Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 14-08: Congenital Disorders of Coagulation + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ The most common inherited bleeding disorder von Willebrand factor (vWF) binds platelets to subendothelial surfaces, aggregates platelets, and prolongs the half-life of factor VIII +++ General Considerations ++ vWF is an unusually large multimeric glycoprotein that binds to subendothelial collagen and its platelet receptor, glycoprotein Ib, bridging platelets to the subendothelial matrix at the site of vascular injury, and contributing to linking them together in the platelet plug vWF also has a binding site for factor VIII, prolonging its half-life in the circulation Type 1 von Willebrand disease (vWD) Seen in 75–80% of patients with vWD It is a quantitative abnormality of the vWF molecule that usually does not feature an identifiable causal mutation in the vWF gene Type 2 vWD Seen in 15–20% of patients with vWD In type 2A or 2B, a qualitative defect in the vWF molecule is causative Types 2N and 2M are due to defects in vWF that decrease binding to factor VIII or to platelets, respectively; importantly, type 2N can clinically resemble hemophilia A because factor VIII activity levels are decreased and vWF activity and antigen (Ag) are normal Type 2M features a normal multimer pattern Type 3 vWD Rare Quantitative defect Mutational homozygosity or compound heterozygosity yielding very low levels of vWF Due to its factor VIII carrier function, a severely low vWF level leads to low factor VIII activity and prolonged aPTT +++ Demographics ++ Common disorder affecting both men and women + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Type 1 vWD: patients usually have mild or moderate platelet-type bleeding (mucocutaneous) Type 2 vWD: patients usually have moderate to severe bleeding that presents in childhood or adolescence Type 3 vWD: patients have severe bleeding in infancy or childhood +++ Differential Diagnosis ++ Other qualitative platelet disorders, eg, uremia, aspirin use, Glanzmann thrombasthenia Thrombocytopenia Hemophilia Waldenström macroglobulinemia + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ See Table 14–9 In type 1 vWD, the vWF activity (by ristocetin co-factor assay) and the vWF Ag are mildly depressed, whereas the vWF multimer pattern is normal In type 2A or 2B vWD, the ratio of vWF Ag:vWF activity is typically approximately 2:1 and there is a multimer pattern that lacks the highest molecular weight multimers In type 2B vWD, thrombocytopenia is common due to a gain-of-function mutation of the vWF molecule; a ristocetin-induced platelet aggregation (RIPA) study shows an increase in platelet aggregation in response to low concentrations of ristocetin aPTT and PT are most commonly normal, except in the more severe forms of vWD that feature a significantly decreased factor VIII activity ++Table Graphic Jump LocationTable 14–9.Laboratory diagnosis of von Willebrand disease.View Table||Download (.pdf) Table 14–9. Laboratory diagnosis of von Willebrand disease. Type vWF Activity vWF Antigen Factor VIII RIPA Multimer Analysis 1 ↓ ↓ Nl or ↓ ↓ Normal pattern; uniform ↓ intensity of bands 2 A ↓↓ ↓ ↓ ↓ Large and intermediate multimers decreased or absent B ↓↓ ↓ ↓ ↑ Large multimers decreased or absent M ↓ ↓ ↓ ↓ Normal pattern; uniform ↓ intensity of bands N Nl Nl ↓↓ Nl Nl 3 ↓↓↓ ↓↓↓ ↓↓↓ ↓↓↓ Multimers absent Nl, normal; RIPA, ristocetin-induced platelet aggregation; vWF, von Willebrand factor. + Treatment Download Section PDF Listen +++ +++ Medications ++ See Table 14–8 DDAVP Useful in the treatment of mild bleeding in most cases of type 1 and some cases of type 2 vWD Causes release of vWF and factor VIII from storage sites (endothelial cells), leading to a twofold to sevenfold increase in vWF and factor VIII A therapeutic trial to document sufficient vWF levels posttreatment is critical Due to tachyphylaxis and the risk of significant hyponatremia secondary to fluid retention, DDAVP is limited to one dose/24 hours and no more than three doses over 5 days Intermediate-purity vWF-containing factor