Disseminated intravascular coagulation (DIC) is an acquired syndrome. It is a complication of an underlying illness, and involves systemic activation of the coagulation system when blood is exposed to procoagulants such as tissue factor.
Thrombin is produced in disproportionate amounts, leading to widespread deposition of excess fibrin. The accumulation of intravascular fibrin impairs circulation via formation of microvascular thrombi. The end results of which are vessel damage and tissue ischemia. The excessive amount of fibrin also causes consumption of platelets and clotting factors. If DIC is left undiagnosed and/or untreated, life-threatening haemorrhage may result.
Acute (decompensated) DIC:
Occurs in a short amount of time when pro-coagulants are expelled into the blood. Thrombin is produced in vast amounts trigging coagulation and excess deposition of intravascular fibrin, resulting in severe bleeding, tissue injury and/or organ failure. Acute DIC is typically seen in severe infection, obstetric complications and massive tissue injury due to trauma or burns.
Chronic (compensated) DIC:
Occurs when the blood is exposed to small amounts of pro-coagulant continuously over an extended period of time. It is seen in conditions such as malignancy and less commonly chronic infections such as tuberculosis, osteomyelitis and in inflammatory bowel disease. More rarely, chronic DIC can be seen in cases of aortic aneurysm and dead fetus in utero. Although these patients are generally asymptomatic, they can manifest with signs such as minor skin/ mucosal bleeds and/or thrombosis.
DIC isnot an isolated condition. Most often, it is secondary to a systemic response of an underlying cause, such as the following:
The most common condition associated with DIC is septicaemia due to bacterial infection, however, systemic infections by other organisms such as viruses or parasites can also cause DIC.
Cancers, obstetric complications, massive tissue injury and systemic diseases follow septicaemia in prevalence. In cases trauma, head trauma with the presence of systemic inflammatory response syndrome (SIRS) is suggested to be most strongly correlated with DIC.
In discussing the general mechanisms underlying DIC, it is imperative to understand and review the normal pathway of coagulation and clotting. Coagulation is split up into primary haemostasis and secondary haemostasis. Primary haemostasis occurs when there is damage to tissue or blood vessels. Platelets are aggregated to form primary clots at the injury site. The primary clots are subsequently strengthened by secondary haemostasis, which involves activation of both the extrinsic and intrinsic pathways.
The control of coagulation
The final common pathway for the aboves generates thrombin, a potent inducer of connective tissue growth factors that converts fibrinogen into fibrin clots. By mediating thrombin activatable fibrinolysis inhibitor (TAFI), thrombin also regulates fibrinolysis, thus prevents the clots from disintegrating.
As thrombin is being swept away from the site of tissue injury, it attaches itself to thrombomodulin to activate protein C, a vitamin-K dependent glycoprotein that inhibits pro-coagulant factors V and VIII. The other potent inhibitor of coagulation also includes antithrombin III.
Plasmin and fibrinolysis
Eventually, the formed clot is degraded and resorbed by a process known as fibrinolysis. The main enzyme responsible for this process is plasmin. Plasmin degrades the fibrin clot into D-dimers and fibrin degradation product (FDPs), also known as fibrin split products. It also degrades intact fibrinogen and various clotting factors.
The major mechanisms that trigger DIC involve
Examples of tissue thromboplastic substances that may trigger DIC are from obstetric complications, trauma and burns, or from the granules of leukemic cells in AML. Bacterial endotoxins in gram-negative sepsis, can cause release of cytokines (e.g. interleukin-1 and tumour necrosis factor (TNF)) from activated monocytes. These cytokines cause activation of tissue thromboplastin on endothelial cell membranes and decrease thrombomodulin expression, thus a shift towards procoagulation.
DIC as a "consumptive" coagulaphy
DIC is a combination of two important hallmarks, i.e. the continuous generation of intravascular fibrin; and consumption of clotting factors and platelets.
In addition, increased clotting is accompanied by decreased fibrinolysis. Without counteraction from the anticoagulant pathway, increased thrombin continuously intensifies the coagulation cascade through positive feedback. The accumulation of intravascular fibrin then results in widespread deposition of microthrombi, causing ischemic damage of various tissues and impaired organ perfusion. If not treated within a timely manner, multi-organ failure may result.
