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DIC

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Disseminated intravascular coagulation

  • pathophysiological process and not a disease

  • inappropriate excessive and uncontrolled activation of haemostatic process

  • systemic circulation of thrombin and plasmin

Pathophysiology

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  • characterised by consumption of clotting factors and platelets within circulation
  • mechanisms which may inappropriately activate haemostatic system:

    • activation of coagulation sequence by release of tissue thromboplastins into systemic circulation (eg extensive tissue trauma, surgery, malignancy, acute intravascular haemolysis, cytokines)

    • induction of platelet activation ( eg septicaemia, viraemia, immune complexes)

  • contact (intrinsic) system does not appear to play an important role in DIC

    • blockade does not prevent activation of coagulation in bacteraemic baboons

    • no increase in markers of activation of coagulation system in humans infused with TNF

  • predominant mediator is tissue thromboplastin. Triggers coagulation cascade with generation of thrombin

  • thrombin effects:

    • cleaves fibrinopeptides A & B from fibrinogen leaving fibrin monomer

    • fibrin monomer polymerizes into fibrin clot in cirulation resulting in micro and macrovascular thrombosis

    • platelets trapped in fibrin mesh resulting in thrombocytopaenia

  • mesh created by platelet-fibrin clots traumatize passing RBCs resulting in microangiopathic haemolytic anaemia

  • circulating plasmin cleaves carboxy-terminal end of fibrinogen into fibrin(ogen) degradation products. These combine with circulating fibrin monomer before polymerization producing soluble fibrin monomer and further impairing haemostasis. FDP also have a high affinity for platelet membranes and induce a profound platelet function defect
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  • circulating plasmin also activates complement causing red cell and platelet lysis and increased vascular permeability, hypertension and shock. Degrades cross-linked fibrin producing D-dimers

  • generation of factor XIIa as a consequence of activation of the clotting cascade results in activation of the kinin system and resultant increased vascular permeability, hypotension and shock

  • ± depression of protein C-protein S system

  • down regulation of thrombomodulin (probably due to TNF) Þ ¯protein C activity in endotoxaemic models

  • treatment with activated protein C can improve coagulopathy in bacteraemic baboons

  • anti-thrombin III concentration markedly reduced in patients with sepsis due to:

    • consumption

    • degradation by elastase released from activated neutrophils

    • impaired AT III synthesis

  • combination of thrombin induced thrombosis and plasmin induced haemorrhage. Important to recognize that although haemorrhage is more clinically obvious these patients are experiencing significant, often diffuse thrombosis. NB. In early DIC fibrinolysis is depressed

Conditions associated with DIC

Infection

  • bacterial

  • viral: CMV, hepatitis viruses, HZV

Obstetric

  • amniotic fluid embolism

  • placental abruption

  • eclampsia

  • retained dead fetus

  • septic abortion

Intravascular haemolysis

  • haemolytic transfusion reaction

  • massive transfusion

  • minor haemolysis

Trauma or burns

Venoms and toxins

Hepatic disease

Vascular disorders

  • hereditary telangiectasia

  • thrombotic thrombocytopaenic purpura

  • vasculitis

  • AV fistula

  • angiosarcoma

  • malignant hypertension

Malignancy

  • adenocarcinoma: prostate, lung, breast, pancreas

  • haematological: acute promyelocytic leukaemia, myeloproliferative disease, myeloma

Prosthetic devices

Clinical features

  • presentation varies

  • mixture of thrombotic, haemorrhagic or mixed manifestations in various organ systems

  • major problem and presenting feature of acute DIC is bleeding

  • when occurs in patients with MOF prognosis is poor

  • presentation in pregnancy may be more sudden and unexpected

Investigations

  • results may be variable and difficult to interpret

  • significant DIC can be present despite normal PT, APTT and TT but conversely patients may have laboratory features of DIC without any clinical sequelae

  • PT normal or short in up to 50%. Thrombin or factor Xa may accelerate the formation of fibrin and early degradation products may be rapidly clottable by thrombin and quickly “gel” the system giving a false normal or short result

  • APTT is even more unreliable than PT

  • TT should be prolonged by the presence of circulating FDP, interference with monomer polymerization and hypofibrinogenaemia. May be normal or fast

  • Fibrinogen not helpful in diagnosing DIC in most cases.

