Disseminated Intravascular

Coagulation
DIC
 An acquired syndrome
characterized by systemic 6

Thrombosis
intravascular
coagulation Platelet
Red Blood Cell

 Coagulation is always the

initial event. Fibrin

 Most morbidity and

mortality depends on
extent of intravascular WWW. Coumadin.com

thrombosis
Hemostasis Review
 Coagulation cascade
 Vascular Endothelium
 Anticlotting Mechanisms
 Fibrinolytic System
 Platelets
 Blood Flow Dynamics

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Vascular Endothelium
 Vascular endothelium
expresses:
 Thrombomodulin
 Tissue Plasminogen
Activator
 Tissue
thromboplastin/Tissue
factor

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Coagulation
 Intrinsic Pathway 5

Coagulation Pathways
 Extrinsic Pathway Intrinsic Pathway Extrinsic Pathway

 Common Pathway Contact

XI
IX TF Pathway
TF-VII a
Tissue Factor + VII
X

 Contact Pathway XIIa HK a PL Common Pathway

Prothrombin
XIa
 Tissue Factor Pathway IXa
PL (Tenase)
PL
VIIIa
Xa
 Primary factor in DIC (Prothrombinase)
Va XIII

Protein C, Protein
Thrombin
S, Antithrombin III
XIIIa
Fibrinogen Fibrin Fibrin
(weak) (strong)

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Anticlotting Mechanisms
 Antithrombin III (ATIII): 5

 The major inhibitor of the Coagulation Pathways

coagulation cascade. Intrinsic Pathway Extrinsic Pathway
 Inhibits Thrombin Contact IX TF Pathway Tissue Factor + VII
XI TF-VIIa X
 Inhibits activated Factors IX, X,
XI, and XII. XIIa HK a PL Common Pathway
Prothrombin
 Activity is enhanced by heparin. XIa
PL (Tenase)
IXa
 Tissue factor pathway inhibitor TFPI VIIIa
Xa
PL
Va XIII
(Prothrombinase)

Protein C, Protein
Thrombin
S, Antithrombin III
XIIIa
Fibrinogen Fibrin Fibrin
(weak) (strong)

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Anticlotting Mechanisms
 Protein C
 Activated by 5

Thrombin/Thrombomodulin Coagulation Pathways

 Anticoagulant and fibrinolytic Intrinsic Pathway Extrinsic Pathway

Contact IX TF Pathway Tissue Factor + VII

activity. XI TF-VIIa X

 Vitamin K and Protein S are XIIa HK a PL Common Pathway

Prothrombin
cofactors XIa
PL (Tenase)
IXa
 Protein S VIIIa
Xa
(Prothrombinase)
PL
Va XIII

Protein C, Protein
Thrombin
S, Antithrombin III
XIIIa
Fibrinogen Fibrin Fibrin
(weak) (strong)

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Fibrinolytic System
 Plasmin
 Produced from 7

Plasminogen by Tissue Fibrinolysis

Plasminogen activator Plasminogen
(TPA) Activation
Extrinsic: t-PA, urokinase
Intrinsic: factor XIIa, HMWK, kallikrein
 Degrades Fibrin and Exogenous: streptokinase

Fibrinogen (Fibrin Fibrin, fibrinogen

degradation products, Plasmin

FDP) Fibrin, fibrinogen

degradation products
 Degrades Factors V, VIII,
IX, XI, and XII.
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 Activity is inhibited by
Antiplasmin.
Fibrinolytic Inhibitors
 Antiplasmin
 Inactivates plasmin rapidly.
 Acts slowly on plasmin 7

sequestered in the fibrin clot. Fibrinolysis

 Inactivates factors XI and XII Plasminogen

slowly. Activation
Extrinsic: t-PA, urokinase
Intrinsic: factor XIIa, HMWK, kallikrein
 Plasminogen -Activator Exogenous: streptokinase

Fibrin, fibrinogen
Inhibitor-1(PAI-1)
Plasmin
 Inhibits the function of TPA
 Also has some inhibitory Fibrin, fibrinogen
degradation products
activity against urokinase,
plasmin, thrombin, activated
Protein C, factors and XII, and Www.coumadin.com

kallikrein
Hemostatic Balance

PAI-1 Prot. S

Antiplasmin Prot. C

Tissue factor* TFPI

Fibrinolytic System
Clotting Factors
ATIII

Procoagulant Anticoagulant
DIC SYSTEMIC ACTIVATION
OF COAGULATION

 An acquired syndrome
characterized by systemic
intravascular Intravascular Depletion of
deposition of platelets and
coagulation fibrin coagulation
factors
 Coagulation is always the
initial event
Thrombosis of
small and midsize Bleeding
vessels

