Review
Hypercoagulability in Kidney Transplant Recipients Sandesh Parajuli, MBBS,1,2 Joseph B. Lockridge, MD,2,3 Eric D. Langewisch, MD,2,3 Douglas J. Norman, MD,2,3 and Jody L. Kujovich, MD4 Abstract: Thrombosis remains an important complication after kidney transplantation. Outcomes for graft and deep vein thrombosis are not favorable. The majority of early kidney transplant failure in adults is due to allograft thrombosis. Risk stratification, early diagnosis, and appropriate intervention are critical to the management of thrombotic complications of transplant. In patients with end-stage renal disease, the prevalence of acquired risk factors for thrombosis is significantly high. Because of hereditary and acquired risk factors, renal transplant recipients manifest features of a chronic prothrombotic state. Identification of hereditary thrombotic risk factors before transplantation may be a useful tool for selecting appropriate candidates for thrombosis prophylaxis immediately after transplantation. Short-term anticoagulation may be appropriate for all patients after kidney transplantation.
(Transplantation 2016;100: 719–726)
T
hrombotic disease is a well-known complication after kidney transplantation. As early as 1970, Clarke et al1 reported a case of allograft renal vein thrombosis requiring thrombectomy. Graft-specific complications, including renal artery thrombosis, renal artery stenosis, and renal vein thrombosis, represent 0.5% to 6.0% of postoperative complications.2,3 Though uncommon, these complications may lead to allograft loss, usually in the early postoperative period,3 or require surgical intervention. The need for early surgical intervention is an independent predictor of graft survival.4 In the North American Pediatric Renal Transplant Cooperative Study, graft thrombosis represented the main cause of graft failure in the first year.5 In a recent large retrospective study of 2381 patients by Phelan et al,6 the incidence of early graft failure in adults within 30 days after Received 17 March 2015. Revision requested 27 May 2015. Accepted 1 June 2015. 1
Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI.
2
Division of Nephrology, Department of Medicine, Oregon Health and Science University, Portland, OR.
3
Portland VA Medical Center, Portland, Oregon.
4
Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR. The authors declare no funding or conflicts of interest. S.P. participated in design, data collection, analysis, manuscript preparation, editing. J.B.L. participated design, data collection, analysis, manuscript preparation, editing. E.L. participated in data collection, analysis, manuscript preparation, editing. D.J.N. design, data collection, analysis, manuscript preparation, editing. J.L.K. participated in design, data collection, analysis, manuscript preparation, editing. Correspondence: Douglas J Norman, MD, Division of Nephrology, Department of Medicine, Oregon Health and Science University, 2611 SW 3rd Ave, Ste 360, Portland, OR 97201. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/16/10004–719 DOI: 10.1097/TP.0000000000000887
Transplantation
■
April 2016
■
Volume 100
■
Number 4
transplantation was 4.6%; 44% of these were due to allograft thrombosis, whereas 17.4% were due to acute rejection. Prompt and accurate diagnoses along with timely management of graft vascular thrombosis after kidney transplant are essential. A delay in the diagnosis or management of these complications can result in serious recipient morbidity with a risk of graft loss and death.7 The initial clinical presentation of vascular allograft thrombosis includes sudden oliguria or anuria, graft tenderness, and swelling, and lower extremity edema that is more pronounced in the ipsilateral limb.8 A high index of clinical suspicion is required for diagnosis because other common conditions, including acute tubular necrosis and acute severe rejection, may have a similar clinical presentation.9 Ultrasound with Doppler is the initial study of choice to exclude graft thrombosis. In the acute setting, ultrasound may reveal an edematous and enlarged kidney with decreased echogenicity caused by diffuse edema, as well as focal or diffuse disruption of parenchymal architecture and/or thrombus in the renal vessels. Duplex Doppler ultrasound demonstrates peaked, abruptly decreasing systolic frequency shifts and retrograde plateau-like shifts during diastole at the level of the main renal artery and its proximal branches, with an absent venous signal.10,11 There is evidence suggesting an association between kidney transplantation and a prothrombotic state. An analysis of long-term renal transplant patients found evidence of a chronic prothrombotic and persistent inflammatory state. Renal transplant recipients (RTRs) had significantly higher levels of fibrinogen, d-dimer, the prothrombin activation fragment F 1 + 2, and IL-6 than controls. These changes reflect activation of coagulation and thrombin generation and may involve interactions between common genetic and environmental factors.12 Thrombophilic disorders may be inherited or acquired. This is outlined in Table 1. Inherited thrombophilic disorders including factor V Leiden (FVL), prothrombin 20210G > A mutation and deficiencies of protein C, protein S, and www.transplantjournal.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
719
720
Transplantation
■
April 2016
■
Volume 100
■
Number 4
TABLE 1.
