Acquired von Willebrand Syndrome in Aortic Stenosis

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Acquired von Willebrand Syndrome in Aortic
Stenosis

• The New England Journal of Medicine
• July 24th , 2003

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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
  

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• 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.

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• 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 .

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Acquired forms of vWD

• 1. Wilms tumor.
• 2. Congenital hear disease.
• 3. Systemic lupus erythmatosus.
• 4. Angiodysplasia.
• 5. Seizures disorders treated with valproate.
• 6. Hypothyroidism.

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ABSRACT

• Background
• Aortic-valve Stenosis can be complicated by
  bleeding that is associated with acquired type 2A
  von Willebrand syndrome . However, the prevalence
  cause of the haemostatic abnormality in aortic
  Stenosis are unknown .

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Methods

• We enrolled 50 consecutive patients with aortic
  Stenosis, who completed a standardized screening
  questionnaire to detect a H/O bleeding. 42
  patients with sever aortic Stenosis underwent
  valve replacement.

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

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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-binding activity 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.

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

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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.

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• Aortic-valve Stenosis can be commonly
  complicated by bleeding
• 1. G. I. Angiodysplasia Heydes syndrome.
• 2. Proteolysis of vWf as it passes via the
  Stenotic valve.

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METHODS patients

• Between 3 7/2001, 50 consecutive pts (20 F
  30 M)referred for evaluation of aortic Stenosis
  were enrolled in the study.
• pts were excluded if they were lt18 year old or
  not competent to give consent, had active
  endocarditis, had multivalvular disease, had ass.
  Coronary disease, or were receiving anti-platelet
  treatment that couldnt be stopped 10 days before
  surgery.

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• 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.

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METHODS screening for bleeding diathesis

• Each patients 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.

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METHODS Echo. evaluation

• One investigator assessed the hemodynamic
  performance of the aortic valve by
  trans-thoracic echo. _at_ base line _at_ 6 months
  post-operatively in the surgical group.

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• 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 lt 0.8 cm2
  /m2/BSA.

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(No Transcript)
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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.

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• 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 pts with
  vWf defect.

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• 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.

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RESULTS bleeding prevalence

• Among the 42 pts 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.

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

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RESULTS Surgical treatment

• 11 pts 65 yrs of age or younger received a
  mechanical bileaflet prosthetic device, 31 pts
  gt 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 pts with
  a preoperative H/O bleeding.

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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.

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

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RESULTS follow-up _at_ 6/12 N pts who underwent
surgery

• Two pts were lost to follow-up _at_ 6 months .
• One pt. Presented with early homograft valve
  Stenosis that required reoperation _at_ 6/12.in this
  pt., repeated epistaxis was observed _at_ the onset
  of restenosis.

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• The other 38 pts were a symptomatic _at_ 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

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• _at_ 6 months the platelet count were normal .
• The platelet-function-analyzer values, were
  abnormal in 66 of the pts.

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DISCUSSION

• This study evaluate the frequency
  determinants of acquired vW Syndrome bleeding
  in consecutive pts with A. Stenosis .
• Careful investigation showed that bleeding
  (mostly from skin mucosa) was present in 20 of
  the pts with sever A. Stenosis

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• 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

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• 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.

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• The present study demonstrates that acquired vW
  Syndrome is a consequence of the mechanical
  obstruction of blood flow that homeostatic
  abnormalities bleeding are symptoms of sever
  Stenosis.

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The End

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