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vWD

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vWD

  1. 1. Von Willebrand Disease Gerald A Soff, MD
  2. 2. Case 1• 18 year old woman, presents with easy bruising, including all 4 extremities, heavy menses, prolonged bleeding after wisdom teeth extractions.• PT: 13”• aPTT: 38” (NL 24- 36”)• Factor VIII: 45%• Factor IX: 105%• Factor XI: 110%• Ristocetin Cofactor: 48%• vWF Antigen: 52%
  3. 3. Case 2• 32 year old woman, presents with 2nd trimester pregnancy. She has had excessive bleeding after arthroscopy, and a history of a brother who died from bleeding at 12 years of age after an appendectomy. No history of excessive bruising.• PT: 13”• aPTT: 58” (NL 24- 36”)• Factor VIII: 3%• Factor IX: 105%• Factor XI: 110%• Ristocetin Cofactor: 105%• vWF Antigen: 110%
  4. 4. Case 3• 55 year old woman, hematology consult for hemorrhage after hysterectomy for cervical cancer.• She has had life-long severe bleeding, with minimal trauma.• At age 13, with first menses, she had massive hemorrhage, and had “radioactive cobalt” implants in her ovaries to stop bleeding.• She had a brother who dies of hemorrhage at age 2 years.• PT: 13”• aPTT: 52” (NL 24- 36”)• Factor VIII: <5%• Factor IX: 105%• Factor XI: 110%• Ristocetin Cofactor: <10%• vWF Antigen: <10%
  5. 5. All Three Cases Have “von Willebrand Disease”Case 1: Type I
  6. 6. All Three Cases Have “von Willebrand Disease”• Case 1: Type I• Case 2: vWD Normandy
  7. 7. All Three Cases Have “von Willebrand Disease”Case 1: Type ICase 2: vWD NormandyCase 3: Type III
  8. 8. Von Willebrand’s Disease Definition; An autosomally inherited hemorrhagic disorder – Defective platelet adhesion – Reduced Factor VIII levels – A mucocutaneous pattern of bleeding First described by the Finnish physician Erik von Willebrand in 1926 Many members of a large family from the Aland Islands in the Gulf of Bothnia had a bleeding disorder with a distinct inherited pattern.
  9. 9. von Willebrand Disease (VWD): Overview Common inherited bleeding disorder Characterized by deficiency of von Willebrand factor (VWF) Variable clinical manifestations A group of disorders, (Different types). – Ewenstein B. Annu Rev Med. 1997;48:525-542; – Hambleton J. Curr Opin Hematol. 2001;8:306-311; – Murray E, Lillicrap D. Transfus Med Rev. 1996;10:93-110.
  10. 10. VWD Prevalence• Von Willebrand disease (VWD) is the most common congenital bleeding disorder.• It is estimated to occur at a frequency of 1-3%, but is symptomatic in only about one in 10,000.• Caused by mutations in von Willebrand factor (VWF).• The gene for von Willebrand Factor is located on chromosome 12, and the disease is inherited in an autosomal manner.
  11. 11. Von Willebrand Factor• vWF is a large adhesive glycoprotein that is present in the circulation as a heterogeneous population of disulfide-linked multimers of 250,000 molecular weight subunit, ranging from a dimer (Mr about 500,000) to a polymer of about 80 subunits (Mr about 20 x 106 ).• Human vWF is synthesized as preprovWF (Mr approximately 350,000) comprising a 22-residue signal sequence, a 741-residue propeptide, and a 2050-residue polypeptide that represents the basic subunit of the mature protein
  12. 12. Von Willebrand Factor• A glycoprotein consisting of disulfide-linked high molecular weight multimeric FVIII proteins (multimers), and is synthesized in megakaryocytes and endothelial cells, and stored in platelets and endothelial cells.• Von Willebrand factor serves as a carrier protein for FVIII and promotes platelet aggregation after vessel injury.
