Von Willebrand Disease - VWD

Von Willebrand disease (VWD) is the most common congenital bleeding disorder. VWD may result from either a quantitative (types 1 and 3) or qualitative (type 2) abnormality of von Willebrand factor (VWF).

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Initial evaluation (personal/family history and physical examination) suggestive of a bleeding disorder

Laboratory Testing

Initial testing
- Important to evaluate other potential causes of mucocutaneous bleeding
  - Disorders of the liver, kidneys, blood, or bone marrow
  - Undiagnosed thrombocytopenia (type 2B and platelet-type VWD [PT-VWD] may have thrombocytopenia)
  - Antiplatelet medications (aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], clopidogrel, others)
- Initial evaluation for a bleeding disorder (to exclude other coagulation defects)
  - CBC with platelet count
    - VWD type 2B and platelet type may have thrombocytopenia
  - Prothrombin time/partial thromboplastin time (PT/PTT)
  - Fibrinogen, or thrombin time (TT)
    - Fibrinogen or TT are optional (American Society of Hematology [ASH], 2012)
- In the presence of a strong history of mucocutaneous bleeding, tests for VWD could be considered as part of the initial evaluation
- VWD may prolong the PTT – it is a carrier for factor VIII
- PTT often normal in VWD
- If PTT abnormal, PTT mixing studies may be useful in the initial evaluation to differentiate factor deficiency from inhibitor as cause of prolonged PTT
  - In VWD, decreased factor VIII may result in a prolonged PTT that corrects with mixing study
- Refer to Anticoagulants and Possible Coagulation Test Interferences table for possible interferences with coagulation parameters based on the specific drug administered

VWD testing

Initial testing
- VWF antigen (VWF:Ag) – measures the amount of protein
- VWF ristocetin cofactor activity (VWF:RCo) – measures the function of the protein
- Factor VIII activity – measures amount of protein

Selected special testing – usually used for subtyping

Multimeric analysis
- Shows the distribution of different-sized multimers
- Not recommended for initial screening except in suspected cases of acquired VWD
  - Multimeric abnormalities may be the only abnormality identified in some cases of acquired VWD
- Types 2A, 2B, and platelet type and acquired cases have abnormal multimeric distributions
- Abnormal result defined as absence of high- and/or intermediate-molecular-weight multimers
VWF:RCo to VWF:Ag ratio
- VWD types 2A, 2B, platelet type, and 2M characteristically have lower levels of VWF:RCo compared to VWF:Ag, resulting in a decreased VWF:RCo-to-VWF:Ag ratio
  - Ratios <0.7 or <0.6 suggest one of these qualitative subtypes
Ristocetin-induced platelet aggregation (RIPA)
- Not sensitive to mild forms of VWD (most type 1 cases)
- Typically used to confirm and distinguish between type 2 subtypes (2A, 2B/platelet type)
  - Low-dose RIPA detects abnormally increased aggregation seen in type 2B and platelet-type VWD
VWF:platelet binding
- Detects abnormally increased platelet binding seen in type 2B
- Differentiates type 2B from platelet-type VWD
  - Test is normal in platelet type
VWF:FVIII binding
- Differentiates between type 2N and hemophilia A
  - Test is normal in hemophilia A
Genetic/molecular testing
- Confirm phenotypic diagnosis of VWD where it affects therapeutic decisions
- Distinguish VWD type 2B from platelet-type VWD
- Distinguish VWD type 2N from hemophilia A
- Evaluate family members of individuals with known variants

