Disseminated intravascular coagulation

A primer for primary care physicians

Harry L. Messmore Jr, MD; William H. Wehrmacher, MD

WEB EXCLUSIVE / MARCH 2002 / POSTGRADUATE MEDICINE

The authors disclose no financial interest in this article.

Although you are not likely to see it often, disseminated intravascular coagulation (DIC) can cause confusion in your diagnostic efforts unless you can anticipate when it may occur. In its acute form, DIC is usually an explosive, often life-threatening disorder. When it is relatively mild or subclinical, DIC may not be so easy to spot. In this article, Drs Messmore and Wehrmacher present an overview of DIC, its causes, and its management.
Messmore HL Jr, Wehrmacher WH. Disseminated intravascular coagulation: a primer for primary care physicians. Postgrad Med 2002;111(3)

DIC is a syndrome arising as a complication of many different serious and life-threatening illnesses. In its acute (overt) form it is a hemorrhagic disorder, characterized by multiple ecchymoses, mucosal bleeding, and depletion of platelets and clotting factors in the blood. Chronic (nonovert) DIC, on the other hand, is more subtle and involves thromboembolism accompanied by evidence of activation of the coagulation system. With chronic DIC, coagulation factors may be normal, increased, or moderately decreased, as may the platelet counts.

Successful management of acute DIC depends almost entirely on prompt, effective control of the underlying disease. Chronic DIC usually can be treated with heparin or low-molecular-weight heparin, but warfarin is sometimes ineffective for long-term control. Successful treatment of the underlying disease is necessary to eliminate DIC, whether it is acute or chronic.

Pathogenesis of DIC

DIC occurs when monocytes and endothelial cells are activated or injured by toxic substances elaborated in the course of certain diseases. The response of monocytes and endothelial cells to injury is to generate tissue factor on the cell surface, activating the coagulation cascade (figure 1). In acute DIC, an explosive generation of thrombin depletes clotting factors and platelets and activates the fibrinolytic system. Bleeding into the subcutaneous tissues, skin, and mucous membranes occurs, along with occlusion of blood vessels caused by fibrin in the microcirculation.

In chronic DIC, the process is the same, but it is less explosive. Usually there is time for compensatory responses to take place, which diminish the likelihood of bleeding but give rise to a hypercoagulable state. These changes in the blood can be detected by testing the coagulation system.1-4 Thromboembolism occurs in this setting, and when oral anticoagulants are given following heparin therapy, there is a tendency for it to recur. Long-term therapy with low-molecular-weight heparin may be a solution to this problem until the underlying cause can be brought under control.

Conditions associated with DIC

The conditions that regularly give rise to the DIC syndrome are outlined in table 1 (1,5-8). Knowledge of this association is helpful to the physician, who may then anticipate onset and intervene in a timely manner.

Table 1. Conditions underlying DIC syndrome

Infections Acute DIC: Bacteria and their toxins, fungi, viruses, rickettsiae Chronic DIC: Any chronic infection (eg, tuberculosis, abscesses, osteomyelitis) Noninfectious inflammatory diseases Inflammatory bowel disease: Crohn's disease and similar disorders Obstetrical complications Acute DIC: Abruptio placentae, abortions (especially therapeutic abortions), amniotic fluid embolism, hemorrhagic shock Chronic DIC: Dead fetus syndrome Malignancy Acute DIC: Acute promyelocytic leukemia, acute myelomonocytic or monocytic leukemia, disseminated prostatic carcinoma Chronic DIC: Lung, breast, gastrointestinal malignancy Vascular disease Acute DIC: Brain infarction or hemorrhage Chronic DIC: Aortic aneurysm, giant hemangioma Venoms Acute DIC: Snake, spider (rare) Trauma Acute DIC: Massive tissue destruction, brain damage Others Acute DIC: Heparin-induced thrombocytopenia with thrombosis (HITT), purpura fulminans in newborns (homozygous protein C deficiency) DIC, disseminated intravascular coagulation.

It is well known that Trousseau described an association between cancer and venous thromboembolism. However, it is less well known that half of his patients did not have cancer but rather had tuberculosis (9). Other inflammatory diseases are also often associated with thromboembolism. Patients with these conditions have the hypercoagulable state known as chronic DIC. Nonbacterial thrombotic endocarditis and arterial thromboembolism constitute "arterial Trousseau's syndrome."

