Deficiencies of Factor VIII-vWF Complex

Hemophilia A and von Willebrand disease, two of the most common inherited disorders of bleeding, are caused by qualitative or quantitative defects involving the factor VIII-vWF

complex. Before we can discuss these disorders, it is essential to review the structure and function of these proteins.[63] [64]

Plasma factor VIII-vWF is a complex made up of two separate proteins (factor VIII and vWF) that can be characterized according to functional, biochemical, and immunologic criteria.

Factor VIII procoagulant protein, or factor VIII ( Fig. 13-28 ;

Figure 13-28Structure and function of factor VIII-von Willebrand factor (vWF) complex. Factor VIII is synthesized in the liver and kidney, and vWF is made in endothelial cells and

megakaryocytes. The two associate to form a complex in the circulation. vWF is also present in the subendothelial matrix of normal blood vessels and the alpha granules of platelets.

Following endothelial injury, exposure of subendothelial vWF causes adhesion of platelets, primarily via glycoprotein lb platelet receptor. Circulating vWF and vWF released from the

alpha granules of activated platelets can bind exposed subendothelial matrix, further contributing to platelet adhesion and activation. Activated platelets form hemostatic aggregates;

fibrinogen (and possibly vWF) participate in aggregation through bridging interactions with the platelet receptor GpIIb/III. Factor VIII takes part in the coagulation cascade as a cofactor in

the activation of factor X on the surface of activated platelets.

TABLE 13-10-- Major Disorders Associated with Disseminated Intravascular Coagulation

Obstetric Complications

Abruptio placentae

Retained dead fetus

Septic abortion

Amniotic fluid embolism

Toxemia

Infections

Gram-negative sepsis

Meningococcemia

Rocky Mountain spotted fever

Histoplasmosis

Aspergillosis

Malaria

Neoplasms

Carcinomas of pancreas, prostate, lung, and stomach

Acute promyelocytic leukemia

Massive Tissue Injury

Traumatic

Burns

Extensive surgery

Miscellaneous

Acute intravascular hemolysis, snakebite, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, liver disease

increase the expression of tissue factor on endothelial cell membranes and simultaneously decrease the expression of thrombomodulin.[72] The net result is a shift in balance toward

procoagulation.

Endothelial injury, the other major trigger, can initiate DIC by causing release of tissue factor, promoting platelet aggregation, and activating the intrinsic coagulation pathway. TNF is an

extremely important mediator of endothelial cell inflammation and injury in septic shock. In addition to the effects previously mentioned, TNF up-regulates the expression of adhesion

molecules on endothelial cells and thus favors adhesion of leukocytes, which in turn damage endothelial cells by releasing oxygen-derived free radicals and preformed proteases.[72] Even

subtle endothelial injury can unleash procoagulant activity by enhancing membrane expression of tissue factor. Widespread endothelial injury may be produced by deposition of antigenantibody

complexes (e.g., systemic lupus erythematosus), temperature extremes (e.g., heat stroke, burns), or microorganisms (e.g., meningococci, rickettsiae).

Several disorders associated with DIC are listed in Table 13-10 . Of these, DIC is most likely to follow obstetric complications, malignant neoplasia, sepsis, and major trauma. The

initiating factors in these conditions are often multiple and interrelated. For example, particularly in infections caused by gram-negative bacteria, released endotoxins can activate both the

intrinsic and extrinsic pathways by producing endothelial cell injury and release of thromboplastins from inflammatory cells; furthermore, endotoxins inhibit the anticoagulant activity of

protein C by suppressing thrombomodulin expression on endothelium. Endothelial cell damage can also be produced directly by meningococci, rickettsiae, and viruses. Antigen-antibody

complexes formed during the infection can activate the classical complement pathway, and complement fragments can secondarily activate both platelets and granulocytes. Endotoxins as

well as other bacterial products are also capable of directly activating factor XII. In massive trauma, extensive surgery, and severe burns, the major mechanism of DIC is believed to be the

release of tissue thromboplastins. In obstetric conditions, thromboplastins derived from the placenta, dead retained fetus, or amniotic fluid may enter the circulation. However, hypoxia,

acidosis, and shock, which often coexist with the surgical and obstetric conditions, also cause widespread endothelial injury. Supervening infection can complicate the problems further.

Among cancers, acute promyelocytic leukemia and carcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC. These tumors release of a variety of

thromboplastic substances, including tissue factors, proteolytic enzymes, mucin, and other undefined tumor products.

The consequences of DIC are twofold. First, there is widespread deposition of fibrin within the microcirculation. This can lead to ischemia of the more severely affected or more vulnerable

organs and to a hemolytic anemia resulting from fragmentation of red cells as they squeeze through the narrowed microvasculature (microangiopathic hemolytic anemia). Second, a

hemorrhagic diathesis can dominate the clinical picture. This results from consumption of platelets and clotting factors as well as activation of plasminogen. Plasmin can not only cleave

fibrin, but also digest factors V and VIII, thereby reducing their concentration further. In addition, fibrinolysis leads to the formation of fibrin degradation products, which inhibit platelet

aggregation and fibrin polymerization and have antithrombin activity. All these influences lead to the hemostatic failure seen in DIC ( Fig. 13-29 ).

Morphology.

In general, thrombi are found in the following sites in decreasing order of frequency: brain, heart, lungs, kidneys, adrenals, spleen, and liver. However, no tissue is spared, and thrombi are

occasionally found in only one or several organs without affecting others. In giant hemangiomas, for example, thrombi are localized to the neoplasm, where they are believed to form due

to local stasis and recurrent trauma to fragile blood vessels. The affected kidneys can reveal small thrombi in the glomeruli that may evoke only reactive swelling of endothelial cells or, in

severe cases, microinfarcts or even bilateral renal cortical necrosis. Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated with pulmonary edema and fibrin

exudation, creating "hyaline membranes" reminiscent of acute respiratory distress syndrome ( Chapter 15 ). In the central nervous system, fibrin thrombi can cause microinfarcts,

occasionally complicated by simultaneous hemorrhage. Such changes are the basis for the bizarre neurologic signs and symptoms sometimes observed in DIC. The manifestations of DIC

in the endocrine glands are of considerable interest. In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the likely basis for the massive adrenal

hemorrhages seen in Waterhouse-Friderichsen syndrome ( Chapter 24 ). Similarly, Sheehan postpartum pituitary necrosis ( Chapter 24 ) is a form of DIC complicating labor and delivery.

In toxemia of pregnancy ( Chapter 22 ), the placenta exhibits widespread microthrombi, providing a plausible

Figure 13-29Pathophysiology of disseminated intravascular coagulation.

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