Week 7: Fibrinolysis and Thrombophilia

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Week 7 Fibrinolysis and Thrombophilia

• Secondary fibrinolysis
• Primary fibrinolysis
• Plasminogen
• FDP
• D-dimer
• DIC
• 3P test

• Hypercoagulable state
• Thrombophilia
• Activated protein C resistance (APCR)
• Factor V Leiden
• Antithrombin deficiency
• Anticoagulant therapy

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Fibrinolysis

• Plasminogen Activators
• Thrombin
• Tissue plasminogen activator (t-PA)
• Streptokinase
• Urokinase
• Kallikrein
• Fibrinolysis Inhibitors
• ?2 antiplasmin
• ?2 macroglobulin

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Fibrin(ogen) Degradation Product

• X fragment D-E-D
• Y fragment D-E
• Smallest fragments D and E
• D-dimers from fibrin degradation only (ie, 2o
  fibrinolysis, not 1o)

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Fibrin Degradation
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FDP Screen

• Thrombo-Wellco
• Anti-fibrinogen coated latex
• D-dimers
• Positive only with 2o fibrinolysis
• Plasma protaminesulfate paracoagulation (3P)
• Dissociate FM-FDP to allow FM to re-associate
• Also specific to 2o fibrinolysis

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Disseminated Intravascular Coagulation

• Triggering mechanism
• Trauma, injury, surgery
• Hemolysis
• AML M3
• Snake venom
• Amniotic fluid
• Dead fetus
• Gram negative endotoxin

• Consumptive
• Low PLT
• Long PT/APTT
• Low fibrinogen
• FDP, D-dimer
• Schistocyte
• Treatment
• Remove source of Tpl
• Heparin to stop cascade

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Disseminated Intravascular Coagulation
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DIC

• Syndrome, not disease
• 11,000 hospitalized patients, but many
  asymptomatic
• Tx removal of underlying cause if possible
• Support with FFP, PLT, RBC, etc.
• Low molecular weight heparin (LMWH)

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Primary Fibrinolysis

• Plasminogen activation without clotting
• Unknown mechanism

• Labs similar to DIC but important differences
• PLT unaffected
• No schistocyte
• Long PT/APTT
• Low fibrinogen
• FDP but no D-dimer

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Thrombophilia

• Tendency to form thombi
• Hereditary and acquired
• Hypercoagulable state
• Arterial thrombi usually in areas of
  atherosclerotic plaques
• Venous thrombi thrombophlebitis, DVT, pulmonary
  embolism

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Venous Thromboembolism

• Venous stasis
• Activated protein C resistance, factor V Leiden
• Protease inhibitor deficiency (antithrombin,
  protein C, protein S)

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Hereditary Thrombophilia

• Antithrombin deficiency
• Recurrent DVT
• Protein C deficiency
• Vitamin K dependent
• Inactivated Va and VIIIa
• Protein S deficiency
• Vitamin K dependent
• Protein C cofactor

• APCR
• Factor V Leiden
• Prothrombin gene mutation 20210

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Acquired Thrombophilia

• Antiphospholipid antibody e.g.,
  Lupus-anticoagulant
• Malignancy
• Oral contraceptives
• Post-op and trauma
• Myeloproliferative disorders

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Therapies

• Heparin
• Monitor with APTT
• LMWH no HIT
• Oral anticoagulants (e.g., Coumadin)
• Monitor with PT
• Thrombolytic agents (plasminogen activators)
• Streptokinase
• Urokinase
• t-PA

• Anti-platelet agents
• Aspirin
• Plavix
• IV inhibitors
• Direct thrombin inhibitors (e.g., hirudin - from
  leech saliva)
• Not dependent on AT-III
• Act on thrombins fibrin binding site

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Problems with Oral Anticoagulants

• GI hemorrhage
• Skin necrosis
• Antidote vitamin K

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Problems with Heparin

• Unfractionated Heparin may cause heparin induced
  thrombocytopenia (HIT) due to antibody against
  heparin-PF4 complex
• LMWH almost exclusively against Xa, less
  osteoporosis, less HIT
• Antidote protamine sulfate