Disseminated Intravascular Coagulopathy

By

Okeke Chinedu N

�Outline�

• Introduction/ Definition
• Aetiology
• Pathophysiology
• Clinical Features
• Investigation
• Differential Diagnosis
• Treatment
• Conclusion

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• Acquired coagulation disorders

1. Disseminated intravascular coagulation

2. Liver disease

3. Vitamin K deficiency

4. Acquired inhibitors of coagulation

5. Heparin, oral anticoagulation, thrombolytic therapy

6. Renal disease

7. Paraproteinaemias

8. Cardiopulmonary bypass

9. Massive transfusion of stored blood

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�Introduction�

• It is an acquired syndrome.
• Characterized
• by activation of the coagulation pathways
• consumption of platelets and coagulation factors due to intravascular thrombi formation
• The above processes may either lead to multi organ failure from fibrin deposition or haemorrhage due to reduced platelet and coagulation factors.

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�Definition�

• DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes.
• The term loss of localization is used because the activation of coagulation is dispersed and uncontrollable leading to intravascular fibrin formation.
• The natural coagulation inhibitors become inefficient.

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Overview of Coagulation�

Initiation Phase: occurs on the TF-bearing cell. It is initiated when injury exposes the TF-bearing cell to the flowing blood. It results in the generation of a small amount of FIXa and thrombin that diffuse away from the surface of the TF-bearing cell to the platelet.

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Amplification Phase: the small amount of thrombin generated on the TF bearing cell activates platelets, releases vWF and leads to generation of activated forms of FV,FVIII, and FXI.

Propagation Phase: on the procoagulant membrane surface of the activated platelet intrinsic tenase is formed (Binding of aFIX to aFVII), resulting in FXa generation on the platelet surface. Prothrombinase complex forms and results in a burst of thrombin generation directly on the platelet.

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Conditions associated with DIC (AETIOLOGY)

• Condition Causes
• Sepsis/severe infections Gram-positive bacteria, Gram-negative bacteria, spirochetes, rickettsiae, protozoa, fungi, viruses
• Trauma Polytrauma, neurotrauma, fat embolism, burns
• Malignancy Solid tumors, myeloproliferative /lymphoproliferative malignancies
• Obstetric complications Amniotic fluid embolism, abruptio placentae, placenta previa, retained dead fetus syndrome
• Vascular disorders Large vascular aneurysms, Kasabach- Merritt syndrome
• Organ destruction Severe pancreatitis, severe hepatic failure
• Toxic reactions Snake bites, recreational drugs
• Immunologic reactions Hemolytic transfusion reaction, transplant rejection

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• The exposure of procoagulant tissue extracts to blood is a major contributory factor in most forms of DIC and is of major pathogenetic importance in cases associated with abruptio placentae, intrauterine fetal death, acute promyelocytic leukemia, amniotic fluid embolism, massive trauma, and various neoplasms
• The active component of such extracts is tissue factor (thromboplastin); that is, tissue factor interacts with factor VIIa to activate the extrinsic pathway of coagulation.

• In abruptio placentae decidual fragments, serum-containing activated coagulation factors, and other substances from the placental site enter the intervillous “maternal lake” and, hence, the venous circulation
• This process is initiated by rupture of the basal decidual plate
• In amniotic fluid embolism, relatively weak thromboplastins that increase in potency with gestational age and large amounts of particulate matter enter the circulation suddenly
• In IUFD, thromboplastic substances from the dead fetus are slowly but continuously absorbed, producing a picture of chronic but progressive DIC

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• In neoplasms, tumor microemboli and tumor “vesicles” are thought to enter the circulation and act as thromboplastins
• Some neoplasms may secrete a factor X activator
• DIC in association with acute leukemia presumably results from the formation or release of tissue factor by leukeamic cells
• The granules of various “blast” forms contain tissue factor, with the promyelocyte containing particularly high concentrations

