Disseminated Intravascular Clotting

Disseminated Intravascular Clotting DONAT P. CYR, M.D. VIJAY B. MEHTA, M.D., M.R.C.P. (London)

Disseminated intravascular clotting (DIC) is a relatively new concept in the pathogenesis of disease. It is not a disease entity per se, but an intermediary pathogenetic mechanism complicating many disease states, a "syndrome within a syndrome." As the term implies, it is a widespread coagulation of the circulating blood throughout the vascular tree. It involves the conversion of fibrinogen to fibrin and may result in extensive obstruction of the microvasculature. DIC has been described under several terms: defibrination syndrome, consumption coagulopathy, and acquired hypofibrinogenemia. All have the same connotation, namely, an excessive, accelerated, in vivo conversion of fibrinogen to fibrin. The consequence of this pathologic process can best be realized after a brief review of the coagulation mechanism as presently understood.

COAGULATION MECHANISM The change in the physical state of the blood from liquid to solid involves a series of reactions in which inactive blood-clotting factors are activated. Thus, factor XII activates factor XI which activates factor IX which in turn activates factor VIII. Activated factor VIII activates factor X which together with factor V and platelet lipid forms thromboplastin (intrinsic system) which converts prothrombin to thrombin. Thrombin then converts fibrinogen to a soluble fibrin which becomes stabilized into a solid irreversible fibrin clot under the action of factor XIII, the fibrin-stabilizing factor. The kinetics of these reactions is not thoroughly understood. Present-day thinking is that the factors act sequentiallyhence the terms "waterfall" or "cascade" type of factor activationprobably in the sequence depicted in Figure 1. The conversion of fibrinogen to fibrin can also be brought about by tissue thromboplastin (extrinsic system). Factors VII, V, and X are required for the activation of tissue thromboplastin. When these two activities are pathologically accelerated, defibrination results and is often accompanied by depletion of factors 11, V, and VIII which, with factor I, are also consumed during the coagulation process. Medical Clinics of North America- Vol. 53, No. 2, March, 1969

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THROMBOPLASTIN

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ACTIVATION

(Extrinsic System)

(Intrinsic System)

Tissue Thromboplastin + F. VII

F. XII F•

P.

1-XI

.

F. IX

1-

F. VIII + Platelet Lipids

~I:l

Ica:+ I

Thromboplastin

proth~ombin t

Thrombin

FibrinOgen-----t~.Fibrin

(soluble)

t F. XIII t Fibrin (insoluble)

Figure 1.

"Cascade" type of factor activation.

MECHANISM OF PRODUCTION OF DIC Disseminated intravascular clotting can be brought about by a number of agents which act either by accelerating the intrinsic system of thromboplastin generation or by activating the extrinsic system. This pathologic phenomenon in vivo has been known to occur when viruses, certain parasites (malaria), bacteria, or bacterial toxins enter the circulation. Hemolyzed red blood cells, tumor emboli or thromboplastin-like material from tumors, and antigen-antibody complexes can trigger DIC. Tissue anoxia resulting from stasis, generalized anoxemia, and shock from any cause may be associated with in vivo coagulation of blood. The release of thromboplastin-like material from the tissues, as in extensive surgery or certain complications of pregnancy, widespread damage to vascular endothelium, and prolonged contact of circulating blood with a foreign surface such as in cardiopulmonary bypass - these factors acting singly or in combination-play a role in the causation of the DIC syndrome. The clearest understanding of this syndrome is illustrated by the Shwartzman reaction produced in experimental animals. Two intravenous injections of endotoxin from gram-negative organisms given to rabbits at an interval of 24 hours produce irreversible shock and a bleeding diathesis. Autopsy shows widespread fibrin thrombus formation in the microvasculature and necrosis of the tissues and organs, especially the kidneys. Each dose of the endotoxin activates the coagulation factors and fibrin formation. These are cleared up by the reticuloendothelial system. If the reticuloendothelial system is blocked, a widespread deposition of fibrin results even after a single injection of endotoxin.

