~ SURGERYTo~~.Y

Surgery Today Jpn. J. Surg. (1992) 22:464-469

© Springer-Verlag 1992

Portal Vein Thrombosis After Splenectomy Successfully Treated by an Enormous Dosage of Fibrinolytic Agent in a Short Period: Report of Two Cases SHOHACHISUZUKI, SATOSHINAKAMURA, SHOZO BABA, SHUKICHISAKAGUCHI,YOSHINORIOHNUK|, YOSHIHIROYOKOI,

and RAISUKE NISHIYAMA The Second Department of Surgery, Hamamatsu University School of Medicine, 3600 Handa-cho Hamamatsu 431-31, Japan

Abstract: Portal vein thrombosis (PVT) after splenectomy in a patient with portal hypertension occurs with unusually high frequency. Recently, two patients with PVT following splenectomy were treated by fibrinolytic therapy with an enormous dosage of urokinase (UK) in a short period. PVT was quickly dissolved without side effects and the patients are now doing well without any recurrence of PVT. Therefore, when there is no evidence of bowel infarction, fibrinolytic therapy with an enormous dosage of UK over a short period is deemed to be both effective and essential as a conservative therapy for PVT. Key Words: portal vein thrombosis, splenectomy, urokinase,

fibrinolytic therapy

Introduction

Portal vein thrombosis (PVT) after splenectomy as first reported by Delatour 1 is a well-known occurrence. Although thrombocytosis after splenectomy is a very common finding, the thromboembolic risk of postsplenectomy thrombocytosis has not yet been clarified. A complete obstruction of the portal vein after splenectomy induces hepatic failure and bowel infarction due to a cessation of portal blood flow to the liver. 2 Appropriate therapy combined with the discovery of PVT in the initial period after splenectomy usually leads to a good outcome. When there is no evidence of bowel infarction, fibrinolytic therapy should be tried first to dissolve the PVT. 3-8 However, the optimum dosages or standard method of fibrinolytic therapy on PVT after splenectomy have not been clearly established yet.

Reprint requests to: S. Suzuki (Received for publication on Jan. 25, 1991; accepted on Sep. 13, 1991)

The purpose of this report is to present the postsplenectomy course of patients with PVT and the effect of fibrinolytic therapy using large doses of UK over a short period.

Case Reports

Case 1

A 37-year-old woman was hospitalized with hematemesis on November 29, 1989. Splenomegaly with hypersplenism was pointed out in 1985. Esophageal varices with red color signs were endoscopically treated by sclerotherapy in 1988. On admission, teleangiectasia with cherry red spots was identified in the lower portion of the esophagus and cardia of the stomach by endoscopy. The laboratory data on admission were: hemoglobin 7.0 g/dl, leucocyte count 1,500/cumin, platelet count 39,000/cu mm, total bilirubin 0.6mg/dl, serum glutamic oxaloacetic transaminase (SGOT) 45IU/1, fibrinogen level 175mg/dl, and activity of prothrombin time (PT) 64%. On December 25, Hassab's operation 9 and a transection of the esophagus were performed. A 1,400-g spleen was then removed. Portal vein pressure of 430mmH20 decreased to 326mmH20 after splenectomy. A pathological diagnosis of the liver indicated liver cirrhosis. Pyrexia had lasted for 10 days from the 7th day after surgery. Upper abdominal pain with leucocytosis (38,500/cumm) suddenly developed 11 days after splenectomy, at which time the platelet count reached a peak of 681,000/cu mm. Hepatic dysfunction developed as evidenced by an increase in the SGOT level from 50 to 464 IU/1 and a decline in PT. FDP D-dimer level rose to 4 ~tg/ml. An echogenic mass in the right portal branch, as well as an umbilical portion of the left branch and portal trunk were revealed by ultrasonography (US) diagnosed as PVT (Fig. 1).

S. Suzuki et al.: Portal Vein Thrombosis After Splenectomy

465 decreased after fibrinolytic therapy. US demonstrated a reduction in both the size and the extent of the thrombus with only a small remnant remaining in the portal vein 3 days after the beginning of fibrinolytic therapy. On subsequent US, the portal vein was observed to be entirely clear of thrombus at 17 days after surgery (Fig. 3). The patient is doing well without any recurrence of thrombus in the portal vein. Case 2

