Symposium on Response to Infection and Injury I

Thrombosis and Intravascular Coagulation

NicholasP. Coe,MB., F.R.C.s. (Eng.) * and Edwin W.Salzman,MD.t

Surgical operations, trauma, sepsis, and other states of "stress" predispose to thrombotic complications. The blood in such patients shows an increased tendency to form thrombi ("hypercoagulability"). In this high risk group, anticipation of the problem, careful monitoring, and appropriate prophylaxis or treatment may achieve a satisfactory clinical result despite the hazard of thromboembolism. Wessler and Yin137 have defined hypercoagulability as "an altered state of circulating blood that requires a smaller quantity of a clot initiating substance to induce intravascular coagulation than is required to produce comparable thrombosis in a normal subject." Trauma or other stress results in an alteration in the vessel wall, in the rate of flow of blood, or in the composition of the blood that results in a thrombotic tendency. Subsequent intravascular coagulation may then occur as a generalized phenomenon or locally as venous or arterial thrombosis. Such events are an abnormal manifestation of normal hemostatic processes (Fig. 1). Thrombotic events are most often set off by vascular injury, particularly disruption of the intima, which may result from direct trauma or as a consequence of circulation of foreign materials extraneous to the blood, such as bacterial cell walls or endotoxins,33.47 viruses,21 antigenantibody complexes,76 animal or insect venoms, abnormally high concentrations of metabolites such as homocystine,57 or carbon monoxide, associated both with cigarette smoking and with air pollution.94 Denudation of endothelium results in adherence of platelets and formation of a From the Department of Surgery, Harvard Medical School, and Beth Israel Hospital, Boston, Massachusetts 'Research Fellow, Harvard Medical School; Research Fellow in Surgery, Beth Israel Hospital, Boston. Massachusetts tProfessor of Surgery, Harvard Medical School; Associate Director of Surgery, Beth Israel Hospital, Boston, Massachusetts Supported by N.I.H. grants HL11414 and HL13754.

Surgical Clinics of North America- Vol. 56, No.4, August 1976

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Figure 1. Abbreviations: XI, coagulation factor (enzyme precursor); XI a, activated factor; Xl', inactivated factor; AT III, antithrombin III; PF3, platelet factor three, PF4, platelet factor four; FPA/B, fibrinopeptides A and B; ADP, adenosine diphosphate; FDP, fibrin (or fibrinogen) digestion products. Activation of Hageman factor (XII) is induced by contact with subintimal tissues or by platelets altered by ADP released from damaged cells or other platelets. Activated factor XII (XIIa) activates factor XI, which in turn activates factor IX. This activates factor X in the presence of calcium, altered platelets (this platelet property is known as platelet factor 3) and factor VIII (antihemophilic factor). Activation of factor X is also produced by tissue thromboplastin, a product of injured tissues in the presence of calcium and activated factor VII. Activated X (Xa), in the presence of calcium, PF3, and factor V, brings about the conversion of prothrombin to thrombin, which then cleaves fibrinogen to fibrin monomer and two short fibrinopeptides, A and B. Thrombin also catalyzes earlier reactions in the cascade,'35 the release of platelet factor 4 (which has an antiheparin action), and the activation of plasminogen. Fibrin monomer polymerizes under the influence of factor XIII activated by thrombin. Conversion of plasminogen to plasmin (fibrinolysin) by natural activators, XIIa, kallikrein, activators released from injured tissues (especially prostate and kidney), and thrombin4• results in the breakdown of fibrin to fibrin digestion products (FDP). Plasmin activation is opposed by a natural circulating antiplasmin and by antithrombin III, this action being greatly accentuated by heparin.· '

