Splanchnic vein thrombosis following renal transplantation: a case report
© Tatar et al.; licensee BioMed Central Ltd. 2013
Received: 8 April 2013
Accepted: 9 July 2013
Published: 22 July 2013
Recurrent episodes of venous thrombosis have been closely correlated with JAK2 V617F mutation. Upto date, JAK2 gene mutation has not been defined as a prothrombic risk factor in renal transplant recipients. Herein; we present a case of portosplenic vein thrombosis in a primary renal transplant recipient with JAK2 V617F mutation who had no history of prior venous thromboembolism or thrombophilia.
A 59 year old female caucasian patient with primary kidney transplant admitted with vague abdominal pain at left upper quadrant. Abdominal doppler ultrasound and magnetic resonance imaging angiography demonstrated splanchnic vein thrombosis (SVT). The final diagnosis was SVT due to MPD (essential thrombocytosis, ET) with JAK2 V617F mutation. After 3 months of treatment with warfarin (≥5 mg/day, to keep target INR values of 1.9-2.5), control MRI angiography and doppler USG demonstrated partial (>%50) resolution of thrombosis with recanalization of hepatopedal venous flow. The patient is still on the same treatment protocol without any complication.
JAK2 V617F mutation analysis should be a routine procedure in the diagnosis and treatment of kidney transplant patients with thrombosis in uncommon sites.
KeywordsThrombosis Portosplenic vein thrombosis JAK2 gene mutation Myeloproliferative disorders Renal transplantation
Kidney transplantation for the management of end-stage renal disease (ESRD) is still the best approach that provides near-normal renal function, excellent survival outcomes and improved quality of life with lowest healthcare costs . This picture is occasionally overshadowed by posttransplant thromboembolic events which negatively influence graft and patient survival. A hypercoagulable state early after transplanation may cause deep venous thrombosis and induces devastating complications like pulmonary embolism and death [2–4].
The description of Janus Kinase 2 (JAK2) gene at the short arm of chromosome 9, brought new insight into thromboembolic events. JAK2 encodes a cytoplasmic tyrosine kinase of growth factors and cytokines like erythropoietin, thrombopoietin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) and functions as a co-factor for cytokine responses in vivo and in cytokine mediated transduction pathways leading to cell proliferation. A recent single point mutation substituting phenylalanine for valine (V617F) of JAK2 has resulted with dysregulation of kinase activity and consequent overactive hematopoesis [5, 6]. Indeed, JAK2 V617F mutation frequently accompanied to chronic myeloproliferative disorders as polycythemia vera (PV) and essential thrombophilia (ET) in recent reports. Furthermore; patients with JAK2 V617F mutation have demonstrated recurrent episodes of venous thrombosis [5, 7, 8].
Splanchnic vein thrombosis (SVT) comprises extrahepatic portal vein, mesenteric vein and splenic vein thrombosis either alone or together and myeloproliferative diseases (MPD) are the most common etiologic factors . Besides, JAK2 mutation has been accounted for the development of SVT, even in the absence of overt MPD . Recent studies suggested JAK2 V617F mutation as a risk factor in the pathogenesis of SVT in general population [9, 11] albeit JAK2 gene mutation as a prothrombic risk factor in renal transplant recipients is yet to be defined.
Herein; we present a case of portosplenic vein thrombosis in a primary renal transplant recipient with JAK2 V617F mutation.
The patient was treated with pulse methylprednisolone, Double-filtration plasmapheresis (every other day for three times) and administration of intravenous immunoglobulins (total dose:2 mg/kg). She had completely recovered in two weeks with good graft function (SCr:1.0 mg/dL and eGFR via MDRD4: 61 mL/min/1.73 m2.) and discharged from the hospital with a maintenance immunosuppression including prednisolone 10 mg/day, mycophenolic acid 900 mg/day and everolimus 0.5 mg/day. Her routine follow-up was normal until the outpatient visit at 20 months after transplantation. She admitted with vague abdominal pain principally located at left upper quadrant. Abdominal ultrasound with color-doppler imaging demonstrated splenomegaly with hyperechoic trombi almost completely occluding splenic vein and portal vein upto portal hilum. The spleen was 150 mm. in longitudinal axis and there were multiple areas of nonvascularized segments both in liver and spleen. Intraabdominal ascites and deep vein thrombosis in lower limbs or in other abdominal organs were not present. These findings were confirmed by abdominal magnetic resonance imaging angiography.
Laboratory data, genetic screening and bone marrow analysis
WBC count, ×103/mm3
Hgb level, g/L.
