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Acquired von Willebrand Syndrome in Aortic Stenosis

Acquired von Willebrand Syndrome in Aortic Stenosis. The New England Journal of Medicine July 24 th , 2003. Von Willebrand Disease. vWD is due to an abnormality ,either quantitative ,absence or qualitative of the vWf. vWf is a large multimeric glycoprotein that function as :

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Acquired von Willebrand Syndrome in Aortic Stenosis

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  1. Acquired von Willebrand Syndrome in Aortic Stenosis The New England Journal of Medicine July 24th , 2003

  2. Von Willebrand Disease vWD is due to an abnormality ,either quantitative ,absence or qualitative of the vWf. vWf is a large multimeric glycoprotein that function as : 1.the factor Vlll carrier protein (vWf protect factor Vlll from degradation). 2.required for normal platelet adhesion (vWf binds on platelet to its specific receptor glycoprotein lb & acts as adhesive bridge between the platelet & damaged sub- endothelium at the site of vascular injury

  3. vWf is composed of dimeric subunits that are linked by disulfide bonds to form complex multimers of low ,intermediate & high molecular weights . The small multimers function mainly as carriers for factor Vlll.

  4. High molecular weight multimers have higher numbers of platelet-binding sites & greater adhesive properties . Each multimeric subunit has binding sites for the receptor glycoprotein lb on non-activated platelets & the receptor glycoprotein llb/llla on activated platelets, this facilitates both platelet adhesion & aggregation .

  5. Acquired forms of vWD 1. Wilm’s tumor. 2. Congenital hear disease. 3. Systemic lupus erythmatosus. 4. Angiodysplasia. 5. Seizures disorders treated with valproate. 6. Hypothyroidism.

  6. ABSRACT Background Aortic-valve Stenosis can be complicated by bleeding that is associated withacquired type 2A von Willebrandsyndrome . However, the prevalence & cause of the haemostatic abnormality in aortic Stenosis are unknown .

  7. Methods: We enrolled 50 consecutive patients with aortic Stenosis, who completed a standardized screening questionnaire to detect a H/Obleeding. 42 patients with sever aortic Stenosis underwent valve replacement.

  8. Platelets function under conditions of high shear stress, vWf collagen-binding activity & Ag levels, & the multimeric structure of vWf were assessed @ base line & 1 day, 7 days, & six months post-operatively.

  9. Results: Skin or mucosal bleeding occurred in 21% of the patients with sever aortic Stenosis. Platelets-function abnormalities under condition of high shear stress, decreased vWf collagen-bindingactivity & the loss of the largest multimers, or a combination of these was present in 67 – 92 % of patients with sever aortic Stenosis & correlated significantly with the severity of valve Stenosis.

  10. 1ry haemostatic abnormalities were completely corrected on the 1st day after surgery but tended to recur @ 6/12, especially when there was a mismatch between pt. & prosthesis (with an effective orifice area of < 0.8 cm2/m2/BSA)

  11. Conclusions: Type 2A vW Syndrome is common in patients with sever aortic Stenosis. vWf abnormalities are directly related to the severity of aortic Stenosis & are improved by valve replacement in the absence of mismatch between patient & prosthesis.

  12. Aortic-valve Stenosis can be commonly complicated by bleeding: 1. G. I. Angiodysplasia [Heyde’s syndrome]. 2. Proteolysis of vWf as it passes via the Stenotic valve.

  13. METHODS [patients] Between 3 & 7/2001, 50 consecutive pt’s (20 F & 30 M)referred for evaluation of aortic Stenosis were enrolled in the study. pt’s were excluded if they were <18year old or not competent to give consent, hadactive endocarditis, had multivalvular disease, had ass. Coronary disease, or were receiving anti-platelet treatment that couldn’t be stopped 10 days before surgery.

  14. 42 patients (18 F & 24 M, 70 +/-10 years) had sever aortic Stenosis & subsequently underwent aortic-valve replacement . 8 Patients ( 66 +/- years) had only moderate aortic Stenosis & did not undergo surgery.

  15. METHODS [screening for bleeding diathesis] Each patient’s bleeding symptoms were evaluated by the use of a standardized screening questionnaire. Only bleeding during the 6 months preceding evaluation was repeated six months post-operatively in group undergoing surgery.

  16. METHODS [Echo. evaluation] One investigator assessed the hemodynamic performance of the aortic valve by trans-thoracic echo. @ base line & @ 6 months post-operatively in the surgical group.

  17. The mean & peak transvalvular pr. Gradients were calculated with Bernoulli equation,the effective orifice area was calculated by the continuity equation & the wall shear stress. At six months post-operatively, a mismatch between the patient & prosthesis was defined as an indexed effective orifice area of < 0.8 cm2 /m2/BSA.

  18. METHODS [blood collecting & lab. Assays] In patients with sever A. Stenosis, blood samples were collected the day before the surgery & one day, 7 days & 6 months after surgery. In patients with moderate A. Stenosis, blood samples were collected on the day of Echo.

  19. Platelet-related hemostasis was tested with a platelet-analyzer (a high shear system for in vitro testing of platelet function that stimulate 1ry hemostasis after injury to a small vessel) by determining closure time of adenine di-phosphate cartilages. It is highly sensitive way to screen pt’s with vWf defect.

  20. Plasma vWf Ag was measured by immuno-tubidimetry,& factor Vlll coagulant activity by 1 stage clotting assay with factor Vlll -deficient plasma. The multimeric structure of plasma vWf was analyzed by electrophoresis with 0.15 Na dodicyl sulfate + 1.5% agarose gel.

  21. RESULTS [bleeding prevalence] Among the 42 pt’s with sever Aortic Stenosis , 11 had episodes of bleeding in the 6 months before surgery. In 2 , the bleeding episode occurred during oral anti-coagulant treatment & was not taken into account in further analysis.

  22. Thus,9 of 42 pt’s had @ least 1 episode of bleeding. One pt. had a H/O major bleeding (epistaxis) that needed a blood transfusion. Among the 8 pt’s with moderate aortic Stenosis, two had H/O hemorrhagic syndrome,both while receiving anti-platelets agents.

  23. RESULTS [Surgical treatment] 11 pt’s 65 yrs of age or younger received a mechanical bileaflet prosthetic device, & 31 pt’s > 65 yrs if age received a biologic device {29 pericardial valves/ 1 stentless porcine valve, & 1 cryopreserved aortic homograft}. Mechanical devices were implanted in 3 pt’s with a preoperative H/O bleeding.

  24. RESULTS [immediate postoperative course] The blood loss 24 hrs after replacement was 120 to 1580 ml. One pt. Underwent re-operation for bleeding on the day after surgery. One other pt. Died from V.F. 10 days after surgery. The multimeric pattern of vWf determined in 1 pt. 3 hrs after surgery was also normalized.

  25. the postoperative blood loss was significantly higher in pt’s with preoperative bleeding than in those without preoperative bleeding 195 to 1580 ml versus 120 to 700 ml. 6 pt’s, all with a preoperative H/O bleeding, had a blood loss greater than 700 ml.

  26. RESULTS [follow-up @ 6/12 N pt’s who underwent surgery] Two pt’s were lost to follow-up @ 6 months . One pt. Presented with early homograft valve Stenosis that required reoperation @ 6/12.in this pt., repeated epistaxis was observed @ the onset of restenosis.

  27. The other 38 pt’s were a symptomatic @ 6 months, without bleeding episodes, even those who had a preoperative H/O bleeding & had a mechanical prosthesis requiring oral anticoagulant therapy. A mismatch between pt. & prosthesis was observed in 10 cases

  28. @ 6 months the platelet count were normal . The platelet-function-analyzer values, were abnormal in 66% of the pt’s.

  29. DISCUSSION Thisstudy evaluate the frequency & determinants of acquired vW Syndrome & bleeding in consecutive pt’s with A. Stenosis . Careful investigation showed that bleeding (mostly from skin & mucosa) was present in 20% of the pt’s with sever A. Stenosis

  30. Moreover, prolongation of the platelet-function analyzer closure time ( a measure of platelet function under high shear stress conditions ), abnormalities of vWf , or both were common in sever aortic Stenosis

  31. We also demonstrated that vWf abnormalities increased with the pr. gradient & the Stenosis-induced shear stress, indicating that vWf abnormalities are related to the severity of the A. Stenosis . Together, these data suggest that the haemostatic defect is related mostly to direct proteolysis of the largest multimers of vWf.

  32. The present study demonstrates that acquired vW Syndrome is a consequence of the mechanicalobstruction of blood flow & that homeostatic abnormalities & bleeding are symptoms of sever Stenosis.

  33. The End thanks

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