  13. 13. Von Willebrand Factor•Adapted from Ginsburg D, Bowie EJW: Molecular genetics of von Willebrand disease.Blood 79:2507, 1992.• In Hoffman’s Hematology, 5th Edition
  14. 14. The sites of cellular biosynthesis Endoplasmic reticulum: – VWF dimer that is disulfide-bonded at the C-terminus. – The signal peptide is then cleaved. Golgi: – Carbohydrate. Post-Golgi: – N-linked multimerization by self-association of the von Willebrand Weibel-Palade bodies: Storage granules termed. Regulated secretion of fully multimerized VWF and self- associated vWF dimmers. A regulated pathway also is assumed to occur in megakaryocytes in which the secretory granule is the platelet -granule, a source of in vivo VWF release
  15. 15. Multimer Structure of vWF • Type 1; Decease in all multimer sizes • Type 2; Decrease in large multimers • Type 3; Absence of VWFImage by Marlies Ledford. InHoffman’s Hematology, 5th Edition
  16. 16. Weibel-Palade Bodies of Endothelial Cells A BA. Immunofluorescence staining of a human umbilical vein endothelial cell.VWF is present in the perinuclear region, where it is synthesized and in the Weibel-Palade bodies (arrowhead) throughout the cytoplasm. Bar = 10 μm.B. Electron micrograph of Weibel-Palade bodies of the same origin. Bar = 0.5 μm. VWF,von Willebrand factor.
  17. 17. The Von Willebrand Factor Receptor (GPIb-V-IX Complex)• Glycoprotein Ib/V/IX is a complex of the products of four genes.• Deficiency of any results in loss of the receptor.
  18. 18. Von Willebrand Disease: Overview Mutations in von Willebrand factor result in deficient or defective von Willebrand factor antigen and von Willebrand factor activity (Ristocetin cofactor). These are usually accompanied by a decrease in FVIII coagulant activity (FVIII:C), because normal expression of FVIII:C in the circulation is dependent on FVIII:C complexing with its carrier protein, von Willebrand factor. The coagulation screening tests typically associated with the defects in von Willebrand factor and FVIII:C include a prolonged activated partial thromboplastin time (APTT) and a long bleeding time.
  19. 19. Symptoms of vWD; Mucocutaneous Bleeding• Easy bruising• Epistaxis• Postoperative or Posttraumatic bleeding• Mucosal Bleeding – Gastrointestinal – Genitourinary tracts.• Menorrhagia.• Rare for hemarthrosis, deep bleeds.
  20. 20. DefinitionsVWD Autosomally inherited bleeding disorder with a reduced amount or function of VWF.VWF The glycoprotein that is abnormal or present in reduced amounts in patients with VWD.vWF:Ag VWF antigen/ the detection and quantitation of VWF by(FVIIIR:Ag) immunoassay.vWF R:Co Ristocetin cofactor; A measure of VWF function using the antibiotic ristocetin, which induces VWF binding to platelets.vWF The multiple molecular forms of VWF.MultimersvWF Subunits The intact or degraded subunits of VWF multimers, identified after the complete reduction of VWF disulfide bonds.F VIII (Anti-hemophilia Factor). VWF serves as a FVIII carrier proteinFVIIIC:Ag Factor VIII coagulant antigen
  21. 21. VWD Mutations(From Nichols WC, Ginsburg D: von Willebrand disease. Medicine 76:1, 1997.)In Hoffman’s Hematology, 5th Edition
  22. 22. Classifications of VWD: Major TypesType 1; Partial Quantitative DefectType 2; Qualitative Defect. Loss of large molecular weight multimersType 3; Complete Deficiency of VWF
  23. 23. Multimer Structure of vWF • Type 1; Decease in all multimer sizes • Type 2; Decrease in large multimers • Type 3; Absence of VWFImage by Marlies Ledford. InHoffman’s Hematology, 5th Edition
  24. 24. Classification of von Willebrand DiseaseType Description 1 Partial quantitative deficiency of VWF 2 Qualitative deficiency of VWF Decreased platelet-dependent VWF function with2A selective deficiency of high-molecular-weight multimers2B Increased affinity for platelet GPIb Decreased platelet-dependent VWF function with high-2M molecular-weight multimers present2N Markedly decreased binding of factor VIII to VWF 3 Complete deficiency of VWF
  25. 25. VWD TypesVWD VIII VWF:Ag R:Co MultimersType 1 Low Low Low Nl in Plasma & Platelets2A Low or Nl Low or Nl Decreased Absent large relative to Ag and medium 2B Low or Nl Low or Nl Increased at Low Absent large Concentrations and medium2N Moderate to Nl Nl Normal Severe decrease 3 Moderate to Absent Absent None or Trace severe decrease (or trace)
  26. 26. VWD: Type 1• Most common form – Approximately 75%-80% of VWD patients – Generally mild to moderate• Characterized by – Proportionately reduced levels of FVIII, VWF:RCo, and VWF:Ag – Functionally and structurally normal VWF
  27. 27. VWD: Type 2 Variants• Approximately 15%-21% of patients with VWD• Qualitative VWF abnormality• Most common variants are 2A, 2B, 2M, 2N
  28. 28. VWD: Type 2AAbsence of large and intermediate- sized VWF multimers10%-12% of all VWD patientsMutations result in either – Increased proteolysis or – Decreased cellular processing and release
  29. 29. VWD: Type 2B• Increased VWF affinity for platelet GPlb and secondary clearance of large-sized multimers• 3%-5% of all VWD patients• Thrombocytopenia may be present.
  30. 30. VWD: Type 2N• Also called VWD Normandy and autosomal hemophilia• 1%-2% of all VWD patients• Mutation in region of FVIII binding• Autosomal recessive inheritance• Compound heterozygotes with type 1 VWD or true homozygotes are those that are clinically affected• Sometimes misdiagnosed as mild hemophilia
  31. 31. VWD: Type 2M• Characterized by decreased binding to platelet GPIb• 1%-2% of all VWD patients• Abnormal multimers, but not associated with selective loss of large molecular weight forms.
  32. 32. VWD: Type 3• 1%-3% of all VWD patients• Characterized by virtually no detectable VWF:Ag and markedly decreased FVIII:C (< 5 U/dL)• Patients suffer from severe, spontaneous bleeds – Mucosal bleeds are common – May experience joint bleeds similar to hemophilia• Inhibitors to VWF may develop following replacement therapy.
  33. 33. Approach to the Assessment of vWD Bleeding history – Family History Complete blood cell count vWD profile testing – vWF:Ag – vWF:RCo – fVIII:C ABO Blood Type
  34. 34. Diagnosing VWD: Initial Evaluation Detailed personal and family history is key Screening laboratory values are often normal – Platelet count – Prothrombin time (PT) – Activated partial thromboplastin time (aPTT) Bleeding time (BT) is an insensitive screening tool for type 1 disease Hambleton J. Curr Opin Hematol. 2001;8:306-311.
  35. 35. Laboratory Diagnosis• vWF activity (Ristocetin Cofactor)• vWF antigen• factor VIII activity• vWF multimeric analysis• ABO Blood Type• Bleeding time (PFA 100)
  36. 36. Ristocetin-Induced Platelet Agglutination
  37. 37. Figure 14-8. Binding of von WiIlebrand factor (VWF) to formalin-fixed platelets
  38. 38. Effects of ABO Blood Group on vWF Levels ABO Type N Mean (%) Mean +/- 2 SD (%) O 456 74.8 (35.6-157.0) A 240 105.9 (48.0-233.9) B 196 116.9 (56.8-241.0) AB 109 123.3 (63.8-238.2)Gill JC, Endres-Brooks J, Bauer PJ, et al: The effect of ABO blood groupon the diagnosis of von Willebrand disease. Blood 1987; 69:1691.
