By Srivardhan Vanka, Intern - Batch of 2014, J.I.P.M.E.R. References from UpToDate and Wintrobe's Hematology 13th Edition and various studies done till December 2019. Quoted when appropriate.

1. The Von Willebrand
disease
Srivardhan Vanka
Intern F3

2. History
• Dr.Erik Adolf von Willebrand
• Finnish physician
• Hereditär pseudohemofili (1926)
• The protein was characterised in 1971,
and is named Von Willebrand factor.
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3. Pedigree studied by Dr. Willebrant
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4. Classified under
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5. Incidence
• 1% worldwide, on screening studies
• Of which 0.1-1% manifest bleeding symptoms.
• Most common Inherited Coagulation disorder.
• India incidence – unknown
• T3 is commoner than T1 followed by T2 in India.
Indian J Med Res. 2005 May;121(5):653-8.
Prevalence and spectrum of von Willebrand disease from western India.
Trasi S1, Shetty S, Ghosh K, Mohanty D
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6. Types , Incidence and Inheritance
• Type 1 : 75%, AD
• Type 2A : 15%, AD
• Type 2B : 5%, AD
• Type 2M: Rare, AD
• Type 2N : Rare, AR
• Type 3 : Rare, AR
• AvWD : Rare
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7. Physiology
• Normal Haemostasis
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8. Physiology
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9. Physiology
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10. VwF Gene
• Chromosome 12
• 52 exons
• Encodes for a protein with multiple copies of homologous motifs with
three A, three B, two C and four D motifs.
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11. VwF Gene
• Primary transcription product of 2800 amino acids with extensive
post translational processing in Golgi.
• Dimerisation and Multimerisation
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12. vWF Protein
• Exists in Multimers
• Multimers of VWF can be extremely large, >20,000 kDa
• Produced constitutively as ultra-large VWF in endothelium (in the
Weibel-Palade bodies), megakaryocytes (α-granules of platelets)
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13. vWF Protein
• Majority of circulating vWF in Plasma.
• About 15% of the total vWF pool in Megakaryocytes.
• t1/2 is 8 -12 hours.
• Normal concentration : >50 IU/dL
• “VWF levels can be affected by ethnicity, ABO blood type”29-04-2020 13

14. Pathophysiology
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15. Pathophysiology
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16. Clinical Presentations
• Type 1 – Variable, from asymptomatic to serious bleeding depending on bleeding
challenges and degree of reduction in VWF levels (the majority are mild);
mucocutaneous
• Type 2A – Usually moderate to severe; mucocutaneous
• Type 2B – Usually moderate to severe; mucocutaneous
• Type 2M – Variable; usually moderate to severe; mucocutaneous
• Type 2N – Moderate to severe; joint, soft tissue, gastrointestinal, or surgical
• Type 3 – Severe; mucocutaneous and joint, soft tissue, gastrointestinal,
or surgical; often presents during infancy (eg, with circumcision)
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17. Features
•Easy bruising
•Cutaneous bleeding
•Prolonged bleeding from mucosal surfaces
•HMB
•PPH
•Gastrointestinal bleeding and GI angiodysplasia
•Joint and soft tissue bleeding
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18. Symptoms – T3 vWD
•Epistaxis – 77 percent
•Oral bleeding – 70 percent
•Muscle hematoma – 52 percent
•Hemarthrosis – 37 percent
Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease.
Lak M, Peyvandi F, Mannucci PM
Br J Haematol. 2000;111(4):1236.
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19. Indications for evaluation
VWD should be considered in individuals with one or more of the following:
• Increased history of bleeding, especially mucocutaneous bleeding (eg,
abnormal bruising, nosebleeds, abnormal uterine bleeding)
• Positive family history of VWD or of a bleeding phenotype suggestive of
VWD.
• Mild thrombocytopenia or a mild prolongation of the activated partial
thromboplastin time (aPTT) that is not explained by another condition.