DISSEMINATED INTRAVASCULAR CLOTTING

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During this process, the clotting factors are used up, so that the blood becomes hypocoagulable and a bleeding diathesis results. This reaction can be prevented by prior administration of heparin. Fibrin deposition can be cleared up by the administration of activators of the fibrinolytic mechanism. No matter what the etiologic agent or the underlying disease state may be in a particular patient, the end result of DIe is twofold: (1) a disruption of the hemostatic mechanism and excessive consumption of certain coagulation factors, which mayor may not result in a bleeding diathesis, and (2) a widespread deposition of fibrin thrombi in the arterioles, capillaries, and venules, which may or may not result in ischem.ic necrosis of the organs involved.

CLINICAL FEATURES OF DIC Not every patient affected with anyone of the disease states listed in Table 1 will manifest disseminated intravascular clotting. The phe-

Table 1. Conditions (Occasionally) Associated with DIC Cancer-especially disseminated cancer from the lungs, breasts, stomach and colon, pancreas and prostate, ovary Surgery Extensi ve operations on lungs, stomach. pancreas, prostate Massive blood transfusions Cardiopulmonary bypass Shock states Septic (especially gram-negative endotoxin) Hemorrhagic Anaphylactic Traumatic Hematologic conditions Acute leukemia Reticulum cell sarcoma Thrombotic thrombocytopenic purpura Purpura fulminans Acute hemolytic crises Transfusions of mismatched blood Hemolytic uremic syndrome Obstetric conditions Abruptio placentae Prolonged retention of a dead fetus Septic abortion and postpartum sepsis Amniotic fluid embolism Infections Septicemia, especially gram-negative Viral Hemorrhagic fevers Rarely following childhood diseases (purpura fulminans) Malaria, especially P. falciparum Rocky Mountain spotted fever Hypersensitivity diseases - systemic lupus, periarteritis nodosa. glomerulonephritis, the hemolytic uremic syndrome, acute allergic vasculitis Miscellaneous Giant hemangioma Dissecting aneurysm Extensive burns with hemoglobinemia Certain snake venoms Drugs and chemicals: meprobamate, high molecular weight dextran, ristocetin Severe liver disease

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nomenon, however, is being recognized with increasing frequency, to judge by the extensive literature of the past few years. The clinical manifestations are those of the underlying disease process complicated by disruption of the hemostatic mechanism. The two major manifestations of the latter are bleeding and thrombosis. The syndrome varies considerably in rapidity of development, intensity, and duration. The acute form of the defibrination syndrome is seen most commonly in obstetric complications or during or following surgical procedures. In its most acute form the clinical manifestations are profuse bleeding from many sites, severe abdominal pain with or without diarrhea (often bloody), low back pain, oliguria or anuria, dyspnea and cyanosis, hypotension and shock, convulsions, and coma. The prognosis is poor and the outcome too often is death in hours or a very few days. More often the syndrome of DIC follows a subacute course lasting a few days to a few weeks. The bleeding manifestations may be slight: excessive oozing at surgery, bleeding into the wound or in body cavities, and ecchymoses around a surgical wound and drainage tubes or at the site of venipunctures. There may be excessive bleeding from a local site of disease, such as a carcinoma in the gastrointestinal tract. Thromboses of the venous or arterial circulation may be clinically evident. More often the fibrin thrombi obstruct the microcirculation in various organs, particularly the kidneys, the liver, and the brain, giving rise to a variety of symptoms and signs referable to the specific organ involved. With an increasing index of suspicion, more and more cases of DIC are being diagnosed without overt bleeding or thrombotic manifestations. The following pattern of multiple deficiencies can lead to a diagnosis of DIC: low fibrinogen concentration, low platelet count, and low prothrombin in a patient with an underlying disease such as carcinoma or systemic lupus. This can be further substantiated by a low level of factors V and VIII and the presence of fibrin-split products in the serum. It must be recognized that the entire constellation of depletion of coagulation factors is not present in all cases. A singular deficiency of fibrinogen together with a low platelet count should at least arouse suspicion of a defibrination syndrome. Correction of the coagulation factor or factors and platelet deficiency by heparin therapy confirms the diagnosis.

LABORATORY DIAGNOSIS The diagnosis of the DIC syndrome and its management require the close collaboration of the clinician and the clinical pathologist. In the proper clinical context the clinician may suspect that a defibrination process is taking place, but a definitive diagnosis and the guide to proper therapy in large part rest upon the laboratory tests. It is not the purpose of this paper to describe in detail the technique of the tests involved but simply to point out certain tests that are necessary to the clinician for the diagnosis and management of this syndrome. The tests can be grouped as follows: SCREENING TESTS. (1) Clot observation: clot is small, friable, and mushy, and the red cells settle to the bottom of the tube; the first clue to

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DISSEMINATED INTRAVASCULAR CLOTTING

diagnosis of hypofibrinogenemia may come from an astute technician who reports abnormal clot formation or even incoagulable blood. (2) Platelet observation on blood smear or platelet count. (3) One-stage prothrombin time. (4) Thrombin time: abnormal tests indicate a low fibrinogen level, which is the most characteristic feature of this syndrome. (5) Fibrinogen estimation. In the acute form of this syndrome the above tests, which can be performed in a short time, are sufficient to initiate urgent therapy. DEFINITIVE TESTS. (1) Demonstration of fibrin-split products in the serum. (2) Demonstration of cryofibrinogen (cryoprofibrin) in the plasma. (3) Quantitative assays for factors V and VIII.

DIFFERENTIAL DIAGNOSIS OF DIe Results of the tests listed, if abnormal, simply indicate a defibrination syndrome and do not distinguish between disseminated intravascular clotting and activation of the fibrinolytic system. A low plasma fibrinogen level is a central characteristic of both mechanisms. Plasmin is a proteolytic enzyme that digests fibrin. If present in high levels in the circulating plasma it will also digest other coagulation proteins. Hence, low plasma levels of fibrinogen, prothrombin, and factors V and VIII may be common to both mechanisms. Nevertheless, for correct management it is essential to differentiate between these two pathologic mechanisms as the cause of defibrination. Whereas not too many years ago it was thought that many cases of acute obstetric or surgical bleeding were the result of fibrinolysis, it is Table 2.

Differentiation of DIe and Primary Fibrinolysis DIC

TEST

PRIMARY FIBRINOLYSIS

Observation of blood clot

Blood clot may be very small and friable owing to low fibrinogen; its presence is confirmed by pouring contents of tube on a gauze piece.

Complete dissolution of clot

Peripheral blood smear

(1) Low platelet count (2) Fragmented red cells

Normal

Fibrinogen

Low

Low

Factors V and VIII

Low

Low

Prothrombin

Low

Low

Fibrin degradation products

Present

Present in a high titer

Euglobulin lysis time

Normal

Very rapid

Serial throm bin time

Normal or abnormal

Abnormal

Cryofibrinogen

Present

Absent

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now recognized that disseminated intravascular clotting is much more common and that primary systemic fibrinolysis is rare. More commonly, DIC is the basic mechanism of defibrination and the breakdown in hemostasis. Fibrinolysis often coexists with DIC as a secondary phenomenon, but in some instances it may be the predominant cause of defibrination and hemorrhage. The commonly performed tests of fibrinolysis are the euglobulin lysis test and the serial thrombin time test with and without addition of epsilon-aminocaproic acid (EACA). An outline of methods of differentiating these two pathologic mechanisms is included in Table 2.

