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Normal Blood Coagulation
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Coagulation represents the method of permanent healing of a vascular injury. It follows vasoconstriction and formation of the platelet plug and maintains hemostasis when normal blood flow is restored. Coagulation is achieved by the interaction of several plasma protein factors (Table 27-5) that ultimately results in formation of fibrin when they are activated sequentially (Figure 27-2).
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Disorders of Blood Coagulation
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There are three principal groups of coagulation disorders.
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Deficiency of Coagulation Factors
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Deficiencies of individual coagulation factors may occur as inherited diseases (Table 27-6). Of these, factor VIII deficiency (hemophilia A and von Willebrand's disease) and factor IX deficiency (Christmas disease) are the most common. Acquired deficiencies of coagulation factors occur in severe liver disease (affects all factors produced by the liver) and in vitamin K deficiency (prothrombin and factors VII, IX, and X).
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Presence of Circulating Anticoagulants
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Factor deficiencies may also be induced by anticoagulant therapy with coumarin derivatives (which interfere with vitamin K, thereby inhibiting synthesis of prothrombin and of factors VII, IX, and X). Directly acting anticoagulants that antagonize some of the coagulation cascade include (a) drugs such as heparin (an antithrombin), (b) antibodies (factor VIII inhibitor and lupus anticoagulant, an antibody in systemic lupus erythematosus), and (c) natural anticoagulants (antithrombin and fibrin degradation products).
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Fibrinolytic Activity
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Increased fibrinolytic activity in the blood results from increased activation of the plasmin system.
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Patients with disorders of coagulation tend to bleed excessively following minor trauma such as dentistry. In severe cases, spontaneous bleeding occurs (ie, bleeding without evident trauma)—commonly into joints (hemarthrosis) and muscles. Bleeding is usually slow but persistent and can be halted by replacement of the deficient factor.
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All coagulation disorders have similar clinical manifestations. Determination of the cause of the abnormality requires bleeding and coagulation testing (Figure 27-3 and Tables 27-7 and 27-8).
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Factor VIII Deficiency
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Factor VIII circulates as a covalently linked complex of two distinct molecules (Figure 27-4): (1) Factor VIII coagulant (VIII:c) is a critical component of the intrinsic coagulation pathway (Figure 27-3) and is also known as antihemophilic globulin (deficiency produces hemophilia A). Factor VIII:C is measured by bioassay or by immunoassay (factor VIII:c antigen). (2) Factor VIII von Willebrand factor (VIII:vWF) is by much the larger part of the factor VIII complex. Factor VIII:vWF serves two functions. First, it plays a critical role in platelet aggregation. Second, it enhances factor VIII:C activity at the site of injury and serves as a carrier of circulating VIII:c. Deficiency of factor VIII:vWF produces von Willebrand's disease. Factor VIII:vWF is measured by a function assay (ristocetin test) or by an immunoassay (factor VIII: related antigen; VIII:R Ag).
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Hemophilia A (classic hemophilia) is inherited as an X-linked recessive trait, occurring mainly in males. Females develop hemophilia only when they have the abnormal gene on both X chromosomes (homozygous)—a rare event that occurs when a hemophiliac male mates with a carrier female or when a single functional X chromosome carries the abnormal gene. The incidence in the United States is 1:10,000 males. Hemophilia occurs throughout the world.
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The presence of the abnormal gene results in deficient synthesis of the coagulant subunit of the factor VIII molecule (VIII:C, Figure 27-4). Factor VIII-related antigen (factor VIII-von Willebrand factor) continues to be present in normal amounts.
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The heterozygous female carrier shows a mild decrease in plasma level of the coagulant subunit of factor VIII (VIII:C). Because factor VIII-related antigen level (VIII:RAg) is normal, the ratio of VIII:C to VIII:RAg is less than 0.75 (normal, 1). Observation of a reduced VIII:C to VIII:RAg ratio is a reliable means of detecting heterozygous carriers of the abnormal hemophilia A gene.
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Pathology & Clinical Features
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Patients with severe hemophilia have less than 1% of factor VIII coagulant activity and bleed spontaneously. Moderately affected patients (1–5% activity) bleed excessively after minor trauma, and mild cases (5–25% activity) are usually asymptomatic. The cause of the variable expression of disease in different patients is not well understood.
