Von Willebrand disease is the most common inherited bleeding disorder. It is caused by deficiencies or defects in von Willebrand factor, which plays a key role in hemostasis. The document discusses the synthesis, structure, and function of VWF, as well as its clearance mechanisms. It then covers the classification of VWD into types 1, 2, and 3 based on the nature and severity of the VWF deficiency. Diagnostic testing and evaluation algorithms are presented. Management strategies for VWD include local hemostatic measures, antifibrinolytic agents, hormonal therapies, desmopressin to increase VWF levels, and VWF/FVIII concentrates for replacement therapy.

1. VON WILLEBRAND DISEASE
DR SOURAV CHOWDHURY
1ST YEAR DNB RESIDENT
INDRAPRASTHA, APOLLO HOSPITALS
NEW DELHI

2. SYNTHESIS, STRUCTURE, CLEARANCE,
AND FUNCTION
• The vWF is synthesized in endothelial cells and megakaryocytes followed by Post-translational Modifications#
• Translation of this gene results in the formation of a 2813-amino-acid-long pre-pro-vWF molecule
• Following translation, the ‘‘pre-pro-vWF’’ is guided by the N-terminal signal peptide into ER & signal peptide
cleaved.

3. SYNTHESIS, STRUCTURE AND FUNCTION
• Further modification continues in the post-Golgi compartment and includes
• Addition of ABO groups and glycosylation;
• Changes that will affect vWF proteolysis by a disintegrin and metalloproteinase family protein with thrombospondin
type 1 motif, member 13 (ADAMTS-13) and protect mature vWF from proteolytic clearance
• Mature sub-unit contains all the adhesive sites
• D’-D3 domain that binds factor VIII,
• A1 domain that binds platelet GpIb receptor,
• A2 domain that serves a site for ADAMTS-13- mediated cleavage of vWF,
• A3 domain that binds exposed collagen, and
• C1 domain that binds platelet glycoprotein IIb/IIIa

4. CLEARANCE
• Macrophages in liver and spleen are believed to internalize and clear circulating vWF.
• The half-life of the plasma-derived therapeutic vWF is approximately 12 to 14 hours
• Factors that influence clearance
• Most prominent of these are the changes in glycosylation of vWF,
• Addition of ABO groups
• Point mutations in domains D3, D4, and A1

5. ROLE IN HEMOSTASIS
• Nascent vWF binds to exposed collagen through A1 & A3
• Once immob. High shear forces = conformational change
exposing GPIb binding site within A1
• GP1b in PLT can bind to exposed GP1b-site on vWF
resulting in platelet adhesion
• Adhered activated plt = conf change GPIIb/IIIa
• Binding of PLT GPIIb/IIIa to vWF=irreversible platelet plug
• vWF also binds & stabilize FVIII by D’-D3 domain
• Activated FVIIIa can form Xa with FIXa and Ca
• Eventually coagulation cascade and fibrin clot

6. VON WILLEBRAND DISEASE
• Incidence – Most commonly inherited bleeding disorder affecting 0.1-1%
• Prevalence- prevalence of symptom is much lower 0.01%
• Due to incomplete penetrance and mild cases pt are asymptomatic until investigated
• Gender- either gender affected as it is Autosomal disorder

7. VON WILLEBRAND DISEASE
• vWD present as Mucocutaneous or Platelet type bleeding
• Yet Type 2N & 3 shows low FVIII factor and Haemophilia type bleeding
• One recognized tool for diagnosis is International Society of Thrombosis and Hemostasis (ISTH) bleeding
assessment tool, which allows a quantitative scoring of bleeding symptoms
• According to the current classification of ISTH, vWD is categorized into 3 types:
• Type 1 is characterized by a partial quantitative deficiency of essentially normal vWF.
• Type 2 is characterized by qualitative defects in vWF.
• Type 3 is characterized by an almost complete quantitative deficiency of vWF.

8. TYPES OF VWD:
• Type 1 most common and with normal vWF conc
• Type 2 accounts for 25% cases & qualitative
deficiency in vWF activity
• Type 2A missense mutation = fewer GpIb binding
sites, multimer assembly, impaired secretion,
increased intracellular retention, enhanced
proteolysis
• Type 2B gain of func of GpIb = clearance along
with plt, characteristic thrombocytopenia
increased binding even with low ristocetin
• Type 2M defect in vWF- Collagen or Plt interaction
normal multimer but reduced RIPA
• Type 2N defect in vWF-FVIII interaction
• Type 3 Absence of multimer or vWF;Ag &
vWF:Rco prolonged PTT reduced FVIII <10IU/ml

9. ACQUIRED VON WILLEBRAND SYNDROME
• Without any family history
• Underlying mechanism
• Reduced synthesis
• Adsorption onto the surface of circulating cells or
platelet
• Antibody-mediated functional interference or
increased clearance
• Complex formation with plasma protein
• Heightened lysis

10. DIAGNOSTIC EVALUATION: PRELIMINARY TESTS
• CBC profile can normal but may have
• Microcytic anaemia due Iron deficiency due to blood loss
• Thrombocytopenia Type 2B
• PTT normal in majority except Type 2N severe Type 1 and Type 3

