An acquired syndrome characterized by systemic intravascular coagulation



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An acquired syndrome characterized by systemic intravascular coagulation

  • An acquired syndrome characterized by systemic intravascular coagulation

  • Coagulation is always the initial event.

  • Most morbidity and mortality depends on extent of intravascular thrombosis

  • Multiple causes



Diseases……DIC

  • Diseases……DIC

  • 2 mechanism

  • Cytokines ….activated….coagulation activation

  • (sepsis and major traumas

  • Procoagulants ….. ın the blood stream

  • (malignancy and obstetric cases)



DIC pathogenesis

  • DIC pathogenesis



Vascular Endothelium

  • Vascular Endothelium

  • Blood Flow Dynamics

  • Platelets

  • Coagulation cascade

  • Anticlotting Mechanisms

  • Fibrinolytic System





An acquired syndrome characterized by systemic intravascular coagulation

  • An acquired syndrome characterized by systemic intravascular coagulation

  • Coagulation is always the initial event











Activation of Blood Coagulation

  • Activation of Blood Coagulation

  • Suppression of Physiologic Anticoagulant Pathways

  • Impaired Fibrinolysis

  • Cytokines



Activation of Blood Coagulation

  • Activation of Blood Coagulation

    • Tissue factor/factor VIIa mediated thrombin generation via the extrinsic pathway
      • complex activates factor IX and X
    • TF
      • endothelial cells
      • monocytes
      • Extravascular:
        • lung
        • kidney
        • epithelial cells


Suppression of Physiologic Anticoagulant Pathways

  • Suppression of Physiologic Anticoagulant Pathways

    • reduced antithrombin III levels
    • reduced activity of the protein C-protein S system
    • Insufficient regulation of tissue factor activity by tissue factor pathway inhibitor (TFPI)
      • inhibits TF/FVIIa/Fxa complex activity


Impaired Fibrinolysis

  • Impaired Fibrinolysis

    • relatively suppressed at time of maximal activation of coagulation due to increased plasminogen activator inhibitor type 1


Cytokines

  • Cytokines

    • IL-6, and IL-1 mediates coagulation activation in DIC
    • TNF-
      • mediates dysregulation of physiologic anticoagulant pathways and fibrinolysis
      • modulates IL-6 activity
    • IL-10 may modulate the activation of coagulation


Presence of disease associated with DIC

  • Presence of disease associated with DIC

  • Appropriate clinical setting

    • Clinical evidence of thrombosis, hemorrhage or both.
  • Laboratory studies

    • no single test is accurate
    • serial test are more helpful than single test


Malignancy

  • Malignancy

    • Leukemia
    • Metastatic disease
  • Cardiovascular

    • Post cardiac arrest
    • Acute MI
    • Prosthetic devices
  • Hypothermia/Hyperthermia



Infectious/Septicemia

  • Infectious/Septicemia

    • Bacterial
      • Gm - / Gm +
    • Viral
      • CMV
      • Varicella
      • Hepatitis
    • Fungal
  • Intravascular hemolysis

  • Acute Liver Disease







Fragments

  • Fragments

  • Schistocytes

  • Paucity of platelets



D-dimer*

  • D-dimer*

  • Antithrombin III*

  • F. 1+2*

  • Fibrinopeptide A*

  • Platelet factor 4*

  • Fibrin Degradation Prod

  • Platelet count

  • Protamine test



Thrombocytopenia

  • Thrombocytopenia

    • plat count <100,000 or rapidly declining
  • Prolonged clotting times (PT, APTT)

  • Presence of Fibrin degradation products or positive D-dimer

  • Low levels of coagulation inhibitors

    • AT III, protein C
  • Low levels of coagulation factors

    • Factors V,VIII,X,XIII
  • Fibrinogen levels not useful diagnostically



Severe liver failure

  • Severe liver failure

  • Vitamin K deficiency

  • Liver disease

  • Thrombotic thrombocytopenic purpura

  • Congenital abnormalities of fibrinogen

  • HELLP syndrome



Stop the triggering process .

  • Stop the triggering process .

    • The only proven treatment!
  • Supportive therapy

  • No specific treatments

    • Plasma and platelet substitution therapy
    • Anticoagulants
    • Physiologic coagulation inhibitors


Indications

  • Indications

    • Active bleeding
    • Patient requiring invasive procedures
    • Patient at high risk for bleeding complications
  • Prophylactic therapy has no proven benefit.

