1 Division of Nephrology, Department of Medicine III, 2 Division of Hematology, Department of Medicine I, 3 Department of Medical and Chemical Laboratory Diagnostics and 4 Division of Angiography and Interventional Radiology, Department of Diagnostic Radiology, University of Vienna, Vienna, Austria
Keywords: antiphospholipid antibodies; hyperhomocysteinaemia; lupus anticoagulants; mesenteric vein thrombosis; portal vein thrombosis; renal transplantation
Introduction
We report a patient in whom acute portal and mesenteric vein thrombosis developed 10 years after successful renal transplantation.
Case
The patient we report on is a 48-year-old third renal graft recipient with excellent state of health. Clinical diagnosis of the basic renal disease was chronic glomerulonephritis. His first renal transplantation was performed in 1984, the second one in 1986 and the third in 1991. The patient's HLA phenotypes were A2, A3, B7, Bw62, Bw6, Cw3, DR1, DR3 and DRw52. The second graft had to be removed because of post-operative renal artery thrombosis. Surgical removal of both native kidneys as well as of both failing grafts had been carried out with no complications. The overall period of dialysis treatment had been 59 months. Up to now the third graft showed an excellent renal function without episodes of graft rejection. The immunosuppression therapy included prednisolone, cyclosporin A and azathioprine. In the follow-up, three episodes of deep vein thrombosis occurred, affecting the right leg in 1986 and the left one in 1987 and 1988. Consequently, anticoagulation therapy with warfarin was initiated; however, it was discontinued in 1994.
In September 2001, 10 years after he had received his third renal graft, the patient complained about sudden abdominal pains, but no diarrhoea, constipation or other symptoms were observed. On clinical examination there was mild epigastric tenderness without signs of peritoneal irritation. Plain abdominal X-ray showed no abnormal findings.
Analgesic drugs caused only temporary relief of the pains. Sonography of the abdomen revealed a normal renal graft and no obvious causes of the abdominal pain. At gastroscopy, signs of minimal chronic gastritis were seen, obviously irrelevant for the persistent patient's complaints. A colonoscopy was uneventful and did not show inflammatory findings, such as diverticulitis, as potential cause. No signs of malignancy were found. The cytomegalovirus and hepatitis serology did not suggest clinical virus infection. The patient was subfebrile; however, C-reactive protein (CRP) values rose continuously, as did the leukocyte count. Because of the persistent abdominal pain, a contrast-enhanced computerized tomography (CT) of the abdomen was performed which revealed an extensive filling defect within the portal vein extending into the superior mesenteric and splenic vein. Furthermore, no contrast enhancement in the mesenteric veins with a blurred vessel wall along the mesenteric veins was observed. The patient was referred for a splenoportogram which was performed using a transjugular intrahepatic portosystemic shunt approach (TIPS). Due to malfunction of the angiographic equipment the TIPS procedure was difficult to perform. Finally, the puncture of the portal vein was successful at an almost extrahepatic location, employing a 4F catheter to selectively catheterize the portal and splenic vein. The angiogram showed multiple thrombi of at least 5x2 cm extension within the portal vein, extending from the confluence of the superior mesenteric vein (Figure 1). A catheterization of the mesenteric vein using a guidewire was unsuccessful due to the complete thrombotic occlusion of the superior mesenteric vein and no further attempts were made to pass the thrombus.
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Discussion
Portal vein and mesenteric vein thromboses seem to be rare occurrences in transplant recipients. In general, portal vein or mesenteric vein thromboses have been described in various predisposing causes.
Hypercoagulable states due to inherited thrombotic disorders are evolving as the most frequent risk factors. In a recent study on mesenteric vein thrombosis, a thrombophilic genotype could be identified in 75% of patients with acute mesenteric vein thrombosis [1]. The methylenetetrahydrofolate reductase TT677 genotype was the most frequent finding (50%); factor V Leiden and the prothrombin transition G20210A were each found in 25% of patients. Combined mutations were present in 33% of cases [1]. Moreover, the importance of a hereditary deficiency of a natural coagulation inhibitor was described by Pabinger and Schneider [2]. Two hundred and thirty patients from 71 families were included in their study comprising 69 patients from 25 families with antithrombin III deficiency, 86 patients from 27 families with protein C deficiency and 75 patients from 19 families with protein S deficiency. Mesenteric vein thromboses occurred in 410% of patients independent of the type of coagulation disorder [2]. Other predisposing conditions are high erythrocyte and platelet counts, as in polycythaemia vera rubra, chronic myeloid leukaemias, paroxysmal nocturnal haemoglobinuria and local abnormalites like cirrhosis, hepatobiliary malignancies and pancreatitis [3].