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platelet thrombus. Whether such a process progresses to total occlusion of the vessel depends on the rate of blood flow, the degree of damage suffered by the intima at that site, the capability of the liver and reticuloendothelial system to remove activated clotting factors from the blood, and the presence in the blood of natural or therapeutic inhibitors of the hemostatiC process. Blood flow influences the local coagulative environment by diluting and dissipating activated procoagulant substances, by controlling the delivery of platelets to an evolving thrombotic deposit, and by washing away platelet aggregates as they form. Sluggish flow, such as that in the lower limb veins during recumbency, predisposes to thrombosis. Platelets may accumulate behind valve cusps and form a nidus for thrombosis.lOl. 131 Lowered visceral perfusion states, as the result of hypotension from hemorrhage or from secondary vasoconstriction as an autonomic response to injury may also predispose to thrombosis. Intimal damage causes exposure of the subintimal collagen and subsequent adhesion of platelets, which then undergo a secretory process - the "release reaction" - resulting in further platelet accumulation.67 . 95.136 Exposure of subintimal tissues, especially collagen, also results in the direct activation of Hageman factor (factor XII)}40 Damage to endothelium or other cells can result in the liberation of adenosine diphosphate, a substance which has been shown to cause platelet aggregation in vitroP ADP may be involved in platelet activities in vivo as well, although the evidence for this is less substantial.68 Walsh132 has suggested that platelets can act as a catalytic surface for activation of clotting factors and as a protective barrier against the naturally occurring inhibitors of coagulation. When stimulated by ADP, platelets have the capacity to activate factor XIIp3 It has also been suggested that platelets activated by contact with collagen have the ability to activate factor XP34 and possibly Xll7 directly. These aspects of platelet and coagulative function have been recently reviewed136 and are summarized in Figure 1. Activation of Hageman factor (XII) by whatever mechanism leads not only to activation of the clotting cascade but to activation of at least three other proteolytic systems present in plasma; kallikreinogen,83 plasminogen,28 and complement.36 The activation of kallikreinogen to kallikrein results in the production of bradykinin, a vasoactive peptide with a marked vasodilatory effect that may have deleterious effects on the circulation. Catecholamines have also been implicated in the potentiation of vascular collapse by initiating or propagating intravascular coaguiationP9 This thrombotic effect of epinephrine is vitiated by the use of an ablocker, phenoxybenzamine. The presence of epinephrine in the blood results in reversible platelet aggregation and promotes the platelet release of serotonin and other platelet constituents.67 . 91, 95 It has been postulated that the vasoconstrictive effects of catecholamines may be opposed by the action of bradykinin, thereby retarding the development of intravascular coagulation. 29 Trauma to tissues results in the release of tissue thromboplastins which, in the presence of factor VII, will activate factor X through the

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extrinsic coagulation pathway. Brain tissue is a partic;:ularly potent source of thromboplastic materials, used in performance of the partial thromboplastin time and the prothrombin time tests. Marked hypercoagulability; and disseminated intravascular coagulation (DIC)4. 52. 74 have been reported following severe head injury, and it has been postulated that this enhanced coagulation is due to the release of brain thromboplastin into the general circulation. There exist in the blood natural circulating antagonists to the factors of the clotting cascade. An antithrombin was postulated before the turn of the century, and subsequently the existence of a heparin co-factor and an inhibitor of activated factor X (anti-X a) was demonstrated. It has since been shown that these three are the same substance,142 and that of all the antifactors, antithrombin III (anti-Xa) is the most important. This substance acts not only on Xa but also on XIa and IXa and probably other serine proteases involved in clotting. The actions of antithrombin III and its interaction with heparin have been recently reviewed by Rosenberg. 110 Wessler138 has suggested that the balance between the plasma concentration of activated factor X (Xa) and its inhibitor, antithrombin III, is a very fine line. Any process tending to increase the activation of factor X, impede the removal of factor Xa by the reticuloendothelial system, or jeopardize its conjunction with antithrombin III will predispose to clotting. Major trauma, operative procedures or sepsis may alter the antithrombin III-Xa balance by any of these means. Observations in families with low antithrombin III levels have shown such persons to be episodically thrombophilic. 39 Low levels of this inhibitor have also been reported in patients taking oral contraceptives,128 who are prone to thrombosis. Wessler has suggested that patients with a low level of inhibitor require less alteration in the coagulation balance to initiate clotting than does the normal subject}38 Trials are at present in progress to assess alterations of antithrombin III levels as a result of routine surgical procedures in patients taking oral contraceptives and in patients on no medication, and as a result of the development of thrombosis. Preliminary results suggest that antithrombin III levels are reduced in patients with thromboembolism lO and in patients undergoing routine surgery}' 37. 122