Platelet count, ×103/mm3
Peripheral blood smear
Antithrombin III (AT III)
Protein C (PC)
Protein S (PS)
Activated PC resistance (APCR)
Lupus anticoagulant (LA)
Lupus anticoagulant confirmation
Factor V Leiden mutation
prothrombin G20210A mutation
JAK2 V617F mutation
Bone marrow biopsy
Clustering of megakaryocytes
The incidence of venous thromboembolism in renal transplant recipients, ranges between 0.6%-25% in the literature [2, 4, 12]. Many risk factors have been implicated in recurrent venous thrombosis or allograft thrombosis after renal transplantation. Among them; the presence of CMV infection and cyclosporine or rapamycine administration after transplantation are basically observations and the mechanism of thrombogenicity about these drugs and infection are not fully demonstrated in high-powered clinical trials [13–15]. In addition; pretransplant hypercoagulable states as vascular access thromboses, prior venous thromboembolism, essential thrombocytemia, ischemic heart disease on antiplatelet therapy, atrial fibrillation on vitamin K antagonist therapy, factor V Leiden and prothrombin G20210A mutation and the presence of antiphospholipid antibodies have all been defined as independant risk factors for renal allograft thrombosis but not for posttransplant SVT in patients with optimal graft function [13, 16, 17]. The impact of JAK2V617F mutation in the pathogenesis of splanchnic vein and peripheral venous thrombosis and thromboses in MPD has been disclosed in detail [5, 7, 8, 18–20]. A very interesting finding in patients with thrombotic complications was the high prevalence of this mutation in female patients with SVT, indicating a gender-related susceptibility, while it was uncommon in patients with venous thrombosis at other locations or with arterial thrombosis [18, 19]. There is strong clinical evidence that JAK2V617F mutation mediates overactivation of platelets in MPD [21, 22]. In one retrospective study including 241 cases of SVT, the JAK2V617F mutation was identified in 34% of MPD patients with portal vein thrombosis (PVT). Here, the investigators suggestted JAK2V617F mutation analysis as an initial test which should replace bone marrow investigations for MPD in patients with SVT . In another series of 99 adult patients with SVT but without an overt MPD, 15% presented JAK2V617F mutation . This finding was reproduced and substantiated in another study group in which this somatic mutation was present in 100% of patients with SVT and overt MPD and 41% of patients with SVT and latent MPD. Interestingly none of the patients with latent MPD have progressed to overt MPD more than 7 years of follow-up . The frequent co-existence of MPD, SVT and JAK2V617F mutation has directed us towards genetic analysis in our patient. The differential diagnosis of SVT late after transplantation in a recipient with normal graft function requires exclusion of the aforementioned risk factors or conditions that frequently contribute to venous thrombosis in common or uncommon locations. As shown in Table 1, this strategy is used in the present case. Factor V Leiden (G1691A) mutation was reported as a predisposing factor for thrombotic complications in renal transplant recipients. Genetic screening for protein C or S deficiency, antiphospholipid and anticardiolipin antibodies and G20210A prothrombin mutation were negative and JAK2V617F mutation was not studied in these patients .
The evaluation of etiology for SVT revealed JAK2V617F mutation accompanied by splenomegaly, thrombocytosis and bone marrow findings (megakaryocyte cellularity and clustering, presence of paratrabecular and dysplastic megakaryocytes without fibrosis) which indicates MPD, particularly essential thrombocytosis. The length of secondary prophylaxis after deep vein thrombosis (DVT) either by standard oral anticoagulation or by low molecular weight heparin is a matter of debate. In one study; 22 (46.8%) out of 47 patients with DVT experienced a recurrence after the withdrawal of antithrombotic treatment . This high risk of recurrence in renal transplant patients should alert physicians for the administration of prolonged, probably life-long treatment, particularly to those with proven genetic susceptibility.
To the best of our knowledge, this is the first case in the literature addressing the association between JAK2V617F mutation with MPD manifested by splanchnic vein thrombosis in a kidney transplant patient. This genetic study should be considered in kidney transplant patients with thrombosis in uncommon sites.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
This study was not granted or funded by any third party.
