Disseminated intravascular coagulation with multiple arterial thromboses responding to antithrombin-III concentrate infusion

THROMBOSIS RESEARCH 54; 709-717, 1989 $3.00 t .OO Printed in the USA. 0049-3848/89 Copyright (c) 1989 Pergamon Press plc. All rights reserved.

DISSEMINATED INTRAVASCULAR COAGULATION WITH MULTIPLE ARTERIAL THROMBOSES RESPONDING TO ANTITHROMBIN-III CONCENTRATE INFUSION

James

L. Wisecarver

and William

D. Haire

Department of Pathology and Microbiology and the Division of Adult Hematology, Department of Internal Medicine, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, NE 68105 USA accepted _... _. in revised form 25.2.1989 by Editor N.U. Bang) _ _____ (Received by Executive Editorial Office 7.4.1989)

(Rece ved 3.11.1988;

ABSTRACT Disseminated intravascular coagulation (DIC) most often manifests itself through hemorrhagic episodes following thrombotic consumption of platelets and coagulation factors in the microvasculature. Rarely patients suffer major arterial thrombosis in the setting of disseminated intravascular coagulation. We treated such a patient, whose thrombotic diathesis was refractory to traditional heparin and fresh frozen plasma therapy, with infusion of anti-thrombin III concentrate. The response was a prompt improvement in both clinical and laboratory parameters followed by recurrent thrombosis when concentrate therapy was discontinued. This is the first reported case where DIC complicated by major arterial thrombosis was treated with antithrombin III concentrate. Our findings demonstrate that antithrombin III concentrates are useful in treating patients with DIC complicated by major arterial thrombosis.

INTRODUCTION Disseminated intravascular coagulation (DIC) is a complication of many disease processes such as sepsis (l), pregnancy and shock (2), and malignancy (3). The usual clinical manifestation of DIC is hemorrhage (4). This bleeding tendency is secondary to consumption of coagulation factors and platelets by activation of the coagulation process within the microvasculature. The thrombotic process generally occurs in the microcirculation in DIC. However, macrovascular thrombosis also occurs (5). Numerous coagulation factors are consumed in DIC, including antithrombin III (AT-III) (6). AT-III is an inhibitor of the activated serine proteases of Key words:

AT-III, Arterial thrombosis, DIC 709

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the coagulation cascade (i.e. Factors XIIa, XIa, IXa and Xa) (7) as well as thrombin (8). Normally AT-III is a slow inhibitor of these clotting factors, binding with the active site on these proteases thus preventing them from activating the subsequent steps in the coagulation pathway. The affinity of AT-III for these factors and, hence its ability to inhibit their activity, is markedly increased in the presence of heparin (7). Recently several investigators have reported using AT-III concentrates in However, no report has been made of utilizing the management of DIC (9-14). AT-III concentrates in patients with DIC complicated by major arterial thrombosis. We report herein the first case of DIC with multiple arterial thromboses treated with AT-III concentrates.

CASE HISTORY A 63 year-old male whose family history was negative for thromboses or heart disease was in his usual state of good health until he experienced an acute myocardial infarction in 1980. This was treated with a four-vessel coronary artery bypass graft. The surgery performed at that time was uncomplicated and the patient remained asymptomatic for 6 years. Approximately 6 weeks prior to presentation, he began having recurrent angina. Coronary angiography revealed total occlusion of 3 of the previous grafts and 95% occlusion of the fourth graft. A repeat bypass graft procedure had been scheduled. However, 3 days prior to surgery the patient was admitted with unremittent chest pain. Physical examination upon admission revealed a blood pressure of 130/84 with a pulse at 60. Bibasilar rales were present and the heart examination was significant for a grade II/VI systolic ejection murmur and an S4 h art sound. Complete blood count performed on admission contained 8,500/m s white blood cells with 14% bands an a hemoglobin of 15.1 g/d1 (normal = 13-17). Platelet count was 2OO,OOO/mn1 (normal = 150,000-450,000). Prothrombin and partial thromboplastin times were both within the normal range at 13 and 27 seconds respectively. Serum electrolytes were all normal and chemistry profile revealed a cholesterol of 235 mg/dl (normal = 12D-240), albumin at 3.8 g/d1 (normal = 3.6-5.0), total bilirubin at 0.5 mg/dl (normal = O-1.2), SGOT (AST) at 37 U (normal = O-40 U), and LDH at 157 U (normal = 95-175 U). The patient was taken to the operating room the next morning for revision of the bypass grafts. The original grafts were removed and two saphenous vein grafts were placed originating from the right anterior portion of the aortic root. The first graft was anastomosed to a left circumflex marginal branch while the second graft was anastomosed to a more distant marginal branch at the left heart border. The right internal mamnary artery was anastamosed to the midpoint of the left anterior descending coronary artery. Following some initial difficulty in removing the patient from the cardiopulmonary bypass pump due to persistent hypotension, an intraaortic balloon pump was placed and the patient was transferred to the intensive care unit. The patient did well in the initial post-operative period and the balloon assist pump was removed on the second post-operative day. During attempted extubation later that same day, the patient vomited and aspirated. He developed imnediate respiratory difficulty, necessitating reintubation later that day. Sputum cultures grew Serratia marscescens and the patient was started on appropriate antibiotic therapy. The same organism was later isolated from blood cultures. Fortunately, the patient's blood pressure during this time was maintained at