• Apparent hemophilia A in a female (low factor VIII in the absence of a
factor VIII inhibitor)
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20. Laboratory Testing
Baseline hemostasis assessment – CBC, aPTT
VWD screening tests
•VWF antigen (VWF:Ag)
– Quantitative measurement of VWF protein level
•VWF activity (VWF:Act)
– Functional assays of VWF binding to platelets or collagen
•Factor VIII activity
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22. Other laboratory tests
•Ristocetin-induced platelet aggregation
(RIPA)
•vWF multimer analysis
•vWF gene testing
•PFA-100
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23. VWF antigen (VWF:Ag)
•Plasma von Willebrand factor antigen (VWF:Ag) measures the
quantity of VWF protein in the plasma.
Preferred assay : ELISA on microtiter plates
•A VWF:Ag level <30 percent (<30 international units/dL) is
consistent with VWD.
Levels between 30 and 50 percent indicate "low VWF."
Levels >50 percent are considered normal.
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24. VWF functional assays (VWF:Act)
• Assess the ability of VWF to bind its normal binding partners, platelet
glycoprotein Ib (GPIb), collagen, and factor VIII.
1) Platelet (GPIb) binding – VWF binding to platelet receptor GPIb allows
VWF to recruit platelets to a site of vascular injury; it can be assayed by
several methods:
VWF:RCo (Ristocetin cofactor)
VWF:GPIbR
VWF:GPIbM
VWF:Ab
Though the VWF:RCo assay remains the "gold standard" for the platelet
binding activity of VWF, the automated tests listed above are generally more
reproducible and are more sensitive in the lower range; they are becoming
widely.
2)Collagen binding
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25. VWF:RCo (ristocetin cofactor)
• Measures the ability of VWF to bind to
platelet membrane receptor GPIb.
•Quantitative
•Uses Platelet-poor patient plasma.
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26. VWF:GPIbR –ability of the patient's VWF to bind
to a recombinant platelet GPIb receptor attached
to a solid phase such as latex beads (in the place
of platelets that contain membrane GPIb).
•Ristocetin is added to enhance binding, as done
in the VWF:RCo assay. VWF:GPIbR is more
sensitive than VWF:RCo and is automated
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27. VWF:GPIbM –
measures the ability of the patient's VWF to bind to a
recombinant mutated GPIb receptor attached to latex
beads.
Ristocetin is not needed due to the gain-of-function
mutation in the recombinant GPIb reagent.
The test is more sensitive than VWF:RCo and is
automated.
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28. VWF:Ab –
VWF:Ab is an automated assay that measures
binding of a specific monoclonal antibody to the
GPIb binding site on VWF.
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29. Platelet function analyzer (PFA) assay –
The PFA-100 assesses platelet plug formation in
citrated whole blood exposed to shear stress.
The plug forms on a membrane that is coated with
collagen, ADP, or epinephrine and has a central
aperture.
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30. Ristocetin-induced platelet aggregation (RIPA)
•patient's platelet-rich plasma (PRP)
•suboptimal concentrations of ristocetin
• does not quantitate VWF
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31. Ristocetin-induced platelet aggregation (RIPA)
• patient's PRP in a series of test tubes and sequentially adding lower
concentrations of ristocetin to each tube, using a range of
concentrations from 0.4 to 1.2 mg/mL.
• Normal VWF does not aggregate at concentrations of ristocetin that
are lower than approximately 0.6 to 0.8 mg/mL
• PRP from patients with type 2B VWD and pseudo vWF will usually
aggregate at concentrations of ristocetin of 0.4 to 0.5 mg/mL.