Inherited and acquired risk factors for thrombosis in renal transplant recipients Inherited
Factor V Leiden mutation Prothrombin 20210G > A mutation Antithrombin deficiency Protein C deficiency Protein S deficiency
Mutation in the tissue plasminogen activator inhibitor-1promoter Mutation of MTHFR Increased lipoprotein
Acquired
Antiphospholipid syndrome and/or antibodies Hyperhomocysteinemia Cryoglobulins Cryofibrinogenemia Acquired deficiencies of protein C, S and antithrombin- sepsis, DIC, liver disease, nephrotic syndrome Malignancy
DIC indicates disseminated intravascular coagulation.
antithrombin affect different sites in the coagulation pathway (Figure 1). Acquired disorders include antiphospholipid antibodies (APLA) and hyperhomocysteinemia.13,14 Additional risk factors for graft thrombosis include immunosuppressive agents, pretransplant dialysis modality mainly peritoneal dialysis (PD), and posttransplant erythrocytosis (PTE). Recurrent proteinuria and acute cytomegalovirus (CMV) infection may also increase the risk of graft thrombosis.15 Other potentially important donor or recipient factors include extreme donor age, cold ischemia time longer than 24 hours, renal vessel atherosclerosis, right kidney compared to left, recipient age, technical surgical problems, hemodynamic instability, delayed graft function (DGF), and a history of thrombosis.16 FVL Mutation
The FVL refers to a specific G-to-A substitution in F5 that predicts a single amino acid replacement (Arg506Gln) that destroys a cleavage site for activated protein C (APC). Activated protein C with its cofactor protein S normally proteolytically inactivates procoagulant factors Va and VIIIa, thereby downregulating further thrombin generation.17 Because of this single amino acid substitution, factor Va is resistant to APC and is inactivated at a 10-fold slower rate than normal. The impaired anticoagulant response to APC results in increased thrombin generation and a prothrombotic state leading to increased thrombin generation.18,19 The FVL is the most common inherited thrombophilic disorder, found in 5% to 8% of the general population, primarily in whites of European descent, in 20% of patients with a first venous thrombosis, and in up to 50% of patients with a personal or family history of recurrent thrombosis.20 The clinical expression of FVL is influenced by coexisting genetic and acquired thrombophilic disorders and circumstantial risk factors. The combination of FVL heterozygosity and most thrombophilic disorders (for example, prothrombin 20210G > A mutation) has a superadditive effect on overall thrombotic risk.21 Several studies reported a significantly higher incidence of venous thromboembolism in RTRs with FVL compared to those without the mutation. The FVL was associated with an overall 4-fold increased risk of graft vein thrombosis and venous thromboembolism.22,23 Heidenreich et al24 reported
www.transplantjournal.com
a higher prevalence of acute rejection and other vascular complications in patients with thrombophilic disorders including FVL. The authors hypothesized that adhesion and chemotaxis of lymphocytes in response to clotting in the allograft vascular bed may trigger acute rejection or aggravate incipient rejection. The FVL has also been associated with increased risk for DGF, acute rejection, and chronic graft dysfunction.25 Renal transplant recipients with FVL had a high incidence of avascular necrosis of the femoral head.26 Prothrombin G20210A Mutation
A single nucleotide substitution (20210G > A) in the 3′ untranslated region of the prothrombin gene (F2) is associated with elevated prothrombin levels and an increased risk of venous thromboembolism. Evidence suggests that the G > A transition increases the efficiency and accuracy of processing of the 3′ end of the mRNA resulting in an accumulation of mRNA and increased prothrombin protein synthesis.27 The prothrombin 20210G > A mutation is found in 2% to 3% of the general population and also occurs primarily in whites.20,28 The evidence implicating prothrombin 20210G > A in complications after renal transplantation is more limited and conflicting. Fischereder et al29 demonstrated that a prothrombin G20210A mutation conferred a 2.95-fold increased risk of graft loss. Median graft survival for 20210G > A heterozygotes was 65.9 months versus 149 months in those without the mutation. Graft failure was due to arterial, venous, or microvascular thrombosis in the majority of carriers. However, another single-center study of 562 transplant recipients found no association between FVL or prothrombin 20210G > A and renal allograft loss.30 Anticoagulant Protein Deficiencies