  39. 39. Modifying Conditions• Conditions associated with higher VWF levels – Age – Acute and chronic inflammation – Diabetes – Malignancy – Pregnancy or oral contraceptive use – Stress; exercise – Hyperthyroidism• Conditions associated with reduced VWF levels – Hypothyroidism – O Blood type
  40. 40. Treatment of vWD
  41. 41. Treatment of vWD DDAVP; 0.3 ug/kg IV daily for 1-2 doses – (Stimate by nasal spray, 100 ug/spray. 10% bioavailability) – Good for mild or prophylactic therapy – Can worsen Type 2B (Thrombocytopenia) and no good for type 3 – Best to test dose in nonemergent setting. Humate P (F VIII Concentrate with large multimers) – Minor bleed; 15-20 Un/kg IV, and repeat q 24 as needed. – Major bleeds; 40-50 U/Kg, then 20-30 U/kg q 12 hr. – (Dose based on R:Co activity, 0.5 R:Co/1.0 FVIII Units)
  42. 42. Treatment: Mild VWD• Specific therapies include – DDAVP (synthetic derivative of vasopressin) • Parenteral (IV or SQ) • Intranasal (high concentrations) – Plasma-derived FVIII products containing high concentrations of VWF • Humate-P (FDA approved), Alphanate, Koate • DO NOT use cryoprecipiate
  43. 43. Treatment: VWD• Adjuvant therapies – Antifibrinolytics • Amicar, cyklocapron – Fibrin glue – PO or parenteral estrogen
  44. 44. DDAVP• A synthetic version of vasopressin• Increases plasma VWF concentrations by stimulating its release from intracellular stores in endothelial cells• Treatment of choice for type 1• Variable response in types 2A, 2B, and 2M• Ineffective in type 3 (cont)
  45. 45. DDAVP• Side effects include – Flushing – Hyponatremia, seizures – Headache – Abdominal cramps – Alteration in blood pressure• Tachyphylaxis may occur if dosed too frequently
  46. 46. DDAVP: Indications Generally used as treatment for spontaneous or trauma-induced injuries in patients with mild to moderate VWD Frequently used to treat – Mucosal bleeding – Menorrhagia – Minor surgical procedures after documenting patient response Contraindicated in individuals with known hypersensitivity or significant side effects
  47. 47. Humate-P: VWF:RCo Dosing Major bleeds – Loading dose of 40-60 IU/kg body weight – Then, 40-50 IU/kg every 8-12 hours for 3 days – Maintain VWF:RCo 50% – Then, 40-50 IU/kg body weight daily 7 days Minor bleeds in moderate to severe patients (eg, menorrhagia, epistaxis) – 40-50 IU/kg body weight – 1 or 2 doses
  48. 48. Humate-P: VWF:RCo Dosing• Major bleeds in moderate to severe patients (eg, CNS trauma, hemarthroses) – Loading dose of 50-75 IU/kg body weight – Then, 40-60 IU/kg body weight every 8-12 hours for 3 days • Maintain VWF:RCo 50% – Then, 40-60 IU/kg body weight daily 7 days
  49. 49. Acquired VWD• Extremely rare – Fewer than 100 well-documented cases• Causes – Circulating inhibitors – Absorption – Proteolysis – Others• Underlying autoimmune disorder or malignancy is common• Treatment must target the underlying disorder as well as acute symptoms of bleeding• VWF concentrates are often required and sometimes less effective; successful use of rFVIIa has been reported
  50. 50. Pseudo-VWD• Rare disorder characterized by an intrinsic platelet defect with increased affinity of GPIb/IX for VWF• Increased aggregation on RIPA as with subtype 2B• Distinction that the patient has a platelet disorder as opposed to VWD is determined by additional testing

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