  • Cons:

  • Fresh frozen plasma(FFP):

    • provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts.
    • Usual dose is 10-15 ml/kg


Indications

  • Indications

    • Active bleeding
    • Patient requiring invasive procedures
    • Patient at high risk for bleeding complications
  • Platelets

    • approximate dose 1 unit/10kg


Replaced as needed to maintain adequate oxygen delivery.

  • Replaced as needed to maintain adequate oxygen delivery.



Antithrombin III

  • Antithrombin III

  • Protein C concentrate

  • Tissue Factor Pathway Inhibitor (TFPI)

  • Heparin



The major inhibitor of the coagulation cascade

  • The major inhibitor of the coagulation cascade

    • Levels are decreased in DIC.
    • Anticoagulant and antiinflammatory properties
  • Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%).

    • Experimental data indicated a beneficial effect in preventing or attenuating DIC in septic shock
      • reduced DIC scores, DIC duration, and some improvement in organ function
    • Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes.
    • A clear benefit has not been established in clinical trials.


Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin.

  • Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin.

  • Protein S is a cofactor

  • Therapeutic use in DIC is experimental and is based on studies that show:

    • Patients with congenital deficiency are prone to thromboembolic disease.
    • Protein C levels are low in DIC due to sepsis.
    • Levels correlate with outcome.
    • Clinical trials show significantly decreased morbidity and mortality in DIC due to sepsis.


Tissue factor is expressed on endothelial cells and macrophages

  • Tissue factor is expressed on endothelial cells and macrophages

  • TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin from prothrombin

  • TF inhibition may also have antiinflammatory effects

  • Clinical studies using recombinant TFPI are promising.



Use is very controversial. Data is mixed.

  • Use is very controversial. Data is mixed.

  • May be indicated in patients with clinical evidence of fibrin deposition or significant thrombosis.

  • Generally contraindicated in patients with significant bleeding and CNS insults.

  • Dosing and route of administration varies.

  • Requires normal levels of ATIII.



Rarely indicated in DIC

  • Rarely indicated in DIC

    • Fibrinolysis is needed to clear thrombi from the micro circulation.
    • Use can lead to fatal disseminated thrombosis.
  • May be indicated for life threatening bleeding under the following conditions:

    • bleeding has not responded to other therapies and:
    • laboratory evidence of overwhelming fibrinolysis.
    • evidence that the intravascular coagulation has ceased.
  • Agents: tranexamic acid, EACA



DIC is a syndrome characterized systemic intravascular coagulation.

  • DIC is a syndrome characterized systemic intravascular coagulation.

  • Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality.

  • Important link between inflammation and coagulation.

  • Morbidity and mortality remain high.

  • The only proven treatment is reversal or control of the underlying cause.



Thrombin....endotelium....TM....TM+ thrombin ....Pr. C act....act FV and FVIII inact

  • Thrombin....endotelium....TM....TM+ thrombin ....Pr. C act....act FV and FVIII inact

  • TM+ thrombin.......fibrin formation decresed





Plazminogen decreased

  • Plazminogen decreased

  • fibrin deposition in tissues

  • fibrinolitic act. İnsufficient

  • multi system involvement



Endotelium …. TM decreased

  • Endotelium …. TM decreased

  • TM dec……… Pr C activation decreased

  • Pr C decreased in blood

  • Fibrinolizis decreased

  • Thrombus increased (APC FV, FVIII protrombinaz and tenaz inhibition)



Bleeding

  • Bleeding

  • 70-90 % of patients

  • skin (petechia, echimozis , hematomas)

  • GIS

  • GUS (hematuria, vaginal)

  • Pulmoner

  • catheter and from surgery lesions

  • Thromboembolic complications

  • 10-40 % of patients

  • especially in cancer patients

  • tissue and organ disfunction



Screening tests

  • Screening tests

  • platelet count

  • Protrombin time

  • aPTT

  • Trombin time

  • Fibrinogen level

  • easy , cheap could be done every where



  • Tests to evaluate Thrombin formation

  • D-dimer

  • Fibrin Monomers

  • Fibrinopeptide A

  • Prothrombin fragment 1-2

  • Trombin-Antitrombin

  • complicated

  • could not be done in every lab

  • more spesific for diagnosis



rTFPI ( Tifacogin )

  • rTFPI ( Tifacogin )

  • APC ( Drotecogin )

  • Recombinant TM

  • AT3 ( Atenativ and Kybernin)

  • C1 inhibitor : C1 PK, and FXII inhibitor



DIC systemic intravaskular coagulation

  • DIC systemic intravaskular coagulation

  • coagulation …..vascular thrombosis

  • Enflamation….. coagulation

  • Morbidity and mortality

  • The best treatment to treat the basic reason





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