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systolic levels between 110-140 mnHg. On the fifth post-operative day (PO) his lower extremities became cyanotic and cool and no pedal pulses were present. Doppler studies revealed bilateral thrombosls of both posterior tibia1 and dorsalls pedis arteries and the left ulnar artery. The patient was taken to the operating room for multiple thrombectomles on both lower extremities and the left ulnar artery. The following day (PO day 6) the patient experienced re-thrombosis of the pedal arteries bilaterally requlring repeat thrombectomles. Hematology consultation was sought regardtng the etiology of the diffuse thrombotic process. The hematologlc findings, consistent with DIC, are presented in Table 1. TABLE 1 -_ Laboratory Values at Time of Hematologic Consultation During the Second Thrombotlc Episode on the Sixth Post-Operative Day Prothrombin time Partial thromboplastin time Platelet count Fibrinogen FlbrinlFibrinogen degradation products Antithrombln III Hemoglobln Nucleated RBC's Schistocytes

18 sec. (lo-13 set) 35 sec. (22-35 set) 37,000 (150,000-400,000) 115mg/dl (150-45Omg/dl) 4Omg/ml (lOmg/ml) 57% (80-110X) 10.3 g/d1 (13-17 g/dl) 15/100 WBC's numerous

Normal values in parenthesls The patient was started on continuous Intravenous heparin therapy at an initial rate of 700 U/hr and fresh frozen plasma later that same day. The rate of heparin infusion was later increased to 1,300 U/hr. On PO day 7 it was determined that the patient had thrombosed the arteries In both lower extremities for a third time and had developed anterior compartment syndrome despite being fully anticoagulated with heparln. He was taken to the operating room for thrombectomies and fas iectomles on both lower extremities. Platelet count at this time was 34,OOO/mn5 with elevated fibrin degradation products and an AT-III level of 39% (normal = 84-1233). The patient's status remained stable, though DIC persisted while being given heparln and daily FFP transfusions. On PO day 13 the patient developed a fourth thrombosis of the left posterior tibia1 artery with a simultaneous antithrombin III level of 45%. AT-III concentrate (Cutter Laboratories) was then given daily in doses sufficient to keep the AT-III levels between 80-120X. Following lnitlatlon of AT-III concentrate therapy, the patient's clinical status and coagulation parameters improved dramatically. The partial thromboplastin time became more responsive to the continuous intravenous infusion of heparln (Figure 1). Platelet levels also rose into the normal range for the first time since the onset of the thrombotic episodes. The AT-III concentrates were administered concomitantly with heparin for 5 days at which time Coumadin was added. The AT-III was then stopped, but the heparin therapy was continued. The AT-III levels stabilized at 75% for the subsequent 72 hours. The day prior to the patient's death, his fibrinogen and platelet count had returned to normal, but his fibrin/fibrinogen degradation products remained markedly elevated at > 40 ng/ml. The few hours imnedlately preceeding his death saw the AT-III level drop acutely from 72 to 63% and the

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platelet count drop from 205,000 to 165,000 - possibily due to an acute exacerbation of the DIC process (Figure 1). The patient suddenly developed acute cardiopulmonary arrest and died. Autopsy revealed fresh thrombus completely occluding all of the coronary artery saphenous vein grafts. The internal mammary graft was fully patent and free of thrombus. However, the native left anterior descending coronary was thrombosed beyond the internal matmmry artery anastomosis. A thrombus was present in the microvasculature of one of the lung sections. Sectioning the brain revealed a thrombotic infarct in the right column of the fornix. There was also a small mural thrombus found in the left atrium of the heart. Aside from one nonulcerated calcific plaque in the abdominal aorta there were no lesions present in the aorta, comnon iliac, renal or mesenteric arteries. No other pathologic abnormalities were present. DISCUSSION Antithrombin-III is a 58 kilodalton glycoprotein of the alpha-2 globulin group that is synthesized in the human liver and also possibly in endothelial cells (15-18). This molecule inhibits the activated serine proteases of the coagulation system. Plasma AT-III levels normally range from 23-40 mg/dl with a plasma half-life of 48-72 hours in normal persons (16, 19-24). Variations in plasma AT-III levels with age and sex have been noted, with women in their childbearing years having slightly lower levels than men or prepubertal or post-menopausal females. Clinical laboratories have found it useful to express AT-III levels in terms of its functional activity as compared to the activity of a standard plasma pool which is given an arbitrary value of 100%. Normal laboratory values for the average patient range from 75-125% of the standard plasma pool value (17). It has been estimated that patients with values ranging from 50-753 are at mild to moderate risk for developing thrombosis while patients whose levels are below 50% are at markedly increased risk of thrombotic complications (17). Continuous intravenous heparin therapy causes reduction in circulating AT-III due to its binding to the AT-III molecule thereby increasing the rate of AT-III interaction with and neutralization by coagulation proteins (17,Zl). There are both congenital and acquired conditions associated with AT-III deficiency. The congenital form is the hereditary AT-III deficiency which has been associated with thrombotic tendencies (22-24). Acquired causes of decreased AT-III levels include diseases that result in decreased production of AT-III such as liver disease or those diseases which lead to increased AT-III utilization or loss such as DIC, pulmonary embolism and nephrotic syndrome (17). Transfusion studies using radio-labelled AT-III have shown that patients with hereditary deficiency of AT-III have a plasma half-life of 17.226.5 hours compared to 48-72 hrs for normal individuals (25). In normal patients the plasma half-life of AT-III in the presence of heparin is 33 hr (26). Approximately 85% of patients with congenital AT-III deficiency have experienced at least one thrombotic episode by age 50 (27). This patient had previously undergone coronary artery bypass surgery and had not experienced any thrombotic complications and none of his inediate family members had ever suffered thrombotic difficulties (consequently, it is unlikely that a congenital AT-III deficiency was present in this case. His liver and renal studies prior to surgery were normal, making liver or kidney disease an unlikely cause of the decreased AT-III level. The half-life of the transfused AT-III in this

