whether the low antithrombin III initiates thrombosis or is a reflection of thrombosis. Protein S is a Vitamin K- dependent plasma protein, which functions as a co- ...
Deep Venous Thrombosis, Inflammatory Bowel Disease, and Protein S Deficiency EDWARD WYSHOCK, M.D., MICHAEL CALDWELL, M.D., AND JAMES P. CROWLEY, M.D.
The authors observed a patient with severe inflammatory bowel disease (IBD) complicated by ten episodes of deep venous thrombosis (DVT). Her unusual thrombotic tendency prompted further investigation for primary hypercoagulability. A nonfamilial deficiency of Protein S was documented suggesting the deficiency was acquired. This occurrence suggests that low Protein S levels should be considered as a potential etiologic factor in patients with IBD and recurrent DVT. (Key words: Thrombosis; Inflammatory bowel disease; Protein S; Protein C; Hypercoagulability) Am J Clin Pathol 1988;90:633-635 VENOUS THROMBOSIS may complicate the course of inflammatory bowel disease (IBD).' 19 Since the finding of accelerated thromboplastin generation by Spittel and associates,18 this complication is considered to be related to hypercoagulability and several abnormalities, which may lead to a hypercoagulable state, including an elevation of clotting factors and platelets.1415 However, fibrinogen and Factor VIII are acute phase reactants, and an elevation of these factors may simply be a response to inflammation. Similarly, platelets are elevated in chronic inflammation and as a response to bleeding, both of which are characteristic of IBD. Furthermore, reactive thrombocytosis is not necessarily associated with thrombosis in IBD.15 Antithrombin III deficiency is associated with recurrent thrombosis.21 Recent studies have demonstrated an acquired deficiency of antithrombin III may exist during exacerbations of IBD.12 Depressed levels of antithrombin III have been observed to return to normal during periods of remission," and normal levels of antithrombin III have been reported in chronic but stable IBD.10 It is not clear whether the low antithrombin III initiates thrombosis or is a reflection of thrombosis. Protein S is a Vitamin Kdependent plasma protein, which functions as a co-factor for another plasma protein, activated Protein C.20 Acti-
Received December 31, 1987; accepted for publication March 18, 1988. Dr. Crowley is a recipient of a Transfusion Medicine Academic Award from the National Heart, Lung and Blood Institute (K07 HL0125901A1). Dr. Wyshock's current address is Temple University School of Medicine, 3400 North Broad Street, Philadelphia, Pennsylvania 19140. Address reprint requests to Dr. Crowley: Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902.
Departments of Medicine and Surgery, Brown University and the Rhode Island Hospital, Providence, Rhode Island
vated Protein C not only inhibits clotting by enzymatic cleavage of activated Factors V and VIII, but also facilitates fibrinolysis by neutralizing an inhibitor of tissue plasminogen activator.3 Deficiencies of Protein C and Protein S are associated with hypercoagulability and recurrent venous thrombosis.4-817 These proteins have not been investigated in IBD. In the present report, a young woman with active Crohn's disease is described who also experienced ten episodes of deep venous thrombosis in a ten-year period. Recently she was found to be partially deficient in Protein S. Report of a Case A 28-year-old white female was hospitalized in March 1985 for her eighth episode of deep venous thrombosis (DVT). She gave a remarkable history of recurrent DVT. At age 17 a chronic analfissurehad developed, which was locally resected. In 1976, at age 19, she experienced her first episode of DVT two weeks after a C-section. The symptoms of DVT resolved while she was at bedrest on intravenous heparin, and she experienced no problem after withdrawal of Coumadin® three months later. In 1979, after three years of persistent vague abdominal pains, progressive weight loss, and anemia, intestinal obstruction developed that necessitated an extensive resection of the small bowel. Pathologic results revealed extensive involvement with Crohn's disease. Two years later she experienced another episode of obstruction, which necessitated a brief course of corticosteroids. During the period of 1981-1983 she had recurrent abdominal pains despite steroid therapy. In addition, she experienced DVT of both lower extremities on four occasions. Each episode of DVT responded promptly to bedrest and anticoagulant therapy. In 1983, symptoms of large bowel obstruction were relieved by a partial left colectomy. She was then relatively asymptomatic until April 1984, when an episode of severe abdominal pain and diarrhea was accompanied by her sixth episode of DVT. Chronic anticoagulant therapy was initiated. While being treated with Coumadin, a seventh episode of DVT occurred in November 1984. Again she responded to heparin and an increased dosage of Coumadin. Her Crohn's disease became increasingly symptomatic, and in February 1985 an indwelling venous catheter was inserted for hyperalimentation because of significant weight loss. An eighth episode of DVT occurred in the right calf and thigh during March 1985. She gave no family history of thromboembolism.