Inherited thrombophilia also includes deficiencies of the natural anticoagulant proteins C, S, and antithrombin. Antithrombin inhibits serine proteases involved in coagulation including thrombin and activated factors X, IX, and XI.31 Protein C and protein S are vitamin K-dependent anticoagulant proteins. Activated protein C requires free protein S as a cofactor to inhibit activated factors V and VIII.32 Anticoagulant protein deficiencies are approximately 10-fold less common than FVL and prothrombin 20210G > A with a combined prevalence of less than 1% of the population.33 They are found in 2% to 5% of individuals with a first venous thromboembolism.34,35 Acquired deficiencies of protein C, S, and antithrombin are far more common and occur during sepsis, disseminated intravascular coagulation,
FIGURE 1. Coagulation pathway affected at different sites in inherited thrombophilic disorders.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Parajuli et al
© 2015 Wolters Kluwer
liver disease, major surgery, and acute thrombosis.36 Protein C and protein S levels are reduced by vitamin K deficiency. Antithrombin levels fall in nephrotic syndrome and are lowered up to 30% by heparin. One study found a marked fall in antithrombin, protein C, and thrombomodulin levels during the first 24 hours after transplantation.37 Protein S levels are often low in RTRs and may reflect acute or chronic inflammation.38 Another study identified a small group of patients with antithrombin deficiency and a high (80%) rejection rate in first 6 months after transplantation.24 It is unknown whether an acquired temporary fall in anticoagulant protein levels contributes to the thrombotic risk in renal transplant patients. Antiphospholipid Antibodies
Antiphospholipid antibodies comprise a heterogeneous group of autoantibodies directed against phospholipids and phospholipid-binding proteins including B2-glycoprotein-I and prothrombin.39 The prevalence of APLA varies with the population studied. Low titer APLA are found in 1% to 3% of the general population and are usually clinically insignificant. The prevalence is higher in patients with thrombotic manifestations (10-26%) and in women with recurrent miscarriage (10-40%).40 Diagnosis of the APLA syndrome (APLS) requires a history of arterial or venous thromboembolism or unexplained pregnancy morbidity and laboratory evidence of persistent APLA: anticardiolipin antibodies (aCL), anti-β2GP I antibodies, and/or a lupus anticoagulant (LAC).41 The APLS can manifest as a primary disease or occur in association with other autoimmune diseases, such as systemic lupus erythematosus (SLE) (secondary APLS).40 The APLA are found in nearly 50% of patients with SLE and nearly 40% of these develop thrombotic complications.40 The APLA predispose to thrombosis by a variety of different mechanisms. The APLA have effects on platelets, endothelial cells (ECs), and monocytes and have been shown to interfere with the protein C pathway, fibrinolysis and complement activation.42 Acquired APC resistance and the presence of anti-protein C and antiprotein S antibodies are reported in patients with APLS43,44. One study found that APLA directed against β2GPI cross-react with APC.45 Renal manifestations of APLA include renal vein thrombosis, renal artery stenosis and thrombosis and thrombotic microangiopathy (TMA). Other renal complications include preeclampsia, glomerulonephritis, renal infarct, and renovascular hypertension.46 Catastrophic antiphospholipid syndrome is a severe form of TMA involving kidneys, lungs, brain and other organs which leads to acute multiorgan failure.47 The APLS is well known to cause graft thrombosis without appropriate thromboembolic prophylaxis. Vaidya et al reported thrombosis leading to graft loss in all 7 patients with APLS who did not receive anticoagulation.48 Patients with APLA have poor renal allograft outcomes. A retrospective study found that RTRs with a lupus inhibitor (+/− other APLA) had a significantly higher overall frequency of thrombotic complications. Graft thrombosis occurred in 27% of patients with APLA compared to 6.9% of those who were APLA negative. The characteristic lesions of APLA associated nephropathy were found in the majority of screening biopsies at 3 and 12 months in recipients with APLA but only rarely in those without APLA.49 Long-term therapeutic anticoagulation is recommended in APLS patients with