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• In DIC associated with massive trauma, major surgical procedures, or large burns, damaged tissue expressing tissue factor activity presumably is a major initiating factor
• In such cases, additional abnormalities and complications are important contributory factors, such as “hypercoagulability,” azotemia, shock, intravascular hemolysis, massive transfusions of stored blood, septicemia, and hypoxia
• Cerebral trauma of sufficient magnitude to produce significant brain destruction induces a brief episode of DIC, which, although transitory, may be significant in that it may perpetuate cerebral bleeding

�Pathophysiology�

• Increased thrombin generation; Mediated predominantly by tissue factor/factor VIIa pathway
• 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)
• 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)
• Activation of inflammatory pathway; Mediated by activated coagulation proteins and by depression of the protein C system

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Clinical Features

• Acute DIC
• Sudden exposure of blood to procoagulants (e.g. tissue factor [TF], or tissue thromboplastin) generates intravascular coagulation.
• Compensatory haemostatic mechanisms are quickly overwhelmed.
• Severe consumptive coagulopathy leading to haemorrhage develops.
• Abnormalities of blood coagulation parameters are readily identified.
• Organ failure is common.
• Chronic DIC
• It is a compensated state that develops when blood is continuously or intermittently exposed to small amounts of TF.
• Compensatory mechanisms in the liver and bone marrow are not overwhelmed.
• There is no obvious clinical or laboratory evidence of the condition.
• Chronic DIC is more frequently observed in patients with solid tumours and in those with large aortic aneurysms.

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• Although bleeding, ranging from oozing at venepuncture sites to major gastrointestinal or intracranial haemorrhage, is the archetypal and most obvious manifestation of DIC, organ failure due to microvascular thrombosis is more common and often unrecognized
• For example, in meningococcal septicaemia and rarely pneumococcal infection, thrombosis of the adrenal vessels can lead to adrenal insufficiency and Waterhouse–Friderichsen syndrome

�Investigation of DIC – Screening Tests�

• Platelet count: usually decreased.
• PT abnormal in 70% of cases (short half-life of FVII).
• APTT abnormal in 50% of cases.
• Thrombin time, usually prolonged, in overt DIC, normal in non-overt DIC.
• FDP and D Dimers
• Fibrinogen low in < 50 % of cases
• Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant: initial high fibrinogen level); repeat testing is better

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BLOOD FILM

�Differential Diagnosis�

• Thrombotic thrombocytopenic purpura
• Dysfibrinogenaemia
• Haemolytic Uremic syndrome
• Heparin Induced thrombocytopaenia
• Immune thrombocytopaenia

�Treatment of DIC�

• The therapeutic strategies are:
• Treat/ remove causative factor.
• Supportive therapy
• Replacement therapy
• Control of coagulation mechanisms

�Supportive therapy�

• Antibiotics use
• ICU care and review
• Oxygen supplementation
• Pain relief
• Dialysis
• Counselling of relatives and care givers which must include prognosis based on assessment.

�Replacement therapy�

• Blood products is advocated especially in patients with bleeding
• Platelet concentrates required if platelet count <50 with bleeding or <20 with no bleeding. 1 unit per 10kg body weight.
• Fresh frozen plasma (FFP) at a dose of 15-20mls/kg if fibrinogen levels <100mg/dl or significant bleeding
• Cryoprecipitate @1 unit/ 10kg body weight.
• Fresh Whole Blood If above not available
• Fibrinogen concentrates not exceeding 2-3g

�Replacement therapy�

• Prothrombin complex concentrates rich in (F2,7,9,10) has been used alone or in combination with FFP.
• Heparin (Anticoagulation)
• Use is controversial as the antithrombin it works on is low in DIC.
• Antifibrinolytic agents
• Tranexamic acid
• ε-aminocaproic acid

Restoration of Deficient Natural Coagulation Inhibitors�

• This is a form of replacement therapy.
• Some of them are still in trial stages and others are already in use.
• Antithrombin
• Protein C and APC concentrates
• Tissue factor pathway inhibitor

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