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Table 1. Laboratory Findings in a Patient with Crohn's Disease and Multiple Venous Thromboses Prothrombin time Partial thromboplastin time Hemoglobin Platelet count Platelet function Antithrombin III Protein C Protein S Other vitamin Kdependent factors
11.2 seconds/11.3 seconds 29.1 seconds/32.0 seconds 105 g/L 268 X 109/L No spontaneous aggregation 250 mg/L (normal, 170-300 mg/L) 4.3 mg/L (normal, 2.7-5.6 mg/L) 18 mg/L (normal, 21-50 mg/L) Normal
Coumadin was again reinstituted with a prothrombin time of 18.4 seconds/11.3 seconds; Protein C and Protein S levels were again performed. The Protein C level was 2.6 mg/L (2.6 Mg/mL) and the Protein S 12 mg/L (12 /jg/mL). Other laboratory studies are shown in Table 1. She was discharged while taking Coumadin and had remained asymptomatic until Coumadin use was briefly interrupted when she had a dental extraction in August 1986, when a ninth episode of DVT developed. A tenth episode occurred in September 1987. Both episodes responded to heparin. Subsequently, her family agreed to be studied, and the results indicated normal levels of Protein C and S in both parents (Fig. 1).
Discussion As in the present report, IBD may be complicated by recurrent thrombosis.119 Several laboratory abnormalities have been observed,10"1214151821 but their role in the pathogenesis of thrombosis is uncertain. Most thromboses are reported to occur during the active phases of IBD,1112 when other risk factors for thrombosis, including surgery, immobility, and dehydration, are often also present. Thus, IBD may be a secondary hypercoagulable state. This patient experienced venous thrombosis during exacerbation of her IBD. Although other risk factors such as pregnancy, surgery, and immobility complicated her history, these
Protein S Normal Ranges Protein S = 21 - 5 0 mg/L
A.J.C.P.-November 1988
factors were not consistently present during each episode of DVT. Drug interactions may also result in ineffective anticoagulation and recurrent thrombosis.6 This patient had recurrent thrombosis while taking Coumadin, but compliance and absorption were not problems. She also received hyperalimentation, which is not, in itself, thrombogenic.7 Prednisone, which the patient received for the last several years, is reported to decrease fibrinolysis by inhibiting plasminogen activator production.13 However, clinical studies have produced variable results regarding the thrombogenicity of corticosteroids.9 Clearly, the only factor associated with thrombosis and present in this patient was a low Protein S level (Table 1, Fig. 1). Primary hypercoagulable states, which may result in thrombosis, include deficiencies of antithrombin III, Protein C, and Protein S.16 With occasional exceptions, these protein defects are familial, and evaluation is advised for patients who have a family history of thrombosis or recurrent thrombosis at a young age. However, a negative family history for thrombosis can be misleading because heterozygotes for such protein defects may not have clinical sequelae.417 Secondary hypercoagulable conditions may provoke thrombosis in heterozygotes with an underlying primary hypercoagulable state.16 Hereditary deficiency of Protein S has been described in several patients with recurrent DVT417; acquired deficiencies of Protein S have also been reported with warfarin and oral contraceptives2,4'5 but not in association with IBD. Although this patient was treated intermittently with warfarin, she was not taking warfarin at the time the Protein S level was done, and her other Vitamin K-dependent factors were normal (Table 1). The negative family history for thrombosis in this patient and the normal values of her parents argue against a familial Protein S deficiency. However, although normal, the value of 26 mg/L (26 fig/ mL) of her father does not rule out a carrier state for Protein S deficiency (John Griffin, personal communication). Further studies of Protein S deficiency in large groups of patients with IBD will be needed to determine the frequency of Protein S deficiency in IBD and its relation to the thrombotic tendency of these patients.