721
thrombosis.44 Management of perioperative anticoagulation requires an individualized assessment of the risk of both thrombosis and bleeding.50,51 Rituximab has been used in combination with other therapies in patients with APLS and renal limited TMA.52 Eculizumab is a humanized monoclonal antibody to C5 that blocks the terminal complement cascade. Eculizumab was effective in the treatment of a fulminant recurrence of APLA-related TMA after kidney transplantation.53 A phase 2 clinical trial is currently investigating the effectiveness of eculizumab in patients with pretransplant catastrophic antiphospholipid syndrome.46 The APLA are hypothesized to cause thrombosis by a variety of different mechanisms. Potential pathogenic mechanisms include APLA-mediated activation of platelets, ECs and monocytes, activation of complement and inhibition of natural anticoagulant and fibrinolytic pathways.54 Recent evidence suggests that the mechanistic target of rapamycin complex (mTORC) pathway is involved in the development of the renal vascular lesions associated with APLS nephropathy. Renal transplant patient with APLS who received the mTOR inhibitor, sirolimus had no evidence of recurrent vascular lesions on biopsy compared to APLA-positive patients not receiving sirolimus, suggesting inhibition of the mTORC pathway may prevent graft loss in this group.55 It remains difficult to predict thrombotic risk in asymptomatic patients with APLA. Lupus anticoagulants are more strongly associated with thrombotic risk than anticardiolipin or anti-B2GP1 antibodies. Increasing evidence that “triple positive” profile of APLA (LAC plus aB2gPI and aCL antibodies) confers the highest thrombotic risk.56 A subset of anti-B2GP1 antibodies directed against B2GP1 domain 1 (anti-D1 antibodies) may also be associated with a high thrombotic risk. However, it is still unclear whether testing for anti-D1 antibodies will enable identification of patients at highest risk for thrombosis.57 Hyperhomocysteinemia
Homocysteine is an amino acid generated during methionine metabolism. It is metabolized by 2 enzymatic pathways that require vitamin B12, vitamin B6, and/or folic acid as essential cofactors.58,59 Hyperhomocysteinemia may result from defects or deficiencies of the enzymes involved in homocysteine metabolism or deficiencies of their vitamin cofactors. The most common polymorphism in the N5, N10 methylenetetrahydrofolate reductase (MTHFR) gene, the C677T variant, results in a thermolabile enzyme with reduced activity for homocysteine metabolism.60 Approximately 12% of the general population is homozygous for this variant. The A1298C variant has a prevalence of 9% to 20% in most ethnic groups. Homozygosity (677TT) and compound heterozygosity (C677T/A1298C) for MTHFR polymorphisms predispose to mild elevations in homocysteine levels in the setting of suboptimal folate levels.61 Deficiencies of folate, vitamin B12, and/or vitamin B6 are the most common acquired causes of hyperhomocysteinemia. Patients with chronic kidney disease exhibit various protein and amino acid abnormalities, including hyperhomocysteinemia. Plasma homocysteine levels are inversely related to glomerular filtration rate, with a prevalence of hyperhomocysteinemia in end stage renal disease (ESRD) as high as 85% to 100%.62 Elevated plasma levels of homocysteine are associated with an increased risk of venous and arterial thrombosis.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
722
Transplantation
■
April 2016
■
Volume 100
■
Number 4
Hyperhomocysteinemia was identified as an independent risk factor for cardiovascular disease and thromboembolic events in RTRs.63 To date, there is no evidence that homocysteine-lowering treatment with folic acid at doses greater than 1 mg per day lowers the risk of vascular events or mortality in patients with ESRD.62 Treatment of stable kidney transplant recipients with increased levels of homocysteine and reduced glomerular filtration rate, with vitamins containing high doses of folic acid, vitamin B6, vitamin B12, did not reduce cardiovascular disease or all-cause mortality compared to a low dose multivitamin without folic acid.64 It is possible that homocysteine levels do not have a direct causal effect on thrombosis and cardiovascular disease but instead may act as a marker for disease. Environmental and Other Factors