  • Acute phase protein and despite on-going consumption plasma levels can remain well within normal range for a long period

  • most reliable tests to diagnose DIC and follow response to therapy are high concentration of  D-dimers, presence of circulating fibrin monomer, increased fibrinopeptide A, reduced platelets, and reduced antithrombin III

  • D dimer formed as a result of plasmin digestion of cross-linked fibrin and therefore only occurs when both clotting and fibrinolytic systems are activated. Most reliable of the commonly available tests

  • FDP elevated in 85-100%. Indicative of the presence of plasmin but not necessarily of intravascular coagulation. Also elevated in women using oral contraceptives, PE, some patients with MI, certain renal diseases, and patients with arterial or venous thromboembolic disease. May be normal. Test only measures D & E fragments. In some cases of DIC there is minimal secondary fibrinolytic response and thus there may be degradation only to X fragment stage. Alternatively if there is massive fibrinolysis degradation beyond the D & E fragment stage may occur

  • fibrinolytic system assays:

    • intensity of secondary fibrinolytic response is of clinical consequence for predicting potential microvascular thrombosis. If there is impaired activation end-organ damage may be greater

    • elevated plasmin and decreased plasminogen provide direct evidence of fibrinolytic activation

    • a2-plasmin inhibitor. Fast acting inhibitor of plasmin. If markedly elevated there may be ineffective fibrinolysis. Decrease provides indirect evidence of fibrinolytic activation and inhibitor consumption. Elevated plasmin a2 plasmin inhibitor complex (PAP) provides direct evidence of both fibrinolytic activation and inhibitor consumption

  • ideally should document procoagulant system activation (eg increased fibrinopeptide A), fibrinolytic system activation (elevated D-dimer or FDP or plasmin or PAP), inhibitor consumption (decreased antithrombin III, elevated PAP) and end-organ damage

  • in chronic DIC usual tests of haemostasis are normal because this is a compensated state. Red cell fragments are usually present on peripheral blood smear

Management

  • controversial. Should probably be individualized to take into account relative importance of thrombosis and fibrinolysis in the individual patient.

  • remove precipitating cause. Aggressive approach to eliminate or treat triggering process key to management. If not achieved attempts at anticoagulation rarely alleviate the disseminated intravascular clotting process

  • NB it is coagulation NOT haemorrhage that has greatest impact on morbidity and mortality

  • most patients except those with DIC due to obstetric accidents (apart from amniotic fluid embolus) or massive liver failure need some form of anti-coagulation (controversial)

    • anticoagulation indicated if patient continues to bleed or clot significantly for 4-6 h after initiation of supportive therapy and therapy for the triggering condition (controversial). Depends in part on site and severity of thrombosis and bleeding. Heparin especially valuable in certain clinical situations including acute promyelocytic leukaemia, early stages of amniotic fluid embolism and immediately following severe incompatible blood transfusion.

    • Give SC heparin 80-100 U/kg Q4-6h. Low dose SC heparin appears to be as effective or possibly more effective than larger doses of IV heparin. Look for lowering of FDP, increases in fibrinogen, correction of other abnormal lab modalities of acute DIC in 3-4 h.

    • Contraindications: DIC with CNS insult, FHF, most obstetric cases

    • in view of low concentration of AT III agents that are not dependent on AT III for their mode of action may be more suitable (eg hirudin)

  • AT III concentrates and other inhibitors of haemostasis (eg tissue factor pathway inhibitor, protein C) may have a therapeutic role in the future

  • FFP contains all the coagulation factors and the main inhibitors AT III and protein C in near normal quantities.

  • cryoprecipitate especially useful if fibrinogen is depeleted (give 5-10 units)

  • some believe that fibrinogen containing blood products should be avoided unless there is evidence that intravascular clotting has been controlled as the fibrinogen may simply “fuel the fire”. However there are no good data to support this view. Fibrinogen free blood products:

    • washed packed red cells

    • platelet concentrates

    • antithrombin concentrates

    • PPF/albumin

  • platelet transfusion in presence of severe thrombocytopenia. Controversial: patients tend to be resistant if the initiating cause of DIC has not been controlled

  • inhibition of fibrinolysis is rarely required (approx 3% of patients) except in patients with DIC associated with acute promyelocytic leukaemia in whom primary activation of fibrinolysis may coexist with DIC. Should not be given routinely to patients with on-going DIC because fibrinolysis required to clear microthrombi. Indicated if triggering disease controlled, intravascular coagulation controlled, deficient blood components replaced, increased plasmin or decreased plasminogen AND patient is still bleeding. Give tranexamic acid: 1-2 g IV bd or tds. NB if used in a patient with on-going DIC may lead to fatal disseminated thrombosis

  • in obstetric cases with massive haemorrhage management should include attempts to empty and contract uterus

Further reading

Levi M et al. Disseminated intravascular coagulation. Thrombosis and Haemostasis, 1999; 82:695-705

 


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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