Expected laboratory values in VWD by subtype

Expected Laboratory Values in VWD by Subtype
Type	1	2A	2B	2M	2N	3
VWF:Ag	Mild to moderate decrease	Frequently mild to moderate decrease	Normal to moderate decrease	Mild to severe decrease	Normal to moderate decrease	Marked decrease or absence
VWF:RCo	Mild to moderate decrease	Moderate to severe decrease	Mild to severe decrease	Mild to severe decrease	Normal to moderate decrease	Marked decrease or absence
FVIII	Normal to moderate decrease	Normal to moderate decrease	Normal to moderate decrease	Normal to moderate decrease	Mild to severe decrease	Marked decrease (<10) or absence
Platelet count	Normal	Usually normal	Often slightly low; exacerbated by surgery, stress, pregnancy	Normal	Normal	Normal
Multimer pattern	Normal pattern, but reduced intensity	Abnormal; loss of HMW and IMW multimers	Abnormal; loss of HMW multimers	Normal	Normal	No VWF present
RIPA^a	Often normal	Reduced aggregation at high ristocetin concentrations	Abnormal; enhanced aggregation at low ristocetin concentrations	Reduced at high ristocetin concentrations	Normal	Absent
VWF:FVIII binding^b	Normal	Normal	Normal	Normal	Decreased	n/a
RCo:Ag ratio	Normal (>0.5-0.7)	Decreased (<0.5-0.7)	Decreased or normal (usually <0.5-0.7)	Decreased (<0.5-0.7)	Normal (>0.5-0.7)	n/a
^aRIPA must be performed by a local laboratory due to limited stability of specimen ^bMeasures ability of VWF to bind to factor VIII Ag, antigen; FVIII, factor VIII; HMW, high molecular weight; IMW, intermediate molecular weight; n/a, not applicable; RCo, ristocetin cofactor activity; RIPA, ristocetin-induced platelet aggregation; VWF, von Willebrand factor Source: Favaloro, 2014

Factors that may affect laboratory testing in VWD
- VWF values fluctuate over time – if clinical suspicion is high and values are normal, repeat testing may be required for diagnosis
- May have normal test results with mild disease
- Mildly decreased VWF values are not diagnostic
- VWF and FVIII are acute phase reactants and may be elevated by stress, illness, or medications (false-negative)
  - Conditions include pregnancy, estrogen-containing medications, inflammation, infection, liver disease, malignancy, exercise, stress/anxiety, and trauma (including traumatic venipuncture)
- VWF values and FVIII activity are affected by ABO blood type
  - Type O individuals have ~25% lower values than non-ABO individuals
- VWF and FVIII results can be affected by preanalytical variables such as collection technique, specimen preparation, storage, and transport
  - Cold storage of citrated whole blood prior to centrifugation
    - Can markedly reduce VWF and FVIII values
    - Can also induce multimeric abnormalities
    - Can lead to incorrect diagnosis or subtyping

Differential Diagnosis

Functional platelet disorders
Hemophilia A or other coagulation factor deficiencies
Underlying malignancy (cause of acquired VWD)
- Lymphoproliferative disease
  - B-cell lymphoma
  - T/NK-cell lymphoma
- Myeloproliferative neoplasms
- Leukemia
  - Acute myeloid leukemia
  - Acute lymphoblastic leukemia

Screening

Population screening not recommended
Screening when other family members have VWD – no specific recommendations but may be considered depending on clinical scenario

Monitoring

In patients initially receiving desmopressin
- Based on therapeutic trial in nonbleeding state after clinical use
- Measure von Willebrand panel at baseline and 1-2 hours after administering desmopressin (depending on preparation used and desired protocol)
- Additional 2-4 measurements in patients with previous history of poor response to evaluate for decreased half-life due to rapid clearance
After major surgery in patients receiving desmopressin
- Monitoring with VWF:RCo and FVIII until bleeding risk is reduced
- Additional postoperative desmopressin, based on bleeding and lab values
- Monitoring of electrolytes if numerous doses of desmopressin given
- In patients with cardiovascular disease, desmopressin has rarely precipitated myocardial infarction or stroke; consider replacement with VWF concentrates rather than desmopressin in patients with thrombotic risk factors

