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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Anticoagulants and Related Drugs

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Heparins and Low Molecular Weight Heparins - Cardiovascular Poison

The name heparin derives from the fact that it is abundantly present in the liver.

Heparins and Low Molecular Weight Heparins

Heparin was discovered by McLean, a medical student, in 1916, and isolated by Howell (who owned the laboratory in which McLean worked), in 1922. The name heparin derives from the fact that it is abundantly present in the liver. Heparin is an anionic sulfated glycosaminoglycan mucopolysaccharide with anticoagulant activity and normally found in mast cells. It is a heterogenous mixture of proteins of various sizes. There is no exact molecular weight for standard heparin; molecular weights have ranged from 4000 to 40,000 daltons.

Low Molecular Weight Heparins (LMWH) are fragments of heparin with anticoagulant activity, and are isolated from standard heparin by gel filtration chromatography or differential precipitation with ethanol.

Uses

■■ Heparin is used in the prophylaxis and treatment of deep vein thrombosis, embolism, and post-surgical arterial embolism.

■■Other uses include diagnosis and treatment of disseminated intravascular coagulation, and prevention of coagulation through an extracorporeal circuit, in dialysis, in blood transfusions, and in blood drawn for laboratory use, and lipid reduction in idiopathic hyperlipaemia.

Toxicokinetics

·              Heparin and LMW heparins are not absorbed through the GI tract and must always be administered parenterally (usually subcutaneously or intravenously). Intramuscular heparin often causes large haematomas at the site of injection. Low doses can be administered subcutaneously or into a fat depot; larger doses can be administered by the continuous or intermittent intravenous infusion.

·              Absorption of heparin from the gastrointestinal tract does occur in experimental animals when it is complexed with amino acids, given with adjuvants such as sodium ethyl-enediamine-tetra-acetate, or encapsulated in liposomes. Onset of action is immediate (IV), or delayed by 1 to 2 hours (SC).

·              Low molecular weight heparins have a bioavailability of more than 85% compared to normal heparin, which has a bioavailability of 15 to 20%, when given subcutaneously. Heparin is primarily distributed into the blood and thera- peutic plasma levels range from 0.2 to 0.6 U/ml. Half-life of heparin varies from 1 to 5 hours, and it is cleared and degraded mainly by the reticuloendothelial system. It is cleaved by heparinase into oligosaccharides in the liver and spleen, after undergoing N and O-desulfation by desulfa- tase in the reticuloendothelial system. A small amount of undegraded heparin appears in the urine.

·              Low molecular weight (LMW) heparins have longer half- lives than heparin. They are metabolized more slowly than normal heparin, and are partially metabolized by desulfation and depolymerization.

Mode of Action

■■Heparin inhibits thrombosis by accelerating the binding of the protease inhibitor antithrombin III to thrombin and other serine proteases involved in coagulation. Thus factors IX to XII, kallikrein, and thrombin are inhibited.

■■   Heparin also inhibits the activation of factor XIII (fibrin stabilising factor) and prevents the formation of a stable fibrin clot.

■■   Heparin also affects plasminogen activator inhibitor, protein C inhibitor, and other components of coagulation.

 

Adverse Effects

·              The primary adverse effect associated with heparin therapy or overdosage is over-anticoagulation and haemorrhage. Common sites of bleeding may include the GI tract, skin, urinary tract, and the pulmonary and cardiovascular systems. The risk of haemorrhage increases with the dura-tion of heparin therapy, but may be reduced by careful control of dosage. Factors associated with an increased risk of minor bleeding while receiving heparin include aspirin use, underlying morbid condition, alcohol consumption, renal failure and female sex.

·              Heparin-induced thrombosis-thrombocytopenia syndrome (HITTS)—may manifest as thrombotic phenomena: deep venous thrombosis, pulmonary emboli, myocardial infarction, cerebral thrombosis, digital vasculitis, adrenal infarction, renal artery embolism, priapism, skin necrosis, aortic and limb arterial thrombosis, or as haemorrhagic phenomena: cerebral haemorrhage, GI bleeding, adrenal haemorrhage, skin bruising, epistaxis, haematuria, intra- muscular haematoma, etc. HITTS carries a 30% death rate.

·              Mild thrombocytopenia (100,000 to 150,000/mcl) may be noted in up to 30% of patients on heparin therapy and is generally transient. Clinically significant thrombocytopenia occurs in less than 10% of patients on heparin therapy, and this too is generally transient.

