The von Willebrand FactorCleaving Protease and Malignancy

1
The von Willebrand Factor-Cleaving Protease and
Malignancy

• By Kolette Brown, M.D.
• GUH Internal Medicine
• August 10, 2006
• Advisor Dr. Craig Kessler

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Proposed Relation among the Absence of ADAMTS 13
Activity in Vivo, Excessive Adhesion and
Aggregation of Platelets, and Thrombotic
Thrombocytopenic Purpura
Moake J. N Engl J Med 2002347589-600
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vWF-cp and Malignancy

• Oleksowicz et al. (1999)
• Design
• 20 patients with disseminated tumors
• 15 controls with corresponding localized tumors
• Findings
• Reduced vWF-cp protease activity lt 15
• Increased of vWF multimers
• No detectable plasma inhibitors

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vWF-cp and Malignancy

• Oleksowicz et al. (1999)
• Implications
• Reduction of vWF-cp pathogenic for tumor
  dissemination
• Deficiency of the vWF-cp predisposes patients
  with disseminated cancers to develop TTP
• vWF-cp activity level a novel prognosticator for
  determining likelihood of dissemination

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vWF-cp and Malignancy

• Other Studies supporting this association
• Koo et al. (2002)
• 6-30 activity level in 6 pts with disseminated
  disease
• Normal (95-100) activity in 5 pts with localized
  disease
• Deficiency of vWF-cp associated with disease
  progression in 17 pts with colon cancer
• Lack of an inhibitor
• Mannucci et. Al (2003)
• Moderate reduction in vWF-cp activity in pts with
  disseminated disease

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vWF-cp and Malignancy

• Bohm et al. (2003)
• No significant difference
• Issue
• Tumor type
• Assay

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vWF-cp and Maligancy

• Blot et al. (2002)
• A deficiency of vWF-cp without evidence of an
  inhibitor is pathogenic for cancer-related TTP
• Gordon et al. (1999)
• 88 of cancer-related TTP/HUS associated with
  adenocarcinoma (stomach, breast, colon)

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Research Question

• Can the vWF-cp activity level be used as a
  prognostic tool for determining the likelihood of
  dissemination in malignancies associated with
  thrombotic thrombocytopenia purpura? 

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Immunohistochemistry
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FRETS-vWF73 Assay
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Expectations

• Demonstrate an inverse relationship between
  vWF-cp activity and disseminated disease in
  cancers associated with TTP
• Suggest a mechanism of reduced production of the
  vWF-cp
• Support the literature that a deficiency of the
  protease indicates metastasis

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Questions?
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References

• Moake JL. Mechanisms of Disease Thrombotic
  Microangiopathies. New England Journal of
  Medicine. 2002347589-600.
• Oleksowicz L, Bhagwati N, Deleon-Fernandez M.
  Deficiency of von Willebrands Factor-cleaving
  Protease in Patients with Disseminated
  Malignancies. Cancer Research. 199959
  2244-2250.
• Koo B, Oh D, Chung SY, Kim NK, Park S, Jang Y,
  Chung K. Deficiency of von Willebrand
  factor-cleaving protease activity in the plasma
  of malignant patients. Thrombosis Research.
  2002105 471-476.
• Mannucci PM, Karimi M, Mosalaei A, Canciani MT,
  Peyvandi F. Patients with localized and
  disseminated tumors have reduced but measurable
  levels of ADAMTS-13 (von Willebrand factor
  cleaving protease). Haematologica. 200388
  454-458.
• Bohm M, Gerlach R, Beecken W, Scheuer T,
  Stier-Bruck I, Scharrer I. ADAMTS-13 activity in
  patients with brain and prostate tumors is mildly
  reduced, but not correlated to stage of
  malignancy and metastasis. Thrombosis Research.
  2003111 33-37.
• Blot E, Decaudin D, Veyradier A, Bardier A,
  Zagame O, Pouillart P. Cancer-related thrombotic
  microangiopathy secondary to Von Willebrand
  factor-cleaving protease deficiency. Thrombosis
  Research. 2002106(2) 127-130.
• Gordon L, Kwaan H. Thrombotic Microangiopathy
  Manifesting as Thrombotic Thrombocytopenic
  Purpura/Hemolytic Uremic Syndrome in the Cancer
  Patient. Seminars in Thrombosis and Hemostasis
  199925(2)217