Another consequence of DIC is microangiopathic haemolytic anaemia (MAHA), where red blood cells become fragmented as they try to squeeze through the narrowed vessels. Thrombocytopenia may also result during this process, as the clot traps and consumes platelets. In addition to platelets, coagulation factors and inhibitors become consumed by the same course.
As plasminogen is activated, plasmin is stimulated, cleaving the fibrin clot. Degradation of fibrin produces the by-products fibrin degradation products (FDPs) and D-dimers. In DIC, FDPs enhance bleeding by interfering with normal fibrin polymerization. They also interfere with platelet aggregation by binding to the platelet surface glycoprotein IIb/IIIa fibrinogen receptor. Furthermore, bleeding diathesis is exacerbated by plasmin, since plasmin can also degrade fibrinogen and other clotting factors.
Diagnosis of DIC can be challenging, as there is no single routine laboratory test available that is sensitive and specific for DIC. However, several laboratory tests often return abnormal giving imperative clues for DIC. In general, combining history (e.g. presence of sepsis, trauma, malignancy), clinical impression and abnormal laboratory results, help to make the diagnosis of DIC.
DIC may not present with any specific sign or symptom, rather the patient may only present with symptoms of the underlying cause. However, a history of spontaneous blood loss from gingiva, venepuncture sites, post-operative surgical sites or drains may provide diagnostic value.
In general, acute DIC, which is associated with sepsis, obstetric complications or major trauma may present with wide spread petechiae and ecchymosis. Blood oozing from wound sites, intravenous lines and catheters is also commonly seen in acute DIC. For those patients that developed DIC after surgical procedures, haemorrhage may develop around surgical sites or drains and tracheostomies. When injury to the pulmonary vasculature has occurred, haemoptysis and dyspnoea may occur. Acute respiratory distress syndrome (ARDS) may result from pulmonary microthrombosis due to DIC. In addition, sepsis, trauma and amniotic fluid embolism can lead to lung injury associated with ARDS.
In chronic DIC (which mayoccur in cancer patients) the patient is usually asymptomatic. The liver and bone marrow are generally able to replenish the depleted coagulation proteins and platelets respectively when the blood is continuously exposed to small amounts of tissue factor. The patient may present with thrombotic complications such as DVTs in the extremities or superficial migratory thrombophlebitis (also known as Trousseau’s syndrome). Minor skin and mucosal bleeding may be present.
Although an accurate history may give clues to a diagnosis of DIC, clinical observation and laboratory studies are necessary for a definite diagnosis.
When investigating a patient for DIC, a wide range of abnormalities can be seen. The laboratory findings seen in acute (decompensated) vs. chronic (compensated) DIC are slightly different. The following laboratory studies provide suspicion of DIC.
In chronic (compensated) DIC, laboratory results are variable because of the coagulation factors are consumed at a slower rate. As the blood is continuously being exposed to small amounts of tissue factor, the liver and bone marrow undergo compensatory mechanisms in order to replenish the depleted coagulation factors and platelets. It is therefore expected to see laboratory values within normal limits.
In addition, to thrombocytopenia a peripheral blood smear can demonstrate evidence of schistocytes (fragmented red blood cells). Although their presence is neither sensitive nor specific for DIC, it can suggest a diagnosis of chronic DIC. When schistocytes are present with normal coagulation values and increased D-dimer levels, one should suspect chronic DIC.
The International Society on Thrombosis and Haemostasis (ISTH) Scoring System for Diagnosis of DIC is another method used to diagnose DIC early in its course. Evidence suggests the use of the scoring system can lead to early identification of DIC and thus reduce mortality. According to several prospective studies, the scoring system has a sensitivity of 91-93% and a specificity of 97-98% for diagnosing DIC. A score of five or more indicates a clear diagnosis of DIC, On the other hand, a score of less than five does not rule out DIC, but suggests that DIC is not definitive. If clinically indicated, the test should be repeated.
The differential diagnosis for DIC is broad since several conditions mimic the clinical manifestations and/or laboratory abnormalities of DIC. The most common conditions to differentiate from DIC are presented below.