DIAGNOSIS Once coagulation proceeds, the initial hypercoagulable state changes to one of hypocoagulability as clotting factors and platelets are consumed. Activation of the fibrinolytic system occurs through the direct effects of plasminogen activators, liberated from vascular walls or indirectly by activated Hageman factor or thrombin. The activation of the fibrinolysis system is a major cause of the hemorrhagic diathesis seen in clinical DIC. Thus, there is consumption of platelets, prothrombin, fibrinogen, and Factors V and VIII, and fibrinopeptides and fibrin degradation products (FDP) appear. It is on the basis of the laboratory

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Table 1. General Diagnostic Tests 1. 2. 3. 4. 5.

Quantitative fibrinogen estimation '05 Thrombin time 7l Fibrin degradation products" Platelet count'6 Prothrombin time'04 6. Partia! thromboplastin time'02

7. 8. 9. 10. 11. 12.

Factor V"" Factor VIII,02 Factor VII_X,02 Euglobulin lysis time 129 Cryofibrinogen 93 Fragmented red celIs I5

demonstration of these phenomena that the clinical diagnosis of DIC is confirmed. Diagnosis of intravascular coagulation can be suspected on clinical grounds, if a generalized bleeding tendency develops in an appropriate setting, but laboratory confirmation is required. Table 1 shows the diagnostic tests available for evaluation of such patients. No single test is specific for DIC, however. The most direct evidence of intravascular coagulation is the presence of fibrin microthrombi, but their demonstration is difficult as they are rapidly cleared from the general circulation by the action of the reticuloendothelial system. Fibrin microthrombi have infrequently been demonstrated ante mortem, and at post mortem less than 50 per cent of cases have demonstrable microthrombi or local infarcts.3, 38 More indirect evidence of DIC may be misleading. Decreased levels of fibrinogen are frequently found in intravascular coagulation,2, 18, 19,29 although low fibrinogen levels may also be due to reduced production, e.g., in liver diseases. Fibrinogen may be lost from the circulation into exudates, externally from burns, into the gut or into an undiagnosed hematoma, and it is consumed rapidly in the process of wound healing and in various inflammatory reactions. 59 DIC has been said to occur in acute hepatic necrosis ,48, 60, 62 but since the serum protein levels dropped as rapidly as fibrinogen and since fibrinogen may be lost in ascitic fluid,123 the presence of DIC must be regarded as unproven. The case is similar in burns, in which the level of gamma globulins has been found to drop even more rapidly than that of fibrinogen. 5o Clotting factors and platelets may equally well be lost from the intravascular space into transudates or exudates. 7 Platelets may also be destroyed in immune reactions and in diseases with splenomegaly, and their production may be decreased by chronic sepsis or marrow involvement by concurrent disease. Similarly, clotting factor production may be decreased by end-stage parenchymal liver disease. The measurement of fibrinogen degradation products in the blood is a useful screen for the presence of DIC, since intravascular coagulation is always accompanied by fibrinolysis. Even though the degradation of extravascular fibrin has also been shown to result in a rise in serum FDP levels,7 the finding of circulating FDP correlates well with clinically observed fibrinolysis and DIC.29 Marder has reviewed the available methods for estimation of FDP.82 Evaluation of an existing thrombotic tendency is difficult and inex-

