Disseminated Intravascular Coagulopathy

Transcription

1 REVIEW ARTICLE Disseminated Intravascular Coagulopathy Lt Col Rajat Kumar Introduction Disseminated Intravascular Coagulopathy (DIC) is an acquired disorder which, in its mildest form is only an aberration of laboratory parameters, while in its florid acute form it gives rise to severe diffuse bleeding with high mortality rate. In one large general hospital the overall incidence was 1:1000 admissions 1. DIC occurs when the normal haemostatic balance is disturbed primarily by excessive thrombin formation. The diagnosis and treatment of this disorder requires an understanding of thrombin explosion, awareness of disorders which can trigger DIC, clinical recognition of this condition, and interpretation of laboratory data. Pathophysiology a. Thrombin generation In most forms of DIC, tissue factor (thromboplastin) is released and it activates the extrinsic pathway of coagulation by interacting with factor VII. Tissue factor-viia complex rapidly activates factors X and IX, thereby initiating coagulation 2. Tissue factor (TF) is released at the sites of tissue damage. Tissue factor activity is abundant in brain, lung, placenta, and can also be induced by endothelial cells and monocytes in response to cytokines like interleukin-1(il-1), tumour necrosis factor (TNF), or by endotoxin. Thus in severe infections like sepsis, cytokines or endotoxin can initiate DIC by release of tissue factor. Tumour cells as in acute promyelocytic leukaemia (AML-M3) or in adenocarcinoma also release TF. Tissue factor is released from tissue damaged by trauma, ischaemia, infectious organisms, tumours, heat, chemicals, or activation of * Medical Specialist and Clinical Haematologist, Army Hospital Research and Referral, Delhi complement sequence 3. Alternatively, leucocytes may release tissue factor into circulation in response to endotoxin or immune complexes. Snake venom can activate many components of the coagulation pathway. In DIC, thrombin formation is excessive, uncontrolled, and overcomes the factors which normally inhibit thrombin generation. b. Controlling thrombin formation Normally thrombin formation is tightly regulated by the natural anti-coagulant mechanisms of antithrombin III (ATIII) and protein C pathways. AT III is an important natural anticoagulant, synthesised in the liver. It inhibits thrombin and activated clotting factors IXa, Xa, XIa, XIIa. Endothelium concentrates AT III on its surface. If thrombin is generated next to healthy endothelium, it is neutralised by AT III. Vascular endothelium also expresses a protein, thrombomodulin, which binds to thrombin and thus thrombin cannot activate fibrinogen to fibrin. Thrombomodulin bound thrombin activates another natural anticoagulant, Protein C. Activated Protein C inactivates factors VIIIa and Va, thereby, reducing thrombin formation. Thus AT III and protein C are the extinguishers of thrombin formation. c. Fibrin deposition In DIC, control mechanisms fail and large amounts of thrombin are generated, leading to fibrin formation and deposition in the microvasculature. Widespread microvascular thrombosis produces tissue ischaemia and organ damage. Microangiopathic haemolytic anaemia may result as red blood cells are sheared by the intravascular fibrin strands. Both platelets and red cells are trapped and

2 consumed by these fibrin deposits. d. Consumption of clotting factors and platelets As DIC continues, fibrinogen, prothrombin, platelets, and other clotting factors are consumed beyond the capacity of the body to compensate and bleeding ensues 4. e. Fibrinolysis As a response to thrombosis, endothelial cells secrete plasminogen activators to initiate fibrinolysis (secondary fibrinolysis). In DIC fibrinolysis is excessive, such that alpha-2 antiplasmin is consumed and free plasmin circulates. Plasmin degrades both fibrinogen and fibrin, leading to fibrin and fibrinogen degradation products (FDPs). Plasmin dissolves clots before adequate haemostasis, thereby increasing the risk of bleeding. FDPs interfere with fibrin polymerisation, thrombin activity, and platelet function, further aggravating bleeding tendency. f. Role of cytokines A common pathway for activation of coagulation pathway in different diseases is the release of various cytokines. DIC occurs as mediators are released from macrophages, monocytes, and endothelial cells to perturb coagulation and fibrinolysis. Tissue necrosis factor (TNF) and interleukin-1 (IL-1) can cause production of tissue factor by endothelial cells and monocytes while reducing the expression of thrombomodulin. Many of the effects of DIC like hypotension or acute lung injury may be due to the effects of these cytokines per se. Causes of DIC The list of diseases which can be associated with DIC is extremely large. It is important to remember the main groups of illnesses causing DIC. These are: (a) Infections : sepsis, malaria, meningococcaemia. (b) Obstetric conditions: abruptio placentae, retained dead foetus, amniotic fluid embolism. (c) Malignancy: AML-M3, adenocarcinomas. (d) Conditions involving tissue necrosis: trauma, ABO incompatible blood transfusion. (e) Snake bite. Clinical presentation and diagnosis The diagnosis of DIC is mainly clinical. Laboratory tests provide confirmatory evidence. The relative rates of formation and breakdown of fibrin determine if the patient is asymptomatic, having features of bleeding, or thrombosis, or both. Haemorrhage is the commonest presentation characterised by spontaneous bruising, mucosal oozing, bleeding from venepuncture sites, and secondary haemorrhage into surgical wounds. Usually bleeding is associated with varying degrees of shock which is often out of proportion to the degree of blood loss 5. Shock is probably due to activation of contact factor XII which leads to production of bradykinin, and interaction between cytokines like TNF and IL-1. Evidence of major organ dysfunction is common, usually involving the pulmonary, renal, hepatic, and central nervous systems. These features are due to a combination of factors, namely microvascular thrombi, shock, and cytokine effects. Acute DIC : This is the most common form of DIC seen in clinical practice. Bleeding manifestations predominate and can be rapidly progressive. In some patients large acral cyanosis is seen due to thrombotic occlusion of dermal vessels. Chronic DIC : This occurs from a weak or intermittent activating stimulus 5. The destruction and production of clotting factors and platelets is balanced, so that the DIC may be considered to be compensated. Chronic DIC is seen most commonly in patients with intrauterine foetal death, adenocarcinoma and other tumours, giant haemangiomas and certain types of vasculitis. Patients may have recurrent episodes of ecchymosis or mild bleeding and thrombophlebitis at unusual sites. Trousseau s sign is a form of chronic DIC. 74 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 1 and 2 January-June 2001

3 Laboratory features The number of sophisticated tests which can be done in DIC are very large 6, but most of them are not available to clinicians working in a routine hospital setting. In most cases, a diagnosis of DIC can be made with the following tests : a. Screening tests : Peripheral blood film examination showing low platelets and schistocytes, platelet count thrombocytopenia, prothrombin time (PT) prolonged, activated partial thromboplastin time (APTT) prolonged, thrombin time (TT) prolonged, fibrinogen levels low. b. Supportive tests : Increased FDPs or increased D-dimers. No single test is diagnostic of DIC and it is the overall clinical picture supported by some investigations which should guide the management. Of these tests, thrombocytopenia and hypofibrinogenaemia (or a 50% drop in either value) are the most sensitive in making a laboratory diagnosis of DIC 4. Some of the limitations and advantages of these tests are : a. Peripheral blood film examination fragmentation of RBCs is seen in approximately 50% cases, and platelets are usually low. But a normal film does not exclude the diagnosis. b. Platelet count thrombocytopenia is an early and consistent sign and usually the platelets are between 50,000 to 100,000/cu mm. But if the initial platelet count was high, even with a 50% fall in counts, the platelet levels may be in the normal range. c. PT, APTT, TT these are prolonged in most cases of DIC. In the early stages and in chronic DIC, these may be normal. d. Fibrinogen levels these are significantly depressed. In conditions where the pre-illness levels are raised (like in pregnancy) the levels may be normal, despite a fall. e. FDPs these are raised in 85% patients 2. But raised levels are not specific for DIC and may be seen in patients with hepatic or renal failure, after surgery, and in patients with haematomas 3. Moreover FDP test is positive if either fibrinogen or fibrin is degraded