Disseminated Intravascular Coagulation

Amanda Tipton Gyn/Onc November 2006

Mechanism

Levi, Marcel MD and Cate, Hugo MD. NEJM Disseminated Intravascular Coagulation Aug 19, 1999. Vol 341:586-592.

Multiple co-existing factors

1.

Increased generation of thrombin

Predominantly via extrinsic pathway and tissue factor Secondary generation of thrombin through intrinsic pathway

2.

Suppressed anti-coagulation
Reduced antithrombin III Suppressed Protein C system Insufficient action of tissue factor pathway inhibitor (TFPI)

3.

Increased availability of negatively charged phospholipid surface facilitating assembly and propagation of coagulation
Externalization of inner leaflet of cell membranes Microparticle formation secondary to cell damage Circulating lipoproteins

4. 5.

Impaired fibrinolysis Inflammation

Cytokines, serine proteases

Frachini, Massimo. Thrombosis Journal Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation Feb 2006, 4:4. Toh, Cheng Hock. BMJ. Disseminated Intravascular Coagulation: Old disease, new hope 2003:327:974-77.

In a Little More Detail

PAI-1 = plasminogen activator inhibitor type 1 TFPI = tissue factor pathway inhibitor

Levi, Marcel MD and Cate, Hugo MD. NEJM Disseminated Intravascular Coagulation Aug 19, 1999. Vol 341:586-592.

Toh, Cheng Hock. BMJ. 2003:327:974-77.

Causes


Infection/septicemia

Any microorganism bacterial, viral, parasitic, rickettsial, mycotic Triggered by membrane components of microorganism, i.e. endotoxin, exotoxin, LPS Soft tissue injury, fat embolism, head injury Combination of triggers: fat, phospholipids, hemolysis, endothelial injury, activation of cytokines Solid tumors, especially metastatic tumors and hematologic Tissue factor involved in mechanism Abruptio placentae, amniotic fluid embolism, retained deceased fetus, 2nd trimester abortion Due to leakage of thromboplastin-like material Degree of placental separation correlates with severity of DIC Usually short-lived and self-limited

Trauma & Burns

Malignancy

Obstetrical complications

More Causes


Vascular disorders

Hemangioma (Kasabach-Merritt syndrome), aortic aneurysm Local activation of coagulation leads to systemic depletion of factors; activated factors reach systemic circulation, causing DIC Pancreatitis, hepatic failure Snake bite, drugs Transfusion reaction, transplant rejection

  

Organ destruction

Toxins

Immunologic mediators

Levi, Marcel MD and Cate, Hugo MD. NEJM Disseminated Intravascular Coagulation Aug 19, 1999. Vol 341:586-592. Toh, Cheng Hock. BMJ. Disseminated Intravascular Coagulation: Old disease, new hope 2003:327:974-77.

Incidence


Varies depending on underlying cause

Gram negative or gram positive sepsis: 30-50% develop clinically overt DIC Severe trauma + SIRS: 50-70% Metastatic tumors, acute leukemia: ~15% Placental abruption, amniotic fluid embolism: >50% Severe preeclampsia: 7% Giant hemangioma: 25% Large aortic aneurysm: 0.5-1%
Levi, Marcel MD and Cate, Hugo MD. NEJM Disseminated Intravascular Coagulation Aug 19, 1999. Vol 341:586-592.

Signs & Symptoms



Diverse range of clinical manifestations

Bleeding Thrombosis Acrocyanosis Organ failure Diffuse bleeding Hemorrhagic tissue necrosis Thrombi of small and larger vessels Fibrin deposition in organs, leading to organ failure
Toh, Cheng Hock. BMJ. Disseminated Intravascular Coagulation: Old disease, new hope 2003:327:974-77.

Autopsy findings

Diagnostic Work-up


Clinical manifestations of bleeding, thrombosis and/or organ failure

PT o aPTT o Platelets q Initial level <100,000 or rapid decline

Laboratory findings

Fibrin degradation products (D-dimer) o Fibrinogen* nl/q Protein C q Antithrombin q Coagulation factors q

*An acute phase reactant, low sensitivity

Frachini, Massimo. Thrombosis Journal Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation Feb 2006, 4:4.

Treatment
 

TREAT THE UNDERLYING DISEASE!! Replacement therapy

Fresh frozen plasma **preferred Platelets, fibrinogen concentrates, cryoprecipitates Heparin or LMWH contradictory results
  

Anticoagulants

Safety in patients prone to bleeding? Low dose 300-500U/hr Likely of benefit in patients with extensive thromboemboli and fibrin deposition

Danaproid sodium, recombinant hirudin TFPI



Blocks tissue factor activity in endotoxin-induced DIC

Recombinant nematode anticoagulant protein c2 (NaPc2) inhibits complex between TF/VIIa and Xa
Frachini, Massimo. Thrombosis Journal Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation Feb 2006, 4:4.

Treatment (cont.)


Restore anticoagulation pathway

Antithrombin III


Might be of benefit in sepsis with improvement of DIC and organ function

Recombinant tissue plasminogen activator Activated protein C

   

Also has anti-inflammatory and anti-apoptotic properties Only anti-coagulant shown to be efficacious in trials with sepsistriggered DIC Given as 96 hr infusion Must use caution with thrombocytopenia increased risk of intracerebral hemorrhage

Frachini, Massimo. Thrombosis Journal Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation Feb 2006, 4:4. Davis-Jackson, Rachel. Thrombosis Journal Antithrombin III and R-TPA used singly and in combination vs. supportive care for treatment of endotoxin-induce DIC in the neonatal pig May 18, 2006, 4:7.