Nr

Abbreviations: AD, autosomal dominant; N, normal; vWF: Ag, von Willebrand factor antigen (FVIII-related antigen); RIPA, ristocetin-induced platelet aggregation; RIPA-LD, low-dose RIPA; NR, no response.

aCauses platelet aggregation.

Abbreviations: AD, autosomal dominant; N, normal; vWF: Ag, von Willebrand factor antigen (FVIII-related antigen); RIPA, ristocetin-induced platelet aggregation; RIPA-LD, low-dose RIPA; NR, no response.

aCauses platelet aggregation.

type 2M vWD

Fig. 11-7. Protein structure of vWF and its large propolypeptide, von Willebrand antigen II (vW AgIl). Domains of the vWF molecule have high degrees of similarity, and various protein interactions have been localized to specific regions such as the interaction with platelet glycoprotein lb or glycoprotein llb/llla. This latter site may be related to an Arg-Gly-Asp-Ser (RGDS) sequence located in the C1 domain. The lower portion of this figure represents the clusters of complementary DNA mutations that cause some of the variants of von Willebrand disease, including types 2A, 2B, 2M, and 2N, as well as the less common variants that prevent propolypeptide cleavage (hereditary persistence of pro-vWF [HPP-vWF]) or a variant that prevents N-terminal multimerization (type 2-md). (From Montgomery RR, Gill JC, Scott JP. Hemophilia and von Willebrand disease. ln: Nathan DG, Orkin SH, editors. Nathan and Oski's Hematology of lnfancy and Childhood. 5th ed. Philadelphia: WB Saunders, 1998;1631-75, with permission.)

type 2M vWD

Fig. 11-7. Protein structure of vWF and its large propolypeptide, von Willebrand antigen II (vW AgIl). Domains of the vWF molecule have high degrees of similarity, and various protein interactions have been localized to specific regions such as the interaction with platelet glycoprotein lb or glycoprotein llb/llla. This latter site may be related to an Arg-Gly-Asp-Ser (RGDS) sequence located in the C1 domain. The lower portion of this figure represents the clusters of complementary DNA mutations that cause some of the variants of von Willebrand disease, including types 2A, 2B, 2M, and 2N, as well as the less common variants that prevent propolypeptide cleavage (hereditary persistence of pro-vWF [HPP-vWF]) or a variant that prevents N-terminal multimerization (type 2-md). (From Montgomery RR, Gill JC, Scott JP. Hemophilia and von Willebrand disease. ln: Nathan DG, Orkin SH, editors. Nathan and Oski's Hematology of lnfancy and Childhood. 5th ed. Philadelphia: WB Saunders, 1998;1631-75, with permission.)

vWD FVIII levels increase following DDAVP infusion but the released FVIII circulates only for a short time because of impaired binding to vWF. For the same reason the half-life of infused high-purity factor VIII is markedly shortened. For major bleeding or surgery, the recommended treatment is a factor VIII concentrate containing high levels of vWF.

Type 2M vWD

Type 2M vWD results from an abnormal binding site on vWF for platelet GP Ib, resulting in reduced ristocetin cofactor (R:Co) activity (functional defect). In this variant multimers of all sizes are present. The vWF protein is released by DDAVP so that patients heterozygous for this variant may respond clinically to standard doses of DDAVP. For homozygotes the vWF released by DDAVP is defective and a poor clinical response occurs. Major bleeding episodes or surgery should be managed with vWF replacement therapy.

Type 3 vWD

This vWD variant occurs in patients with homozygous or doubly heterozygous null mutations or deletions. The clinical phenotype is a severe bleeding disorder with major deficits in both primary and secondary hemostasis. The plasma level of FVIII and vWF is virtually undetectable. Patients are unresponsive to DDAVP (no releasable vWF stores) and require episodic treatment with vWF containing FVIII concentrates. Alloantibodies that inactivate von Willebrand factor develop in 10-15%

Table 11-20. Recommended Treatment in von Willebrand Disease

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