An acquired syndrome characterized by systemic intravascular coagulation

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.

• Blood loss due to bleeding
• RBC destruction (hemolysis)

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