COAGULATION DISORDERS

Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel), wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or obstructive clotting (thrombosis).


Aspirin permanently inhibits the synthesis of thromboxane A2, a product of cyclooxygenase in platelets that induces platelet aggregation, for the life of the platelet.

Dipyridamole exerts its antithrombotic effects by increasing cellular cyclic adenosine monophosphate (cAMP) levels. Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells, and erythrocytes, causing an elevation of adenosine levels. Increased adenosine activity at the platelet A2 receptor increases cAMP levels which promotes inhibition of platelet aggregation in response to platelet activating factor, collagen, and adenosine diphosphate.

GP IIb/IIIa BLOCKERS: When platelets are activated by thrombin, collagen, or thromboxane, the platelet surface receptor GP IIb/IIIa forms binding sites for fibrinogen and von Willebrand factor. By binding to GP IIb/IIIa receptors, fibrinogen and von Willebrand factor promote platelet aggregation as well as platelet adhesion to vascular endothelial cells. GP IIb/IIIa blockers (eptifibatide, tirofiban, abciximab) bind to GP IIb/IIIa and prevent these adhesive ligands from binding to activated platelets, thereby exerting their antithrombotic effects.Eptifibatide and tirofiban both reversibly inhibit GP IIa/IIIb. Platelet function generally recovers approximately 120 minutes after cessation of eptifibatide and 4-8 hours after cessation of tirofiban. Abciximab irreversibly blocks activity at the GP IIb/IIIa receptors through steric hindrance and conformational changes. In addition, abciximab inhibits cell adhesion by binding to vitronectin receptors that mediate the coagulant properties of platelets and the proliferation of vascular endothelial cells and smooth muscle cells. , Itand also inhibits monocyte adhesion by binding to activated Mac-1 receptors. Platelet function usually recovers over 48 hours after cessation of abciximab.

Heparin: Heparin promotes antithrombin III induced inhibition of free circulating Factor Xa and thrombin. By inactivating Factor Xa, heparin prevents the conversion of prothrombin to thrombin. When thrombin is already present, heparin binds to AT-III and induces a conformational change that increases thrombins accessibility to its binding site on AT-III, thereby increasing the rate of thrombin inactivation by AT-III and subsequently inhibiting the conversion of fibrinogen to fibrin. Heparin also inhibits activation of fibrin stabilizing factor thus preventing the formation of a stable fibrin clot. Heparin does not, however, have fibrinolytic activity. Activated partial thromboplastin times (aPTT) should be monitored daily once a dosing regimen has been established. Plasma concentrations of heparin may be elevated and aPPT aPTT prolonged in elderly patients >60 years of age. The half-life of heparin may be affected by pulmonary embolism (shortened) and in patients with cirrhosis or end-stage renal disease (prolonged).

LOW-MOLECULARWEIGHT HEPARIN (eg, dalteparin, tinzaparin, enoxaparin): Each low-molecularweight heparin has a distinct pharmacological profile and thus, based upon their anti-Factor Xa activity, may not produce comparable antithrombotic effects. Compared to heparin, low-molecularweight heparins have more predictable pharmacokinetic properties and longer half-lives and thus, allow for fixed or weight-adjusted once daily or twice daily dosing that does not require routine monitoring.

THIENOPYRIDINES: Thienopyridines (eg, clopidogrel, ticlopidine) are irreversible platelet aggregation inhibitors that block activity at the platelet P2Y12 receptors necessary for platelet activation. When activated, P2Y12 receptors reduce the levels of cAMP causing a decrease in cAMP-dependent inhibition of platelet activation. Activated P2Y12 receptors also produce a conformational change and promote platelet aggregation. The thienopyridines also exert their antiplatelet effects through other mechanisms. Ticlopidine interferes with platelet membrane function by inhibiting adenosine diphosphate (ADP)-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. Like ticlopidine, clopidogrel exerts its antiplatelet effects through inhibition of ADP. Clopidogrel irreversibly modifies the platelet ADP receptor and selectively inhibits binding of ADP to its platelet receptor, thereby preventing ADP-mediated activation of the GP IIb/IIIa receptor. Clopidogrel has a more favorable side effect profile than ticlopidine and is associated with a lower incidence of thrombocytopenia and leukopenia.

THROMBIN INHIBITORS: Direct reversible thrombin inhibitors (eg, bivalirudin, argatroban) exert their effects by binding to the active sites on both free circulating and clot-bound thrombin. These agents inhibit coagulation reactions induced or catalyzed by thrombin, including fibrin formation, platelet aggregation, and activation of Factors V, VII, XIII, and protein C. Bivalirudin and argatroban differ in their routes of metabolism and elimination. Bivalirudin is eliminated via the kidneys and dose reductions are recommended in moderate to severe renal impairment. Argatroban is metabolized by the CYP450 enzymes, thus dose reductions are required in patients with hepatic impairment. Antithrombin III (AT-III) is a major inhibitor of thrombin found normally in human plasma. AT-III covalently bonds to thrombin to form an inactive complex. Additionally, AT-III also inactivates Factors IXa, Xa, XiaXIa, XIIa, and plasmin.

TISSUE PLASMINOGEN ACTIVATORS (tPA): Tissue plasminogen activators (eg, alteplase, reteplase, tenecteplase) promote the conversion of plasminogen to plasmin, which is enhanced in the presence of fibrin. Plasmin is fibrinolytic and breaks down the fibrin matrix of existing thrombi. Compared to alteplase, reteplase has shown a lower affinity for fibrin and a lower catalytic efficiency.

Warfarin is a coumarin anticoagulant that inhibits the enzyme vitamin K epoxide reductase that is responsible for catalyzing the reduction of vitamin K, a necessary step in the synthesis of vitamin K-dependent coagulation factors (eg, Factors II, VII, IX, and X, as well as anticoagulant proteins C and S)
The full antithrombotic effects of warfarin may not be observed for several days.