11. TESTS TO ESTABLISH DIAGNOSIS
a) vWF Antigen levels (vWF:Ag) Enzyme-linked immunosorbent assay (ELISA) or latex immunoassay (LIA) method
is used. Normal range is 50 to 200 IU/dL.
b) Ristocetin cofactor activity assay (vWF:RCo) determines the capacity of vWF to agglutinate exogenous
platelets in the presence of Ristocetin. Rate of agglutination related to conc of func. normal vWF.
Aggregometer or LIA# method is used. Normal range is 50 to 200 IU/dL.
c) vWF:RCo/VWF:Ag ratio assesses the ratio of vWF activity to antigen in plasma. A ratio of <0.6 is indicative of a
qualitative vWF deficiency. A value of <0.6 is seen in all type 2 vWD subtypes.
d) Factor VIII coagulant assay (FVIII:C) measures the plasma concentration of FVIII. To assay the ability of plasma
to shorten PTT of FVIII-deficient plasma. Normal range is 50 to 200 IU/dL

13. TESTS TO CLASSIFY VWD SUBTYPES:
• vWF multimer analysis is a qualitative assay that determines the size distribution of vWF multimers.
Sodium dodecyl sulfate protein electrophoresis method is used.
• Low-dose RIPA(Ristocetin-induced platelet aggregation) testing: measures the affinity with which vWF
binds to platelet GpIb receptor, by limiting the quantity of ristocetin.#
In this approach, when Mod. RIPA is performed using
patient’s plasma (vWF) and exogenous platelets, normal
aggregation pattern will be seen. However, when RIPA is
performed using patient’s platelets and exogenous plasma
(vWF), increased aggregation at low concentration becomes
evident, thus identifying abnormality in platelets rather than
vWF

15. TESTS TO CLASSIFY VWD SUBTYPES:
• vWF-FVIII binding assay (vWF/FVIII:B) measures
the ability of vWF to bind exogenous FVIII. ELISA
is used.
• Colorimetric assay is performed, and the curve
generated from patient’s plasma is plotted
against a standard or control curve. Defective
vWF/FVIII:B is seen in type 2N vWD

16. TESTS TO CLASSIFY VWD SUBTYPES:
• vWF-collagen binding assay (vWF:CB)* measures the affinity of vWF for collagen. Patient and control plasma
are applied to collagen-coated ELISA plates, followed by immune detection of collagen bound vWF using
antihuman vWF antibodies. Defective CB seen in 2M which have normal vWF:Rco so require this test to
diagnose.
• vWF propeptide/vWF antigen ratio (vWFpp/vWF:Ag) measures the ratio of vWF pro-peptide levels and mature
vWF in plasma. An increased ratio, implying increased vWFpp concentration in comparison to mature vWF
antigen in a patient with vWD, is indicative of adequate synthesis and secretion of vWF but an increased
clearance of vWF as the likely underlying etiology of vWF deficiency.
• The DDAVP challenge testing (DDAVP responsiveness) is advisable after a diagnosis of vWD is established,
especially in mild-moderate types 1 and 2 vWD. Normally 2-4 fold increase in vWF:Ag and vWF:Rco and at least
30% increase in FVIII that last 6-12hrs. Response <4hrs = increased clearance.#
• Genotyping:

17. DIAGNOSTIC CONSIDERATIONS IN AVWS
• To screen for AVWS, a vWF:RCo mixing study should be performed next, using control plasma.
• Failure to normalize vWF:RCo on addition of control plasma indicates the presence of an inhibitor. Such inhibitory
autoantibodies can then be detected using ELISA.
• Note that autoantibodies to nonfunctional domains, which may accelerate vWF clearance in vivo but confer no
functional interference, will be missed on such functional testing.

19. CDC POCKET GUIDE: INITIAL EVALUATION

20. CDC POCKET GUIDE: LABORATORY ASSESSMENT

21. CDC POCKET GUIDE: MAKING THE DIAGNOSIS

22. OVERVIEW AND SUMMARY OF MANAGEMENT:
STRATEGIES FOR VWD
• Local measures: Minor bleeding from nasal or oral bleeding may be managed with prolonged local
pressure to the injury site or with the use of certain topical hemostatic agents#
• Pharmacologic agents for indirect hemostatic effect:
• Fibrinolysis inhibitors: Epsilon aminocaproic acid inhibitor and tranexamic acid act by preventing dissolution of
hemostatic plug, especially in mucosal bleeding. In Type 1
• Hormonal treatments: Estrogen–progesterone combined oral contraceptives (OCPs) The OCPs are thought to
induce changes in the endometrium, making it less likely to bleed; however in vitro data OCP vWF

23. THERAPIES THAT DIRECTLY INCREASE VWF:
• Desmopressin: DDAVP, promotes the release of stored vWF from endothelial cells into circulation. The DDAVP
responsiveness should be tested in all patients with type 1 and type 2A vWD. Contraindicated in Type 2B and
Variable response in 2N & 2M.
• vWF/FVIII concentrates: Patients with bleeding associated with severe vWD (all types) and those with mild-
moderate vWD requiring major surgeries require replacement therapy.
• Plasma-derived intermediate purity, since most patients with vWF are also deficient in FVIII, intermediate purity
concentrate replacement is preferred
• High-purity vWF concentrates
• Recombinant vWF: A recombinant human vWF was approved by US Food and Drug Administration in
December 2015 for on-demand use in adult patients with severe bleeding.
• Special issues in AWVS: Diagnosis and management of the underlying disorder is of utmost importance in the
management of AVWS. Remove inhibitors by IVIg, TPE and Immuno-suppressive drugs. Recomb FVII to bypass
in emergency condition

24. Grateful for patient Hearing!
THANK YOU……