by plasmin while fibrin degradation products are more specific for DIC. f. D-dimer this is a specific test for fibrin degradation and in one study its sensitivity was 94% with a specificity of 80% 7. Treatment of DIC Theoretically, intervention at the various pathophysiologic steps involved in the genesis of DIC should be of benefit, but clinical trials have revealed only a few measures are of therapeutic use. 1. Treatment of underlying cause and general care The disease causing DIC should be vigourously treated to reverse the process. For example, in case of sepsis, antibiotics should be started and if a snake bite is the precipitating factor, anti-snake venom (ASV) should be initiated. Tissue perfusion and respiratory function must be maintained by replacing intravenous fluid and providing oxygen support to correct hypoxia. Folic acid deficiency can develop acutely in the critically ill leading to impaired platelet production, and should be supplemented. Coagulopathy may be contributed by vitamin K deficiency and 10 mg on two consecutive days should be given. 2. Haemostatic support (Replacement therapy) In patients who have low levels of platelets, fibrinogen, and other clotting factors as shown by prolonged PT, APTT, TT, replacement of these factors is useful. Although there has been some concern that this replacement provides fuel to the fire, there are no clinical data to support such concerns 4. Replacement therapy is indicated only if the patient is bleeding or if some invasive procedure is required, like insertion Journal, Indian Academy of Clinical Medicine Vol. 2, No. 1 and 2 January-June

4 of a central line. Replacement is monitored by the immediate effect after transfusion and a few hours later to determine the need to continue further replacement. The blood components which are used are 8 : a. Fresh frozen plasma (FFP) This contains all the clotting factors of blood including fibrinogen as well as the natural anticoagulants like AT III and protein C. FFP is given in doses of 15 ml/kg. b. Cryoprecipitate When fibrinogen levels are less than 80 mg/dl, cryoprecipitate is given in addition to FFP. Each unit of cryoprecipitate contains around 250 mg of fibrinogen. For an adult of 70 kg with fibrinogen levels of 50 mg/dl, administration of 1.5g fibrinogen (6units of cryoprecipitate) should raise fibrinogen levels to 100 mg/dl 2. c. Platelet concentrates When platelet counts are less than 50,000/cu mm, platelets are transfused at the initial dose of 1 single donor unit per 10 kg body weight. The initial dose is a rough guide and further doses would vary depending on the degree of consumption and whether the DIC is coming under control. Replacement can be stopped when there is a rise in platelet counts, fibrinogen levels, and a fall in FDPs. Monitoring of PT, PTTK, and TT should be done but may not always be a good guide as the FDPs may interfere with these values. 3. Heparin therapy The use of heparin is theoretically attractive as it should stop formation of thrombin and the process of DIC, but in actual practice this benefit is seen only rarely. For a patient who is actively bleeding, heparin would aggravate the bleeding before any potential benefits. In most of the typical acute DIC situations (which probably include 95% or more of patients) heparin therapy has not proved to be useful and may be harmful 9. Heparin has been shown to have a beneficial effect in small, uncontrolled studies of patients with disseminated intravascular coagulation, but not in controlled clinical trials 10. There are some limited indications of heparin therapy: (a) Chronic DIC of malignancy (Trousseau s syndrome). (b) Patients with clinical evidence of fibrin deposition such as dermal necrosis in purpura fulminans, acral ischaemia, or those with venous thromboembolism. (c) Retained dead foetus with hypofibrinogenaemia, prior to induction of labour. (d) In AML-M3, prior to initiation of chemotherapy. However, heparin is hardly used nowadays with the use of ATRA therapy for this leukaemia. (e) Excessive bleeding associated with giant haemangioma. (f) When the patient does not demonstrate rises in platelet count and coagulation factors following replacement therapy and continues to bleed, implying ongoing consumption. In this situation heparin may neutralise consumption of clotting factors by inhibiting thrombin formation, and replacement therapy would then succeed in stopping the bleeding. It is important