Background

Epidemiology

Incidence

May be as high as 1/100

Frequency and definition of VWD subtype

VWD Type – Frequency and Definition of Subtype
Type	Frequency	Definition of Defect
1	~80%	Partial quantitative deficiency of functionally normal VWD protein
2A	10%	Loss of HMW VWF
2B^a	<5%	Enhanced binding of VWF to platelets, leading to loss of HMW VWF
2M	<2%	VWF dysfunction not associated with loss of HMW VWF
2N	<1%	Loss of VWF-FVIII binding
3	rare	Complete deficiency of VWF
^aSimilar lab and clinical features also exhibited by platelet-type VWD due to abnormalities in GP1b receptor; use genetic testing or VWF platelet-binding assay (also called type 2B binding) to distinguish FVIII, factor VIII; HMW, high molecular weight; VWD, von Willebrand disease; VWF, von Willebrand factor

Sex – M:F, equal
Ethnicity – more common in Caucasians

Pathophysiology

VWF is a large multimeric plasma protein that mediates adherence of platelets to the vessel wall at sites of injury and is a carrier for factor VIII
VWD results from VWF deficiency or dysfunction
Acquired VWD is associated with other conditions
- Autoantibody formation
  - Lymphoproliferative diseases – B-cell lymphoma, T/NK-cell lymphoma, plasma cell dyscrasias
  - Autoimmune diseases (eg, systemic lupus erythematosus)
- Shear-induced proteolysis – structural heart defects (eg, ventricular septal defect, aortic stenosis), pulmonary hypertension
  - Increased platelet binding in conditions with markedly increased platelet counts (eg, myeloproliferative neoplasms)
- Hypothyroidism
- Medication induced – valproic acid, ciprofloxacin, griseofulvin

Clinical Presentation

Clinical characteristics of VWD subtypes

Clinical Characteristics of Subtypes
Type	Genetics	Defect	Clinical Presentation
Type 1	AD with incomplete penetrance (60%) VWF variants	Quantitative defect Partial deficiency of VWF	Mild mucocutaneous bleeding
Type 2 Subtype frequency in the Caucasian population – 2A>2N>2M/2B	2A – AD (20%) 2B – AD 2M – AD 2N – AR VWF variants	Qualitative defect Structurally or functionally abnormal VWF	Highly variable 2A – mild to moderate mucocutaneous bleeding; may have thrombocytopenia 2B – mild to moderate mucocutaneous bleeding; thrombocytopenia may be present 2M – mild to moderate mucocutaneous bleeding, no thrombocytopenia 2N – symptoms are similar to mild hemophilia A
Type 3	AR or compound inheritance of null VWF allele VWF variants	Quantitative defect Absence of VWF	Severe mucocutaneous and musculoskeletal bleeding – mimics severe hemophilia A
PT-VWD or pseudo-VWD	AD GPIBA variants	Abnormal high-affinity interaction between platelet glycoprotein Ib/V/IX complex and VWF	Often indistinguishable from VWD type 2B
AD, autosomal dominant; AR, autosomal recessive; PT-VWD, platelet-type von Willebrand disease; VWD, von Willebrand disease; VWF, von Willebrand factor

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Recommended Use

Initial testing for suspected bleeding disorder

Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Recommended Use

Initial testing for suspected bleeding disorder

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Recommended Use

Initial testing for suspected bleeding disorder

von Willebrand Panel 0030125
Method: Electromagnetic Mechanical Clot Detection/Platelet Agglutination/Microlatex Particle-Mediated Immunoassay

Recommended Use

Recommended panel for the initial workup of suspected VWD

Panel includes VWF antigen, ristocetin cofactor activity, and factor VIII activity

von Willebrand Panel with Reflex to von Willebrand Multimeric Analysis 2003387
Method: Electrophoresis/Clotting/Microlatex Particle-Mediated Immunoassay/Platelet Agglutination

Recommended Use

Recommended panel to subclassify VWD when high suspicion for VWD exists

Panel includes VWF multimers, factor VIII activity, VWF antigen, and VWF activity (ristocetin cofactor)