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act at best, and until recent years there has been no means whereby a thrombotic tendency may be anticipated. Table 2 shows newer laboratory tests that have been developed both to aid evaluation of a patient with established bleeding and to predict the development of a thrombotic tendency. These estimations appear to be more specific and less influenced by concurrent disease than the tests listed in Table 1. The formation of fibrin from fibrinogen results in the production of two fibrinopeptides A and B (FP A and FPB). Nossel has recently reported the use of FP A estimations as a clinical monitor of thrombotic tendency.98 He found that FPA estimation was of use to detect patients with established thrombosis but was not at present sufficiently specific for prediction of a thrombotic tendency. This topic is being actively pursued in several laboratories, and the method may prove of considerable use when clinical validity has been established. The addition of protamine sulphate (PS) to plasma results in the formation of visible strands (paracoagulation) in the presence of fibrin monomers or early FDP.97 Investigation of the PS test in patients with venous thromboembolism has shown a good correlation with radiographic and clinical evidence of venous thrombosis. 53, 118 In vitro platelets undergo aggregation in response to the addition of ADP,116 epinephrine, or collagen. 13, 136 It has been reported that the dose of aggregating agents required to produce this reaction is less in patients with diabetes or prediabetes and in patients with type II hyperbetalipoproteinemia,23 recent myocardial infarction,51 or angina. 4S No such reduction in the aggregating dose is found in those with type IV hyperlipoproteinemia. Patients with angina and an increased doseaggregation response reverted to normal when the angina was treated with propranolo1. 45 Clofibrate has been reported to normalize the aggregation response in patients with type II hyperlipoproteinemia22 Platelet aggregates have been shown to occur in the circulation of patients with arterial disease through the use of a simple method described by Wu and Hoak. 141 That such aggregates may also occur as the result of stress has been demonstrated experimentally,55,72 although their relevance to the clinical situation has yet to be established. Walsh has recently studied platelet procoagulant activities in patients undergoing hip operations. 131 Patients who developed deep vein thrombosis showed an increase in platelet antiheparin and coagulant activity even before the detection' by 125I-fibrinogen scanning of the thrombi. The increase in platelet coagulant activity was found to be well Table 2.

Specific Diagnostic Tests

1. Fibrinopeptide A/BoB

2. 3. 4. 5. 6. 7. 8.

Fibrin monomer (protamine sulfate, paracoagulation)97 Platelet aggregation dose response"· Circulating platelet aggregates'4l Platelet procoagulant activity'31 j3-Thromboglobulin79 Antithrombin IIp· Screen filtration test'2. '2.

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correlated with the extent of thrombosis. Examination for platelet aggregates was negative, and plasma coagulation studies were normal in these patients. These results are particularly exciting, since they are virtually unique in anticipating the formation of a thrombus rather than merely indicating its presence. Other laboratory methods that show promise include measurement of antithrombin III levels,., 10. 37.122 screen filtration test (in vivo platelet aggregation),42.126 and demonstration of a circulating platelet product, ~­ thromboglobulin, in patients with a thrombotic state.79 Further work is required in these areas. Patients subject to stress, including trauma, sepsis, and perhaps hemorrhage, or those taking oral contraceptives, are at risk of developing thrombotic complications, which may have a wide range of clinical presentations. The clinical picture of diffuse intravascular coagulation (DIC) has been increasingly recognized over the last 25 years, and many comprehensive reviews are available. 29. 34. 35. 43.85.89 However, it is important to note that either local or generalized thrombosis may occur. The "hypercoagulable state" in stress proceeds to actual thrombosis only upon the initiation of some further stimulus, which may be local or diffuse. For example, recumbency and venous stasis will predispose to thrombosis in the deep veins of the calf, a ruptured atheromatous plaque may lead to the formation of platelet Inicrothrombi or actual arterial thrombosis, and narrowing of the coronary vessels by atheromata may alter the flow rate and initiate thrombosis with subsequent myocardial infarction. On the other hand, such generalized stimuli as septicemia, fat embolism, or amniotic fluid embolism may lead to disseminated microthrombi. GENERALIZED THROMBOSIS The clinical presentation of DIC varies from an acute fulminating hemorrhagic disorder to a chronic state recognized only by interpretation of laboratory findings. Acute DIC is characterized by hemorrhage, such as frank bleeding from the vagina or gastrointestinal tract or persistent oozing from venipuncture and cut-down sites or surgical incisions. Circulatory collapse is a common feature, but it is frequently unclear whether this is due to the coagulopathic state or was pre-existent and predisposed to the thrombotic disorder. In the full blown case, multiple intravascular thrombi form in the microcirculation and progressive ischeInic changes in various organs may result. Cerebral occlusion may lead to psychiatric abnormalities,69 coma, or convulsions. 19 Hemorrhagic necrosis of the gut has been reported in experimental animals,56 but is not a major feature in man. Progressive renal involvement leads to oliguria or anuria. Microscopic studies of the kidneys initially show acute focal tubular necrosis and subsequently bilateral cortical necrosis. 86 Deposits of fibrin microemboli or in situ clots in the lungs lead to progressive pulmonary dysfunction,66. 99.111 exacerbated by marked vasoconstrictive effects in the pulmonary vasculature6 and in the general circulation30 from the release of fibrinopeptides A and B.

