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 consulted 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 died 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     Characterized by deficiency/dysprotein of von Willebrand factor (VWF) Variable clinical manifestations A group of disorders, (Different types). It is estimated to occur at a frequency of 1-3%, but is symptomatic in only about one in 10,000. – 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;10:93110.
  10. 10. Von Willebrand Factor  A heterogeneous population of disulfide-linked multimers: – Basic unit is dimer of 250,000 Dalton subunits – vWF Molecules in circulation range from a single dimer (Mr about 500,000) to a polymer of about 80 subunits (Mr about 20 x 106 ).  Synthesized in megakaryocytes and endothelial cells, and stored in platelets and endothelial cells.
  11. 11. Von Willebrand Factor  Von Willebrand factor serves as a carrier protein for FVIII and promotes platelet aggregation after vessel injury.
  12. 12. 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
  13. 13. Cellular Biosynthesis  Endoplasmic reticulum: – VWF dimer 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 in endothelium. Regulated secretion of fully multimerized VWF and selfassociated vWF dimmers. Megakaryocytes/Platelets -granule
  14. 14. Structural Organization of Weibel-Palade bodies of Endothelial Cells: Tomogram sections and images showing VWF tubules. Berriman J A et al. PNAS 2009; 106:17407-17412
  15. 15. Multimer Structure of vWF  Image by Marlies Ledford. In Hoffman’s Hematology, 5th Edition   Type 1; Decrease in all multimer sizes Type 2; Decrease in large multimers Type 3; Absence of VWF
  16. 16. ADAMTS13 Processing of “UltraLarge” Molecular Weight vWF
  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 of Common Types  Decrease in vWF function (Ristocetin cofactor) and antigen. – Abnormal bleeding time or platelet function screen.  Decrease in FVIII coagulant activity (FVIII:C), – activated partial thromboplastin time (APTT) may be high-normal or elevated.
  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. Definitions VWD 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 (FVIIIR:Ag) VWF antigen/ the detection and quantitation of VWF by immunoassay. vWF R:Co Ristocetin cofactor; A measure of VWF function using the antibiotic ristocetin, which induces VWF binding to platelets. vWF Multimers The multiple molecular forms of VWF. vWF 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 protein FVIIIC: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  Image by Marlies Ledford. In Hoffman’s Hematology, 5th Edition   Type 1; Decrease in all multimer sizes Type 2; Decrease in large multimers Type 3; Absence of VWF
  24. 24. Classification of von Willebrand Disease Type 1 2 2A 2B 2M 2N 3 Description Partial quantitative deficiency of VWF Qualitative deficiency of VWF Decreased platelet-dependent VWF function with selective deficiency of high-molecular-weight multimers Increased affinity for platelet GPIb Decreased platelet-dependent VWF function with high-molecular-weight multimers present Markedly decreased binding of factor VIII to VWF Complete deficiency of VWF
  25. 25. VWD Types VWD Type 1 VIII VWF:Ag R:Co Multimers Low Low Low 2A Low or Nl Low or Nl Decreased relative to Ag 2B Low or Nl Low or Nl 2N Moderate to Severe decrease Moderate to severe decrease Nl Increased at Low Concentrations Nl Nl in Plasma & Platelets Absent large and medium Absent large and medium 3 Absent (or trace) Absent Normal None 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. Binding of von WiIlebrand factor (VWF) to formalin-fixed platelets
  38. 38. Effects of ABO Blood Group on vWF Levels ABO Type N Mean (%) O A B AB 456 240 196 109 74.8 105.9 116.9 123.3 Mean +/- 2 SD (%) (35.6-157.0) (48.0-233.9) (56.8-241.0) (63.8-238.2) Gill JC, Endres-Brooks J, Bauer PJ, et al: The effect of ABO blood group on 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  F VIII Concentrate with intact vWF multimers  – Humate P ®  Antifibrinolytic, Adjuvant therapies. – Amicar ®
  42. 42. 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, and 2M Ineffective in type 3 Can worsen Type 2B (Thrombocytopenia). Best to test dose in non-emergent setting. (cont)
  43. 43. DDAVP  0.3 ug/kg IV daily for 1-2 doses – (Stimate® by nasal spray, 100 ug/spray. 10% bioavailability) – Good for mild bleeds or prophylactic therapy  Side effects include – – – – –  Flushing Hyponatremia, seizures Headache Abdominal cramps Alteration in blood pressure Tachyphylaxis may occur if dosed too frequently
  44. 44. 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
  45. 45. Humate-P: VWF:RCo Dosing  Major bleeds – – – Maintain VWF:RCo  50% –  Loading dose of 40-60 IU/kg body weight Then, 40-50 IU/kg every 8-12 hours for 3 days 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
  46. 46. Acquired VWD  Extremely rare –  Causes – – – –    Fewer than 100 well-documented cases 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.
  47. 47. 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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