Reflex pattern – if VWF:RCo or VWF:Ag or factor VIII is low, von Willebrand multimeric analysis testing will be added; if the ratio of VWF:RCo/VWF:Ag is less than 0.7, VW multimeric analysis testing will be added

Limitations

Medical Experts

Miller, Christine E., MS, LCGC, Genetic Counselor, Molecular Genetics at ARUP Laboratories; Faculty, Graduate Program in Genetic Counseling, University of Utah

Rodgers III, George M., MD, PhD, Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Professor of Internal Medicine and Adjunct Professor of Clinical Pathology, University of Utah

Smock, Kristi J., MD, Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

The Diagnosis, Evaluation, and Management of von Willebrand Disease. National Heart, Lung, and Blood Institute. Bethesda, MD [Accessed: May 2018]
2012 Clinical Practice Guideline on the Evaluation and Management of von Willebrand Disease (VWD). American Society of Hematology. Washington DC [Revised : 2012; Accessed: May 2018]
Keeney S, Bowen D, Cumming A, Enayat S, Goodeve A, Hill M, UK Haemophilia Centre Doctors' Organisation (UKHCDO). The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory Network. Haemophilia. 2008; 14(5): 1099-111. PubMed
Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008; 14(2): 171-232. PubMed

General References

Castaman G, Hillarp A, Goodeve A. Laboratory aspects of von Willebrand disease: test repertoire and options for activity assays and genetic analysis. Haemophilia. 2014; 20 Suppl 4: 65-70. PubMed

Favaloro EJ, Bodó I, Israels SJ, Brown SA. von Willebrand disease and platelet disorders. Haemophilia. 2014; 20 Suppl 4: 59-64. PubMed

Federici AB. Clinical and laboratory diagnosis of VWD. Hematology Am Soc Hematol Educ Program. 2014; 2014(1): 524-30. PubMed

Franchini M, Montagnana M, Lippi G. Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand disease. Int J Lab Hematol. 2008; 30(2): 91-4. PubMed

James PD, Lillicrap D. von Willebrand disease: clinical and laboratory lessons learned from the large von Willebrand disease studies. Am J Hematol. 2012; 87 Suppl 1: S4-11. PubMed

Lillicrap D. Von Willebrand disease - phenotype versus genotype: deficiency versus disease. Thromb Res. 2007; 120 Suppl 1: S11-6. PubMed

Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol. 2006; 81(8): 616-23. PubMed

Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood. 2015; 125(13): 2029-37. PubMed

Robertson J, Lillicrap D, James PD. Von Willebrand disease. Pediatr Clin North Am. 2008; 55(2): 377-92, viii-ix. PubMed

Yawn B, Nichols WL, Rick ME. Diagnosis and management of von Willebrand disease: guidelines for primary care. Am Fam Physician. 2009; 80(11): 1261-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology^®

Desai DS, Lyon E, Rodgers GM, Jama MA, Wallentine SL, Smock KJ. Elderly female with a personal and family history of a bleeding disorder. Clin Chem. 2015; 61(7): 909-12. PubMed

Tang H, Lee M, Kim EH, Bishop D, Rodgers GM. siRNA-knockdown of ADAMTS-13 modulates endothelial cell angiogenesis. Microvasc Res. 2017; 113: 65-70. PubMed

Testing Algorithms

von Willebrand Disease Testing Algorithm

Read more about von Willebrand Disease Testing Algorithm

Educational Videos

Last Update: October 2018

Von Willebrand Disease - VWD

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology^®

von Willebrand Disease Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Von Willebrand Disease - VWD. ARUP Consult^©. Retrieved December 17, 2018, from: https://arupconsult.com/content/von-willebrand-disease

Von Willebrand Disease - VWD

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

von Willebrand Disease Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult

References from the ARUP Institute for Clinical and Experimental Pathology^®