In renal patients, a thrombophilic state is well known in cases with nephrotic syndrome [4]. It is not clear whether cyclosporin or tacrolimus treatment increases the risk of thrombosis in renal transplant recipients [5]. In principle, both drugs can trigger thrombotic microangiopathy [5]. Although the mechanism involved remains speculative, many prothrombotic effects may be responsible. These include toxic effects on endothelial cells, reduction of prostacyclin synthesis, alterations in thromboxane A2 to prostacyclin ratio, causing vasoconstriction, platelet aggregation and thrombus formation [5,6]. Additional factors might be a diminished production of activated protein C from endothelial cells and an increased release of thromboplastin from mononuclear and endothelial cells as well as an increased release of the von Willebrand factor from endothelial cells [57]. Concerning portal vein and mesenteric vein thromboses, sporadic cases in patients with nephrotic syndrome have been reported in the literature, however, none in renal transplant recipients without pancreas transplantation [8].
Our patient revealed, besides a slightly increased serum homocysteine level, which is probably too low to have an impact as thombophilic factor [9], one documented abnormalitythe existence of a lupus anticoagulant (LA).
Lupus anticoagulants are acquired antibodies belonging to a heterogeneous group of antibodies directed against phospholipidprotein complexes (=antiphospholipid antibodies). They can be directed against plasma proteins (prothrombin or annexin V), which are bound to anionic phospholipids, against cardiolipin and ß2-glycoprotein-I or can result in a false serologic test for syphilis [10]. Yet, in vivo, these anticoagulants' are associated frequently with thrombotic manifestations and not with bleeding disorders, leading to venous and arterial thromboses, recurrent spontaneous miscarriages, thrombocytopenia and infrequently to valvular thickening, the occurrence of vegetations and renal microvascular thrombi (antiphospholipid syndrome [10]). One out of various potential thrombophilic mechanisms involved could be a reduced binding of annexin-V, a naturally occurring phospholipid-binding anticoagulant protein [10].
Laboratory identification of a possible LA in the presented patient was performed according to the recommendation of the Scientific Subcommittee of the International Society of Thrombosis and Haemostasis [11]. That is, demonstration of an abnormal phospholipid dependent screening test [e.g. diluted Russell's viper venom time (dRVVT)] and, furthermore, failure to correct the prolonged screening coagulation test upon mixing with normal platelet poor plasma and shortening of the prolonged screening test upon the addition of excess phospholipids or hexagonal phase phospholipids (conformation tests). As shown in Table 1, we found a prolonged dRVVT that was partially corrected in the mixing study. As we were able to rule out any coagulation factor deficiency that could be the cause for this result, we assume the presence of a weak LA in the patient plasma. This conclusion was further confirmed by the positive results of the two confirmation tests.
Retrospectively, the deep vein thrombosis which occurred three times in the patient's history seems to be related to the documented existence of a LA. The mesenteric vein thrombosis developed in the patient several years after anticoagulation therapy had been discontinued.
The reason why the patient developed a LA without lupus erythematodes is unclear. However, various studies suggest that the overall prevalence of these antibodies might be increased in haemodialysis patients and renal graft recipients [12,13]. Data show that in most patients the antibodies appeared before transplantation and seem to be associated with a higher risk of thrombosis [13]. It is assumed that oxidative stress during haemodialysis might cause this occurrence [14]. Interestingly, its frequency seems to increase with time on haemodialysis [12,13]. Hepatitis C virus infection and a HLA-DR7 or HLA-DQ7 locus could also be predisposing factors [15,16] as might be bacterial infections and drugs [17,18].
The prognosis of both the acute and the chronic forms of portal vein and mesenterial vein thromboses is determined by the resulting acute or chronic portal hypertension and the therapeutic approach of choice is controversial. An active approach should be encouraged in patients with this condition employing TIPS and local thrombolysis, preferable with rTPA in the combination of surgical thrombectomy and bowel resection. In our patient a TIPS approach and a local thrombolysis using urokinase was applied for 24 h. Although we were not fully successful in our patient, early results on successful thrombolysis are encouraging and local thrombolysis warrants further study [19].
Our case demonstrated that besides deep vein thrombosis and potential pulmonary thromboembolism, portal vein and mesenteric vein thromboses can be a serious complication of this thrombophilic state in renal graft recipients. Long-term anticoagulation seems to be a need in such cases, since antiphospholipid antibodies carry a high risk of recurrent thrombosis and seem to be relatively resistant to immunosuppressive therapy [20].
Teaching point
Notes
Correspondence and offprint requests to: Dr Anna-Christine Hauser, Department of Medicine III, Division of Nephrology and Dialysis, University of Vienna, Währinger Gürtel 1820, A-1090 Vienna, Austria. Email: anna-christine.hauser{at}univie.ac.at
References