Organ failure DEATH

Pathophysiology of DIC
 Activation of Blood Coagulation
 Suppression of Physiologic Anticoagulant
Pathways
 Impaired Fibrinolysis
 Cytokines
Pathophysiology of DIC
 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
Pathophysiology of DIC
 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
Pathophysiology of DIC
 Impaired Fibrinolysis
 relativelysuppressed at time of maximal activation of
coagulation due to increased plasminogen activator inhibitor
type 1
Pathophysiology of DIC - 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

Inflamation Coagulation
Diagnosis of DIC
 Presenceof 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
Conditions Associated With DIC
 Malignancy  Pulmonary
 Leukemia  ARDS/RDS
 Metastatic disease  Pulmonary embolism
 Cardiovascular  Severe acidosis
 Post cardiac arrest  Severe anoxia
 Acute MI
 Collagen vascular disease
 Prosthetic devices
 Anaphylaxis
 Hypothermia/Hyperthermia
Conditions Associated With DIC
 Infectious/Septicemia  Tissue Injury
 Bacterial  trauma
 Gm - / Gm +  extensive surgery
 Viral  tissue necrosis
 CMV
 head trauma
 Varicella

 Hepatitis
 Obstetric
 Fungal  Amniotic fluid emboli
 Placental abruption
 Intravascular hemolysis
 Eclampsia
 Acute Liver Disease
 Missed abortion
 Clinical Manifestations of DIC
ORGAN ISCHEMIC HEMOR.
Ischemic Findings Skin Pur. Fulminans Petechiae
are earliest! Gangrene Echymosis
Acral cyanosis Oozing
CNS Delirium/Coma Intracranial
Infarcts bleeding
Renal Oliguria/Azotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial
Dysfxn
Pulmonary Dyspnea/Hypoxia Hemorrhagic Bleeding is the most
Infarct lung obvious
GI Ulcers, Infarcts Massive clinical finding
Endocrine Adrenal infarcts hemorrhage.
Clinical Manifestations of DIC
Microscopic findings in DIC

 Fragments
 Schistocytes
 Paucity of platelets
Laboratory Tests Used in DIC
 D-dimer*  Thrombin time
 Antithrombin III*  Fibrinogen
 F. 1+2*  Prothrombin time
 Fibrinopeptide A*  Activated PTT
 Platelet factor 4*  Protamine test
 Fibrin Degradation Prod  Reptilase time
 Platelet count  Coagulation factor levels
 Protamine test
*Most reliable test
Laboratory diagnosis
 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
Differential Diagnosis
 Severe liver failure
 Vitamin K deficiency
 Liver disease
 Thrombotic thrombocytopenic purpura
 Congenital abnormalities of fibrinogen
 HELLP syndrome
Treatment of DIC
 Stop the triggering process .
 The only proven treatment!
 Supportive therapy
 No specific treatments
 Plasma and platelet substitution therapy
 Anticoagulants
 Physiologic coagulation inhibitors
Plasma therapy
 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
Platelet therapy
 Indications
 Active bleeding
 Patient requiring invasive procedures
 Patient at high risk for bleeding complications

 Platelets
 approximate dose 1 unit/10kg
Blood
 Replaced as needed to maintain adequate oxygen
delivery.
 Bloodloss due to bleeding
 RBC destruction (hemolysis)
Coagulation Inhibitor Therapy
 Antithrombin III
 Protein C concentrate
 Tissue Factor Pathway Inhibitor (TFPI)
 Heparin
Antithrombin III
 The major inhibitor of the coagulation cascade
 Levelsare 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
 Clinicaltrials have shown laboratory evidence of attenuation of
DIC and trends toward improved outcomes.
 A clear benefit has not been established in clinical trials.
Protein C Concentrates
 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:
 Patientswith 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 Pathway Inhibitor
 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.
Heparin
 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.
Antifibrinolytic Therapy
 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

Summary
 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.