A 48-year-old man was hospitalized with recurrent esophageal varices on March 16, 1990. He had been diagnosed as having a liver tumor with liver cirrhosis in March 1987. He underwent a partial hepatectomy for the liver tumor after sclerotherapy of the esophageal varices in July 1987. The laboratory data on admission were: total bilirubin 0.7mg/dl, SGOT 32IU/1, PT 65 per cent, fibrinogen level 179 mg/dl, and platelet count 44,000/cu mm. On April 11, 1990, Hassab's operation and an esophageal transection were performed. The spleen weighed 665 g. Portal vein pressure of 462mmHzO decreased to 353mmH20 after splenectomy. The patient was asymptomatic and the clinical examination, except for pyrexia, was normal. The total bilirubin and SGOT levels reached a peak of 1.8mg/dl, 69IU/1 3 days after splenectomy, respectively. FDP D-dimer rose to 8 gg/ml on day 3 and fibrinogen level reached a peak of 459 mg/dl on day 5 after surgery. Pyrexia of more than 38.5°C continued for 11 days postoperatively and the platelet count increased to 383,000/cumm on the 10th postoperative day. Extensive thrombus was demonstrated in the stump of the splenic vein and in the portal trunk on computed tomography (CT) 10 days

Fig. 1. Ultrasonography 12 days after surgery. A Echogenic mass is visible in the portal vein trunk and B right branch of the portal vein Systemic intravenous administration with urokinase (UK) at a dose of 960,000U/day and heparin of 10,000U/day was started in order to dissolve the thrombus. UK was administered for 3 days, with doses tapering from 960,000 to 720,000 and to 480,000 U/day, respectively. Heparin was also stopped at the same time. PGE1 and aspirin, inhibitory agents of platelet aggregation, were followed with doses of 80gg/day and 600 mg/day, respectively (Fig. 2). There were no side effects noted due to these agents. Although a prolongation of activated partial thromboplastin time (APTT) associated with heparin administration was observed, the SGOT level gradually

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466

S. Suzuki et al. : Portal Vein Thrombosis After Splenectomy

Fig. 3. Ultrasonography 7 days after fibrinolytic therapy. A Thrombus of trunk and B right branch of the portal vein has almost completely disappeared

after surgery (Fig. 4). There was no biochemical evidence of marked hepatic dysfunction compared with the preoperative laboratory findings: SGOT 39IU/1, total bilirubin 0.7mg/dl, and PT 60 per cent. UK and heparin therapy were performed with the same regimen as case 1 (Fig. 5). No bleeding tendency was observed for the period of therapy in spite of a prolongation of APTT due to heparin. A disappearance of PVT was shown by CT at 30 days after surgery (Fig. 6). The patient's subsequent progress was uneventful and aspirin was followed by p e r os.

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S. Suzuki et al.: Portal Vein Thrombosis After Splenectomy

467 Discussion

Fig. 6. Abdominal CT scan 20 days after fibrinolytic therapy shows a reduction of thrombus A leaving only a small remnant in the portal vein and B a disappearance of thrombus in the splenic vein

The incidence of P V T after splenectomy ranges from 13.3 to 68.4 per cent, 2'1°'11 based on both autopsy and clinical experiences as well as angiographical findings. P V T is commonly associated with mesenteric vein thrombosis and this complication has a high mortality rate due to hepatic failure and small intestine infarction. 2'12-14 The clinical symptoms of P V T are variable and include crampy abdominal pain, nausea, vomiting, diarrhea, and fever. 1°'15 Since our two cases had a m o d e r a t e febrile status, occurrence of P V T has to be considered in patients with prolonged and unexplained febrile courses after splenectomy.15 As soon as P V T is suspected, the presence of P V T must be confirmed by serial US or CT to prevent a fatal outcome. Rossi et al. 1~ proposed postoperative thrombocytosis, infection, operative trauma, and flow stasis as the pathogenesis of this complication after splenectomy. A rise in the platelet count is a usual sequel to splenectomy 16 as seen in case 1. T h o m p s o n et a1.17 reported the platelet count was more than 500,000/cu m m in most patients with P V T after splenectomy. However, the literature on the thromboembolic risk of postsplenectomy thrombocytosis is inconclusive. Several studies have failed to show an increased incidence of t h r o m b o e m b o l i s m in patients in whom thrombocytosis develops after splenectomy in comparison with patients whose platelet counts remain normal. ~5'~8 In both our reported cases, fibrinogen levels at the early phase after splenectomy (366 and 459mg/dl) were higher than preoperative levels (175 and 179 mg/dl). The coagulation function abnormalities are considered to be only one of a n u m b e r of factors in developing PVT.