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32. VWF multimer analysis
Qualitative visual assessment of the
size spectrum and the banding
pattern of VWF multimers that can
be seen on gel electrophoresis
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33. VWF multimer analysis
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34. Genetic testing
• Diagnosis or confirmation of type 2N
• Distinguishing type 2N from mild hemophilia A in males
• Distinguishing type 2N from hemophilia A carrier status in
female carriers of hemophilia A
• Diagnosis or confirmation of type 2M
• Distinguishing type 2B from platelet-type (pseudo) VWD
• Prenatal testing for type 3 VWD
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35. Diagnostic ratio
•Ratio of VWF activity to VWF antigen
>0.7 - Good Concordance. Seen in T1 and T3
<0.5 – Discordant. Consistent with T2.
Racial differences in this ratio have been noted.
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36. Diagnosis
The National Heart, Lung, and Blood Institute (NHLBI) guidelines
-With positive personal or family history
VWF:Act or VWF:Ag - <30 international units/dL (<30 percent) are
given the diagnosis of VWD
-With positive personal or family history
VWF:Act or VWF:Ag - 30 – 50 international units/dL (30-50 percent)
Are given the diagnosis of Low vWF
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37. Differentials
1) Mild Haemophilia A (inheritance, symptoms;
vWF:Ag, vWF:Act, vWF-FVIII binding studies)
2) Bernard-Soulier
3) Pseudo VWD
4) AVWD
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38. Association with other systemic diseases
Malignant diseases
Lymphoproliferative disorders
•Monoclonal gammopathy of undetermined significance (MGUS)
•Multiple myeloma
•Non-Hodgkin lymphoma (NHL)
•Chronic lymphocytic leukemia (CLL)
•Waldenström macroglobulinemia
Myeloproliferative neoplasms (MPNs)
•Essential thrombocythemia (ET)
•Polycythemia vera (PV)
•Chronic myeloid leukemia (CML)
•Primary myelofibrosis (PMF)
Wilms tumor
Other carcinomas
Immune disorders
Systemic lupus erythematosus (SLE)
Other autoimmune diseases
States of high vascular flow
Ventricular septal defect
Congenital heart disease with high flow state
Aortic stenosis
Mitral valve prolapse
Ventricular assist device (LVAD)
Extracorporeal membrane oxygenation (ECMO) device
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39. Laboratory Panel
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41. Differentiating Tests
• T2A and T2M – VWD multimer analysis
• Mild Haemophilia and T1 – Normal VWD:Ag, Normal VWD:Act,
Normal VWD-FVIII binding in former.
• T2B and Pseudo VWD – Mixing studies, VWF gene analysis, in-
vitro Cryo-Platelet aggregation
• T2N and Haemophilia - Normal VWD-FVIII binding in latter.
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42. Treatment options
• DDAVP following Trial of DDAVP
IV trial- 0.3 mcg/kg (maximum 20 mcg),
is given in 50 mL of saline over 20 to 30 minutes.
Intranasal – 300mcg in >50kg, 150mcg in <50 kg.
Blood samples taken at 0,1,4 hours.
Effective response to DDAVP:
VWF activity of at least 30 IU/dL and ideally at least 50 IU/dL and sustained for 4-6
hours.
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43. DDAVP – Mainstay drug for Mild, Moderate T1
and T2, Minor surgery or bleeding.
• MOA
• Dose may be repeated after 12 hours and 24 hours
• Goal of therapy – The goal is an increase in VWF and
factor VIII activities to >30 IU/dL (ideally >50 IU/dL)
Adverse effects: Hyponatremia and Tachyphylaxis
Flushing, Headache, Hyper/hypotension
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44. VWF Concentrates – Mainstay for Severe VWD,
Major surgery or life threatening hemorrhage
• For Major Surgeries
Loading dose with 40 to 60 ristocetin cofactor units per kg
Maintenance with 20 to 40 ristocetin cofactor units per kg
every 12 to 24 hours
to keep VWF level 50 to 100 international units/dL
for 7 to 14 days
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45. VWF Concentrates – Mainstay for Severe VWD,
Major surgery or life threatening hemorrhage
• For Minor Surgeries
Loading dose with 30 to 60 ristocetin cofactor units per kg
Maintenance with 20 to 40 ristocetin cofactor units per kg
every 12 to 24 hours
to keep VWF level above 30 international units/dL
for 3 to 5days
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46. VWF Concentrates – Mainstay for Severe VWD,
Major surgery or life threatening hemorrhage
• In cases of serious bleeding that does not respond to
intermittent dosing
Continuous infusion (2 to 15 international units of
VWF per kg per hour).