TTP is caused by a congenital or acquired defect in ADAMTS13, a von Willebrand factor (vWF) cleaving protease. When damage to the endothelium occurs, large multimers of vWF are released into the circulation causing increased platelet adhesiveness. Formation and accumulation of microscopic thrombi occur, resulting in ischemic damage to various organs including the kidneys, heart and brain. Thrombocytopenia is likely to cause purpura of the skin (e.g. bruising). Furthermore, intravascular haemolysis and schistocytes formation result due to the shear stress on the red blood cell by the microscopic clots. Although TTP may present as DIC clinically, it is imperative to note the distinguishing factor. Unlike DIC, laboratory studies in TTP demonstrate a normal PT, aPTT and thrombin time. In addition, FDP’s are normal.
HUS is a disease characterized by haemolytic anaemia, acute kidney failure (uraemia), and thrombocytopenia. Most cases of HUS follow an episode of bloody diarrhoea caused by E.coli O157:H7 or certain strains of shiga toxin secreting Shigella dysenteriae. Rarely, HUS may develop from S.pneumoniae. By a mechanism poorly understood, the bacteria cause endothelial damage leading to platelet activation and formation of microthrombi. Widespread accumulation of microthrombi results in the ischemic damage of various organs, particularly the kidneys. In addition to fever, abdominal pain, unexplained purpura and haemorrhage, the patient may complain of decreased urine output with or without haematuria. Contrary to DIC, coagulation factors are not consumed in HUS and a normal PT and aPTT are seen. Furthermore, in spite of thrombocytopenia, laboratory results demonstrate normal levels of fibrinogen and FDP’s.
HIT is an autoimmune mediated condition resulting in thrombocytopenia and thrombosis. Antibodies formed against heparin form a complex with heparin resulting in platelet activation and the formation of arterial/venous microthrombi. Like DIC, HIT can lead to ischemic damage of various organs. HIT should be suspected in patients receiving heparin therapy within 5-10 days, or patients receiving prolonged treatment of low molecular weight heparin. Necrotic skin lesions at heparin injection sites may also raise the possibility of HIT.
Trousseaus syndrome, also known as migratory thrombophlebitis is characterized by reoccurring migratory thrombi. Occurring in either the arterial or venous system, Trousseaus syndrome is typically associated with an underlying malignancy. Pancreatic cancer has the highest risk associated with this condition. For reasons only partly understood, factors released by tumour cells cause spontaneous formation of microthrombi in superficial vessels throughout the body. Patients typically present with DVT’s. Trousseaus syndrome is considered to be a chronic compensated DIC. Laboratory data therefore mimics that of compensated DIC.
Severe liver disease can mimic the laboratory results seen in DIC. Decreased synthesis of coagulation factors lead to prolongation of PT and aPTT. FDPs are also elevated since their metabolism by the liver is ultimately affected. In addition, thrombocytopenia may be present due to hypersplenism secondary to portal hypertension. To differentiate liver disease from DIC, liver function tests can be obtained. If elevated, one can suspect liver disease over DIC. In addition, D-dimers are within normal limits and produce a negative D-dimer test.
HELLP syndrome is characterized by Haemolysis, Elevated Liver enzymes and a Low Platelet count with severe pregnancy-induced hypertension. It usually occurs after 28 weeks of gestation, or post-partum. It is similar to DIC in that it presents with a low platelet count, however there should be no signs and symptoms of thrombosis. A peripheral smear can also display schistocytes. HELLP syndrome is a known underlying cause of DIC. It is therefore important to differentiate HELLP from DIC. A patient with an elevated liver function test (LFT’s) and serum bilirubin with normal levels of FDP’s may give clues toward HELLP. In addition, hypertension in DIC is rare.
Vitamin K deficiency can be mistaken for DIC due to the positive signs of bleeding. However, unlike DIC, signs and symptoms of thrombosis are absent. This condition is usually associated with a poor diet in alcoholics, patients with bulimic anorexia, and in conditions that affect GI absorption (e.g. cystic fibrosis, inflammatory bowel disease, primary biliary cirrhosis). Laboratory results demonstrate decreased vitamin K level, an elevated INR and normal FDP levels. In addition, D-dimer test is negative.
Although DIC is a serious and complicated disease, treatment can be considered simple and concise. The major focus of treatment lies in treating the underlying condition that gave rise to DIC (in both decompensated and compensated DIC). For example, in obstetric complications, the treatment strategy should be evacuation of the uterus; or drainage of an abscess caused by bacterial sepsis; or debridement of damaged tissues in trauma and burn patients. In majority of cases, the DIC component resolves when the underlying condition has been rectified.
First - ABCDE!
Speaking in general terms, when dealing with the critically ill, patients may become unresponsive and unconscious. When this type of situation presents itself it is imperative to take the appropriate measures. The first step is to assess the patient’s Airway; if inadequate the patient may need intubation. Next, the patient’s breathing adequacy is assessed. Consider ventilatory support if necessary. In addition, if there is suspicion of a pneumothorax/haemothorax, decompression and drainage should be performed. Thirdly, the patient’s circulation is evaluated. Administrating fluids and giving inotropes/vasopressors can aid the situation if circulation is compromised. Applying direct pressure to an external haemorrhage may also improve the patient’s circulation.
Transfusion of platelets
Providing supportive therapy with intravenous fluid is vital to maintain fluid volume and organ perfusion. As for treating the deficiency of coagulation factors seen in DIC, there are certain conditions to which administration apply. Although DIC causes a significant reduction in platelet count and prolonged bleeding times (PT and aPTT), replacement therapy is only indicated in those patients with active bleeding or those who are at high risk of bleeding. Literatures recommend that patients with severe thrombocytopenia (<20,000/microL) or with a platelet count below 50,000/microL should receive platelet transfusion. To maintain an appropriate platelet count, it is recommended that transfusion of 1 to 2 units per 10 kg per day is necessary.
Cryoprecipitates and FFP's
When a patient demonstrates a fibrinogen concentration < 50 mg/dL (with active bleeding) transfusion of cryoprecipitate should be administered. 10 units of cryoprecipitate should be transfused until fibrinogen levels reach a level greater than 100 mg/dL. Fresh frozen plasma is typically transfused in order to replace depleted coagulation factors.
Antithrombin III, Protein C and heparin - what evidence are there
Studies have shown administration of antithrombin III is beneficial in patients with severe sepsis and septic shock. When antithrombin III levels are significantly reduced, these patients have an unfavourable prognosis thus administration of antithrombin III should be preformed. In addition administration of coagulation inhibitors, particularly protein C has been proven beneficial in treating DIC in sepsis also.
It is logical to think that heparin administration may correct decompensated DIC, however, the use of heparin in treatment of DIC is controversial. Heparin is a widely used injectable anticoagulant that produces its major anticoagulant effects by inactivating thrombin and factor Xa by binding to antithrombin III. The problem lies in the fact that DIC is associated with reduced levels of antithrombin III. Therefore the effectiveness of heparin therapy is limited and has administration has little benefit. In addition, heparin may worsen the bleeding problems associated with DIC, as bleeding is the major risk factor related to heparin use. Heparin on the other hand may be of value to patients who suffer from chronic, compensated DIC.
The most serious complication seen in cases of DIC is death. However, other less serious, but potentially dangerous complications include:
Keeping your patient informed of their condition as well as treatment strategy is a vital step in patient care. While taking anticoagulants such as heparin, patients must be advised of their increased risk for bleeding. Patients must be educated on easy bruising and monitoring for bleeding from any body part and to manage bleeding if it occurs. For example, patients may experience epistaxis, bleeding gums, haemoptysis, haematuria, melena or haemarthrosis. In addition, inform your patient to avoid any type of contact sport. It is important for the patient to receive regular follow-ups, however, in the event of major bleeding, advise the patient to seek immediate attention and to stop heparin therapy immediately. A thorough head-to-toe patient assessment and laboratory monitoring is required and if necessary, protamine sulphate may be administered.
It is imperative to recognize and resolve the underlying cause of DIC but not to be swayed to correct the abnormal laboratory results. A combination of treating the underlying condition with supportive therapy will often improve DIC.
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