Physiology of Hemostasis

The mechanisms by which blood loss in mammals is stopped after vascular disruption are complex. Small vascular injuries are sealed by platelets that adhere to the site of damage, where they attract other circulating platelets, so as to form an occlusive aggregate or plug that can close small gaps. Larger defects in vessel walls are occluded by coagu lation of blood - that is, by its transformation from a fluid to a gel-like state. Uncontrolled bleeding and its antithesis, thrombosis (the formation of a clot within a blood vessel), are important pathogenetic factors for human disease, including a large variety of hereditary disorders.

The basic structure of both the occlusive clots that halt blood loss and pathological intravascular clots (or thrombi) is a meshwork of fibrous protein (fibrin) that entraps blood cells. Plato and Aristotle both described the fibers found in shed blood. When the blood vessel wall is disrupted, whether by trauma or disease, a soluble plasma protein, fibrinogen (factor I), is transformed into the insoluble strand of fibrin. Fibrin formation takes place through three steps: First, a plasma proteolytic enzyme, thrombin, cleaves several small peptides from each molecule of fibrinogen. Molecules of the residue, called fibrin monomers, polymerize to form the fibrin strands. Finally, these strands are bonded covalently by a plasma transamidase, fibrin-stabilizing factor (factor XIII), itself activated by thrombin, increasing their tensile strength.

Thrombin is not found in normal circulating plasma, but evolves after vascular injury from its plasma precursor, prothrombin (factor II), via either or both of two interlocking series of enzymatic events, the extrinsic and intrinsic pathways of thrombin formation. The steps of the extrinsic pathway begin when blood comes into contact with injured tissues (such as the disrupted vascular wall). The tissues furnish a lipoprotein - tissue thromboplastin or tissue factor (factor III) - that reacts with a plasma protein, factor VII. Factor VII then converts a plasma proenzyme, Stuart factor (factor X), to its active form. Thus activated, Stuart factor (factor Xa), acting in conjunction with a nonenzymatic plasma protein, proaccelerin (factor V), releases thrombin from prothrombin, and in this way initiates the formation of fibrin.

The intrinsic pathway of thrombin formation is launched when vascular disruption brings plasma into contact with certain negatively charged substances, such as subendothelial structures or the oily sebum layer of skin. Exposure to negative charges changes a plasma protein, Hageman factor (factor XII), to an enzymatic form, activated Hageman factor (factor XHa), that participates in both clotting and inflammatory reactions. In the latter role, activated Hageman factor converts a plasma proenzyme, prekallikrein, to kallikrein, an enzyme that releases small peptides from a plasma protein, high molecular weight kininogen. These peptides, notably bradykinin, increase vascular permeability, dilate small blood vessels, and induce pain.

The role of activated Hageman factor in the intrinsic pathway is to initiate a series of proteolytic reactions that lead ultimately to the release of thrombin from prothrombin. These reactions involve the sequential participation of several plasma proteins, including plasma thromboplastin antecedent (PTA, factor XI), high molecular weight kininogen, plasma prekallikrein, Christmas factor (factor IX), antihemophilic factor (factor VIII), Stuart factor (factor X), and proaccelerin (factor V). Of these various proteins, PTA, plasma prekallikrein, Christmas factor, and Stuart factor are the precursors of proteolytic enzymes, whereas high molecular weight kininogen, antihemophilic factor, and proaccelerin serve as nonenzymatic cofactors. The ultimate product, activated Stuart factor (factor Xa), releases thrombin from prothrombin through the same steps as those of the extrinsic pathway. Hageman factor also enhances clotting via the extrinsic pathway by augmenting the activity of factor VII, whereas factor VII in turn can directly activate Christmas factor. Thus, the steps of the extrinsic and intrinsic pathways are intertwined.

Certain steps of both the extrinsic and intrinsic pathways require the presence of calcium ions and phospholipids, the latter furnished, in the extrinsic pathway, by tissue thromboplastin and, in the intrinsic pathway, by platelets and by plasma itself.

Antihemophilic factor (factor VIII) is of peculiar interest as it circulates in plasma loosely bound to another plasma protein, von Willebrand factor (vWf), which fosters hemostasis by promoting adhesion of platelets to injured vascular walls. The plasma proteins participating in coagulation are synthesized at least in part by the liver, except for von Willebrand factor, which is synthesized in vascular endothelial cells and megakaryocytes.

Synthesis of certain of the plasma clotting factors - namely prothrombin, factor VII, Stuart factor (factor X), and Christmas factor (factor IX) - is completed only in the presence of vitamin K, furnished by leafy vegetables and by bacterial flora in the gut.

The clotting process is modulated by inhibitory proteins present in normal plasma. Plasmin, a proteolytic enzyme that can be generated from its plasma precursor, plasminogen, can digest fibrin clots as well as certain other plasma proteins. Antithrombin III inhibits all of the plasma proteases of the clotting mechanism, an action enhanced by heparin, a glycosaminoglycan found in various tis sues but not in plasma. Heparin cofactor II, a protein distinct from antithrombin III, also inhibits clotting in the presence of heparin. CI esterase inhibitor (Cl-INH) originally detected as an inhibitor of the activated form of the first component of the immune complement system (CI), also blocks the activated forms of Hageman factor and PTA as well as plasmin. Alpha-1 -antiproteinase (alpha-1 -antitrypsin) is an inhibitor of activated PTA. Protein C, when activated by thrombin, blocks the coagulant properties of antihemophilic factor (factor VIII) and proaccelerin (factor V), an action enhanced by protein S; proteins C and S both require vitamin K for their synthesis. Activated protein C also enhances the conversion of plasminogen to plasmin. Alpha-2-macroglobulin is an inhibitor of plasma kallikrein, and plasmin can be inhibited by several plasma proteins, notably by alpha-2-plasmin inhibitor.

