The most formidable and daunting disorder of hemostasis is DIC. This life-threatening complication is commonly encountered in a variety of medical, surgical, and obstetric settings. The pathophysiology of DIC is complex, but at its core is the release of tissue factor or the exposure of blood to endotoxin in sufficient amounts to activate blood coagulation and overwhelm normal hemostatic regulatory mechanisms. As a result, the coagulation cascade is ignited to such a degree that coagulation factors are consumed along with platelets. This process is accompanied by secondary fibrinolysis due to activation of plasmin, which may digest any fibrin that is formed. Depending on the balance of pro-thrombotic and anti-thrombotic derangements, pathology sections may show widespread deposition of fibrin and platelets throughout the microcirculation accompanied by tissue damage, hemorrhage, or a combination of both.
ETIOLOGY AND PATHOGENESIS
DIC never arises de novo but rather as a consequence of an underlying pathologic process. Further insight into the pathogenesis of DIC can be gained by a consideration of the myriad of disorders that are known triggers, the most important of which are shown in Table 16-1.
TABLE 16-1Underlying Disorders That Trigger Disseminated Intravascular Coagulation ||Download (.pdf) TABLE 16-1 Underlying Disorders That Trigger Disseminated Intravascular Coagulation
|Vascular Damage Leading to Release of Tissue Factor |
Gram negative organisms
|Release of Tissue Factor from Injured or Pathologic Tissue |
Amniotic fluid embolus
Solid tumors, mucin-secreting adenocarcinomas
Acute promyelocytic leukemia
In many of these conditions, the release of tissue factor from injured vessels or extravascular cells plays a central role in unleashing the full potential of the blood coagulation pathway (Fig. 16-4). In addition, injury to the endothelium can cause in situ thrombus formation due to both adhesion of platelets and down-regulation of thrombomodulin, which normally converts circulating thrombin into an anticoagulant (Chapter 17). Sepsis is the most common trigger of DIC among medical or surgical in-patients. The production of endotoxin by the offending organism activates monocytes, provoking the release of both endogenous tissue factor and inflammatory cytokines such as tumor necrosis factor and interleukin-1, which in turn induce robust expression of tissue factor. DIC also may be initiated by diffuse vascular injury caused by hypoxia, acidosis, and shock, often coexisting in very sick patients, as well as by antigen–antibody complexes, such as are present in systemic lupus erythematosus.
Scheme summarizing the pathogenesis of disseminated intravascular coagulation.
Intravascular coagulation can also be triggered by release of tissue factor from pathologic tissue. DIC occurs in obstetrical patients as a result of a number of complications listed in Table 16-1. In many of these patients, DIC is induced by the release of fetal cells or fluid into the maternal circulation. Obstetrical DIC usually resolves promptly with surgical correction of the problem. In addition, procoagulant material can be released in certain malignant conditions. In acute promyelocytic leukemia (Chapter 21), the turnover of granule-laden leukemic cells releases procoagulants that often lead to severe DIC. Patients with certain solid tumors, particularly mucus-producing adenocarcinomas, sometimes have a more chronic and indolent form of DIC.
Clinical presentation and manifestations are variable, as shown in Figure 16-5. Patients with severe acute DIC commonly have diffuse bleeding, most often ecchymoses in skin and mucous membranes as a result of thrombocytopenia, but occasionally more serious and extensive blood loss. Some patients have profuse gastrointestinal bleeding, usually from multiple sources. Others develop pulmonary or uterine bleeding, hematuria, wound hemorrhage, or spontaneous bleeding from venipuncture sites. The more serious bleeding is due to a combination of thrombocytopenia, deficiency of coagulation factors, and secondary fibrinolysis. A much smaller subset of patients presents with thrombosis, often localized to the fingertips and toes, but sometimes causing necrosis of internal organs such as the renal cortex or bowel. Critically ill patients with the underlying conditions listed in Table 16-1 often have no clinically apparent bleeding or thrombosis but yet have the laboratory abnormalities of DIC. Obviously, these patients require close surveillance.
Clinical spectrum of disseminated intravascular coagulation.
Patients with DIC have both thrombocytopenia and global abnormalities in the coagulation profile, as shown in the sidebar. Examination of the peripheral blood smear not only confirms the thrombocytopenia but also reveals relatively large platelets, indicative of enhanced platelet consumption rather than impaired production. In addition, in about one-quarter of patients with DIC, the red cell morphology is abnormal, with fragmented, triangular, and helmet-shaped cells, shown in Figure 16-6B, identical to the morphology encountered in microangiopathic hemolytic disorders such as thrombotic thrombocytopenic purpura (Chapter 14). However, patients with DIC have much less hemolysis than those with thrombotic thrombocytopenic purpura. Abnormal red cell morphology in DIC is due to shear stress as red cells are catapulted through a meshwork of fibrin strands. The markedly abnormal coagulation profile is due in part to low levels of clotting factors, owing to ongoing consumption. In addition, fibrin degradation products generated by ongoing fibrinolysis are potent inhibitors of thrombin.
Disseminated intravascular coagulation. A) Scanning electron micrograph of a microclot showing red cells caught on strands of fibrin. (From Bull BS and Kuhn IN. Production of schistocytes by fibrin strands [an electron microscopic study]. Blood, 1968; 35:104-11.) B) Blood film from a patient with disseminated intravascular coagulation showing red cell fragmentation: schistocytes (lower left and center) and a helmet cell (lower right).
DIC: Lab Findings
The cardinal mandate in the management of DIC is to first treat the underlying disease. The patient's bleeding, thrombosis, and accompanying laboratory abnormalities may be promptly and fully reversed by effective therapy of the underlying condition—that is, antibiotic treatment of sepsis, surgical debridement of trauma wounds, and removal of fetal and placental tissue from the uterus. Unfortunately, in many (and perhaps most) cases of DIC, it is not possible to effectively treat the underlying disease. In these patients, active bleeding can be controlled by the administration of platelets, fresh frozen plasma, and sometimes coagulation factor concentrates. In patients with thrombosis, careful administration of heparin may be effective. In the absence of either bleeding or thrombosis, close monitoring is crucial because the clinical status of patients with DIC can deteriorate very rapidly.