Disseminated Intravascular Coagulation

DR.M.KRISHNA VASUDEV

DEFINITION

Disseminated intravascular coagulation (DIC) is a clinicopathologic syndrome characterized by widespread intravascular fibrin formation in response to excessive blood protease activity that overcomes the natural anticoagulant mechanisms.

CAUSES

Type CauseInfectious Bacterial (eg, gram-negative sepsis, gram-positive infections,

rickettsial)Viral (eg, HIV, cytomegalovirus [CMV], varicella-zoster virus [VZV], and hepatitis virus)Fungal (eg, Histoplasma)Parasitic (eg, malaria)

Malignancy Hematologic (eg, acute myelocytic leukemia)Metastatic (eg, mucin-secreting adenocarcinoma)

Obstetric Placental abruptionAmniotic fluid embolismAcute fatty liver of pregnancyEclampsia

Trauma BurnsMotor vehicle accidentsSnake envenomation

Transfusion Hemolytic reactionsTransfusion

Other Liver disease/acute hepatic failure*Prosthetic devicesShunts (Denver or LeVeen)Ventricular assist devices

*Some do not classify this as DIC; rather, it is liver disease with reduced blood coagulation factor synthesis and reduced clearance of activate products of coagulation.

ACUTE DIC

Type CauseMalignancies Solid tumors

Leukemia

Obstetric Retained dead fetus syndromeRetained products of conception

Hematologic Myeloproliferative syndromesVascular Rheumatoid arthritis

Raynaud disease

Cardiovascular Myocardial infarctionInflammatory Ulcerative colitis

Crohn diseaseSarcoidosis

Localized DIC Aortic aneurysmsGiant hemangioma (Kasabach-Merritt syndrome)Acute renal allograft rejection

CHRONIC DIC

PATHOPHYSIOLOGY

1. Increased thrombin generation: Mediated predominantly by tissue factor/factor VIIa pathway

2. Impaired function of physiological anticoagulant pathway a) Reduction of antithrombin levels -- The result of a combination of increased consumption, enzyme degradation, impaired liver synthesis and vascular leakage b) Depression of protein C system -- The result of a combination of increased consumption, impaired liver synthesis, vascular leakage and down- regulation of thrombomodulin c) Insufficient tissue factor pathway inhibitor (TFPI)

3. Impaired fibrinolysis: Mediated by release of plasminogen activators from endothelial cells immediately followed by an increase in the plasma levels of plasminogen activator inhibitor type 1 (PAI-1)

4. Activation of inflammatory pathway: Mediated by activated coagulation proteins and by depression of the protein C system

SIGNS AND SYMPTOMS

The symptoms of disseminated intravascular coagulation (DIC) are often those of the underlying inciting condition 1. Bleeding

• GI bleed• petechiae and ecchymosis,• intravenous (IV) lines and catheters bleed• surgical sites, drains, and tracheostomies and within serous cavities.

2. Renal Failure3. Pulmonary involvement

• dyspnea, hemoptysis, and cough4. Jaundice

HISTORY

Circulatory signs include the following:1. Signs of spontaneous and life-threatening hemorrhage2. Signs of subacute bleeding3. Signs of diffuse or localized thrombosis4. Bleeding into serous cavities

Central nervous system signs include the following:5. Nonspecific altered consciousness or stupor6. Transient focal or neurologic deficits

Cardiovascular signs include the following:7. Hypotension8. Tachycardia9. Circulatory collapse

Respiratory signs include the following:10. Pleural friction rub11. Signs of acute respiratory distress syndrome (ARDS)

SYMPTOMS

GI signs include the following:1. Hematemesis2. Hematochezia

Genitourinary signs include the following:3. Signs of azotemia and renal failure4. Acidosis5. Hematuria6. Oliguria7. Metrorrhagia8. Uterine hemorrhage

Dermatologic signs include the following:9. Petechiae10. Jaundice (liver dysfunction or hemolysis)11. Purpura12. Hemorrhagic bullae13. Acral cyanosis14. Skin necrosis of lower limbs (purpura fulminans)15. Localized infarction and gangrene16. Wound bleeding and deep subcutaneous hematomas17. Thrombosis

Features Affected Patients, %

Bleeding 64%

Renal dysfunction 25%

Hepatic dysfunction 19%

Respiratory dysfunction 16%

Shock 14%

Central nervous system dysfunction

2%

DIFFERENTIAL DIAGNOSIS

1. Atypical hemolytic-uremic syndrome2. Hemolytic-Uremic Syndrome3. Heparin-induced thrombocytopenia and thrombosis syndrome4. Idiopathic Thrombocytopenic Purpura5. Liver disease6. Primary hemostatic disorders (eg, dysfibrinogenemias; inhibitors

to factors II, V, X)7. Thrombotic Thrombocytopenic Purpura

DIAGNOSIS

•Platelet -- moderate-to-severe thrombocytopenia is present in DIC. •Activated partial thromboplastin time [aPTT] and prothrombin time [PT]) are typically prolonged.•Protein C and antithrombin are 2 natural anticoagulants that are frequently decreased in DIC.•Elevated levels D-dimer and FDPs•Thrombomodulin is elevated in DIC, a marker for early identification and monitoring of DIC.•Chronic DIC diagnosis when the schistocytes are seen in concert with normal coagulation values and increased D-dimer levels.

Clinical conditions that should be ruled out

ThrombocytopeniaDilution and abnormal distributionMassive blood loss, massive infusionITP, TTP-HUS, HIT, HELLP syndromeDisorders of hematopoiesisLiver diseaseHypothermiaSpurious laboratory results

Diagnostic algorithm for SIRS

Temperature >38°C or < 36°CHeart rate >90 beats/minRespiratory rate >20 breaths/min or PaCO2 < 32 mm Hg (< 4.3 kPa)WBC count >12,000 cells/µL, < 4000 cells/ µL, or 10% immature (band) forms

Diagnostic algorithmSIRS criteria

Score

>3 1

0-2 0

Platelet count (× 109/L)

< 80 or >50 % decrease within 24 hours 3

>80 and < 120 or >30% decrease within 24 hours 1

>120 0

Prothrombin time (value of patient/normal value)

>1.2 1

< 1.2 0

Fibrin/FDPs (mg/L)

>25 3

>10 and < 25 1

< 10 0

Diagnosis4 points or more

DIC

TREATMENT

1) Replacement therapy - Fresh-frozen plasma

2) Anticoagulants- Unfractionated and low-molecular-weight heparin

- Danaparoid sodium

- Recombinant hirudin

- Recombinant tissue factor pathway inhibitor

- Recombinant nematode anticoagulant protein c2

3) Restoration of anticoagulant pathways - Antithrombin

- Recombinant human activated protein C

4) Other agents - Recombinant activated factor VII

- Antifibrinolytic agents

- Antiselectin antibodies

- Recombinant interleukin-10

- Monoclonal antibodies against TNF and CD14

Management of Underlying Disease•The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder.

Administration of Blood Components and Coagulation Factors•Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding •The PT (>1.5 times the normal) Replacement with FFP is indicated•Low levels of fibrinogen (<100 mg/dL) or brisk hyperfibrinolysis will require infusion of cryoprecipitate. The replacement of 10 U of cryoprecipitate for every 2–3 U of FFP is sufficient to correct the hemostasis.•In case of a (relative) vitamin K deficiency in the face of consumption, administration of vitamin K may be required.

Anticoagulation•Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC. However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials.•Therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates (eg, purpura fulminans or acral ischemia).• A dose of 4-5 U/kg constant infusion without a 80-U/kg bolus is a safe means to deliver heparin to the DIC without increasing the bleeding risk.

Restoration of Anticoagulant Pathways•Antithrombin concentrate, recombinant human APC, tissue factor (TF) pathway inhibitor (TFPI) and recombinant thrombomodulin (rTM)

Antifibrinolytic treatmentIn the coagulopathy associated with acute promyelocytic leukemia (AML-M3) and in some cases of DIC secondary to malignancies (e.g. prostate carcinoma) lysine analogues such as tranexamic acid can be utilized

Investigational TreatmentsTissue factor (TF)-VIIa complex include inactivated factor VII and recombinant nematode anticoagulant peptide (NAPc2)