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patient was determined to be approximately 12 hours. This rapid decline in AT-III levels following concentrate infusion demonstrates that this man's deficiency was due to catabolism, probably due to consumption in the DIC process.

Figure 1. Graphical representation of patient's platelet count, partial thromboplastin time and antithrombin III levels during postoperative period. Acute arterial thromboses occurred on days 5, 6, 7 and 13 (arrows). Heparin-induced thrombosis frequently results in arterial thromboses and This phenomenon was initially considered as a posoccasionally DIC (28,29). sible mechanism for the patient's recurrent thromboses. However, since the

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platelet count normalized and the thrombotic episodes ceased during AT-III therapy, despite continued heparin administration, it is unlikely that heparin contributed to the thrombotic diathesis in this patient. Despite receiving intravenous heparin infusion, the patient's partial thromboplastin time decreased during the period from day 9 to day 13 PO. The thrombotic episode that occurred on day 13 may have resulted from insufficient heparin infusion. However, the prompt response noted when AT-III was added to his regimen suggested that this may be a valuable adjunct to traditional heparin therapy which may lower the risk of the hemorrhagic complications associated with heparin. The patient had numerous problems that predisposed him to DIC and thrombosis. During the coronary bypass surgery the patient was placed on cardiorespiratory bypass which necessitated full heparinization. This may have lowered his AT-III level. The intraaortic balloon assist pump may have also played a minor role in the development of low AT-III levels by inflicting damage on the vascular endothelium and serving as a nidus for thrombus formation and causing further consumption of AT-III. The gram negative sepsis that ensued in the face of already an diminished AT-III level resulted in DIC that culminated in thromboses of the large arteries. The ischemic damage done to the tissues of the legs as a result of the thrombosis potentiated and continued the thrombogenic stimulus, thus prolonging the DIC. Although the majority of the DIC monitoring parameters had normalized following AT-III concentrate therapy, at 24 hours prior to death the fibrin/fibrinogen degradation products remained elevated. Over the several hours inmediately preceeding his death, the platelet count and AT-III levels declined precipitously indicating that the underlying DIC process was becoming more active. This suggests that the patient's fatal coronary graft thromboses, like his previous peripheral vascular thromboses, was caused by DIC. Scattered reports have appeared in which patients in DIC have been treated with AT-III concentrates and the results have been favorable (9-14). However, in none of these cases was major arterial thrombosis a clinical problem. In these reported cases there were also other measures taken concomitantly to correct the underlying causes of DIC. In the case described here, all of the attempts at treating the cause of DIC were ineffective in stopping the thrombosis. While in an otherwise stable clinical and laboratory state, the addition of only AT-III concentrates to the patient's therapy resulted in a prompt normalization of clotting parameters and elimination of further thrombosis. This is a very complex clinical scenario but the fact remains that the simple addition of AT-III concentrate therapy resulted in a dramatic improvement in the patient's clinical status. Prior to withdrawal of the AT-III therapy, the patient was placed on warfarin, which has been shown to be effective in preventing thrombosis in patients with hereditary AT-III deficiency (22,27). Intravenous heparin therapy was also continued at doses sufficient to keep the partial thromboplastin time between 60-70 sec. Once the AT-III concentrate therapy was stopped, he again suffered major thrombosis, this time involving his coronary artery bypass grafts and he died. Since the patient's clinical status and coagulation parameters both stablized imnediately upon instituting therapy and promptly deteriorated following cessation of AT-III therapy we feel this case demonstrates for the first time the utility of AT-III concentrates in the treatment of DIC complicated by major arterial thrombosis. The definitive treatment of DIC is the correction of the underlying disease process that is disturbing the coagulation system. However, AT-III concentrate may help stabilize the patient's condition and minimize the likelihood of thrombosis while the clinician determines the etiology of the DIC process and corrects the underlying problem.

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PERSONAL ACKNOWLEDGEMENT The authors would like to thank Ms. Michelle Fisher for assistance in preparing this manuscript.

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