DYSFIBRINOGENEMIA AND THROMBOSIS

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DYSFIBRINOGENEMIA AND THROMBOSIS

• BY AML GIRGIS,MD

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CASE HISTORY

• A 31 year old male went to his physician for
  evaluation of right leg pain.
• A DVT was diagnosed.
• The patient has family history for thrombosis.
• Laboratory tests for common inherited thrombosis
  disorders were negative.
• The patient was anticoagulated with
  unfractionated heparin and warfarin ,and he was
  referred to a hematologist for further evaluation.

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Dysfibrinogenemia and Thrombosis

• FIBRINOGEN Fibrinogen is a large plasma protein
  composed of 2 identical subunits linked by
  disulfide bonds and divided into 2 outer D
  domains and a central E domain.
• Each subunit is formed by 3 polypeptide chains,A
  alpha,B beta,and gamma,encoded as separate genes
  on chromosome 4.

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• The conversion of fibrinogen to an insoluble
  fibrin clot requires that the molecule be cleaved
  by thrombin in the E domain, so fibrinopeptide A
  and B been released.
• The release of fibrinopeptide A exposes new
  sites,which leads to spontaneous fibrin
  polymerization.
• After these molecules have polymerized, they are
  stabilized by covalent bonds formed through the
  action of factor XIII.
• The fibrin polymer then in turn stabilizes the
  friable platelet plug.

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• The final step in this pathway involves the
  digestion of the fibrin polymer by the
  fibrinolytic system during the process of wound
  healing and tissue remolding.

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Hemostasis

• (1) Vascular Phase
• the endothelial cells at the site of an injury
  will Have the basement membrane exposed.
  Released a variety of chemicals. Become
  sticky
• the smooth muscle cells in the blood vessel wall
  also respond to damage. They CONTRACT. By
  contracting , the blood vessel diameter decreases
  which help to reduce blood loss.

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Vascular Phase
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Coagulation Phase

• The coagulation phase is a sequence of chemical
  reactions that culminate in the conversion of
  fibrinogen into a meshwork of insoluble protein
  fibrin.
• The fibrin meshwork will grow and cover the
  surface of the platelet plug. RBCs and additional
  platelets are trapped in this tangle forming a
  blood clot that will seal the walls of the
  damaged blood vessel.

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SO WHAT IS DYSFIBRINOGENEMIA???

• DYSFIBRINOGENEMIA can thus result in impaired
  release of fibrinopeptides, defective fibrin
  polymerization,defects in fibrin cross-linking by
  factor XIII,or impaired fibrinolysis .
• The clinical presentation of dysfibrinogenemia
  can be a bleeding tendency,thrombophilia,impaired
  wound healing,or no clinically apparent disease.

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Dysfibrinogenemia Phenotypes and Mutations

• Dysfibrinogenemia can be either
  hereditary-transmitted as autosomal dominant
  trait -or acquired.
• The prevalence of hereditary thrombophilias in
  patients diagnosed with their first DVT is
  (factor V Leiden is 20,prothrombin mutation
  6,protein C deficiency 3,protein S deficiency
  1-2,antithrombin deficiency 1)

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Factor V Leiden

• Genetic mutation in the factor V gene causes
  change in the factor V protein making it
  resistant to inactivation by protein C.
• the result is that factor V Leiden is inactivated
  by activated protein C at a much slower rate ,
  thus leading to a thrombophilic state by having
  increased activity of factor V in the blood.

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Antithrombin Deficiency

• Anti thrombin is a potent inhibitor of the
  reactions of the coagulation cascade.
• Although the name , antithrombin , implies that
  it works only on thrombin , it actually serves to
  inhibit virtually all of the coagulation enzymes
  to at least some extent.
• Antithrombin acts as a relatively inefficient
  inhibitor on its own.However , when it is able to
  bind with heparin, the speed with which the
  reaction that causes inhibition occurs is greatly
  accelerated.

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Protein S Deficiency

• The function of protein S is to inactivate factor
  Va and factor VIIIa .This function is carried out
  directly by protein C ,and protein S serves as a
  cofactor.

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Protein C Deficiency

• The function of protein C is to inactivate factor
  Va and factor VIIIa.
• For patient that is born with both the copies of
  the protein C gene abnormal ,the result is often
  a sever form of thrombosis called purpura
  fulminans.

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Prothrombin Gene Mutation

• Prothrombin is the precursor to thrombin in the
  coagulation cascade.
• Thrombin is required in order to convert
  fibrinogen into fibrin, which is the primary goal
  of the coagulation cascade.
• The exact mechanism by which the prothrombin gene
  mutation results in a thrombophilic state is
  unclear

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Clinical presentation of hereditary
dysfibrinogenemia

• Approximately 55 are asymptomatic.
• 25 are associated with bleeding tendency.
• 20 are associated with thrombophilia by 2
  mechanismsFirst,impaired anticoagulant function
  which caused by mutations in the fibrin molecule
  that lead to defective binding of thrombin and
  result in the release of thrombin into
  circulation,which result in pathologic thrombosis.

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• Second, impaired profibrinolytic function which
  caused by defective binding of profibrinolytic
  proteins (tissue plasminogen activator,
  plasminogen) to fibrin or resistance of fibrin to
  the digestive action of plasmin, which also lead
  to pathologic thrombosis.