Table 1. Cases treated by UK therapy for portal vein thrombosis after splenectomy Authors

Disease

Dose/day (U)

Matsuda et al. 4 Nagao et al. 7

LC IPH

120,000 x 25 days 240,000 x 9 days 120,000 x 21 days

Shiraishi et al. 6

LC

360,000 x 3 days

UK Total dose (U) 3,000,000 4,680,000

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Dissolution (45th day) Dissolution (34th day)

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Indissolution (21st day)

PGE1 Warfarin NR

Dissolution (36th day)

2,080,000 1,000,000 x 1 day Kai et al. s

IPH

120,000 x 7 days 240,000 x 12 days

3,480,000

Itamoto et al, 5 Suzuki et al. (present cases)

IPH LC

120,000 × NR 960,000 720,000 480,000 x 1 day

NR 2,160,000

~'Day from starting of UK therapy NR, Not reported

Outcome (verified day) a

Ticlopidine warfarin Heparin PGE1 Aspirin

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Indissolution Death Dissolution (7th and 20th days)

468 If the spleen is massively enlarged, the splenic vein after splenectomy tends to b e c o m e a cul-de-sac with a very low flow. 1° In both our cases, the ligated splenic vein, with a diameter about 2.5 to 3 c m , seemed to b e c o m e a cul-de-sac. F u r t h e r m o r e , portal vein pressure was also evidently reduced in both patients after splenectomy. Therefore, a change in h e m o d y n a m i c flow may take place in the portal system, which is thought to be one of the factors of thrombus formation in the portal vein. 19 G o r d o n et al. 2 suggested that platelet-induced thromboses generally resulted from intimal damage and exposure of subendothelial collagen rather than to venous stasis. Thus, the combination of stasis, exposure of traumatized endothelium and coagulation function abnormalities may have additive effects. At the time of splenectomy, if possible, an attempt should be m a d e to ligate the splenic vein as close as possible to its junction with the inferior mesenteric vein. Fibrinolytic therapy 3-8 is one of the treatments for P V T in addition to bowel resection or thrombectomy. 2° When thrombosis starts in the periphery of the mesentery, the extent of infarction in the bowel may be limited and treatment by resection of the thrombosed mesentery and adjacent gut may be successful. In the case when the thrombosis is proximal, fibrinolytic therapy should first be tried. U K has been used as a thrombolytic agent for PVT, but neither the o p t i m u m dose or standard method of U K therapy have yet to be researched in detail. The daily U K dosage was from 120,000 to 240,000U and the total U K dose reached m o r e than 2,000,000 U while the maximal dose was 4,680,000U (Table 1). I t a m o t o et al. 5 reported a death case due to hepatic failure in spite of an administration of 120,000U/day of U K for P V T after splenectomy. F u r t h e r m o r e , Kai et al. 8 reported a case without any m a r k e d dissolution of P V T in spite of U K administration of a total dose of 3,480,000 U. Since U K is a costly medicine, it is important to decide on the standard m e t h o d of U K therapy for P V T to ensure effective economization. Because the use of an e n o r m o u s amount of U K in a short period demonstrated a significant fibrinolytic effect on peripheral thrombosis, al the dose of U K for P V T in our cases was modeled after U K therapy for deep vein thrombosis which was tapered f r o m 960,000 to 480,000 U/day, with the total dose being 2,160,000U. The effect of fibrinolytic therapy should be judged from both sides of P V T imaging and coagulationfibrinolytic tests. Since coagulation-fibrinolytic examinations were insufficiently p e r f o r m e d , the usefulness of the therapy was evaluated only by a reduction in size of P V T due to serial US and CT in the present cases. It has been shown that F D P D-dimer immediately increases after U K therapy for t h r o m b o e m b o l i c disease.22 The reasons that F D P D-dimer did not increase after

S. Suzuki et al.: Portal Vein Thrombosis After Splenectomy fibrinolytic therapy in our cases are suggested as follows: First, F D P D-dimer was only semi-quantitatively analysed. Second, the m e a s u r e m e n t of F D P D-dimer was not immediately carried out after fibrinolytic therapy. Coagulation-fibrinolytic tests in detail for splenectomized patients should thus be investigated from now on. On the other hand, heparin would be effective in preventing an extention of existing thrombus in respect to a prolongation of A P T T . In both our cases, the P V T was quickly dissolved without any side effects compared with that in other cases treated by UK. Fibrinolytic therapy with an enormous dosage of U K over a short period was considered to provide a satisfactory effect for PVT.