Protein C= 2 . 8 - 5 - 6 mg/L
Acknowledgments. The authors thank Dr. John Griffin from Scripps Clinic and Research Foundation, who performed the Protein C and S measurements, and Drs. Angelina Carvalho and Walter Thayer, who offered helpful suggestions during the preparation of the manuscript.
References MOTHER
FATHER
PATIENT
FIG. 1. Family studies on a patient with recurrent deep venous thrombosis and inflammatory bowel disease.
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2. Boerger LM, Morris PC, Thurman GR, et al: Oral contraceptives and gender affect Protein S status. Blood 1987;69:692-694. 3. Clouse LH, Comp PC: The regulation of hemostasis: the Protein C system. N Engl J Med 1986;314:1298-1304. 4. Comp PC, Esmon CT: Recurrent venous thromboembolism in patients with a partial deficiency of Protein S. N Engl J Med 1984;311:1525-1528. 5. Comp PC, Thurman GR, Welsh J, et al: Functional and immunological Protein S levels are decreased during pregnancy. Blood 1986;68:881-885. 6. Deykin D: Warfarin therapy. N Engl J Med 1970;283:801-803. 7. Fischer JE: Hyperalimentation. Med Clin North Am 1979;63:973983. 8. Griffin HJ, Evatt B, Zimmerman TS, et al: Deficiency of Protein C in congenital thrombotic disease. J Clin Invest 1981,68:13701373. 9. Isacson S: Effect of prednisone on the coagulation and fibrinolytic systems. Scand J Hematol 1970;7:212-216. 10. Knot E, Tencate JW, Leeksma OC, et al: No evidence for a prethrombotic state in stable chronic inflammatory bowel disease. J Clin Pathol 1983;36:1387-1390. 11. Lake AM, Stauffer JQ, Stuart MJ: Hemostatic alterations in inflammatory bowel disease. Dig Dis Sci 1978;23:897-902.
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12. Lam A, Borda IT, Inwood MJ, et al: Coagulation studies in ulcerative colitis and Crohn's disease. Gastroenterology 1975;68:245-251. 13. Laug WE: Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Hemostas 1983;50:888-892. 14. Lee JC, Spittell JA, Sauer WG, et al: Hypercoagulability associated with chronic ulcerative colitis: changes in blood coagulation factors. Gastroenterology 1968;54:76-85. 15. Morowitz DA, Allen LW, Kirsner JB: Thrombocytosis in chronic inflammatory bowel disease. Ann Intern Med 1968;68:1013-1021. 16. Schafer Al: The hypercoagulable states. Ann Intern Med 1985; 102: 814-828. 17. Schwarz HP, Fischer M, Hopmeier P, et al: Plasma Protein S deficiency in familial thrombotic disease. Blood 1984;64:1297-1300. 18. Spittell JA, Owen CA, Thompson JH, et al: Hypercoagulability and thrombosis in chronic ulcerative colitis. Collective Papers of Mayo Clinic 1964;55:53-57. 19. Talbot RW, Heppell J, Dozois R, Beart R: Vascular complications of inflammatory bowel disease. Mayo Clin Proc 1986,61:140145. 20. Walker FJ: Regulation of Protein C by a new protein: a possible function of bovine Protein S. J Biol Chem 1981 ;256:1128-1131. 21. Winter JH, Fenech A, Ridley W, et al: Familial anti-thrombin III deficiency. Quarterly Journal of Medicine 1982;51:373-395.
