von Willebrand Disease

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Chapter 471 von Willebrand Disease

Robert R. Montgomery, J. Paul Scott

The most common hereditary bleeding disorder is von Willebrand disease (VWD), and some reports suggest that it is present in 1-2% of the general population. VWD is inherited autosomally, but most centers report more affected women than men. Because menorrhagia is a major symptom, women may be more likely to seek treatment and thus to be diagnosed. VWD is classified on the basis of whether the protein is quantitatively reduced, but not absent (type 1); qualitatively abnormal (type 2); or absent (type 3) (Fig. 471-1). Mutations in different loci that code for different functional domains of the von Willebrand factor (VWF) protein cause the different variants of VWD.

Figure 471-1 Common variants of von Willebrand disease (VWD) and other related disorders. Laboratory testing is listed on the left, and the results most commonly identified in patients with these conditions are shown. A graphic representation of von Willebrand factor (VWF) multimers is shown at the bottom of each column. A lighter shade illustrates a reduction in staining intensity, and figure length represents the relative size of the multimers. BSS, Bernard-Soulier syndrome; BT, bleeding time; DDAVP, desmopressin; FVIII, factor VIII; N, normal; PFA, platelet function analyzer; LD-RIPA, ristocetin induced platelet aggregation to low dose ristocetin; PT-VWD, platelet-type pseudo-VWD; RIPA, ristocetin reduced platelet aggregation to standard dose ristocetin; Tx, treatment; VWF:Ag, von Willebrand antigen; VWF:RCo, ristocetin cofactor activity; VWF conc, VWF concentrate; ↑, degree of increase; ↓, degree of decrease.

Pathophysiology

A large multimeric glycoprotein that is synthesized in megakaryocytes and endothelial cells, VWF is stored in platelet α-granules and endothelial cell Weibel-Palade bodies. The highest molecular weight multimers of VWF are responsible for the normal interaction of VWF with the subendothelial matrix and platelets. During normal hemostasis, VWF adheres to the subendothelial matrix after vascular damage. When VWF binds to the subendothelial matrix, the conformation of VWF is altered by shear so that it causes platelets to adhere to VWF through their glycoprotein IB (GPIb) receptor. These platelets are then activated, causing the recruitment of additional platelets and exposing platelet membrane phosphatidylserine, which is an important regulatory step for factor V– and factor VIII–dependent steps in the clotting cascade. VWF also serves as the carrier protein for plasma factor VIII. A severe deficiency of VWF causes a secondary deficiency in factor VIII, even though the gene for factor VIII is normal, explaining autosomal deficiency of factor VIII, now known to be a molecular abnormality of VWF and known as type 2N VWD.

Clinical Manifestations

Patients with VWD usually have symptoms of mucocutaneous hemorrhage, including excessive bruising, epistaxis, menorrhagia, and postoperative hemorrhage, particularly after mucosal surgery, such as tonsillectomy or wisdom tooth extraction. Because a teenager’s menstrual history is usually put in the context of other family members, excessive menstrual bleeding is not always recognized as being abnormal, because others in the family may be affected with the same disorder. If a menstruating female has iron deficiency, a detailed history of bruising and other bleeding symptoms should be elicited and further hemostatic evaluation undertaken.

Because VWF is an acute-phase protein, stress will increase its level. Thus, patients may not bleed with procedures that incur major stress, such as appendectomy and childbirth, but may bleed excessively at the time of cosmetic or mucosal surgery. Bruising symptoms may diminish during pregnancy, because VWF levels may physiologically double or triple as an acute phase response. Rarely, patients with VWD may have gastrointestinal telangiectasia. This combination results in major bleeding and accounts for numerous hospital admissions for patients with severe disease. In patients with type 3, or homozygous, VWD, bleeding symptoms are much more profound. These patients are usually diagnosed early in life and may have severe epistaxis or menorrhagia that results in major blood loss and possibly shock. Patients with severe type 3 VWD may have joint hemorrhages or spontaneous central nervous system hemorrhages.

Laboratory Findings

Although patients with VWD were described historically as having a long bleeding time and a long partial thromboplastin time, these findings are frequently normal in patients with type 1 VWD. Normal results on screening tests do not preclude the diagnosis of VWD. Because there is no single assay that has demonstrated the ability to rule out VWD, if the history is suggestive of a mucocutaneous bleeding disorder, VWD testing should be undertaken, including a quantitative assay for VWF antigen, testing for VWF activity (ristocetin cofactor activity), testing for plasma factor VIII activity, determination of VWF structure (VWF multimers), and a platelet count. Although the platelet count is usually normal in most patients, those with type 2B disease or platelet-type disease (pseudo-VWD) may have lifelong thrombocytopenia. Figure 471-1

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