Drugs affecting coagulation

Antiplatelet drugs: They can be classified according to their mechanism of action as follows:

i) Cyclooxygenase inhibitors: This group includes aspirin and triflusal. Aspirin irreversibly inhibits the enzyme COX 1 or prostaglandin H synthase in platelets and megakaryocytes thereby blocking the synthesis of thromboxane A2. As it is irreversible, the effect of aspirin lasts for the entire lifespan of the platelet, which is about 8-10 days. Most common side effects of aspirin are nausea, heartburn and epigastric pain. There is increased risk of intracranial hemorrhage. Enteric coated aspirin causes less GI irritation.

ii) ADP P2Y12 inhibitors: They include clopidogrel (Plavix), prasugrel, ticlopidine and ticagrelor. Clopidogrel and prasugrel are prodrugs that need to be activated in the liver by Cyt P450 enzymes. Clopidogrel is added to aspirin in patients undergoing percutaneous coronary intervention (PCI) for ACS. Common side effects include diarrhea and skin rash. Ticlopidine is associated with neutropenia, thrombocytopenia and TTP.

iii) GPIIb/IIIa inhibitors: They include abciximab, eptifibatide and tirofiban. Abciximab is a humanised mouse antibody fragment with a high binding affinity for the glycoprotein IIb/IIIa receptor. Tirofiban and eptifibatide mimic part of the structure of fibrinogen that interacts with the glycoprotein IIb/IIIa receptor and thus compete with ligand binding of fibrinogen to the glycoprotein IIb/IIIa receptor. Thrombocytopenia can occur. They are indicated in patients undergoing PCI.

iv) Phosphodiesterase inhibitors: They include dipyridamole and cilostazol. They raise intraplatelet cAMP levels. Cilostazol is metabolised by the cyt p450 system and levels will rise when given concomitantly with inhibitors of cyt p450 like omeprazole.

Anticoagulants: They prevent blood from clotting.

i) Warfarin (coumarin): It acts by blocking the enzyme vitamin K-epoxide reductase, thereby preventing formation of the active form of the vitamin K-dependent clotting factors such as factors II, VII, IX and X. The anticoagulants protein C and protein S are also vit K dependent. Warfarin is used for long term anticoagulation and prevention of thrombotic events in high risk patients such as post-operative state, atrial fibrillation and patients with artificial valves. Blocking of proteins C and S synthesis, leads to an initial period of hypercoagulability. Hence, a rapid acting anticoagulant like heparin should be added to warfarin at the initiation of treatment. Monitoring is with INR (indicates PT or prothrombin time). Risk of hemorrhage is high when INR is >5. Hemorrhage during warfarin therapy is managed with vitamin K (phytonadione), fresh frozen plasma (FFP) or prothrombin complex concentrates. Recombinant factor VIIa may help.

Warfarin is contraindicated in pregnancy. It is teratogenic and also associated with increased risk of hemorrhage. Warfarin is associated with nasal hypoplasia, limb deformities, respiratory distress, Dandy Walker syndrome, renal defects, mental retardation, microcephaly, deafness, cerebellar atrophy and abortions. Heparin is preferred as it does not cross the placenta.

ii) Heparins: Antithrombin III is an inhibitor of several clotting factors. Unfractionated heparin (UFH) binds to and increases the activity of antithrombin III, thereby enhancing the ability of AT III to inactivate thrombin (factor IIa) and factors Xa and IXa. At very high heparin doses, it inactivates thrombin by an AT III independent mechanism also, via heparin cofactor 2.

Low molecular weight heparins or LMWH also bind to AT III, but have greater effect on inactivation of factor Xa than IIa.

UFH is used in the treatment and prophylaxis of venous thromboembolisms, thrombus prophylaxis in atrial fibrillation, and treatment of disseminated intravascular coagulation. Effect occurs immediately with intravenous use and within 20-60 minutes of subcutaneous use. UFH dose need not be adjusted in renal failure (versus warfarin) and it has a shorter half life than warfarin. Activity of UFH is monitored by aPTT. Hemorrhage occurring from heparin therapy can be reversed with protamine sulfate.

LMWH includes enoxaparin, dalteparin and tinzaparin. Indications are the same as UFH. Advantages over UFH include a more predictable dose-response curve and do not need to be monitored. Risk of major bleeding is less with LMWH as compared to heparin. Dose needs to be reduced in renal failure. Dosing depends on body weight. LMWH activity can be measured using the assay of antifactor Xa. Severe hemorrhage due to LMWH is treated with FFP and cryoprecipitate. Other agents used to control bleeding are protamine sulfate (60% efficacy) and antifactor Xa.

iii) Factor Xa inhibitors: Apart from indications of UFH, factor Xa inhibitors are used as a heparin substitute in the setting of heparin induced thrombocytopenia or HIT. They inhibit factor Xa, either directly or indirectly. They include apixaban, rivaroxaban and fondaparinux. Apixaban and rivaroxaban directly bind to the active site of factor Xa, while fondaparinux is an indirect inhibitor that binds to AT III. Fondaparinux is contraindicated in renal failure. Adverse effects include hemorrhage and thrombocytopenia. Recombinant factor VIIIa and prothrombin concentrate may help to control bleeding from overdose.

iv) Direct thrombin inhibitors: These drugs inhibit thrombin directly, without the help of any cofactors. They include argatroban, bivalirudin and dabigatran (oral). They are used for prophylaxis and treatment of atrial fibrillation, venous thromboembolism and ACS. They are also used as alternatives to UFH in the setting of HIT. Their activity is monitored by thrombin time and ecarin clotting time or ECT. aPTT can also be used, although less accurate. Hemorrhage due to direct thrombin inhibitors is treated with transfusion of packed RBCs, FFP and prothrombin concentrates. Hemodialysis is needed to control bleeding in the presence of renal failure.

Thrombolytics or fibrinolytics: These drugs are used to lyse clots. They include tPA or tissue plasminogen activator, alteplase, tenecteplase, reteplase and urokinase, streptokinase etc. Streptokinase is derived from beta hemolytic streptococci. They convert inactive plasminogen to active plasmin, which degrades the fibrin matrix responsible for stabilizing a thrombus. Streptokinase is less selective than tPA and is associated with higher risk of hemorrhage. tPA selectively binds to fibrin in a thrombus. They are used in the treatment of acute cerebrovascular accidents (CVA), myocardial infarction, pulmonary emboli and to lyse clots within indwelling catheters like intrapleural, intraperitoneal etc. PT/INR and aPTT will rise, while fibrinogen levels will decrease after treatment. Hemorrhage occurring during therapy is controlled with tranexamic acid and epsilon amino caproic acid. Other agents like FFP, platelet transfusion and prothrombin concentrates may help.