von Willebrands Disease

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von Willebrands Disease

• December 3, 2004

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Outline

• vWF
• Structure
• Location
• Function
• vWD
• History
• Clinical manifestations
• Categories
• Diagnosis
• Treatment

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vWD

• Family of bleeding disorders
• Caused by a deficiency or an abnormality of von
  Willebrand Factor

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vWF

• VWF gene short arm of chromosome 12
• VWF gene is expressed in endothelial cells and
  megakaryocytes
• vWF is produced as a propeptide which is
  extensively modified to produce mature vWF
• Two vWF monomers bind through disulfide bonds to
  form dimers
• Multiple dimers combine to form vWF multimers

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vWF Production

• Vascular endothelial cells
• Megakaryocytes
• Most vWF is secreted
• Some vWF is stored
• Weibel-Palade bodies in endothelial cells
• Alpha granules of platelets
• Constitutive and stimulus-induced pathways

• Release stimuli (EC)
• Thrombin
• Histamine
• Fibrin
• C5b-9 (complement membrane attack complex)
• Release stimuli (platelets)
• Thrombin
• ADP
• Collagen

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vWF Function

• Adhesion
• Mediates the adhesion of platelets to sites of
  vascular injury (subendothelium)
• Links exposed collagen to platelets
• Mediates platelet to platelet interaction
• Binds GPIb and GPIIb-IIIa on activated platelets
• Stabilizes the hemostatic plug against shear
  forces

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vW Factor Functions in Hemostasis

• Carrier protein for Factor VIII (FVIII)
• Protects FVIII from proteolytic degradation
• Localizes FVIII to the site of vascular injury
• Hemophilia A absence of FVIII

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vWD History

• 1931 Erik von Willebrand described novel
  bleeding disorder
• Hereditary pseudohemophilia
• Prolonged BT and normal platelet count
• Mucosal bleeding
• Both sexes affected

• 1950s Prolonged BT associated with reduced FVIII
• 1970s Discovery of vWF
• 1980s vWF gene cloned

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Frequency

• Most frequent inherited bleeding disorder
• Estimated that 1 of the population has vWD
• Very wide range of clinical manifestations
• Clinically significant vWD 125 persons per
  million population
• Severe disease is found in approximately 0.5-5
  persons per million population
• Autosomal inheritance pattern
• Males and females are affected equally

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vWD Classification

• Disease is due to either a quantitative
  deficiency of vWF or to functional deficiencies
  of vWF
• Due to vWF role as carrier protein for FVIII,
  inadequate amount of vWF or improperly
  functioning vWF can lead to a resultant decrease
  in the available amount of FVIII

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vWD Classification

• 3 major subclasses
• Type I Partial quantitative deficiency of vWF
• Mild-moderate disease
• 70
• Type II Qualitative deficiency of vWF
• Mild to moderate disease
• 25
• Type III Total or near total deficiency of vWF
• Severe disease
• 5
• Additional subclass
• Acquired vWD

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Clinical Manifestations

• Most with the disease have few or no symptoms
• For most with symptoms, it is a mild manageable
  bleeding disorder with clinically severe
  hemorrhage only with trauma or surgery

• Types II and III Bleeding episodes may be severe
  and potentially life threatening
• Disease may be more pronounced in females because
  of menorrhagia
• Bleeding often exacerbated by the ingestion of
  aspirin
• Severity of symptoms tends to decrease with age
  due to increasing amounts of vWF

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Clinical Manifestations

• Epistaxis 60
• Easy bruising / hematomas 40
• Menorrhagia 35
• Gingival bleeding 35
• GI bleeding 10
• Dental extractions 50
• Trauma/wounds 35
• Post-partum 25
• Post-operative 20

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vWD Type I

• Mild to moderate disease
• Mild quantitative deficiency of vWF
• vWF is functionally normal
• Usually autosomal dominant
• Penetrance may vary dramatically in a single
  family

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vWD Type 2

• Usually autosomal dominant
• Type 2A
• Lack high and intermediate molecular weight
  multimers
• Type 2B
• Multimers bind platelets excessively
• Increased clearance of platelets from the
  circulation
• Lack high molecular weight multimers

• Type 2C
• Recessive
• High molecular weight vWF multimers is reduced
• Individual multimers are qualitatively abnormal
• Type 2M
• Decreased vWF activity
• vWF antigen, FVIII, and multimer analysis are
  found to be within reference range
• Type 2N
• Markedly decreased affinity of vWF for FVIII
• Results in FVIII levels reduced to usually around
  5 of the reference range.