Adverse reactions: Thrombosis and Allergic reactions
Allo-antibodies
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47. Recombinant VWF – alternative to VWFC
• For Major Surgeries
Loading dose with 50 to 80 International units per kg
Maintenance with 40 to 60 International units per kg
every 8 to 24 hours
to keep VWF level between 50-100 international units/dL
for 2 to 3days
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48. Recombinant VWF – alternative to VWFC
• For Minor Surgeries
Loading dose with 40 to 50 International units per kg
Maintenance with 40 to 50 International units per kg
every 8 to 24 hours
to keep VWF level above 30 international units/dL
as clinically implicated.
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49. Platelet transfusions
• Appropriate for individuals who have
thrombocytopenia or platelet dysfunction.
• Occurs in individuals with type 2B VWD or from other
causes unrelated to VWF.
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50. Refractory bleeding in VWD
• Consider Continuous infusion of VWFC along with Anti-
fibrinolytic agents
• Review the possibility that other deficiencies ( Vit.k, Platelets)
• Pro-Haemostatic agents
1) Recombinant activated factor VII (rFVIIa)
2) Activated prothrombin complex concentrate (APCC)
3) Factor eight inhibitor bypassing agent (FEIBA)
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51. Bleeding in Inhibitors
• Allo-antibodies against infused VFWC.
• rFVIII is used. Even though VWF contribution to
platelet function is not present, the FVIII contribution
to clot formation appears to be sufficient in these
situations.
• A shortened half-life of rFVIII can be expected, and
frequent doses of rFVIII may be necessary.
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52. Antifibrinolytic drugs
1) Tranexamic acid
25 mg/kg per dose orally every 6 to 8 hours
2) Aminocaproic acid
25 to 50 mg/kg per dose orally (maximum 5 g dose) qid
-Especially useful for mucosal bleeding (often for dental
procedures)
-Used in conjunction with DDAVP or VWFC.
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53. IVIG
• 1 g/kg intravenously 1 time per day for 2 days
• For AvWD along with DDAVP.
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54. Topical agents
• Human Thrombin
• Bovine Thrombin
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55. Estrogens
• OCPs are indicated in HMB in VWD women not willing
to conceive.
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56. Lenalidomide
•For GI bleeding associated with Angiodysplasia
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57. VWD in special circumstances
• In Acute VTE:
UFH without Loading dose is started only if VWF > 15 IU/dl
If no bleeding occurs, switch to Oral anticoagulation after 2 days.
- In ACS:
VWFC to raise Vwf:Ag to >30 IU/dl during Angiography or
Stent placement.
Life long anticoagulant or anti-platelet therapy can be started with close
monitoring of Plasma VWF:Ag.
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58. VWF prophylaxis
• A study involving 2790 VWD patients followed over 22 years
showed that individuals with VWD had twice as many
hospitalizations and outpatient visits as matched controls; in
a subgroup of the VWD patients, prophylactic therapy
decreased hospitalizations by half
• For individuals with severe, recurrent bleeding (eg, recurrent
GI bleeding, epistaxis, joint bleeding similar to hemophilia)
Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis:
Results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network.
Holm E, Carlsson KS, Lövdahl S, Lail AE, Abshire TC, Berntorp E
Haemophilia. 2018;24(4):628. Epub 2018 Apr 6
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59. SUMMARY
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60. Assays under development
•ELISA assay for classification
•Assays using flow (shear stress)
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