Bleeding and Hemostasis in Acute Renal Failure

Coagulation

Coagulation is divided into the intrinsic pathway , initiated by contact with negatively charged surfaces, and the extrinsic pathway , initiated by tissue factor (TF).

The coagulation cascade is started by blood vessel disruption and the exposure of subendothelial cells to circulating factors. Subendothelial cells expose TF, which binds factor VII, promoting its proteolysis and leading to the formation of TF–factor VIIa complex. This complex in turn may activate factor IX and factor X.

Factor Xa activates factor V to factor Va, leading to the formation of the factor Xa–factor Va complex, which is capable of converting prothrombin (factor II) to thrombin. Factor IXa binds factor VIIIa, which further promotes the activation of factor X. Thrombin then may activate factors VIII, V, and XI and separate factor VIII from VWF, thus enhancing prothrombinase activity. Once formed, thrombin cleaves the fibrinogen molecule to create fibrin monomers that are cross-linked to form polymers through the action of thrombin-activated factor XIIIa.

In recent years the factor XI-factor XII intrinsic pathway, which classically was thought of as a simple amplification loop for the coagulation cascade initiated by the TF, has been reevaluated: new evidence suggests that this pathway is triggered in parallel with the extrinsic pathway through different stimuli, which include collagen and polyphosphates.

There are several anticoagulatory mechanisms for tightly controlling the coagulation cascade. These systems can be divided roughly into two categories: circulating protease inhibitors (e.g., antithrombin and tissue factor pathway inhibitor), which act as inhibitors of coagulation factors by binding to their active sites, and the enzymatic protein C/protein S pathway.

Antithrombin (AT) is one of the most important circulating inhibitors of thrombin formation, which exerts its function through the inhibition of factors IXa, Xa and IIa. The ability of AT to inhibit its targets is accelerated greatly by heparin and heparin-like glycosaminoglycans present on the endothelial cell surface.

Tissue factor pathway inhibitor (TFPI) is another protease inhibitor that is located either in platelets, on the microvascular endothelium, or in a circulating form associated with lipoproteins. TFPI exerts its anticoagulation function by inhibiting factor Xa and the transient TF/FVIIa/FXa complex.

Thrombin is also inhibited by thrombomodulin, a thrombin receptor expressed by endothelial cells. Thrombin-bound thrombomodulin together with the endothelial protein C receptor (EPCR) activates protein C. Activated protein C is then complexed with its cofactor protein S, which in turn proteolytically inactivates factor Va and factor VIIIa, thus preventing the activation of factor X and II. The protein C/protein S pathway is necessary to prevent clot formation on healthy endothelial cells that present thrombomodulin.

Fibrinolysis

Fibrinolysis is a regulated mechanism that aims to remove blood clots during wound healing and prevent coagulation in intact vascular beds. The activation of fibrinolysis is achieved by converting plasminogen to plasmin through the action of either tissue plasminogen activator (tPA), which is released by activated endothelial cells, or urokinase plasminogen activator (uPA), which is produced mainly by macrophages and monocytes. Once produced, plasmin cleaves factor V, factor VIII, fibrinogen, and the GPIb-V-IX on platelets. Finally, fibrin and fibrinogen degradation products (FDPs) interfere with fibrin formation and impair platelet function through α _IIb β ₃ complex occupancy.

Fibrinolysis is controlled primarily by three serine protease inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) and α2-antiplasmin (A2AP). Other inhibitors include α2-macroglobulin, C1-esterase inhibitor, thrombin-activated fibrinolysis inhibitor (TAFI), and members of the contact pathway of the coagulation cascade.