, and biological properties. [21] [22] [23] According to international guidelines, the choice of an individual LMWH should be based on its proven clinical safety and efficacy for each indication. [13] Therefore, switching from LMWH to another LMWH during treatment is not recommended during clinical practice. [24]

Differences from unfractionated heparin

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

Generics and biosimilars

When the commercial patent of LMWH expires, a generic or biosimilar LMWH can be marketed. The Food and Drug Administration approved the first "generic" LMWH in July 2010. The FDA has used five 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 LMWH biologicals, so their regulatory approval – as biosimilars – is approached differently than the FDA's. [28] [29]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Thrombosis</span> Formation of blood clots inside the blood vessels

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Heparin</span> Anticoagulant

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of heart attacks and unstable angina. It can be given intravenously or by injection under the skin. Its anticoagulant properties make it useful to prevent blood clotting in blood specimen test tubes and kidney dialysis machines.

<span class="mw-page-title-main">Deep vein thrombosis</span> Formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms.

<span class="mw-page-title-main">Protein S deficiency</span> Medical condition

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.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation increasing the risk of blood clotting (thrombosis)

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 thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

<span class="mw-page-title-main">Factor X</span> Mammalian protein found in Homo sapiens

Coagulation factor X, or Stuart factor, is an enzyme of the coagulation cascade, encoded in humans by F10 gene. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

<span class="mw-page-title-main">Fondaparinux</span> Chemical compound

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

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). 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.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

<span class="mw-page-title-main">Dalteparin sodium</span> 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 to reduce the risk of a stroke or heart attack. Dalteparin acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin. It is normally administered by self-injection.

<span class="mw-page-title-main">Phenprocoumon</span> Drug

Phenprocoumon is a long-acting blood thinner drug to be taken by mouth, and a coumarin derivative. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders such as heart attacks and pulmonary (lung) embolism. The most common adverse effect is bleeding. The drug interacts with a large number of other medications, including aspirin and St John's Wort. It is the standard coumarin used in Germany, Austria, and other European countries.

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.

<span class="mw-page-title-main">Bemiparin sodium</span> Chemical compound

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

<span class="mw-page-title-main">Reviparin sodium</span> Pharmaceutical drug

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

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.

<span class="mw-page-title-main">Thrombosis prevention</span> Medical treatment

Thrombosis prevention or thromboprophylaxis is medical treatment to prevent the development of thrombosis in those considered at risk for developing thrombosis. Some people are at a higher risk for the formation of blood clots than others, such as those with cancer undergoing a surgical procedure. Prevention measures or interventions are usually begun after surgery as the associated immobility will increase a person's risk.

References

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