Disorders of Hemostasis: Thrombosis

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Disorders of Hemostasis Thrombosis

• John Lazarchick, M.D.
• Director, Hematopathology/Hemostasis
• August 30, 2001

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Hypercoagulability

• Definition Alteration in the hemostatic balance
  between blood fluidity and clot formation. This
  is due to genetic and acquired disorders which
  shift this balance toward excessive or
  inappropriate platelet aggregation and fibrin
  formation and predispose to thrombosis.

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Prethrombotic States

• 10 - inherited abnormalities resulting from
  mutations affecting the function of coagulant
  proteins and natural inhibitors
• 20 - acquired defects that either affect the
  endothelium, fluid flow or blood components.
  These defects are often superimposed on 10 defects

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HypercoagulabilityPrethrombotic States

• Virchow (1856)
• Abnormalities of blood vessels
• Abnormalities of fluid flow
• Abnormalities of blood components

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Blood Vessel Abnormalities

• Endothelial cell antithrombotic properties- PGI2,
  NO2, TFPI, PAI-1, heparans, thrombomodulin
• Genetic predisposition and acquired defects in
  these functions increase the risk of arterial and
  venous thrombosis
• Role of dietary excesses, hypertension, diabetes
  mellitus, obesity, smoking, lipid abnormalities
  in atherosclerosis

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Atherosclerosis

• Endothelial injury and dysfunction
• LDL cholesterol oxidized LDL--- foam cells
• Diabetes mellitus glycated LDL cholesterol
• Smoking free radical production
• Hypertension smooth muscle proliferation
• Genetic alterations MTHFR mutations

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R. Ross. Atherosclerosis. NEJM 340115-126, 1999
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Atherosclerosis

• Site specific
• Bifurcations
• Branching vessels
• Curvatures
• Decreased shear stress and increased turbulence
• Plaque formation and rupture

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Unstable plaque. R.Ross NEJM 340115-126, 1999.
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Blood Flow Abnormalities

• Stasis is the underlying mechanism as the cause
  of venous or arterial thrombosis
• Conditions - immobilization, surgery, congestive
  heart failure, pregnancy, obesity.
• Increased blood viscosity
• RBCs - polycythemias, sickle cells
• WBCs myeloproliferative disorders especially
  CML
• Platelets - primary thrombocytosis
• Paraproteins - Myeloma, Waldenstroms
  Macroglobulinemia

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HypercoagualbilityHereditary/Acquired

• Factor V Leiden
• Prothrombin 20210
• Protein C
• Protein S
• Anti-thrombin III
• Dysfibrinogenemia

• Hyperhomocysteinemia
• PAI-I
• Platelet glycoprotein IIb/IIIa

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Factor V Leiden

• Mutation at position 506 rendering FV insensitive
  to degradation by activated protein C.
• Autosomal dominant 5 Caucasian population.
• Heterozygote - 7x increased risk for venous
  thrombosis
• Homozygote - 80x increased risk
• Often found in association with other risk
  factors - protein C and S deficiencies

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Prothrombin 20210 Mutation

• Mutation results in increased synthesis of
  prothrombin resulting in elevated plasma levels
  of biochemically normal prothrombin
• Autosomal dominant 1-2 of population
• Increased risk of venous thrombosis - 2x

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Protein C Deficiency

• Autosomal dominant
• Mutation results in mild to severe deficiency
  increase risk for venous thrombosis
  homozygote purpura fulminans
• 0.2 of US population
• Acquired - DIC, liver disease, oral
  contraceptives, oral anticoagulant use

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Protein S Deficiency

• Autosomal dominant
• Increased risk of venous thrombosis
• Acquired deficiencies - DIC, liver disease.
  coumarin therapy, pregnancy (2nd and 3rd
  trimesters), estrogen replacement therapy,
  L-asparginase chemotherapy

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Hyperhomocysteinemia

• Increased levels are associated with increased
  risk of arterial and venous thrombosis.
• Multiple effects on endothelial cells - decreased
  thrombomodulin, increased TF activity,
  inhibition of NO and TPA

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Hyperhomocysteinemia

• Primary - mutation of MTHFR gene
• Acquired - vitamin B12, B6 or folic acid
  deficiency, hypothyroidism, isoniazid,
  methotrexate, theophylline

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Hereditary Thrombophilia

• Consider if
• family history of thrombosis
• history of recurrent thrombosis
• thrombosis at a young age
• no acquired predisposing factors for thrombosis

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Malignancy

• Risk for thrombosis is multifactorial.
• Predominantly venous thrombosis - stasis, tumor
  invasion of vessels, chemotherapy effects
  superimposed on acquired or primary defects in
  hemostasis.
• Distinct procoagulant (cysteine protease) found
  in many patients which can activate FX directly.

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Antiphospholipid Antibody Syndrome

• Autoimmune disorder, either primary or secondary,
  associated with an increased risk for arterial
  and venous thrombosis.
• Antibody is to cardiolipin in APA (ELISA assay)
  antibody is to beta 2 glycoprotein 1 and platelet
  phospholipids in patients with lupus
  anticoagulants (aPTT and/or PT).

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Thrombus

• Size, shape and morphology
• Mural thrombus
• Infected thrombus bacterial endocarditis
• Verrucous thrombus Libman-Sacks
  endocarditis

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Thrombus

• Natural history
• Resolution
• Propagation
• Fragmentation/embolization
• Organization

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Resolution
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Propagation complete occlusion
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Fragmentation and Embolization
F
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Organization Fibroblast proliferation
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Organization Endothelial cell differentiation
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Resolution
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Organization - Rethrombosis
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Thrombus

• Clinical presentation
• Arterial coronary, carotid and femoral
• Acute MI, Angina
• CVA, TIA
• Claudication
• Venous superficial veins, deep veins
• Thrombophlebitis, swollen, painful extremity
• Pulmonary embolus

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