TREATMENT OF DIe The specific therapeutic agent for DIC is heparin. Heparin acts by blocking the action of thrombin. It will thus effectively decelerate the defibrination process and inhibit the excessive consumption of other clotting factors, particularly fibrinogen and factors V and VIII. The dosage of heparin must be tailored to the individual case on the basis of repeated laboratory tests. In acute problems heparin should be given intravenously by continuous drip. As a rule an initial dose of 5000 to 10,000 units is repeated every 6 hours, adjusted as necessary according to the progress of the case. In the subacute cases it can be given subcutaneously in a dose sufficient to double the normal clotting time. Because of the great diversity of agents capable of triggering DIC and the variety of disease states associated with this syndrome, the decision to use heparin must be considered carefully. Not every patient with disseminated intravascular clotting will require heparin. The syndrome may resolve itself with appropriate treatment of the underlying disease before any significant hemorrhagic or thrombotic manifestations develop. Other patients may require heparin therapy for many days or several weeks to prevent serious hemorrhagic complications or extensive damage to many organs by fibrin blockage of the microvasculature. The acute severe bleeding problems encountered, particularly in obstetrics and in surgery, present a challenge. The decision to use heparin in a hemorrhagic state is a courageous therapeutic act which must at least be supported by strongly positive screening tests, later confirmed by the more definitive tests for DIC. The patient's condition must be monitored closely, both at the bedside and by appropriate laboratory tests. An attempt must be made to determine whether the primary process is disseminated intravascular clotting or fibrinolysis. This may be difficult in an acute bleeding problem where prompt treatment is mandatory. Indeed, in such emergency situations it may be advisable to administer both heparin and EACA, since both mechanisms may contribute to the hemorrhagic diathesis. The dose of EACA is 3 to 5 gm. intravenously or orally followed by 0.5 to 1.0 gm. every hour until the hemorrhage is controlled. In such acute, life-threatening situations it is also advisable to administer a fibrinogen concentrate in a dose of 4 to 6 gm. intravenously. Fresh whole blood or plasma may also be necessary to maintain circulatory stability.

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SUMMARY Disseminated intravascular clotting is a syndrome which may be associated with a great variety of disease states. It may develop acutely and require prompt recognition and aggressive treatment, or it may follow a subacute course over many days and weeks. The specific agent for therapy is heparin. The syndrome may be associated with a significant degree of fibrinolysis, the specific treatment for which is epsilonaminocaproic acid.

SELECTED REFERENCES Dennis, L. H., Eichelberger, J. W., Inman, M. M., et al.: Depletion of coagulation factors in drug·resistant Plasmodium falciparum malaria. Blood, 29:713·721 (May), 1967. Hardaway, R.: Syndromes of Disseminated Intravascular Coagulation. Springfield, Ill., Charles C Thomas, 1966. Hardisty, R. M., and Ingram, G. I. C.: Bleeding Disorders: Investigation and Management. Philadelphia, F. A. Davis Co., 1965, pp. 103-143. McKay, D. G.: Disseminated Intravascular Coagulation: An Intermediary Mechanism of Disease. New York, Hoeber Medical Division, Harper & Row Publishers, 1965. McKay, D. G.: Diseases of hypersensitivity. Arch. Int. Med., 116:83·94 (July), 1965. McKay, D. G., and Margaretten, W.: Disseminated intravascular coagulation in virus diseases. Arch. Int. Med., 120:129-152 (Aug.), 1'967. Merskey, C., J ohnson, A. J., Kleiner, G. J., et al.: The defibrination syndrome: Clinical features and laboratory diagnosis. Brit. J. Haemat., 13:528-549 (July), 1967. Mosesson, M. W., Coleman, R. W., and Sherry, S.: Chronic intravascular coagulation syndrome. New Eng. J. Med., 278 :815-821 (April 11), 1968. Rodriguez-Erdmann, F.: Bleeding due to increased intravascular blood coagulation. Hemorrhagic syndromes caused by consumption of blood-clotting factors (consumptioncoagulopathies). New Eng. J. Med., 273:1370-1:n8 (Dec. 16), 1965. Rosner, F., and Ritz, N. D.: The defibrination syndrome. Arch. Int. Med., 117:17-24 (Jan.), 1966. Verstraete, M., Vermylen, C., Vermylen, J., et al.: Excessive consumption of blood coagulation components as cause of hemorrhagic diathesis. Amer. J. Med., 38:899-908 (.June), 1965.