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Acquired Dysfibrinogenemia

• Most acquired dysfibrinogenemia are found in the
  setting of hepatocellular disease,includingcirrh
  osis,obstructive jaundice,acute liver failure,and
  hepatoma.
• The mechanism of acquired dysfibrinogenemia
  associated with liver disease involves impaired
  fibrin monomer polymerization .
• Dysfibrinogenemia in the setting of liver disease
  not associated with thrombosis.However
  thrombophilia associated with acquired
  dysfibrinogenemia without evidence of liver
  disease has been reported.

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Other Causes Of Acquired Dysfibrinogenemia

• Renal cell carcinoma.
• Allogenic bone marrow transplantation.
• Medications,includesmithramycin and
  L-asparaginase.
• Acquired dysfibrinogenemia has resolved with
  treatment of the underlying disease.

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Laboratory Testing For Dysfibrinogenemia

• THROMBIN CLOTTING TIME It is the primary test
  for dysfibrinogenemia.
• The thrombin time measures the rate of fibrin
  clot formation after the addition of a standard
  concentration of thrombin to citrated plasma.
• Thrombin cleaves the fibrinogen
  molecule,releasing 2 molecules of fibrinopeptide
  A and 2 molecules of fibrinopeptide B.

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• The fibrin monomers are then free to polymerize
  and form the fibrin clot.
• Dysfibrinogenemia prolong the thrombin time by
  inhibiting fibrinopeptide release or by
  inhibiting fibrin monomer polymerization.
• However, the specificity of this test is poor.
  High or low fibrinogen level, amyloidosis, the
  presence of fibrin degradation products,
  radiocontrast agents, monoclonal immunoglobulin ,
  acquired antibodies to bovine thrombin, and
  heparin have all prolong the thrombin time.

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• REPTILASE TIME the reptilase time is an
  alternative screening test.
• Reptilase is a snake venom, that cleaves
  fibrinogen in a manner that release only
  fibrinopeptide A.
• dysfibrinogenemia prolongs the reptilase time by
  inhibiting fibrinopeptide release or inhibiting
  fibrin monomer polymerization.
• The reptilase time is unaffected by heparin, and
  it can therefore improve the specificity of this
  test.

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• Prothrombin time and partial thromboplastin time
  had sensitivities of 96 and 65 respectively, in
  detecting dysfibrinogenemia .However , despite
  their low cost and wide availability, their lack
  of specificity make them poor screening tests.

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• CONFIRMATORY TESTING Fibrinogen concentration
  measured both functionally and antigenically,
  then expressed as a fibrinogen activity-antigen
  ratio,can be used as a confirmatory test if the
  screening test is positive.

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• TESTING FOR INHERITED VERSUS AQUIRED After the
  presence of dysfibrinogenemia has been
  established,whether the abnormality is inherited
  or acquired must be determined.
• If the liver function tests are normal and
  acquired dysfibrinogenemia secondary to renal
  cell carcinoma ,bone marrow transplant,or
  treatment with mithramycin or L-asparaginase has
  been excluded,then dysfibrinogenemia is likely
  inherited.

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• The most useful way to prove that an abnormality
  is hereditary is to demonstrate the presence of
  the defect in another family member.
• Other options include fibrinogen electrophoresis
  and molecular genetic analysis of the fibrinogen
  genes.

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TREATMENT

• The majority of patients with dysfibrinogenemia
  do not required any specific treatment.
• Bleeding complications can be managed with
  transfusion of either plasma or cryoprecipitate.
• Patients with repeated venous thrombotic episodes
  may require long term antithrombotic therapy.

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Case Conclusion

• Additional testing was done at a time when the
  patient not receiving heparin .
• The results are Thrombin time prolonged,
  Reptilase time prolonged, Fibrinogen functional
  and antigenic assay both are normal.
• CBC and chemistry panel were unremarkable.

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DIAGNOSIS AND TREATMENT

• Inherited dysfibrinogenemia was diagnosed, and
  the patient was anticoagulated with warfarin for
  1 year. The dysfibrinogenemia was not further
  characterized, and the patient has done well off
  anticoagulation for 2 years.

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SUMMARY

• Dysfibrinogenemia is a rare cause of
  thrombophilia.
• Dysfibrinogenemia,has varied clinical expression,
  including thrombophilia,increased bleeding
  tendency, impaired wound healing,or no apparent
  symptomatology.

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• The acquired forms of dysfibrinogenemia are
  frequently associated with liver disease and may
  have a reversible course with treatment of the
  underlying condition.
• The screening tests for dysfibrinogenemia are
  based on abnormal fibrin clot formation,
  reflected in abnormal thrombin and reptilase
  times.The poor specificity of these screening
  tests requires that they be confirmed by
  evaluation of the ratio of functionally active
  fibrinogen compared with fibrinogen detected by
  antigenic methods.

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• The acquired and hereditary forms of
  dysfibrinogenemia can be differentiated by liver
  function tests, testing family members, and ,if
  necessary ,analysis of fibrinogen protein or
  fibrinogen genes in the patient.
• Diagnosis of inherited dysfibrinogenemia as a
  cause of thrombosis should be pursued only when
  the more common causes of hereditary
  thrombophilia have been excluded.
• Treatment of thrombophilic dysfibrinogenemias
  should be assessed on a case -by-case basis
  because the expression of the disease can
  modulated by many coexisting factors.