VIII concentrates are used in all other clinical scenarios and when bleeding is not controlled with DDAVP Cryoprecipitate should not be given due to lack of viral inactivation Antifibrinolytic agents (eg, aminocaproic acid or tranexamic acid) may be used adjunctively for mucosal bleeding or procedures Pregnant patients with type 1 vWD Usually do not require treatment at the time of delivery because of the natural physiologic increase in vWF levels (up to threefold that of baseline) that are observed by parturition However, levels need to be confirmed in late pregnancy, and if low or if excessive bleeding is encountered, vWF products may be given Patients are at risk for significant bleeding 1–2 weeks postpartum when vWF levels fall secondary to the fall in estrogen levels ++Table Graphic Jump LocationTable 14–8.Treatment of bleeding in selected inherited disorders of hemostasis.View Table||Download (.pdf) Table 14–8. Treatment of bleeding in selected inherited disorders of hemostasis. Disorder Subtype Treatment for Minor Bleeding Treatment for Major Bleeding Comment Hemophilia A Mild DDAVP1 DDAVP1 or factor VIII product Treat for 3–10 days for major bleeding or following surgery, keeping factor activity level 50–80% initially. Adjunctive aminocaproic acid (EACA) may be useful for mucosal bleeding or procedures Moderate or severe Factor VIII product Factor VIII product Hemophilia B Mild, moderate, or severe Factor IX product Factor IX product von Willebrand disease Type 1 DDAVP1 DDAVP1, vWF product Type 2 DDAVP,1 vWF product vWF product Type 3 vWF product vWF product Factor XI deficiency — FFP or EACA FFP Adjunctive EACA should be used for mucosal bleeding or procedures 1Mild hemophilia A and type 2A or 2B vWD patients: therapeutic trial must have previously confirmed an adequate response (ie, elevation of factor VIII or vWF activity level into the normal range) and (for type 2B) no exacerbation of thrombocytopenia. DDAVP is not typically effective for type 2M vWD. A vWF-containing factor VIII concentrate is preferred for treatment of type 2N vWD.Notes: DDAVP dose is 0.3 mcg/kg intravenously in 50 mL saline over 20 minutes, or nasal spray 300 mcg for weight > 50 kg or 150 mcg for < 50 kg, every 24 hours, maximum of three doses in a 72-hour period. If more than two doses are used in a 48-hour period, free water restriction and monitoring for hyponatremia is essential. EACA dose is 50 mg/kg orally four times daily for 3–5 days; maximum 24 g/day, useful for mucosal bleeding/dental procedures. Factor VIII product dose is 50 units/kg for severe hemophilia A intravenously initially followed by 25 units/kg every 8 hours followed by lesser doses at longer intervals once hemostasis has been established. Factor IX product dose is 100 units/kg (120 units/kg if using Benefix) intravenously initially for severe hemophilia B followed by 50 units/kg (60 units/kg if using Benefix) every 8 hours followed by lesser doses at longer intervals once hemostasis has been established. vWF-containing factor VIII product dose is 60–80 RCoF units/kg intravenously every 12 hours initially followed by lesser doses at longer intervals once hemostasis has been established. FFP is typically administered in 4-unit boluses and may not need to be re-bolused after the initial administration due to the long half-life of factor XI.DDAVP, desmopressin acetate; EACA, epsilon-aminocaproic acid; FFP, fresh frozen plasma; vWF, von Willebrand factor. + Outcome Download Section PDF Listen +++ +++ Prognosis ++ Prognosis is excellent In most cases, bleeding disorder is mild In more serious cases, replacement therapy is effective + References Download Section PDF Listen +++ + +De Jong A et al. Developments in the diagnostic procedures for von Willebrand disease. J Thromb Haemost. 2016 Mar;14(3):449–60. [PubMed: 26714181] + +Kouides PA. Present day management of inherited bleeding disorders in pregnancy. Expert Rev Hematol. 2016 Oct;9(10):987–95. [PubMed: 27459638] + +Sharma R et al. Advances in the diagnosis and treatment of Von Willebrand disease. Blood. 2017 Nov 30;130(22):2386–91. [PubMed: 29187375]