Diagnosis of DIC

Diagnostic findings in DIC are outlined in table 2. The clinical and laboratory features of acute DIC differ from those of chronic DIC. This is only a general rule, however, in that chronic DIC in dead fetus syndrome and in certain vascular disorders (eg, aortic aneurysm) may show coagulation abnormalities similar to those found in acute DIC (10,11).

Table 2. Clinical and laboratory findings in DIC

Acute DIC Clinical findings Multiple bleeding sites Ecchymoses of skin, mucous membranes Visceral hemorrhage Ischemic tissue Laboratory abnormalities Coagulation abnormalities: prolonged prothrombin time, activated partial thromboplastin time, thrombin time; decreased fibrinogen levels; increased levels of FDP (eg, on testing for FDP, D dimer) Platelet count decreased as a rule but may be falling from a higher level yet still be normal Schistocytes on peripheral smear Chronic DIC Clinical findings Signs of deep venous or arterial thrombosis or embolism Superficial venous thrombosis, especially without varicose veins Multiple thrombotic sites at the same time Serial thrombotic episodes Laboratory abnormalities Modestly increased prothrombin time in some patients Shortened or lengthened partial thromboplastin time Normal thrombin time in most patients High, normal, or low fibrinogen level High, normal, or low platelet count Increased levels of FDP (eg, on testing for FDP, D dimer) Evidence of molecular markers* (eg, thrombin-antithrombin complexes, activation markers on platelet membranes, prothrombin fragment F1+2) DIC, disseminated intravascular coagulation; FDP, fibrin-fibrinogen degradation products. *These tests are used primarily in research.

Diagnosis of acute DIC can be established without performing all of the laboratory tests we know to have abnormal findings in most cases of this syndrome. This is especially true when the clinical setting is consistent with DIC and results of routine tests (eg, platelet count, prothrombin time, partial thromboplastin time, fibrinogen level) are all abnormal (table 2). Disorders such as hepatic insufficiency, hepatic necrosis, anticoagulant overdose, and the presence of certain circulating anticoagulants should also be considered in the differential diagnosis, particularly when there is no obvious underlying disease to account for DIC (10-13).

A number of other laboratory markers are associated with DIC, including prolonged thrombin time and decreased levels of antithrombin III, protein C, plasminogen, and alpha₂-antiplasmin. However, these same abnomalities may be seen in severe liver disease and in severe hemorrhage caused by plasma loss. The one coagulation system test that helps distinguish between DIC and liver disease is D dimer. This test is usually negative in liver disease unless there is massive necrosis, which can cause DIC.

Another laboratory clue to chronic DIC is a shortened activated partial thromboplastin time (14,15). Platelet counts may be normal, high, or moderately low. In addition, platelet counts may rise with heparin therapy and fall when heparin is stopped in the presence of a hypercoagulable state or chronic DIC.

Management of DIC

Treatment of the underlying disease is the mainstay of management of either acute or chronic DIC (table 3). Additionally, acute DIC is treated with blood products that control bleeding if necessary. Experimental drugs (eg, concentrate of the tissue factor pathway inhibitors antithrombin III, protein C, or thrombomodulin) are currently undergoing clinical trials (5,16).

Table 3. Treatment options for DIC syndrome

Treat the underlying disease Avoid delay Treat vigorously (eg, shock, sepsis, obstetrical problems) Manage the DIC Acute DIC    Without bleeding or evidence of ischemia       No treatment    With bleeding       Blood components as needed       Fresh frozen plasma       Cryoprecipitate       Platelet transfusions    With ischemia       Anticoagulants (see "with thromboembolism" below) after       bleeding risk is corrected with blood products Chronic DIC    Without thromboembolism       No specific therapy needed but prophylactic drugs       (eg, low-dose heparin, low-molecular-weight heparin)       may be used for patients at high risk of thrombosis    With thromboembolism       Heparin or low-molecular-weight heparin, trial of warfarin       sodium (Coumadin). (If warfarin is unsuccessful, long-term use       of low-molecular-weight heparin may be helpful.)* DIC, disseminated intravascular coagulation. *Some patients respond to warfarin, others do not. Use of low-molecular-weight heparin for prolonged periods has potential hazards and is expensive but can be useful when warfarin therapy fails despite good control (international normalized ratio [INR], 2-3).

