hence the final common pathway of coagulation. In DIC, there is unregulated and uncontrolled activation of the coagulation cascade and platelets, leading to thrombotic occlusion of the microvascular capillaries and vessels and resulting in dysfunction of critical organs, such as acute kidney injury (AKI) and pulmonary dysfunction (ARDS). The consumption of coagulation factors and platelets by intravascular activation outpaces production, and the levels of coagulation factors and platelets fall. Simultaneously, there is activation of the fibrinolytic cascade, generating plasmin and resulting in fibrinogen degradation (high D‐dimers), together with depletion of components of the natural anticoagulant pathway (Antithrombin, Protein C, and Protein S) that contribute to systemic bleeding diathesis.1,2 Hence the paradox of DIC is that the clinical manifestations are of bleeding while the patient suffers morbidity and mortality due to organ damage due to microvascular thrombosis. The most common cause of DIC is sepsis, which occurs in 20–80% of severe cases and has a mortality of 20–50%. DIC usually has an acute onset with bleeding manifestations dominating the clinical picture; however, a chronic form can occur, the manifestations of which are very different, usually with presentation as recurrent thrombosis together with bruising, low platelets, and high D‐dimers. The management of this form of condition likewise differs.
Pathophysiology
DIC is a pathophysiological syndrome characterized by clinical manifestations of generalized bleeding together with laboratory features of severe coagulopathy. It is not a discrete pathological entity but a final common pathway for a variety of triggers and precipitating factors and can be initiated by a number of different mechanisms (Table 23.1). DIC is characterized by great variation both between patients and within the same patient over time. It is a dynamic condition that will progress if untreated but can rapidly improve with appropriate treatment of the underlying cause. Recognition and treatment of the underlying cause are more important in treating DIC than support with haemostatic factors and platelets – giving more coagulation factors, fibrinogen, and platelets without treating the cause results in more substrate for uncontrolled coagulation and more microvascular thrombosis and end organ damage. Due to its severity and dynamic nature, it has been difficult to perform adequate randomized controlled trials in the management and treatment of DIC, although there have been several recent advances in its early diagnosis and treatment.3
The primary triggers of DIC in the elderly are bacterial sepsis and malignancy, particularly disseminated malignancy. Other causes include massive trauma and major surgery. ABO‐incompatible blood transfusions, pancreatitis, and snake bites are rarer but recognized causes. DIC may be precipitated by activation of the coagulation cascade following tissue factor exposure, for example, as in massive trauma and major surgery; activation of the fibrinolytic cascade, e.g. the liberation of plasminogen activators by leukaemic blasts in acute promyelocytic leukaemia or carcinoma of the prostrate; or intravascular platelet activation, e.g. heparin‐induced thrombocytopenia, haemolytic uraemic syndrome, by endotoxins and endothelial cell activation in Gram‐negative sepsis and meningococcal septicaemia or by direct proteolytic cleavage of circulating haemostatic proteins, as occurs in pancreatitis and with some snake venoms (Table 23.1). In addition to uncontrolled activation of and consumption of platelets and the coagulation cascade, there is depletion of the proteins of the natural anticoagulant pathway. Depletion of these further enhances the microvascular thrombosis and also leads to activation of the complement system, resulting in an inflammatory response and generation of vasoactive peptides, such as bradykinin. DIC also provokes a poorly characterized neuroendocrine response involving elevated catecholamines and glucocorticoids.4
Clinically, DIC manifests as simultaneous bleeding and microvascular thrombosis leading to multiple organ dysfunction, including acute kidney injury (AKI), adult respiratory distress syndrome (ARDS), and hepatic and neurological dysfunction, and is often associated with fever, hypotension, lactic acidosis, hypoxia, and proteinuria. While bleeding is the most obvious and commonly recognized manifestation, death by bleeding is rare due to the use of blood and platelet transfusions in the treatment of hypovolaemia. The usual cause of death in DIC is multiorgan failure as a consequence of microvascular thrombosis, which is not immediately clinically apparent. Treatment of multiorgan failure, which is a consequence of anoxia and ischaemic necrosis of vital organs, is far more difficult to treat satisfactorily.5
Figure 23.1 Mechanism of microvascular thrombosis and bleeding in DIC. Broken lines indicate inhibition.
Table 23.1 Mechanisms and precipitating factors in DIC.
| Mechanism | Example |
|---|---|
| Coagulation cascade activation | Tissue factor exposure in trauma and extensive surgery |
| Fibrinolytic cascade activation | Plasminogen activators liberated in acute promyelocytic leukaemia or disseminated prostatic cancer |
| Intravascular platelet aggregation | Haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, heparin‐induced thrombocytopenia |
| Endothelial cell activation | Gram‐negative sepsis, disseminated malignancy |
| Direct proteolytic cleavage of haemostatic proteins | Pancreatitis, snake venoms |
The bleeding in DIC is multifactorial in origin as a result of depletion of fibrinogen, all coagulation factors, and platelets as a consequence of consumption due to uncontrolled and excessive activation of the coagulation cascade, diminished platelet number due to consumption, and an additional or acquired platelet defect consequent to proteolytic degradation of platelet surface glycoproteins and partial degranulation of α and dense platelet granules. Hyperfibrinolysis leads to elevated levels of fibrinogen and fibrin degradation products (measured as highly increased D‐dimers), which act as competitive inhibitors of fibrin polymerization. The uncontrolled generation of free thrombin and plasmin degrades fibrin, fibrinogen, and coagulation factors, particularly factors V and VIII. Consequently, there is a systemic bleeding diathesis resulting in not only bleeding from local surgical incisions or traumatic wounds but also generalized bruising, petechiae, and purpura, together with bleeding from sites of venepuncture, arterial lines, drains, catheters, and endotracheal tubes. There is also frequent gastrointestinal bleeding, haemoptysis, haematuria, and even intramuscular or intracerebral bleeding. Clinically, the widespread occurrence of abnormal and excessive bleeding is the hallmark of DIC. Excessive bleeding from a single site, particularly following surgery, is usually more indicative of a specific failure of local haemostasis than DIC and requires specific local measures. The microvascular thrombosis results in anoxic damage and ischaemic infarction of vital organs, including lungs, kidneys, brain, pituitary, liver, adrenal, heart, and skin.6
Diagnosis
The diagnosis of DIC is made in the presence of a predisposing cause, the clinical manifestations of systemic bleeding and multiorgan dysfunction, and appropriate laboratory investigations (Table 23.2). The haemoglobin is usually reduced owing to intravascular red cell fragmentation, resulting in a microangiopathic haemolytic anaemia (MAHA), and there is profound thrombocytopenia. Coagulation times are abnormal, with a prolongation of the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin