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Sepsis has frequently been reported as a cause of DIC. The Grampositive and Gram-negative bacteria, viruses, Rickettsia, tubercle bacilli, and fungi have all been implicated. Infectious agents probably initiate DIC by widespread intimal damage or by direct activation of the coagulation system. Intimal damage with DIC is also seen in heat stroke 120 and in anoxic or low flow states. 70 Obstetric emergencies were the first clinical situations in which "defibrination" was described. DIC has been reported in association with abruptio placentae, retained dead fetus, septic abortion, and amniotic fluid embolism. 12 Hemorrhage in experimental animals has been used as a model for study of the hypercoagulable state,111 and many workers claim to have demonstrated increased coagulability following blood loss. There is, however, some question as to the validity of such experiments because of difficulty of extrapolation to the human (e.g., the bacteria that normally exist commensally in the liver of the dog may contribute to DIC or coagulative changes by bacteremic spread following hemorrhage). Furthermore uncomplicated hemorrhage is uncommon in the clinical situation, where the effects of transfusion may confuse the issue. At present, hemorrhage remains unproven as a cause of local or generalized thrombosis. ll2 It does appear likely that hemorrhage may make the patient more susceptible to other complications associated with increased coagulabili ty. Consumption of hemostatic elements is initiated by flow over abnormal surfaces in giant hemangiomata (Kasabach-Merritt syndrome)65. 103, 109 and in cardiopulmonary bypass. 14 Platelet activation and the potential for development of DIC may exist where any abnormal or artificial surface comes in contact with the blood. s , 58, 113 DIC may also occur where red cells are damaged in the capillary meshwork of a giant hemangioma or in microangiopathic hemolytic anemia. Hemolysis may be an effect rather than a cause of DIC, the red cells being fragmented in the fibrin mesh produced by intravascular clotting,20 Hemolytic anemia has been described as the result of fragmentation of red cells in the plexiform pulmonary lesions seen in primary pulmonary hypertension. 125 Red cells are destroyed in a malarial crisis, following mismatched blood transfusion, and after massive fat embolism,lOo and DIC has been described in association with hemolysis in these conditions. DIC has also been described in experimental hemolysis but does not seem to be associated with the classical hemolytic anemias. Antigen-antibody reactions are also said to lead to red cell and platelet damage/ 07 and DIC has been reported in association with systemic lupus erythematosus,96 It has been suggested that the rejection of renal allografts may be due to local intravascular coagulation,121 and both heparin 88 and oral anticoagulants,84 and various platelet antiaggregating agents (sulfinpyrazone,119 dipyridamole,84 and cyproheptidine lO6 ) have been shown to prevent both the acute and chronic rejection reactions. Advanced neoplasia may be associated with DIC. Damaged tissues, especially prostate and kidney, release plasminogen activators. Fibrinolysis has been described in isolation in this situation, but it is more likely that it is always part of DIC.108 In neoplastic states with extensive infil-

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tration of the bone marrow, interpretation of the laboratory results may be especially difficult.

TREATMENT Treatment of the underlying condition is of far greater importance than attempting treatment of DIC itself and is the prime objective of therapy. Removal of the initiating stimulus and vigorous treatment of the underlying disease will result in resolution of most cases of DIC. If the basic disorder cannot be controlled, correction of the hemostatic defect by replacement transfusion is likely to be of limited effectiveness. The use of heparin has been advocated to inhibit the consumption of hemostatic elements, and epsilon-amino caproic acid (EACA) has been recommended to inhibit fibrinolysis. Although these drugs may be highly effective, consideration of their use should not detract from the treatment of the principal disease. Unless the underlying illness is susceptible to management, the ultimate prognosis is usually bleak.3 EACA inhibits plasmin activation and, in higher concentrations, the action of plasmin itselfY The drug inhibits fibrinolysis but does not actively promote a thrombotic tendency. Nevertheless, the use of EACA in severely ill patients has sometimes produced localized thrombosis. 29 . 46. 87 It has been suggested that isolated primary fibrinolysis is extremely rare 90 and that most cases are in fact examples of DIC with secondary fibrinolysis predominant. 29 . 108. 124 These should probably be treated with heparin in combination with EACA. In the treatment of DIC, EACA has been used with concurrent heparin therapy without thrombotic complications,9 and the combination is probably safer in this situation than the use of EACA alone. The need for either should be approached with caution. The initial impetus for the use of heparin in DIC arose from its efficacy in the generalized Shwartzmann reaction (GSR), an experimental model of DIC, produced in rabbits by the time-spaced double injection of bacterial endotoxin... · 64. 86 The decision to give heparin to patients with DIC should be based on consideration of four criteria: correction of abnormalities in laboratory studies, an improvement in the clinical manifestations of DIC, an improvement in the mortality, and evidence that heparin does not worsen an already dire situation. The dispute over the use of heparin for the treatment of DIC revolves around the latter three criteria and the fact that very few properly controlled clinical trials have been conducted. There is good evidence that heparin will correct abnormalities in laboratory studies.3. 29 Improvement in the clinical state was reported by Colman29 in a retrospective study. Other reports however show that despite an improvement in laboratory tests the clinical picture and mortality are unaffected. 3. 31. 32. 62. 77.123 In a prospective trial in patients with paracetamol induced hepatic necrosis, Gazzard found no improvement in prognosis. 48 There have been reports of DIC and bleeding developing or progressing during heparin therapy.3.75 Patients who develop DIC almost invariably have a severe underly-

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ing disease process, and it is difficult to assess the role of heparin in any change in the clinical state or mortality, as such changes may be related either to treatment or to progression of the primary disease. Since the use of heparin in treatment of DIC is not without hazard, the drug should be reserved for particular indications. In the majority of cases DIC will resolve spontaneously, and the need for treatment with heparin will not arise, especially when the source of the procoagulant stimulus can be controlled. However, when hemorrhage is a major problem, when full treatment of the basic disease process has already been instituted, when the laboratory results have been carefully evaluated in the light of other possible explanations for the observed abnormalities, and when other causes of bleeding have been thoroughly excluded, then a cautious trial of heparin may be in order. Heparin should be given by constant intravenous infusion with frequent monitoring. 114 Dosage estimations are difficult since the release of platelet factor 4 (PF4) may make the requirements greater,SO or a thrombocytopenia may make the dosage requirements less than normal. The course of therapy can be assessed by the clinical response (cessation of bleeding), by the return of the fibrinogen level and platelet count toward normal, and by shortening of the one stage prothrombin time, a clotting test relatively insensitive to heparin but likely to be prolonged in DIC by consumption of clotting factors and by the anticoagulant effects of FDP. Measurement of circulating FDP levels is also a useful guide to the course of therapy.

