Type 1 is the classic and most common variant of von Willebrand disease. It is an autosomal dominant disorder in which the quantity of circulating vWF is reduced. There is also a measurable but clinically insignificant decrease in factor VIII levels.
Type II is divided into several subtypes characterized by the selective loss of high–molecular-weight multimers of vWF. Because these large multimers are the most active form, there is a functional deficiency of vWF. In type IIA, the high-molecular-weight multimers are not synthesized, leading to a true deficiency. In type IIB, abnormal “hyperfunctional” high-molecular-weight multimers are synthesized that are rapidly removed from the circulation. These high-molecular-weight multimers cause spontaneous platelet aggregation (a situation reminiscent of the very-high–molecular-weight multimer aggregates seen in TTP); indeed, some people with type IIB von Willebrand disease have mild chronic thrombocytopenia, presumably resulting from platelet consumption.
Hemophilia A is the most common hereditary cause of serious bleeding. It is an X-linked recessive disorder caused by reduced factor VIII activity. It primarily affects males. Much less commonly, excessive bleeding occurs in heterozygous females, presumably due to preferential inactivation of the X chromosome carrying the normal factor VIII gene (unfavorable lyonization). Approximately 30% of cases are caused by new mutations; in the remainder, there is a positive family history. Severe hemophilia A is observed in people with marked deficiencies of factor VIII (activity levels < 1% of normal). Milder deficiencies may only become apparent in the face of trauma or other hemostatic stressses. The varying degrees of factor VIII deficiency are explained by the existence of many different causative mutations, including deletions, inversions, and splice junction mutations. In about 10% of patients, the factor VIII concentration is normal by immunoassay, but the coagulant activity is low because of a mutation in factor VIII that causes a loss of function.
In symptomatic cases there is a tendency toward easy bruising and massive hemorrhage after trauma or operative procedures. In addition, “spontaneous” hemorrhages frequently are encountered in tissues that normally are subject to mechanical stress, particularly the joints, where recurrent bleeds (hemarthroses) lead to progressive deformities that can be crippling. Petechiae are characteristically absent. Specific assays for factor VIII are used to confirm the diagnosis of hemophilia A. Typically, patients with hemophilia A have a prolonged PTT that is corrected by mixing the patient’s plasma with normal plasma. Specific factor assays are then used to confirm the deficiency of factor VIII. In approximately 15% of those with severe hemophilia A, replacement therapy is complicated by the development of neutralizing antibodies against factor VIII, probably because factor VIII is seen by the immune system as a “foreign” antigen. In these persons, the PTT fails to correct in mixing studies.
Hemophilia A is treated with factor VIII infusions. Historically, factor VIII was prepared from human plasma, carrying with it the risk of transmission of viral diseases. As mentioned in Chapter 5, before 1985 thousands of hemophiliacs received factor VIII preparations contaminated with HIV and subsequently developed AIDS. The availability and widespread use of recombinant factor VIII and more highly purified factor VIII concentrates have now eliminated the infectious risk of factor VIII replacement therapy.
Severe factor IX deficiency is an X-linked disorder that is indistinguishable clinically from hemophilia A but is much less common. The PTT is prolonged. The diagnosis is made using specific assays of factor IX. It is treated by infusion of recombinant factor IX.
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Canbedominatedbybleeding,vascularocclusionandtissuehypoxemia,orboth
Commontriggers:sepsis,majortrauma,certaincancers,obstetriccomplications
Maybetriggeredbydrugs,infections,orlymphomas,ormaybeidiopathic