Various environmental and other factors are associated with vascular thrombosis in RTRs. This is outlined in Table 2. Immunosuppressive agents used to prevent rejection may predispose to thrombosis of small vessels leading to TMA. Calcineurin inhibitors may increase the expression of plasminogen activator inhibitor resulting in hypofibrinolysis.5 Cyclosporine is associated with endothelial injury resulting in irreversible intrarenal allograft thrombosis and allograft loss even without rejection.65 Cyclosporine and tacrolimus increase the risk of TMA due to endothelial injury secondary to vasoconstriction associated ischemia and possibly increased platelet aggregation and other prothrombotic effects.66 Dose reduction or discontinuation of calcineurin inhibitors or substitution of mTOR inhibitors to limit drug-related nephrotoxic insults has been attempted without improved outcomes.67 Thrombotic microangiopathy has also been reported with mTOR inhibitors.68 Belatacept a novel CTLA4 Ig fusion protein was used as an alternative to calcineurin inhibitors in several cases of drug-induced TMA.69,70 The monoclonal antibody OKT3 has prothrombotic effects and is associated with an increased risk of allograft thrombosis, especially in patients treated with high dose steroids.5 Glucocorticoids may have hypofibrinolytic effects by inhibiting EC production of plasminogen activator.71,72 TABLE 2.
Potential important recipient and donor factors for graft Thrombosis Recipient
Previous history of thromboembolism Extreme of recipient age Diabetes Systemic lupus erythematosus Peritoneal dialysis Renal vessel atherosclerosis Technical surgical problem Delayed graft function Hemodynamic instability—hypotension Cytomegalovirus infection Posttransplant erythrocytosis Use of calcineurin inhibitor, high dose steroid, and OKT3
Donor
Extreme of donor age ( >60 or A, and MTHFR C677T mutations). Patients with thrombophilia received intravenous heparin adjusted to achieve an activated partial thromboplastin time (PTT) of 50 to 60 seconds for 14 days and were then switched to low-molecular-weight heparin for
FIGURE 2. Hypercoagulability screening and anticoagulation protocol.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
724
Transplantation
■
April 2016
■
Volume 100
■
Number 4
8 weeks, followed by aspirin for the first year. Patients without thrombophilia received low dose heparin for 14 days followed by aspirin. There were no thromboembolic events in either group. One serious bleeding complication occurred in the setting of activated PTT >180 seconds and required surgical intervention.95 Friedman et al96 demonstrated a 2.6-fold reduction in expected incidence of allograft thrombosis in patients with thrombophilic disorders states who received prophylactic anticoagulation with unfractionated heparin followed by warfarin after transplantation. Identifying patients at high risk for thrombosis is difficult and still requires an individual risk assessment. Outside of the renal transplant setting thrombosis occurs in the absence of identifiable risk factors or thrombophilia. Renal transplant recipients carry a unique combination of surgical, donor, and recipient predisposing factors. Thrombophilia testing does not reliably predict graft thrombosis post transplantation and different transplant centers vary in their strategies for identifying high risk patients. Alakulppi et al97 investigated whether detection of polymorphisms in candidate genes with a role in thrombosis or cytokine mediated vascular inflammation would facilitate identification of patients at high risk for vascular complications or acute rejection after renal transplantation. There was no association between any of the genetic polymorphisms and venous thrombosis, rejection or graft survival. Screening for genetic and acquired thrombophilic disorders before transplantation remains controversial. Some programs screen all patients, while others selectively screen high risk of patients with a personal or family history of thrombosis.98 At our institution, all patients are screened at the time of transplant with the following tests: INR, PTT, prothrombin, 20210G > A mutation, APC resistance assay, antithrombin III activity, protein C activity, free protein S antigen, aCL, and LAC panel. Patients considered at high risk for thrombosis are those with a history of deep vein thrombosis (DVT) and/or pulmonary embolism, ESRD due to lupus, previous allograft loss due to a vascular complication or early rejection, history