What are the causes, clinical presentation, laboratory findings, and management of acquired von Willebrand disease in adults?

Acquired von Willebrand Syndrome

Suspect acquired von Willebrand syndrome (AVWS) in any adult presenting with new-onset mucocutaneous bleeding without personal or family bleeding history, particularly if they have lymphoproliferative disorders, monoclonal gammopathies, autoimmune diseases, or cardiovascular conditions. 1

Causes and Underlying Mechanisms

AVWS develops through several distinct pathophysiologic mechanisms that differ from hereditary disease:

Primary Associated Conditions

• Lymphoproliferative disorders and monoclonal gammopathies are the most common associations 2, 3, 4
• Myeloproliferative disorders 3, 5
• Autoimmune diseases 2, 4
• Cardiovascular disorders, particularly those requiring mechanical circulatory support 4, 5
• Hypothyroidism 2, 6
• Certain medications 2

Pathophysiologic Mechanisms

The syndrome develops through three main mechanisms:

• Autoantibody formation: Circulating antibodies bind to high molecular weight multimers (HMWM) of von Willebrand factor, forming immune complexes that are cleared by the reticuloendothelial system or adsorbed onto tumor cells 2
• Tumor cell adsorption: Direct binding of vWF to malignant cells, particularly in lymphoproliferative disorders 2, 3
• Nonimmunologic destruction: Mechanical shearing of vWF multimers, especially in cardiovascular disease and ECMO 7, 3

Clinical Presentation

Bleeding Pattern

Patients present with predominantly mucocutaneous bleeding including 1, 3, 4:

• Easy bruising and ecchymoses
• Epistaxis (nosebleeds)
• Gingival bleeding
• Gastrointestinal bleeding
• Heavy menstrual bleeding in women
• Bleeding following surgery or invasive procedures

Key Distinguishing Features from Hereditary VWD

• New-onset bleeding in previously hemostatically normal individuals 6, 3
• Older age at presentation (typically elderly patients) 3, 5
• Absence of personal and family bleeding history 1, 3
• Presence of underlying associated condition 1

Physical Examination Findings

Look specifically for 1:

• Ecchymoses, hematomas, petechiae
• Evidence of liver disease (jaundice, splenomegaly)
• Signs of lymphoproliferative disorders (lymphadenopathy)
• Telangiectasia
• Signs of anemia
• Joint and skin laxity suggesting connective tissue disorders

Laboratory Findings

Initial Screening Tests

Order the following initial hemostasis panel 1, 8:

• Complete blood count (CBC) with platelet count
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)

Critical caveat: PT and aPTT alone will miss VWD entirely and should never be relied upon to exclude bleeding disorders 8

Specific VWD Assays

When clinical suspicion exists, order these three tests simultaneously 1, 8:

• VWF antigen (VWF:Ag): Measures total vWF protein
• VWF ristocetin cofactor activity (VWF:RCo): Measures functional activity
• Factor VIII coagulant activity (FVIII): Often decreased due to loss of vWF carrier function

Interpretation of Results

• Low VWF:Ag, VWF:RCo, and FVIII levels similar to hereditary VWD 1
• VWF:RCo/VWF:Ag ratio <0.5-0.7 suggests qualitative defect and triggers specialized testing 1, 8
• Multimer analysis typically shows:
  • Type 2A pattern (absence of HMWM) in most cases 6, 4
  • Type 1 pattern (proportional decrease) in some cases 6
  • Rarely, Type 3 pattern (complete absence) 6

Specialized Testing

• Inhibitor screening: Autoantibodies against vWF detected in only 20-40% of cases 6, 4
• Mixing studies: Useful only if vWF-antibody complexes can be removed in vitro 2
• VWF multimer electrophoresis: Essential for characterizing the pattern 6, 4

Management Approach

Treat the Underlying Condition First

The most effective long-term strategy is treating the associated disorder, which can lead to complete resolution of AVWS 2, 6, 3:

• Resolution of hypothyroidism normalizes coagulation parameters 6
• Successful treatment of multiple myeloma can reverse the syndrome 6
• Control of autoimmune disease may eliminate the bleeding diathesis 2

Acute Bleeding Management

First-Line Therapy: Desmopressin

• Dose: 0.3 μg/kg IV (maximum 28 μg) 7
• Mechanism: Stimulates release of stored vWF from endothelial cells, increasing levels 3-6 fold within 30-90 minutes 7
• Repeat dosing: May be given at 12-24 hour intervals, but tachyphylaxis occurs after 3-5 doses due to endothelial store depletion 7
• Efficacy: Successfully controls bleeding in many cases 6, 3

Second-Line: VWF/FVIII Concentrates

• Use when desmopressin is ineffective or contraindicated 7, 3
• Particularly important for surgical procedures 7

Intravenous Immunoglobulin (IVIG)

IVIG is the most effective therapy for AVWS associated with lymphoproliferative disorders or monoclonal gammopathies 2, 4:

• Works by disrupting immune complex clearance
• High-dose IVIG is the most frequently administered treatment 4
• Improvement in plasma vWF levels observed in most treated cases 4

Adjunctive Therapy

• Tranexamic acid: Combine with other treatments as appropriate 7
• Cryoprecipitate: Alternative source of vWF when concentrates unavailable 7

Perioperative Management

For patients requiring surgery 7:

• Target VWF activity ≥50 IU/dL throughout procedure and postoperative period
• Achieve through desmopressin, VWF/FVIII concentrates, or cryoprecipitate
• Combine with tranexamic acid
• For neuraxial anesthesia, maintain VWF activity ≥50 IU/dL

Special Scenario: ECMO-Associated AVWS

AVWS develops within hours of ECMO initiation and persists throughout support 7:

• Requires multidisciplinary approach
• Minimize anticoagulation when possible
• Use blood product replacement for active bleeding
• Consider desmopressin or VWF concentrates for refractory bleeding
• AVWS resolves rapidly after ECMO weaning 7
• Evidence for prophylactic VWF concentrate remains limited 7

Common Pitfalls to Avoid

• Do not rely on PT/aPTT alone to exclude bleeding disorders—this misses AVWS entirely 8
• Do not use non-resorbable nasal packing in patients with suspected or confirmed AVWS 7
• Do not assume negative inhibitor screen excludes AVWS—autoantibodies are detected in only a minority of cases 6, 4
• Do not overlook underlying conditions—always search for lymphoproliferative, autoimmune, or cardiovascular disorders 1, 4, 5
• Do not expect desmopressin to work indefinitely—tachyphylaxis limits repeated dosing 7