Human disorders due to the functional deficiency of each of the factors needed for the formation of a clot have been recognized and extensively studied. In some instances, the patient's plasma appears to be deficient or totally lacking in a specific clotting factor or inhibitor. In others, plasma contains a nonfunctional variant of the normal plasma protein.

Classic Hemophilia Clinical Manifestations

The best known of all the bleeding disorders is classic hemophilia (hemophilia A, the hereditary functional deficiency of factor VIII), which is the prototype of an X chromosome-linked disease, limited to males but transmitted by female carriers. Necessarily, all daughters of those with the disease are carriers, as are half the daughters of carriers. In turn, half the sons of carriers inherit the disease. A typical family history of bleeding inherited in the manner described is found in about two-thirds of cases; in the rest, the disorder appears to arise de novo, either because a fresh mutation has occurred or because cases were unrecognized in earlier generations.

Classic hemophilia varies in severity from family to family. In the most severe cases, in which plasma is essentially devoid of factor VIII, the patients may bruise readily and bleed apparently spontaneously into soft tissues and joints, with the latter resulting in crippling joint disease. Trauma, surgical procedures, and dental extractions may lead to lethal bleeding. The life expectancy of those with severe classic hemophilia is foreshortened, death coming from exsanguination, bleeding into a vital area, or infection. The prognosis of classic hemophilia has been greatly improved by modern therapy in which episodes of bleeding are controlled by transfusion of fractions of normal plasma containing the functionally missing proteins. This therapy is not without hazard, for transfusion of concentrates of factor VIII derived from normal plasma has been complicated by transmission of the viruses of hepatitis and the acquired immunodeficiency syndrome (AIDS).

In those families in which classic hemophilia is milder, bleeding occurs only after injury, surgery, or dental extraction. The severity of clinical symptoms is paralleled by the degree of the deficiency of antihemophilic factor (factor VIII), as measured in tests of its coagulant function.

Geography

Classic hemophilia appears to be distributed worldwide but geographic differences in its incidence have been described. In the United States, Great Britain, and Sweden, estimates of the prevalence of classic hemophilia range from about 1 in 4,000 to 1 in 10,000 males; a somewhat lower prevalence has been estimated in Finland. Whether classic hemophilia is less prevalent in blacks than in other groups, as has been suggested, is uncertain since milder cases may not be brought to medical attention for socioeconomic reasons.

Christmas Disease Clinical Manifestations

Christmas disease (hemophilia B), the hereditary functional deficiency of Christmas factor (factor IX), is clinically indistinguishable from classic hemophilia, and can be differentiated only by laboratory tests. It is inherited in the same way as an X chromosome-linked disorder and is therefore virtually limited to males. As is true of classic hemophilia, the disorder varies in severity from family to family in proportion to the degree of the clotting factor deficiency. Christmas disease is heterogeneous in nature, for in some families the plasma is deficient in Christmas factor, whereas in others the plasma contains one or another of several nonfunctional variants of this clotting factor. Therapy for hemorrhagic episodes in Christmas disease is currently best carried out by transfusion of normal plasma, which contains the factor deficient in the patient's plasma. An alternative therapy, infusion of concentrates of Christmas factor separated from normal plasma, may be needed in some situations, but its use may be complicated by the transmission of viral diseases as well as by other problems.

VIII. Major Human Diseases Past and Present Geography

Worldwide, Christmas disease is perhaps one-eighth to one-fifth as prevalent as classic hemophilia. Most reported cases have been in individuals of European origin, but in South Africa and in the United States, as reflected by Ohio data, Christmas disease is relatively as common in blacks as in whites. Christmas disease of moderate severity is particularly prevalent among inhabitants of the village of Tenna, in Switzerland, and among Ohio Amish. This disorder is said to be rare in Japan.

Von Willebrand's Disease Clinical Manifestations

Classic hemophilia is not the only hereditary deficiency of antihemophilic factor. Von Willebrand's disease is a bleeding disorder of both sexes which in its usual form is present in successive generations; thus, it is inherited as an autosomal dominant trait. The plasma of affected individuals is deficient in both parts of the antihemophilic factor complex — that is, the coagulant portion (factor VIII) and von Wille-brand factor (vWf). The bleeding time - the duration of bleeding from a deliberately incised wound - is abnormally long, distinguishing von Willebrand's disease from classic hemophilia or Christmas disease. The disorder is usually mild, although variants have been observed in which severe bleeding episodes are frequent. Inheritance in these cases is probably recessive in nature.

Geography

The prevalence of von Willebrand's disease is uncertain because mild cases are easily overlooked. Using Ohio as something of a proxy for the United States, von Willebrand's disease is about one-fourth as prevalent as classic hemophilia, meaning about 2 or 3 cases per 100,000 individuals. Estimates of 3 to 6 cases per 100,000 have been made in the United Kingdom and Switzerland, whereas the prevalence is somewhat higher in Sweden, about 12 per 100,000. A study conducted in northern Italy on a population of school children revealed that 10 of 1,218 had laboratory evidence of the disease as well as a family history of hemorrhagic problems. By contrast, the disorder is relatively uncommon in blacks. Similarly, although the severe, autosomal recessive form of von Willebrand's disease is unusual in most individuals of European extraction (perhaps 1 per 1 million), it is particularly prevalent among Israeli Arabs, in whom it can be detected in about 5 individuals per 100,000, and in Scandinavia.

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