·              Vasospastic reactions may develop 6 to 10 days after initia-tion of heparin therapy. Vasospasm may present as painful, ischaemic, cyanotic extremities, or with tachypnoea, head-ache, chest pain, arthralgia, or hypertension depending on the site of arterial spasm. The duration of vasospasm is typically 4 to 6 hours

·              Delayed, transient alopecia may occur.

·              Chemosis and subconjunctival injection as well as hyphaema have been reported with intravenous heparin. Epistaxis has been reported with therapeutic doses.

·              Occasionally, cardiovascular collapse may occur with significant haemorrhage or cardiac tamponade. Hypersensitivity reactions are occasionally reported:urticaria, conjunctivitis, rhinitis, asthma, and anaphylaxis.

·              Hallucinations and distorted perceptions have been reported among humans given heparin sodium by subcutaneous route. Minor reversible elevations in serum transaminases have been reported in up to 95% of patients receiving heparin. Priapism has been noted after discontinuation of heparin therapy.

·              Heparin use during pregnancy may be associated with increased susceptibility to premature delivery, foetal loss, neonatal death, and maternal death.

·              Skin necrosis has been reported following heparin and low molecular-weight heparin (LMWH) therapy. Skin necrosis and tender erythematous nodules (panniculitis) at the sites of subcutaneous heparin injections have been ascribed to the complications of heparin -induced throm-bocytopenia. Given its association with thrombosis and increased mortality, the onset of skin reactions warrants prompt discontinuation of heparin and close monitoring for thrombocytopenia and platelet-aggregating antibodies.

·     Hyperkalaemia and secondary hypoaldosteronism have been reported following either unfractionated heparin therapy or low-molecular-weight heparin therapy, espe-cially in patients with diabetes mellitus or renal insuf-ficiency. Osteoporosis and spontaneous fractures may be noted with long-term heparin therapy with heparin (15,000 units daily for over 6 months).

Drug Interactions

·              Potentiation of oral anticoagulants, methotrexate, and oral hypoglycaemics.

·              Salicylates and dipyridamole enhance activity of heparin. Bleeding tendency enhanced with NSAIDs and aspirin.

·              Incompatible with aminoglycoside antibiotics.

·              The combination of heparin and dihydroergotamine carries a risk of vasospasm and ischaemia.

Toxic (Clinical) Features

·      Overdose of heparin results in rapid prolongation of coagu-lation time and active bleeding.

·      Hypotension and respiratory distress develop.

·      Chronic heparin therapy is associated with hyperkalaemia due to aldosterone suppression.

·      Abrupt withdrawal of heparin can put the patient at increased risk for transient ischaemic attack or cerebral stroke.

Treatment

·      Admit patient to intensive care and monitor blood clotting parameters. Orally ingested heparin is not absorbed from the gastrointestinal tract and will not result in toxicity.

·      Evaluate airway, breathing, and circulatory status.

·      Undertake complete blood count, platelet count, coagulation profile (bleeding time, clotting time), and activated partial thromboplastin time. The most reproducible and frequently used monitoring tool for assessment of anticoagulation with heparin is the activated partial thromboplastin time (aPTT). Thromboembolism is prevented by “therapeutic” values of 1.5 to 2.5 times baseline. There is a large interpatient vari-ability in anticoagulant response to heparin as evaluated by the aPTT. Similar doses of heparin may lead to 12-fold variations in aPTT. The baseline aPTT accounts for most of the variability and should be determined prior to initiating therapy. Blood samples for aPTT should be collected as close to the steady state of heparin infusion as possible (i.e. at least 6 and preferably 8 hours after initiating or changing infusion rates).

·              Other coagulation tests (PT, TT, and aCT) may be used for monitoring heparin effects. Thrombin time (TT) measuresFactor IIa conversion of fibrinogen to fibrin. Normal adult values range from 13 to 20 seconds. Therapeutic heparin therapy results in a thrombin time of 50 to 100 seconds at a 1:4 dilution. The activated coagulation time (aCT) is less sensitive to effects of low heparin concentrations, but is a global test that can be performed rapidly at the bedside. Normal adult values are 80 to 130 seconds, with therapeutic heparinisation at 150 to 190 seconds.

·      Urinalysis should be obtained for detection of haematuria. Examine sputum and stool for the presence of blood.

·      Because of the short duration of action of aqueous heparin after therapeutic doses, treatment of extremely prolonged clotting time or minor bleeding during therapy is usually managed simply by decreasing or stopping the heparin dose or frequency of injections. In the event of significant hemorrhage, a heparin antagonist should be used to reverse the effects of heparin on coagulation (vide infra). Replace blood loss with whole blood or plasma. Exchange transfu-sion has been successful in neonates.

