0270-9139/88/0805-11 10$02.00/0 HEPATOLOGY Copyright 0 1988 by the American Association for the Study of Liver Diseases Vol. 8, No. 5, pp. 1110-1111, 1988

Printed in U. S. A.

Deficiency of Protein C in Patients with Portal Vein Thrombosis

HECTOR OROZCO, EDMUNDO GURAIEB, TAKESHI TAKAHASHI, GUADALUPE GARCIA-TSAO, RAFAEL HURTADO, ROGER ANAYA, GUILLERMO RUIZ-ARGUELLES, JORGE HERNANDEZ-ORTIZ, MARCO A. CASILLAS AND

LUIS GUEVARA Portal Hypertension and Liver Clinics and Departments of Radiology and Hematology, Instituto Nacwnal de la Nutricion

“Salvador Zubiran, ” Mexico City, Mexico

Portal vein thrombosis has been considered idiopathic in 50% of cases reported in adults. Protein C deficiency is a recently described disorder characterized by a pre- disposition to develop thromboembolic disease.

We report the findings in two patients with portal hypertension and bleeding varices due to portal vein thrombosis in whom a deficiency of protein C was pres- ent. Both cases were very similar, with a history of recurrent episodes of systemic thromboembolic disease, mesenteric venous thrombosis that required intestinal resection and upper gastrointestinal bleeding from gas- troesophageal varices. Portal hypertension as well as portal vein thrombosis were demonstrated. The hema- tologic work-up revealed a deficiency of protein C.

Both patients were subjected to the Sugiura proce- dure, and anticoagulation was instituted thereafter. At the time of surgery, a liver biopsy was performed, which was reported as “normal.” Two years and 3 months, respectively, after surgery both patients are in good condition.

We conclude that protein C deficiency should be in- vestigated in all cases of portal vein thrombosis, espe- cially in those with a history of thromboembolic disease elsewhere.

Portal vein thrombosis (PVT) is a well-known cause of portal hypertension. Intraabdominal infections are the most common etiologic factor in the development of PVT, although other factors, such as postoperative thrombosis (after splenectomy or portosystemic shunts), trauma, tumor invasion, hypercoagulable states, etc., have also been identified (1). However, in about one-half of the patients with PVT, the cause cannot be identified (1, 2).

Protein C deficiency is a recently described disorder characterized by a predisposition to develop thromboem- bolic disease (3). Although deficiency of protein C has been shown to occur in patients with liver diseases (4), there have been no reports of PVT and portal hyperten- sion associated with this entity.

The purpose of this paper is t o report the findings in

Received August 11,1987; accepted February 29,1988. Address reprint requests to: Hector Orozco, M.D., Instituto Nacional

de la Nutricion “Salvador Zubiran,” Vasco de Quiroga 15,14000 Mexico, D.F., Mexico.

two patients with hemorrhagic portal hypertension in whom a deficiency in protein C was present.

CASE REPORTS A 27-year-old man was admitted to the Instituto

Nacional de la Nutricion “Salvador Zubiran” because of a history of upper gastrointestinal bleeding that had occurred 6 months before admission. He had a family history of mesenteric vein thrombosis in an uncle. Two years before admission he had an acute abdominal episode due to mesenteric venous thrombosis that required intestinal resection. At the time of admission the patient was asymptomatic. Physical examination and routine laboratory tests, which included liver function tests, prothrombin time, partial thromboplastin time and platelet count, were normal. Esophageal varices were demonstrated by X-rays and esophagoscopy. Venous phase of splenic and supe- rior mesenteric arteriography revealed the presence of PVT with evidence of flow through gastric and esophageal collater- als. Both portions of the Sugiura procedure were performed with a 2-month interval. During the abdominal portion, a liver biopsy was taken which was reported as normal. After surgery, the patient presented with recurrent episodes of lower extrem- ity venous thrombosis. A clotting profile was then performed, which included determinations of antithrombin 111, circulant anticoagulants, platelet aggregometry, cryofibrinogen and pro- tein C. The only abnormality encountered was a deficiency of protein C (10% of normal). Protein C was assessed by electroim- munoassay, a method that has been described and validated previously (5). The patient was then put on oral anticoagulants and since he developed a new thrombotic episode when at- tempting to taper them off, anticoagulation has been main- tained for 2 years. In this time, the patient has remained asymptomatic, having resumed his normal activities. He has not had a recurrence of variceal hemorrhage or of thromboem- bolic disease.