- Jofre R, Lopez-Gomez JM, Moreno F, et al: Changes in quality of life after renal transplantation. Am J Kidney Dis. 1998, 32: 93-100. 10.1053/ajkd.1998.v32.pm9669429.View Article
- Poli D, Zanazzi M, Antonucci E, et al: Renal transplant recipients are at high risk for both symptomatic and asymptomatic deep vein thrombosis. J Thromb Haemost. 2006, 4: 988-992. 10.1111/j.1538-7836.2006.01917.x.View Article
- Kazory A, Ducloux D: Acquired hypercoagulable state in renal transplant recipients. J Thromb Haemost. 2004, 91: 646-
- Heidenreich S, Junker R, Wolters H, et al: Outcome of kidney transplantation in patients with inherited thrombophilia: data of a prospective study. J Am Soc Nephrol. 2003, 14: 234-239. 10.1097/01.ASN.0000039567.22063.9D.View Article
- Levine RL, Pardanani A, Tefferi A, Gilliland DG: Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007, 7: 673-683. 10.1038/nrc2210.View Article
- James C, Ugo V, Le Couedic JP, et al: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera. Nature. 2005, 434: 1144-1148. 10.1038/nature03546.View Article
- Baxter EJ, Scott LM, Campbell PJ, et al: Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005, 365: 1054-1061.View Article
- De Stefano V, Fiorini A, Rossi E, et al: Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost. 2007, 5: 708-714. 10.1111/j.1538-7836.2007.02424.x.View Article
- De Stefano V, Martinelli I: Splanchnic vein thrombosis: clinical presentation, risk factors and treatment. Intern Emerg Med. 2010, 5: 487-494. 10.1007/s11739-010-0413-6.View Article
- Riva N, Donadini MP, Dentali F, et al: Clinical approach to splanchnic vein thrombosis: risk factors and treatment. Thromb Res. 2012, 130 (Suppl 1): S1-S3.View Article
- Donadini MP, Dentali F, Ageno W: Splanchnic vein thrombosis: new risk factors and management. Thromb Res. 2012, 129 (Suppl 1): S93-S96.View Article
- Irish AB, Green FR: Environmental and genetic determinants of the hypercoagulable state and cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant. 1997, 12: 167-173. 10.1093/ndt/12.1.167.View Article
- Irish A: Hypercoagulability in renal transplant recipients. Identifying patients at risk of renal allograft thrombosis and evaluating strategies for prevention. Am J Cardiovasc Drugs. 2004, 4: 139-149. 10.2165/00129784-200404030-00001.View Article
- Lijfering WM, de Vries AP, Veeger NJ, et al: Possible contribution of cytomegalovirus infection to the high risk of (recurrent) venous thrombosis after renal transplantation. Thromb Haemost. 2008, 99: 127-132.
- Trotter JF: Sirolimus in liver transplantation. Transplant Proc. 2003, 35: 193-200. 10.1016/S0041-1345(03)00234-3.View Article
- Ripert T, Menard J, Schoepen Y, et al: Preventing graft thrombosis after renal transplantation: a multicenter survey of clinical practice. Transplant Proc. 2009, 41: 4193-4196. 10.1016/j.transproceed.2009.07.106.View Article
- Murashima M, Konkle BA, Bloom RD, et al: A single-center experience of preemptive anticoagulation for patients with risk factors for allograft thrombosis in renal transplantation. Clin Nephrol. 2010, 74: 351-357.View Article
- Xavier SG, Gadelha T, Rezende SM, et al: JAK2V617F mutation in patients with thrombosis: to screen or not to screen?. Int J Lab Hematol. 2011, 33: 117-124. 10.1111/j.1751-553X.2010.01275.x.View Article
- Colaizzo D, Tiscia GL, Bafunno V, et al: Sex modulation of the occurrence of jak2 v617f mutation in patients with splanchnic venous thrombosis. Thromb Res. 2011, 128: 233-236. 10.1016/j.thromres.2011.03.024.View Article
- Kiladjian JJ, Cervantes F, Leebeek FW, et al: The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood. 2008, 111: 4922-4929. 10.1182/blood-2007-11-125328.View Article
- Austin SK, Lambert JR: The JAK2 V617F mutation and thrombosis. Br J Haematol. 2008, 143: 307-320. 10.1111/j.1365-2141.2008.07258.x.View Article
- Vannucchi AM: JAK2 mutation and thrombosis in the myeloproliferative neoplasms. Curr Hematol Malig Rep. 2010, 5: 22-28. 10.1007/s11899-009-0038-x.View Article
- Xavier SG, Gadelha T, Pimenta G, et al: JAK2V617F mutation in patients with splanchnic vein thrombosis. Dig Dis Sci. 2010, 55: 1770-1777. 10.1007/s10620-009-0933-y.View Article
- Orr DW, Patel RK, Lea NC, et al: The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto-splenomesenteric venous thrombosis. Aliment Pharmacol Ther. 2010, 31: 1330-1336. 10.1111/j.1365-2036.2010.04299.x.View Article
- Wüthrich RP, Cicvara-Muzar S, Booy C, Maly FE: Heterozygosity for the factor V Leiden (G1691A) mutation predisposes renal transplant recipients to thrombotic complications and graft loss. Transplantation. 2001, 72: 549-550. 10.1097/00007890-200108150-00037.View Article
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/161/prepub
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