About the Condition

Description/definition:

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder caused by a reduced concentration and/or function of von Willebrand factor (vWF) that is not directly inherited, but rather is a consequence of other medical disorders. AVWS is rare. It comprises 1-5% of all cases of von Willebrand disease (VWD).

Classification of VWD

1. Congenital vs. acquired:

Congenital:

  • Type 1 – quantitative decrease in vWF
  • Type 2 – qualitative decrease in vWF
  • Type 3 – complete absence of vWF

Acquired:

  • Majority of AVWS cases are type 1 or type 2A.

2. Classification according to the underlying medical condition:

Most common:

  • Lymphoproliferative disorders:
    • Waldenstrom’s macroglobulinemia
    • Lymphoma
  • Myeloproliferative neoplasms:
    • Essential thrombocythemia
    • Polycythemia vera
  • Plasma cell dyscrasias:
    • Multiple myeloma
    • Monoclonal gammopathy of unknown significance (MGUS)
  • Cardiac conditions:
    • Aortic stenosis
    • Congenital cardia defects
    • Left ventricular devices (LVAD)
    • Extracorporeal membrane oxygenation (ECMO)

Less common:

  • Autoimmune disorders, especially systemic lupus erythematosus
  • Wilms tumor
  • Hypothyroidism
  • Medications:
    • Ciprofloxacin
    • Griseofulvin
    • Valproic acid

3. Classification according to underlying mechanism:

  • Autoimmune clearance or inhibition of vWF
  • Increased shear-induced proteolysis of vWF
  • Increased binding of vWF to platelets or other cell surfaces
  • Decreased synthesis of vWF

Pathophysiology:

Various mechanisms are implicated in the pathophysiology of AVWS, the majority of them leading to increased degradation or clearance of circulating vWF.

Mechanisms of reduced vWF in AVWS include:

  • Immune -mediated:
    • Antibody-mediated clearance of vWF
    • Antibody-mediated inhibition of vWF
  • Shear stress-induced proteolysis:
    • High shear stress results in unfolding of vWF, thereby increasing its susceptibility to proteolysis by ADAMTS-13.
  • Adsorption onto platelets or tumor cells:
    • An inverse relationship exists between the platelet count and vWF multimer size, probably because increased interactions with platelets promote increased cleavage of vWF by ADAMTS13.
  • Decreased vWF synthesis
Cause of AVWSMechanism of reduced vWF antigen/activity
Aortic stenosisElevated shear stress around stenotic valve
Congenital heart defectsElevated shear stress around a septal
defect
Hypertrophic obstructive cardiomyopathyShear forces
ECMO/LVADShear forces
Myeloproliferative neoplasmsIncreased binding of vWF to platelets, especially high molecular weight multimers
Lymphoproliferative disordersAntibody-mediated clearance of vWF or inhibition of vWF function
MGUSAntibody-mediated clearance of vWF or inhibition of vWF function
Autoimmune disordersAntibody-mediated clearance of vWF or inhibition of vWF function
MedicationsMultiple mechanisms including decreased production of vWF
HypothyroidismDecreased production of vWF
Solid tumorAdsorption of vWF on malignant cells
ECMO, extracorporeal membrane oxygenation; LVAD, left ventricular device; vWF, von Willebrand factor; MGUS, monoclonal gammopathy of unknown significance

Diagnosis:

Consider diagnosis of AVWS in a patient with:

  • Bleeding and laboratory results suggesting abnormal vWF activity.
  • Underlying disease known to cause AVWS.
  • Negative family history of bleeding diathesis.

Laboratory values supporting a diagnosis of AVWS include:

  • Reduced von Willebrand factor antigen (vWF:Ag).
  • Reduced von Willebrand factor ristocetin cofactor (vWF:RCo), often disproportionately low relative to vWF:Ag.
  • Reduced FVIII levels.

Additional supporting labs include:

  • Decreased von Willebrand factor collagen binding (vWF:CB).
  • Reduced VWF:CB/Ag ratio.
  • Abnormal multimer pattern – decreased high molecular weight multimers found in one-third or more of patients with AVWS.
  • vWF propeptide.

Note: Antibodies to vWF have been detected in <20% of patients in whom they have been sought. Results of testing for autoantibodies to vWF using mixing studies are often negative, even if such an antibody exists.

Lab profile of AVWS

ParameterType 1 AVWSType 2 AVWS
vWF:AgLowLow, normal or high
vWF:RCoLow in proportion to vWF:AgLow, out of proportion to vWF:Ag
vWF multimersNormal distributionReduced or absent high molecular weight multimers
AVSW, acquired von Willebrand syndrome; vWF, von Willebrand factor; Ag, antigen; RCo, ristocetin cofactor

Distinguishing between AVWS and congenital VWD

AVWSCongenital VWD
Family history of VWD or bleedingNoYes
History of underlying medical condition associated with AVWSYesNo
Typical age of diagnosisLater (median age at diagnosis is 62 years)Earlier
Relative prevalence1-5%95-99%
Mutation in vWF geneNoYes
AVWS, acquired von Willebrand syndrome; VWD, von Willebrand disease; vWF, von Willebrand factor

Treatment:

General principles of management:

  • Treat active bleeding.
  • Treat underlying condition.

Treatment of active bleeding:

  • vWF/FVIII concentrates:
    • Rapid onset
    • Short duration of effect
    • vWF:RCo and FVIII levels should be measured pre- and postinfusion to determine the extent and duration of response and to guide subsequent dosage and dosing intervals.
  • Desmopressin (DDAVP):
    • Rapid onset
    • Short duration of effect
    • DDAVP response less common than in hereditary VWD.
    • DDAVP reported to produce clinical and laboratory improvement in one-third of cases, although this effect is often short lived.
    • vWF:RCo and FVIII levels should be measured pre- and postinfusion of DDAVP.
  • Intravenous immunoglobulin (IVIG):
    • May be helpful in cases of AVWS associated with MGUS, Waldenstrom’s macroglobulinemia, and autoimmune disorders.
    • Takes 24-48 hours before FVIII and VWF levels start to rise.
    • Effect may last for 2-4 weeks.
    • Useful in cases of scheduled surgery.
    • Off-label use but should be considered when DDAVP and VWF/FVIII concentrate therapy fail to control bleeding symptoms adequately.
    • In the international registry series, one-third of the 63 patients (with presumed immune-mediated AVWS, including those with MGUS) treated with high-dose IVIG had a good response (source).
    • Can be used to increase the half life of VWF/FVIII concentrates.
  • Antifibrinolytics – adjunctive therapy for bleeding refractory to other treatments.
  • Recombinant FVIIa – only when all other therapeutic modalities fail to control bleeding adequately.

Treatment of underlying conditions:

  • Lymphoproliferative disorders – B-cell-directed therapy.
  • Cardiac causes:
    • Patients who have aortic stenosis or other cardiac valvular disorders infrequently responded to any of the therapies described above.
    • Surgical correction may result in normalization of vWF multimer pattern.
  • Myeloproliferative neoplasms – reduction of the platelet count can restore a normal vWF multimer distribution.
  • Hypothyroidism – the decrease in VWF is corrected by thyroid hormone replacement.