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Spontaneous bleeding (probably caused by minimal trauma resulting from normal activity) occurs into subcutaneous tissues, skeletal muscle, joints, and mucous membranes. Intracranial hemorrhage is rare but is a major cause of death. Hemorrhage into muscle and joints occurs mainly in the extremities and is followed by organization and fibrosis leading to contractures in affected muscles and to stiffness of joints.
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Bleeding after dental surgery is typical. The bleeding is not dramatic but consists of a slow and persistent ooze lasting many days. Oozing commonly begins several hours after surgery and not in the immediate postoperative period.
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Acquired immune deficiency syndrome (AIDS) is a major complication in some patient populations due to the presence of human immunodefiency virus (HIV) in factor VIII concentrate.
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Diagnosis & Treatment
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The partial thromboplastin time is prolonged in almost all patients, and there is a significant decrease in factor VIII coagulant activity (to less than 20% of normal). Factor VIII-related antigen is normal, and the VIII:C to VIII:RAg ratio is markedly decreased. Prothrombin time and bleeding time are normal, indicating that the defect is in the intrinsic pathway. Assays for factor VIII coagulant activity and factor VIII-related antigen are diagnostic and reflect the severity of the disease.
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Treatment of hemophilia consists of maintaining plasma factor VIII coagulant activity at a level that permits normal physical activity without bleeding. This may require prophylactic treatment in severe cases. Factor VIII.C is labile and must be provided as fresh plasma, or in concentrated form as cryoprecipitate or as lyophilized factor VIII concentrate. The availability of cryoprecipitate and lyophilized factor VIII concentrate has markedly improved the outlook for patients with hemophilia. Treatment with synthetic vasopressin analogues has been shown to produce elevation of factor VIII levels, producing benefit in mild cases.
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Cryoprecipitate is prepared in blood banks from fresh individual plasma units. Lyophilized factor VIII concentrate is made from pooled plasma obtained from a large number of blood donors. As with all such blood components prepared from multiple donors, administration of factor VIII concentrate greatly increases the risk of infections such as hepatitis B, cytomegalovirus infection, and, more recently, HIV. Consequently, hemophiliacs represent a high-risk group for AIDS, and many have developed overt disease. Factor VIII concentrate is now heat-treated, a procedure believed to eliminate these risks.
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Von Willebrand's Disease
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Von Willebrand's disease is inherited as an autosomal dominant trait characterized by deficiency of the entire circulating factor VIII complex (Figure 27-4). Factor VIII coagulant activity and the von Willebrand factor (factor VIII-related antigen) are decreased to the same extent, so that the ratio of these two components is normal. Variants exist in which factor VIII:C is near normal.
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Clinically, patients show bleeding after minor trauma. The onset of symptoms is in childhood and may decrease with age. The most common sites of bleeding are the skin (easy bruising) and mucous membranes (epistaxis). Hemarthrosis, muscle hemorrhage, and intracranial hemorrhage are uncommon.
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The diagnosis is made by demonstrating (1) prolonged partial thromboplastin time with normal prothrombin time, (2) decreased factor VIII coagulant activity and Von Willebrand factor (factor VIII-related antigen), and (3) prolonged bleeding time due to platelet dysfunction (Table 27-8). In vitro, there is decreased platelet aggregation after addition of the antibiotic ristocetin, and the ristocetin test is useful for the diagnosis of Von Willebrand's disease. Von Willebrand factor is present in cryoprecipitate, which can therefore be used in treating von Willebrand's disease.
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Factor IX Deficiency (Christmas Disease; Hemophilia B)
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Christmas disease is uncommon, with an incidence of 1:50,000 population, and results from a deficiency of factor IX.
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Christmas disease is characterized by X-linked recessive inheritance, greater prevalence in males, and a clinical picture identical to that of hemophilia A. The diagnosis is made when factor VIII coagulant activity is normal in a patient with symptoms of hemophilia. Plasma factor IX assay shows greatly decreased levels and is diagnostic. Treatment is with fresh plasma or factor IX concentrate; factor IX is not present in cryoprecipitate.
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Disseminated Intravascular Coagulation & Fibrinolysis
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Disseminated intravascular coagulation (DIC) is an important cause of bleeding that is due to consumption of platelets and several clotting factors during widespread thrombosis in the microcirculation (consumption coagulopathy). DIC and fibrinolysis are discussed in Chapter 9: Abnormalities of Blood Supply.