·      Antidote: Protamine sulfate is used in severe overdose involving heparin or LMW heparins. Protamine is a low-molecular-weight protein found in the sperm and testis of salmon, and forms ionic bonds with heparin rendering it devoid of anticoagulant activity. Protamine reacts with heparin to form a stable salt, resulting in neutralisation of heparin’s anticoagulant activity (within 30 to 60 seconds). Each milligram of protamine (given IV) inactivates 100 U of heparin.

a. Dose: 2 mg/kg (maximum 50 mg), slow IV over 10 minutes. Alternatively, protamine can be given in a ratio of 0.75 to 2.1 : 1 times the total operative heparin dose. Since the half-life of heparin is very short (about 1½ hours), protamine administration should take into account the time elapsed since overdose. Paradoxically, protamine sulfate has weak anticoagu-lant activity when given in the absence of heparin. Therefore, the maximum recommended dose is 100 mg over a short period. After an initial dose, further protamine therapy should be guided by monitoring aPTT or aCT every 5 to 15 minutes. Protamine is associated with a low (0.2%), but clinically signifi-cant, incidence of complications which have a high mortality (30%). It should therefore only be reserved for patients with evidence of severe haemorrhage.

b. Adverse effects:

–– Hypotension, bradycardia, dyspnoea, pulmonary oedema, vomiting, lassitude.

–– Protamine interacts with platelets, fibrinogen, and other plasma proteins and may cause an antico-agulant effect of its own.

–– There is a significant risk of anaphylaxis which is enhanced in patients with a history of allergy to fish. Diabetic patients receiving protamine-containing insulin (NPH) are also at increased risk.

–– Sometimes neutralisation of blood heparin with protamine may be followed by a resurgence of anticoagulant activity (“heparin rebound”).

·      Treatment of HITTS:

o     Withdraw heparin.

o     Substitute with LMW heparins. However, current opinion is that low-molecular weight heparins are not recommended to be used as alternative anticoagulant therapy in patients with heparin-induced thrombocy-topenia. Immunological cross-reactivity may occur resulting in a recurrence of the thrombocytopenia.

o     Warfarin as sole therapy may be risky, because in some patients, a thrombus may grow or embolise before warfarin becomes effective. This is not a problem with ancrod or other alternative thromboembolic therapy. If oral anticoagulation is used, it should initially be given in conjunction with danaparoid or a direct thrombin inhibitor. Warfarin has also reportedly been associated with the development of skin necrosis and venous limb gangrene in HIT patients who received warfarin as sole alternative anticoagulant therapy.

o     Dextran therapy.

o     Administer antiplatelet drugs (aspirin, dipyridamole).

o     When re-exposure to heparin is essential and platelet-aggregating antibodies are still present, aspirin, dipy-ridamole, sulfinpyrazone, and iloprost have been used with variable success to prevent recurrence of throm-bocytopenia and thrombosis. Because the concurrent use of heparin and aspirin carries a risk for hemor-rhagic complications, shorter-acting nonsteroidal anti-inflammatory agents have been recommended, such as ibuprofen, instead of aspirin.

o     Incidence of venous thrombosis can be minimised with IV streptokinase.

o     Heparin-associated thrombocytopenia has been treated successfully with IV immunoglobulin (0.4 gm/kg), followed by platelet transfusion.

o     Lepirudin (rDNA) is indicated specifically for antico-agulation in patients with heparin-induced thrombo-cytopenia and associated thromboembolic disease, in order to prevent further thromboembolic complications. It is a synthetic recombinant hirudin derived from yeast cells. Lepirudin should be administered as a slow (15 to 20 seconds) intravenous bolus dose of 0.4 mg/kg body weight (up to 110 kg), followed by 0.15 mg/kg body weight (up to 110 kg) as a continuous intravenous infu-sion for 2 to 10 days or longer as needed. The infusion rate should be adjusted according to the aPTT ratio. The target range for the aPTT ratio during treatment should be 1.5 to 2.5.

o     Recently, argatroban, a synthetic direct thrombin inhibitor derived from L-arginine has been approved as an alternative anticoagulant for the prevention and treatment of thromboembolism in patients with heparin-induced thrombocytopenia. Elimination is primarily by the liver, making its use preferable over lepirudin in patients with renal insufficiency. The recommended initial dose is 2 mcg/kg/min administered as a continuous infusion. Dose can be adjusted as clini-cally indicated, not exceeding 10 mcg/kg/min, until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed an aPTT of 100 seconds).

 

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