Blood, Coagulants and Anticoagulants

The conversion of inert procoagulant glycoproteins to coagulant glycoproteins via proteolytic processing involves delicately balanced interaction between many different proteins, proteases, phospholipids, and the divalent cation calcium. The coagulation process can be activated and proceed through one of two possible sequential pathways: the intrinsic system path, components present within the circulating blood, and the extrinsic system, components present in the extravascular and intravascular compartment. Cooperative integration of these two systems, along with circulating platelets, maintains vascular integrity and preserves hemostasis. Biochemically, coagulation of the blood results from proteolytic processing of many different inert glycoproteins that originate in or migrate into the circulating blood. The participants in this complex process have been designated factors, and most have been assigned roman numerals. They are I (fibrinogen), II (prothrombin), III (thromboplastin), IV (calcium), V (proaccelerin, plasma acglobulin), VII (SPCA, proconvertin), VIII (antihemophilic globulin, AHG, antihemophilic factor, AHF), VIII:vWFAg (von Willebrand protein), IX (plasma thromboplastin component, PTC, Christmas factor), X (Stuart-Prower Factor), XI (plasma thromboplastin antecedent, PTA), XII (Hageman Factor), XIII (fibrin-stabilizing factor), Protein Ca, protein S, and Protein Z. The more recently identified participants in coagulation of the blood are designated by the name of the person who recognized the given factor, eg, von Willebrand protein, or by a name that indicates the composition of the substance, eg, high molecular weight kininogen. All these factors are present in plasma except III, and all are present in serum except for I, II, III, V, and VIII, though XIII is decreased to trace quantities. Factor IIa (thrombin) may be present in serum. Factors I, VIII, and XIII are present in Cohn's fraction I; Factors II, V, VII, IX, X, XI, and XII are present in Cohn's fraction III; Factors II, VII, IX, XI, and XII are present in Cohn's fraction IX. Recently, the following factors, not previously reported, have been detected: Fletcher (prekininogenin [prekallikrein]), Fitzgerald (high molecular weight) kininogen (also designated as Williams or Flaujeac trait), and Passovoy (bleeding diathesis-prolonged partial thromboplastin time, normal known coagulation factors, autosomal dominant). Roman numerals have not yet been assigned to these factors. Factor VI is obsolete. The optimal technique for the treatment of hemorrhage associated with congenital factor deficiency states, including hemophilia A, hemophilia B, and von Willebrand disease, is intravenous replacement of the missing factor. Because of the frequency of transmission by transfusion of these blood products of certain diseases, such as hepatitis A, hepatitis B, hepatitis delta, HIV, etc, recently there has been a concerted effort to pasteurize these sources. The pasteurization techniques utilize such methodologies as monoclonal antibody-specific selective separation of the factor from all other proteins in the plasma, dry and wet heat, and molecular biologic recombinant expression of these individual proteins by mammalian cells. Recombinant factor VIII:C is now available. A number of substances have been identified that prevent coagulation of the blood when it is removed from the body. Most remove a vital constituent of the blood. Ethylenediamine tetraacetic acid (EDTA) (Sequestrene), removes calcium, , from the blood. Oxalate, citrate, and fluoride ions chelate calcium from the blood. Salts containing these anticoagulants include lithium oxalate, Li2C2O4; sodium polyanetholesulfonate (Liquoid); and heparin. Fourteen naturally occurring compounds that normally exert an inhibiting effect on the activity of coagulation, platelet function, and fibrinolytic activity. Therapeutic anticoagulants include heparin and coumarinic acid compounds, eg, warfarin. There are some patients who cannot receive heparin or warfarin but who need anticoagulation. To deal with this need, several new anticoagulant agents are on the horizon. The human fibrinolytic system is a proteolytic enzyme system consisting of several components found in different locations in the body including the blood, vascular endothelium, and several tissues extrinsic to the vascular compartment. The central component of the human fibrinolytic system is plasminogen synthesized by the liver. This inert precursor or proenzyme can be activated by an agent intrinsic to the blood designated proactivator. Additional agents extrinsic to the vascular compartment, designated tissue plasminogen activators, have been extracted from the uterus, pancreas, lung, kidney, and prostate. The fibrinolytic system in humans participates in biological functions including ovulation, embryo implantation, neoplastic transformation, tissue repair, and macrophage function. Fibrin is the principal physiologic substrate of plasmin. Other elements of the coagulation cascade, including Factor VIII, Factor V, and fibrinogen, are degraded by plasmin. When the coagulation system is activated, an insoluble fibrin clot is formed. The anticoagulant effects of plasmin result not only from the destruction or inactivation of fibrin, fibrinogen, and other procoagulants, but also from the coagulation-inhibiting properties of the fibrin(ogen) degradation products themselves. There are several different pathways that lead to the activation of the plasminogen–plasmin proteolytic enzyme system. However, therapeutic utilization of this system occurs only by the exogenous administration of agents that initiate the conversion of inert plasminogen to the potent proteolytic enzyme plasmin. Four thrombolytic agents have been approved for worldwide clinical use: streptokinase (SK), urokinase (U.K.), recombinantly produced tissue plasminogen activator (rTPA), and acylated Lys-plasminogen–streptokinase activator complex (APSAC). Inhibitors of the fibrinolytic system are either endogenous, naturally occurring inhibitors or modulators, or exogenous inhibitors employed primarily for therapeutic reasons. Some of the naturally occurring endogenous inhibitors/modulators increase in concentration during certain physiologic states, ie, pregnancy when PAI-1 increases three to fourfold above normal and decreases the normal degree of fibrinolytic activity. Several synthetic amino acids have been identified that excite inhibition of the fibrinolytic system. These agents experience wide use whenever there is a need to reduce the activity of the fibrinolytic system. In addition, these agents prevent excessive blood loss in patients with ulcerative colitis; post-surgical prostatectomy; and oral surgery of any type.