Case 2. A 55-year-old man was referred to us because of a history of recurrent episodes of upper gastrointestinal hemor- rhage over the preceding 3 years. He had a family history of cerebral embolism in his father and a personal history of deep venous thrombosis of lower extremities that required bilateral saphenectomy at age 35. Three years before admission he had an acute abdominal episode of mesenteric venous thrombosis that required intestinal resection, 6 months after which he had his first episode of gastrointestinal bleeding. At the time of admission the patient was asymptomatic. Physical examination and routine laboratory tests, which included liver function tests, prothrombin time, partial thromboplastin time and platelet

Case 1.

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Vol. 8, No. 5, 1988 PROTEIN C DEFICIENCY IN PORTAL VEIN THROMBOSIS 1111

count, were normal. Esophageal varices were demonstrated by esophagogram and endoscopy. Venous phase of superior mes- enteric and splenic arteriography revealed P V T and visualiza- tion of gastric and esophageal collaterals. Hepatic arteriography demonstrated changes similar to those seen i n hepatic fibrosis (tortuosity of intrahepatic arterial branches). While in the hospital the patient developed a spontaneous episode of upper extremity thrombosis. A clotting profile was then performed, which included determinations of antithrombin 111, circulant anticoagulants, platelet aggregometry, cryofibrinogen and pro- tein C. The only abnormality was a deficiency of protein C (11% of normal). Protein C was determined by electroimmu- noassay, a method that has been described and validated pre- viously (5). The abdominal portion of the Sugiura procedure was performed, at which time a liver biopsy was obtained. This was reported as normal. T h e patient has been maintained on oral anticoagulants and, 2 months later, he is asymptomatic and awaiting the thoracic portion of the Sugiura procedure.

DISCUSSION

Protein C is a thrombin-dependent anticoagulant en- zyme whose functions are to inactivate coagulation co- factors V and VII and to stimulate fibrinolysis (6, 7). Protein C deficiency is a recently described clinical entity characterized by a tendency to develop thromboembolic disease (3). Patients with this disorder have been re- ported to present with superficial and deep venous thrombosis of extremities, pulmonary thromboembolism and mesenteric venous thrombosis (8-11). Treatment has consisted of lifetime oral anticoagulation. Although the condition appears to be hereditary, acquired cases have been described in association with disseminated intravascular coagulation, adult respiratory distress syn- drome, treatment with L-asparaginase and liver diseases (4; Barbui, T. et al. Thromb Haemost 1984; 52:216, Correspondence).

To our knowledge, this is the first time that protein C deficiency has been found to be associated with PVT and hemorrhagic portal hypertension.

Portal vein thrombosis has been considered to be idiopathic in 50% of the cases reported in adults. We consider that our findings warrant the search for protein C deficiency in all cases of “idiopathic” PVT, especially in those that have a history of thromboembolic disease elsewhere.

Some authors (12-15) have considered cases of unex- plained PVT in which hepatic function and morphology are “normal” as cases of idiopathic portal hypertension (IPH), since both the clinical features and the evolution of these cases are similar to those of patients with portal hypertension in whom neither hepatic pathology nor extrahepatic portal vein occlusion can be demonstrated (IPH as defined by the Japan Research Committee) (16). Furthermore, a case of IPH has been reported in which an initially patent portal vein developed thrombosis after

1 month of follow-up (17). Additionally, Sama et al. (18) described one patient with recurrent thrombophlebitis in their group of patients with noncirrhotic portal fibro- sis. These findings, in addition to the postmortem find- ings by Boyer et al. (13) of thrombosis of intrahepatic portal veins in many cases of IPH, may suggest the presence of a clotting abnormality in the pathogenesis of this disease of heretofore unknown etiology. On the other hand, a primary hepatic abnormality may be present in IPH which could be associated with an acquired clotting abnormality.

Further research needs to be done to clarify these interesting issues.

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