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vWD Type III

• Recessive disorder
• vWF protein is virtually undetectable
• Absence of vWF causes a secondary deficiency of
  FVIII and a subsequent severe combined defect in
  blood clotting and platelet adhesion

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Acquired vWD

• First described in 1970's
• fewer than 300 cases reported
• Usually encountered in adults with no personal or
  family bleeding history
• Laboratory work-up most consistent with Type II
  vWD
• Mechanisms
• Autoantibodies to vWF
• Absorption of HMW vWF multimers to tumors and
  activated cells
• Increased proteolysis of vWF
• Defective synthesis and release of vWF from
  cellular compartments
• Myeloproliferative disorders, lymphoproliferative
  disorders, monoclonal gammopathies, CVD, and
  following certain infections

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vWD Screening

• PT
• aPTT
• (Bleeding time)

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vWD aPTT and PT

• aPTT
• Mildly prolonged in approximately 50 of patients
  with vWD
• Normal PTT does not rule out vWD
• Prolongation is secondary to low levels of FVIII
• PT
• Usually within reference ranges
• Prolongations of both the PT and the aPTT signal
  a problem with acquisition of a proper specimen
  or a disorder other than or in addition to vWD

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vWD and Bleeding Time

• Historically, bleeding time is a test used to
  help diagnose vWD
• Lacks sensitivity and specificity
• Subject to wide variation
• Not currently recommended for making the
  diagnosis of vWD

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vWD Diagnostic Difficulties

• vWF levels vary greatly
• Physiologic stress
• Estrogens
• Vasopressin
• Growth hormone
• Adrenergic stimuli
• vWF levels may be normal intermittently in
  patients with vWD
• Measurements should be repeated to confirm
  abnormal results
• Repeating tests at intervals of more than 2 weeks
  is advisable to confirm or definitively exclude
  the diagnosis, optimally at a time remote from
  hemorrhagic events, pregnancy, infections, and
  strenuous exercise
• vWF levels vary with blood type

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vWD Diagnosis

• Ristocetin
• Good for evaluating vWF function,
• Results are difficult to standardize
• Method
• Induces vWF binding to GP1b on platelets
• Ristocetin co-factor activity measures
  agglutination of metabolically inactive platelets
• RIPA metabolically active platelets
• Aggregometer is used to measure the rate of
  aggregation
• vWF Antigen
• Quantitative immunoassay or an ELISA using an
  antibody to vWF
• Discrepancy between the vWFAg value and RCoF
  activity suggests a qualitative defect
• Should be further investigated by
  characterization of the vWF multimeric
  distribution

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Additional Assays

• Multimer analysis
• PFA-100 closure time
• Screens platelet function in whole blood
• Prolonged in vWD, except Type 2N
• FVIII activity assay

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vWD Treatment

• DDAVP
• Cryoprecipitate
• FVIII concentrate

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vWD and DDAVP

• Treatment of choice for vWD type I
• Synthetic analogue of the antidiuretic hormone
  vasopressin
• Maximal rise of vWF and FVIII is observed in
  30-60 minutes
• Typical maximal rise is 2- to 4-fold for vWF and
  3- to 6-fold for FVIII
• Hemostatic levels of both factors are usually
  maintained for at least 6 hours
• Effective for some forms of Type 2 vWD
• May cause thrombocytopenia in Type 2b
• Ineffective for vWD Type 3

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Factor VIII Concentrates

• Alphanate and Humate P
• Concentrates are purified to reduce the risk of
  blood-borne disease
• Contain a near-normal complement of high
  molecular weight vWF multimers

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vWD Treatment

• Platelet transfusions
• May be helpful with vWD refractory to other
  therapies
• Cryoprecipitate
• Fraction of human plasma
• Contains both FVIII and vWF
• Medical and Scientific Advisory council of the
  National Hemophilia Foundation no longer
  recommends this treatment method due to its
  associated risks of infection
• FFP
• An additional drawback of fresh frozen plasma is
  the large infusion volume required

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References

• Castaman G, et al. Haematologica, 88(01)January
  2003
• Harmening, Denise. Clinical Hematology and
  Fundamentals of Hemostasis. 1997.
• http//www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?i
  d193400

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