to continue the replacement therapy along with heparin and monitor the effect of heparin by repeated platelet counts, fibrinogen levels and PT, APTT, and TT. When prescribed, the dose of heparin is usually 15 units/kg/hr by continuous infusion 8 or 300 to 500 units per hour 10. There are no data on dose responses and the coagulopathy makes it extremely difficult to monitor treatment Antithrombin III As patients of DIC have low levels of AT III due to consumption and since AT III replacement theoretically should inhibit initiation of coagulation and ameliorate DIC, various studies have assessed the effect of AT III replacement in DIC. In DIC, low levels of AT III predict poor outcome and death. In experimental animal models of DIC, AT III 76 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 1 and 2 January-June 2001

5 concentrates have been beneficial 11. High doses of AT III ( units/kg/day) for 2 or 3 days have been shown to have reversed DIC in 4 patients with full recovery 12. Most other studies have demonstrated improvement in coagulation values and a shortened duration of DIC with the use of AT III concentrates, but definitive clinical benefits have yet to be demonstrated Controversial and novel therapies (a) Epsilon-aminocaproic acid (EACA) and tranexamic acid are antifibrinolytic agents which prevent the dissolution of fibrin clots. They are not used in DIC because they may lead to serious thromboembolic complications. Occasionally they are given to patients who continue to bleed despite adequate replacement therapy 3, where there is significant fibrinolytic activity 2. Heparin is often combined with these drugs 4. (b) Protein C infusions have prevented DIC in animal models of sepsis but a benefit in humans has yet to be established 3,8. (c) Gabexate mesylate is a synthetic inhibitor of serine proteases including thrombin and plasmin. It is a potentially useful drug for management of DIC. The drug has been extensively studied in Japan with clinical and laboratory improvement in DIC patients, but a clear survival advantage has yet to be reported 2. (d) An inhibitor of tissue-factor activity is a logical therapeutic intervention. One such inhibitor, recombinant nematode anticoagulant protein C2, is a specific inhibitor of the complex formed by tissue factor and factor VIIa with factor Xa and is currently being evaluated in a clinical study 10. management of the underlying disorder. Patients with acute DIC will require replacement therapy with platelet concentrates, FFP, and cryoprecipitate. Most patients with acute DIC will not benefit from heparin therapy. The role of newer agents is still to be determined. References 1. Siegal T, Seligsohn U, Aghai E, Modan M. Clinical and laboratory aspects of disseminated intravascular coagulation (DIC): A study of 118 cases. Thromb Haemost 1978; 39: Carey MJ, Rodgers GM. Disseminated intravascular coagulation: Clinical and laboratory aspects. Am J Hematol 1998; 59: Baglin T. Disseminated intravascular coagulation: Diagnosis and treatment. BMJ 1996; 312: Parker RI. Etiology and treatment of acquired coagulopathies in the critically ill adult and child. Critical Care Clinics 1997; 13: Grosset ABM, Rodgers GM. Acquired coagulation disorders. In Wintrobe s Clinical Hematology, 10th ed, William & Wilkins London, 1999; Bick RL. Disseminated intravascular coagulation. Objective criteria for diagnosis and management. Med Clin North Am 1994; 78: Bick RL, Baker WF. Diagnostic efficacy of the D-dimer assay in disseminated intravascular coagulation (DIC). Thromb Res 1992; 65: Colvin BT. Management of disseminated intravascular coagulation. Br J Haematol 1998; 101 (suppl 1): Feinstein DI. Diagnosis and management of disseminated intravascular coagulation: The role of heparin therapy. Blood 1982; 60: Levi M, Cate TH. Disseminated intravascular coagulation. N Engl J Med 1999; 341: Bucur SZ, Levy JH, Despotis GJ et al. Uses of antithrombin III concentrate in congenital and acquired deficiency states. Transfusion 1998; 38: Fuse S, Tomita H, Yoshida M et al. High doses of intravenous antithrombin III without heparin in the treatment of disseminated intravascular coagulation and organ failure in four children. Am J Hematol 1996; 53: Summary DIC is primarily a clinical diagnosis. Investigations are meant to confirm the diagnosis and monitor therapy. Treatment of DIC consists primarily of Journal, Indian Academy of Clinical Medicine Vol. 2, No. 1 and 2 January-June