References 1. Delatour HB (1895) Thrombosis of mesenteric veins as a cause of death after splenectomy. Ann Surg 21:24-28 2. Gordon DH, Schaffner D, Bennett JM, Schwartz SI (1978) Postsplenectomy thrombocytosis. Its association with mesenteric, portal, and/or renal vein thrombosis in patients with myeloproliferative disorders. Arch Surg 113:713-715 3. Freling NJM, Shum KH, Haagsma EB, Meer J (1986) Ultrasound as first imaging modality in superior mesenteric and portal vein thrombosis. J Clin Ultrasound 14:554-557 4. Matsuda M, Odani K, Ito M, Seo T, Tsuda K, Igaki H, Ogiso S, Ishigure H (1986) Two cases of portal vein thrombosis following splenectomy (in Japanese with English abstract). Nihon Rinsho GekaIgakkaizasshi (J Jpn Soc Clin Surg) 47:1102-1110 5. Itamoto T, Etho T, Tanaka T, Kodama O, Asahara T, Matsuyama T, Dohi K (1988) Portal thrombosis occuring after esophageal transection (in Japanese with English abstract) Nihon Rinsho GekaIgakkaizasshi (J Jpn Soc Clin Surg) 49:2193-2197 6. Shiraishi M, Yonekawa H, Shima S, Gotoh M, Makiyama T, Tanaka S, Ogata T (1988) A case of portal thrombosis after esophageal transection and splenectomy: One shot injection of urokinase to superior mesenteric artery (in Japanese). Nihon Shokaki Gekagakkaizasshi (Jpn J Gastroenterol Surg) 21: 2324-2327 7. Nagao Y, Yamashita S, Baba M, Yamamoto H, Hironaka T, Okanoue T (1989) Portal vein thrombosis following splenectomy successfully treated with thrombolytic therapy (in Japanese). Nihon Shokakibyo Gakkaizasshi (Jpn J Gastroenterol) 86: 1710-1714 8. Kai N, Ikenaga K, Ura K, Tanaka K, Matsumoto T, Segawa T, Motoshima K, Tsunoda T, Tsuchiya R, Izawa K (1990) A case report of idiopathic portal hypertension with diffuse portal thrombosis after splenectomy (in Japanese with English abstract). Nihon Shokaki Geka Gakkaizasshi (Jpn J Gastroenterol Surg) 23:2663-2667 9. Hassab HA (1964) Gastroesophageal decongestion and splenectomy: A method of prevention and treatment of bleeding from esophageal varices associated with bilharzial hepatic fibrosis: Preliminary report. J Int Coll Surg 41:232-248 10. Broe PJ, Couley CL, Cameron JL (1981) Thrombosis of the portal vein following splenectomy for myeloid metaplasis. Surg Gynecol Obstet 152:488-492 11. Rossi P, Passariello R, Simonetti G (1976) Portal thrombosis: High incidence following splenectomy for portal hypertension. Gastrointest Radiol 1:225-227 12. Ito K, Naito A, Saito T, Naito K, Fukuoka H, Fujikawa K, Mori M, Ito S, Katsuta S, Kodama O, Asahara T, Dohi K, Todani K,

S. Suzuki et al.: Portal Vein Thrombosis A f t e r Splenectomy

13. 14.

15. 16.

17.

18.

Ichiki T, Yukaya H, Ogawa Y (1988) Thrombosis of the superior mesenteric and portal veins after splenectomy and/or distal splenorenal shunts. Hiroshima J Med Sci 37:71-76 Carr N, Jamison MH (1981) Superior mesenteric venous thrombosis. Br J Surg 68:343-344 Polk HC (1966) Experimental mesenteric venous occlusion: 3.Diagnosis and treatment of induced mesenteric venous thrombosis. Ann Surg 163:432-444 Salter PP, Sherlock EC (1959) Splenectomy, thrombocytosis and venous thrombosis. Am Surg 23:549-554 Rosenthal N (1923) Clinical and hematologic studies on Banti's disease. I. The blood platelet factor with reference to splenectomy. JAMA 84:1887-1891 Thompson EN, Sherlock S (1964) The aetiology of portal vein thrombosis with particular reference to the role of infection and exchange transfusion. Q J Med 33:465-80 Davis WM, Ross AO (1973) Thrombocytosis and thrombo-

469

19.

20. 21.

22.

cythemia: The laboratory and clinical significance of an elevated platelet count. Am J Clin Pathol 59:243-247 Nakamura T, Moriyasu F, Ban N, Nishida O, Tamada T, Kawasaki T, Miura K, Sakai M, Miyake T, Uchino H, Kumada K, Ozawa K (1987) Hemodynamic analysis of postsplenectomy portal thrombosis using ultrasonic Doppler duplex system. Am J Gastroenterol 82:1212-1216 Harrison TA (1978) Portal phlebothrombosis: The role of thrombectomy. Ann R Coll Surg Engl 60:320-323 Urano T, Kamiya T, Sakaguehi S, Takada Y, Yakada A (1984) Fibrinogenolysis and fibrinolysis in normal volunteers and patients with thrombus after infusion of urokinase. Thromb Res 36:429-435 Oguma Y, Hasegawa H, Kawakami Y (1988) Fibrinolytic therapy of urokinase on pulmonary thromboembolism. In: Gaffney PJ et al. (eds) Fibrinolysis: Current prospects. John Libby, London, pp 197-203