When there is no serious hemorrhage or unusual risk of bleeding or thromboembolism in acute DIC, it is appropriate to observe rather than treat. As Milton stated in On His Blindness, "They also serve who only stand and wait."

Chronic DIC is primarily a hypercoagulable state that may result in venous or arterial thrombosis. In some vascular and obstetrical disorders, chronic DIC manifests primarily by consumption coagulopathy of mild to modest degree. Standard treatment of thromboembolism with heparin or low-molecular-weight heparin is appropriate, although it is important to be aware of warfarin resistance. Should thrombosis recur while a patient is receiving warfarin, it is advisable to use heparin or low-molecular-weight heparin until the underlying disease is fully controlled or cured.

Summary

An awareness of the clinical settings in which DIC can occur and the diagnostic features that warn of its presence should enable the physician to diagnose and treat DIC appropriately. New treatments that are more effective and less hazardous are clearly needed, and a number of such agents are now undergoing clinical trial.

References

1. Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341(8):586-92
2. Bick RL. Disseminated intravascular coagulation: pathophysiologic mechanisms and manifestations. Semin Thromb Hemost 1998;24(1):3-18
3. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998;24(1):33-44
4. Robinson RA, Worfolk L, Tracy PB. Endotoxin enhances the expression of monocyte prothrombinase activity. Blood 1992;79(2):406-16
5. Carey MJ, Rodgers GM. Disseminated intravascular coagulation: clinical and laboratory aspects. Am J Hematol 1998;59(1):65-73
6. Baglin T. Disseminated intravascular coagulation: diagnosis and treatment. BMJ 1996;312(7032):683-7
7. Messmore HL Jr, Nijm W, Gawlik G, et al. Overwhelming sepsis and bleeding in a previously splenectomized patient. Clin Appl Thromb/Hemost 1995;1(1):80-4
8. Penner JA. Disseminated intravascular coagulation in patients with multiple organ failure of non-septic origin. Semin Thromb Hemost 1998;24(1):45-52
9. Kwaan HC. Preface. The thrombophilic state in cancer patients. Semin Thromb Hemost 1999;25(2):127-9
10. Müller-Berghaus G, ten Cate H, Levi M. Disseminated intravascular coagulation: clinical spectrum and established as well as new diagnostic approaches. Thromb Haemost 1999;82(2):706-12
11. Levi M, de Jonge E, van der Poll T, et al. Disseminated intravascular coagulation. Thromb Haemost 1999;82(2):695-705
12. Falanga A, Rickles FR. Pathophysiology of the thrombophilic state in the cancer patient. Semin Thromb Hemost 1999;25(2):173-82
13. Gouin-Thibault I, Samama MM. Laboratory diagnosis of the thrombophilic state in cancer patients. Semin Thromb Hemost 1999;25(2):167-72
14. Reddy NM, Hall SW, MacKintosh FR. Partial thromboplastin time: prediction of adverse events and poor prognosis by low abnormal values. Arch Intern Med 1999;159(22):2706-10
15. Korte W, Clarke S, Lefkowitz JB. Short activated partial thromboplastin times are related to increased thrombin generation and an increased risk for thromboembolism. Am J Clin Pathol 2000;113(1):123-7
16. Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation. Thromb Haemost 1999;82(2):718-21

Dr Messmore is professor of medicine, Loyola University of Chicago Stritch School of Medicine, and staff physician, Hines Veterans Affairs Hospital. Dr Wehrmacher is clinical professor of medicine and adjunct professor of physiology, Loyola University of Chicago Stritch School of Medicine. Correspondence: Harry L. Messmore Jr, MD, Loyola University of Chicago Stritch School of Medicine, Cardinal Bernardine Cancer Center, 2160 S First Ave, Maywood, IL 60153. E-mail: rshines@lumc.edu.

Please send technical questions related to the Web site to Ann Harste