Von Willebrand Disease

Von Willebrand disease (vWD) is a bleeding disorder characterized by a qualitative or quantitative deficiency of von Willebrand factor (vWF). Most cases are hereditary, but acquired forms have been described. Von Willebrand factor is a multimeric protein involved in the plate adhesion phase of hemostasis by forming a bridge between platelets and damaged portions of the vessel wall. Von Willebrand factor also regulates the levels of coagulation factor VIII (FVIII) by acting as its carrier. Clinical features vary depending on the plasma vWF levels. Most cases are asymptomatic, but patients may present with petechiae, gingival bleeding, epistaxis, or menorrhagia. The diagnosis primarily depends on the clinical history and laboratory assays, including quantitative measurement of vWF, vWF ristocetin cofactor activity (vWF:RCo) assay, and FVIII coagulant assay. Management is based on the subtype of the disease. The most common agents used are desmopressin acetate and concentrates containing recombinant vWF and FVIII.

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Overview

Definition

Von Willebrand disease (vWD) is a bleeding disorder caused by deficiency or dysfunction of the von Willebrand factor.

Epidemiology

  • Most common inherited bleeding disorder
  • Affects 1% of the general population
  • Equal prevalence between men and women, but women more likely to be symptomatic 
  • Inherited vWD:
    • Type 1: 60%–80% of cases
    • Type 2: 20%–30% of cases
    • Type 3: < 5% of cases
  • Acquired vWD:
    • The true prevalence is not established.
    • Has been described in 20% of patients with malignancies, with metallic cardiac valves, and on ECMO

Classification and etiology

Table: Classification and etiology of vWD
TypeEtiologyPathologic mechanism
InheritedType 1Autosomal dominant inheritance
  • Partial quantitative deficiency of vWF
  • Caused by mutations that lead to decreased secretion and increased clearance of vWF subunits
Type 2AAutosomal dominant inheritance
  • Qualitative defect (dysfunction)
  • Loss of high- and intermediate-molecular-weight vWF multimers because of increased susceptibility to ADAMTS13 antibodies or decreased multimerization
Type 2BAutosomal dominant inheritance
  • Qualitative defect (dysfunction)
  • Caused by a gain-of-function mutation that results in increased affinity for the platelet GpIb receptor and increased clearance of large vWF multimers along with platelets
Type 2MAutosomal dominant inheritance
  • Qualitative defect (dysfunction)
  • Caused by loss-of-function mutations resulting in decreased interaction with platelet receptors
Type 2NAutosomal recessive inheritance
  • Qualitative defect (dysfunction)
  • Caused by mutations resulting in decreased binding to FVIII
Type 3Autosomal recessive inheritance
  • Quantitative defect
  • Results in undetectable vWF levels
  • Caused by missense or nonsense mutations
AcquiredOccurs secondary to other pathological processesSeveral mechanisms have been proposed:
  • Increased degradation of vWF under high shear stress conditions (e.g., mechanical valves, aortic stenosis, extracorporeal devices)
  • Decreased production of vWF (e.g., hypothyroidism)
  • Immune-complex formation and autoantibodies (e.g., Hashimoto thyroiditis, lupus)
  • Adsorption of vWF into tumor cells (e.g., Wilms tumor, lymphoproliferative disorders)
  • Drug-induced proteolysis of vWF (e.g., ciprofloxacin)
FVIII: blood clotting factor VIII

Pathophysiology

Normal physiology of the von Willebrand factor

  • A glycoprotein produced by platelets and endothelial cells
  • Platelet vWF is stored in α-granules of platelets.
  • Circulating vWF is stored in Weibel-Palade bodies of the endothelium.
  • VWF binds to collagen, the GpIb receptor of platelets, and FVIII.
  • Functions:
    • Prevention of the degradation of FVIII
    • Adhesion of platelets to collagen of the exposed subendothelium
    • Aggregation of platelets (platelet adhesion)

Pathophysiology of VWF

  • Intrinsic pathway coagulation defect: ↓ vWF → ↓ binding to FVIII → ↓ FVIII activity → ↑ PTT
  • Defect in platelet plug formation: ↓ vWF → ↓ binding to platelet GpIb receptor → ↓ platelet-to-platelet and platelet-to-collagen adhesion

Clinical Presentation

Clinical presentation varies and depends on the disease subtype. Presentation is mild or even asymptomatic in type 1, with progressively increasing severity in types 2 and 3.

  • Most patients are asymptomatic.
  • Symptomatic individuals develop:
    • Mucocutaneous bleeding:
      • Gum bleeding
      • Epistaxis
      • Petechiae
      • Recurrent and easy bruising
    • Menorrhagia
    • Excessive bleeding after dental or surgical procedures
    • GI bleeding (usually associated with arteriovenous malformations)
    • Postpartum hemorrhage
    • Hemarthrosis (bleeding within the joint cavity that usually presents with pain, swelling, and a decreased range of motion)
    • Hematomas
    • In the pediatric population:
      • Umbilical stump bleeding
      • Cephalohematomas
      • Cheek hematomas
      • Conjunctival hemorrhage
      • Post-vaccination bleeding
      • Post-circumcision bleeding

Diagnosis

VWD should be suspected in individuals with an increased history of bleeding, positive family history of vWD or increased bleeding, unexplained mild thrombocytopenia, or unexplained mild prolongation of aPTT. Specific vWF and FVIII blood tests are needed to confirm the diagnosis.

History

  • Bleeding history
  • Medications that may increase bleeding time
  • Family history of bleeding or hypocoagulable states

Physical exam

  • Bruises/hematomas
  • Petechiae
  • Hemarthrosis
  • Spontaneous gingival bleeding

Diagnostic testing

  • CBC: Platelets are normal in all types of vWD, except for type 2B.
  • Coagulation profile:
    • ↑ Bleeding time
    • Normal PT
    • Normal or ↑ aPTT
  • VWF antigen (vWF:Ag):
    • Evaluates quantitative defects
    • Decreased in types 1, 2A, 2B, and 3
    • Normal or decreased in type 2M
    • Normal in type 2N
  • VWF activity:
    • Evaluates qualitative defects (dysfunction) 
    • Tested through vWF ristocetin cofactor activity (vWF:RCo) assay:
      • Ristocetin promotes vWF binding to GpIb receptors of platelets.
      • The normal range is 50–200 IU/dL.
    • Decreased in types 1, 2A, 2B, and 3
    • Normal or decreased in type 2M
    • Normal in type 2N
  • FVIII coagulant assay (FVIII:C):
    • Evaluates the ability of vWF to carry FVIII
    • Decreased in types 2N and type 3

Management

Inherited von Willebrand disease

  • Desmopressin acetate:
    • Stimulates the release of vWF from endothelial cells
    • Best initial treatment for mild-to-moderate bleeding
    • Contraindicated in type 2B because it exacerbates thrombocytopenia
    • Not effective in type 3
  • VWF replacement:
    • Considered in cases of severe bleeding
    • Considered when desmopressin acetate is not effective
    • Used as prophylaxis before surgery
  • Oral contraceptives are used in cases of menorrhagia.
  • Antifibrinolytic therapy (e.g., aminocaproic acid, tranexamic acid):
    • Inhibits fibrinolysis by inhibiting the conversion of plasminogen into plasmin
    • Used in mild mucocutaneous bleeding

Acquired von Willebrand disease

  • The most effective approach is to treat the underlying disease.
  • Desmopressin acetate
  • VWF-containing concentrates
  • Recombinant factor VIIa replacement therapy is especially effective in patients with vWF autoantibodies.
  • Intravenous immunoglobulin (IVIG) therapy and plasmapheresis are effective in lymphoproliferative and autoimmune diseases.

Differential Diagnosis

  • Hemophilia A: an X-linked disorder caused by the deficiency of FVIII. Hemophilia A is the most common type of hemophilia. Patients present with hemarthrosis, soft-tissue hematomas, intracranial bleeding, and recurrent bruising. Diagnosis is based on history, physical examination, and evaluation of clotting factor activity. Management includes the replacement of FVIII. Desmopressin acetate may be administered in mild cases.
  • Hemophilia B: an X-linked disorder caused by the deficiency of clotting factor IX. Hemophilia B is also called “Christmas disease.” Patients present with muscular and soft-tissue hematomas, hemarthrosis, GI bleeding, and recurrent bruising. Diagnosis is based on history, physical examination, and laboratory investigations such as coagulation studies and factor IX assay. Treatment includes the administration of recombinant factor IX.
  • Bernard-Soulier disease: a rare autosomal recessive blood clotting disorder caused by mutations in the gene that codes for the GpIb receptor. The defective GpIb receptor results in impaired platelet adhesion. Patients present with purpura, easy bruising, and mucocutaneous bleeding. Diagnosis is based on peripheral smears that show thrombocytopenia and large platelets. No treatment is needed in most cases. Bleeding episodes are treated with antifibrinolytics, platelet transfusions, and desmopressin acetate.
  • Factor X deficiency: an autosomal recessive blood clotting disorder caused by deficiency of the vitamin K-dependent serine protease. Patients present with hemarthrosis, hematomas, and GI and CNS bleeding. Diagnosis is based on history and coagulation studies that demonstrate increased aPTT, PT, and normal bleeding time (BT). The Russell viper venom time is prolonged. Treatment includes fresh frozen plasma or prothrombin complex concentrates, vitamin K supplements, and replacement with recombinant factor X.

References

  1. De Larochellière, H, Puri, R, Eikelboom, JW, & Rodés-Cabau, J. (2019). Blood disorders in patients undergoing transcatheter aortic valve replacement: A review. JACC: Cardiovascular Interventions, 12(1), 1–11. https://doi.org/10.1016/j.jcin.2018.09.041
  2. Franchini, M, & Mannucci, PM. (2020). Acquired von Willebrand syndrome: Focused for hematologists. Haematologica, 105(8), 2032–2037. https://doi.org/10.3324/haematol.2020.255117
  3. James, PD, & Goodeve, AC. (2011). Von Willebrand disease. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 13(5), 365–376. https://doi.org/10.1097/GIM.0b013e3182035931
  4. Sanders, YV, Fijnvandraat, K, Boender, J, Mauser-Bunschoten, EP, van der Bom, JG, de Meris, J, Smiers, FJ, Granzen, B, Brons, P, Tamminga, RY, Cnossen, MH, Leebeek, FW, & WiN Study Group (2015). Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding. American Journal of Hematology, 90(12), 1142–1148. https://doi.org/10.1002/ajh.24195
  5. Rick, ME. (2021). Clinical presentation and diagnosis of von Willebrand disease. UpToDate. Retrieved June 19, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-von-willebrand-disease
  6. Kuter, DJ. (2020). Von Willebrand disease. MSD Manual Professional Version. Retrieved June 19, 2021, from https://www.msdmanuals.com/professional/hematology-and-oncology/thrombocytopenia-and-platelet-dysfunction/von-willebrand-disease

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