LOCAL THROMBOSIS Although a serious and frequently lethal disease, disseminated intravascular coagulation is fortunately relatively rare. Colman reports 45 cases;29 Brodsky, 6;19 Al Mondhiry, 89;3 Corrigan, 26;32 and other authors, similar small numbers of cases of special interest. The hypercoagulable state following trauma is more commonly manifested locally as peripheral venous thrombosis and occasionally as thrombosis in the arterial tree. These diseases are potentially as serious and are much more amenable to prophylaxis or treatment than DIC. Improved methods for diagnosis of deep vein thrombosis have in recent years made assessment of the response to various therapies more accurate. Recent comprehensive reviews of diagnosis,115 therapY,49.63 and prophylaxis27. 63. 73. 127 are available. Acute occlusion of an artery during a hypercoagulable period is uncommon unless there exists underlying atherosclerotic disease or direct injury to the vessel in the initiating trauma. 92 Thrombosis of arteries remote from the site of trauma is not frequent in the absence of hypotension. This freedom from arterial thrombosis is probably due chiefly to the fact that, in a high pressure rapid flow system, platelet aggregates or activated clotting factors are rapidly washed away from their point of origin. Platelet aggregates have been demonstrated experimentally in small

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vessels of the coronary and cerebral circulations in response to infusion of epinephrine and ADP.55, 72 Injections of adrenocorticotrophic hormone have been shown to produce acute lipid mobilization and intimal damage with the formation of platelet aggregates. 81 Platelet aggregates have been found in the peripheral blood of patients with arterial disease. 141 In a series of patients who died suddenly, platelet aggregates were observed in the small coronary vessels. 54 There is evidence that they may arise from rupture of an intimal plaque. 24 In recent reviews25 ,26 it was claimed that patients resuscitated from ventricular fibrillation and subsequently showing no evidence of myocardial infarction may have fibrillated as the result of a shower of platelet aggregates or microthromboemboli. Platelet thromboemboli have been implicated in the etiology of transient cerebral ischemic attacks and amaurosis fugaxY The ability to measure the formation of platelet aggregates 141 may enable more accurate assessment of therapy in situations where platelet aggregates or thrombosis have been shown to occur, e.g., following cardiac catheterization,44 during renal dialysis,18 and in patients with peripheral arterial insufficiency.13o At present there is no conclusive evidence that drugs that alter platelet function, such as aspirin, dipyridamole, and sulfinpyrazone, have any significant effect on the complications resulting from platelet aggregate formation, whether as a result of stress or resulting from underlying atherosclerotic disease,63 although preliminary results show improvement in patients with transient cerebral ischemia following treatment with sulfinpyrazone. 41

SUMMARY Stress, including trauma and sepsis, is associated with a state of hypercoagulability. In these circumstances the patient is at risk of generalized or local thrombotic complications. New laboratory investigative procedures facilitate diagnosis and permit improved assessment of therapy, which at present remains of unproven efficacy both in the general and local situation.

REFERENCES 1. Aberg, M., Nilsson, I. M., and Hedner, U.: Antithrombin III after operation. Lancet, 2:1337, 1973. 2. Abildgaard, C. F.: Recognition and treatment of intravascular coagulation. J. Paed., 74:163,1969. 3. AI-Mondhiry, H.: Disseminated intravascular coagulation. Thromb. Diath. Haem., 34:181,1975. 4. Anzil, A. P.: Defibrination after head trauma. Letter to the editor. N. Eng. J. Med., 291 :632, 1974. 5. Attar, S., Boyd, D., Layne, E., et aI.: Alterations in coagulation and fibrinolytic mechanisms in acute trauma. J. Trauma, 9:939,1969. 6. Bayley, T., Clements, J. A., and Osbahr, A. J.: Pulmonary and circulatory effects of fibrinopeptides. Circ. Res., 21 :469, 1967. 7. Benz, J. J.: Clotting factors and fibrinogen split products in the extravascular space. Thromb. Diath. HaemoIT., 19:226,1968.

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