of recurrent miscarriage, and pancreas transplant recipients. All kidney transplant recipients receive prophylaxis with low molecular weight heparin (enoxaparin) beginning on the second postoperative day and continuing until discharge, in the absence of contraindications. After discharge, patients start low-dose aspirin. Patients who required a complex arterial or venous anastomosis receive low-dose intravenous heparin (500 units/hour) until enoxaparin is begun on the second postoperative day. Patients with abnormal thrombophilia screening tests are discharged on a 4- to 6-week course of prophylactic dose (30 mg/day) enoxaparin. Our protocol is outlined in Figure 2. From July 1, 2009, through June 30, 2014, there were no cases of graft loss due to thrombosis in 444 kidney transplants performed at our center. In the same timeframe, there were 11 (2.5%) cases of DVT during the 3 month posttransplant period. Of these, 45% of the patients who developed DVT had abnormal thrombophilia testing and/or a high-risk clinical risk factor identified at the time of transplant. Postoperative anticoagulation after renal transplantation remains controversial, and there are no evidence-based guidelines for its use. Despite concerns about the safety of low molecular weight heparin in immediate postoperative period, we previously reported that dalteparin was safe as well as effective for preventing graft thrombosis and DVT during
www.transplantjournal.com
the perioperative period.99 Low-risk patients with a normal thrombophilia panel received a single 2500 U dose of dalteparin subcutaneously immediately after surgery and then daily during their hospitalization. Those with an abnormal thrombophilia screen and/or a medical history suggestive of a hypercoagulable state received a single daily dose of 5000 U of dalteparin for 1 month after transplantation followed by warfarin for 4 weeks. There were no cases of allograft arterial or venous thrombosis among the 120 patients transplanted between December 1996 and November 1997. One patient developed a right subclavian vein thrombosis. Importantly, there were no significant bleeding complications during the treatment period.99 Similarly, prophylactic enoxaparin was effective for preventing renal graft thrombosis without severe complications among pediatric recipients with multiple risk factors for graft thrombosis.100
CONCLUSIONS To date, there has been no established method to predict thrombotic events in RTRs. Patients with ESRD have specific acquired risk factors for thrombosis, some of which are ameliorated after successful transplantation. Other risk factors and comorbid conditions include a previous history of thrombosis, inherited disorder of coagulation, donor and recipient age, diabetes, SLE, DGF, and many more. Outcomes of graft thrombosis are not favorable, and preventive strategies are recommended. When evaluating patients for transplantation, a proper history and identification of risk factors for thrombosis is important. With proper use of prophylactic anticoagulation, graft and patient survival may increase. Further studies are needed to identify a proper therapeutic strategy to reduce thrombosis in the transplant population.
REFERENCES 1. Clarke SD, Kennedy JA, Hewitt JC, et al. Successful removal of thrombus from renal vein after renal transplantation. Br Med J. 1970;1:154–155. 2. Kocak T, Nane I, Ander H, et al. Urological and surgical complications in 362 consecutive living related donor kidney transplantations. Urol Int. 2004;72:252–256. 3. Zilinska Z, Chrastina M, Trebaticky B, et al. Vascular complications after renal transplantation. Bratisl Lek Listy. 2010;111:586–589. 4. Barba Abad J, Rincón Mayans A, Tolosa Eizaguirre E, et al. Surgical complications in kidney transplantation and their influence on graft survival. Actas Urol Esp. 2010;34:266–273. 5. Ponticelli C, Moia M, Montagnino G. Renal allograft thrombosis. Nephrol Dial Transplant. 2009;24:1388–1393. 6. Phelan PJ, O'Kelly P, Tarazi M, et al. Renal allograft loss in the first postoperative month: causes and consequences. Clin Transplant. 2012;26: 544–549. 7. Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial. 2005;18:505–510. 8. Winsett F RP, Martin J, Reed L, Bateman C. Kidney Transplantation 2002. Available at: http://www.medscape.com/viewarticle/443490_14. Published 2002. Accessed April 8, 2014. 9. Chu WP. Ultrasonography diagnosis of renal arterial thrombosis: an important cause of renal allograft loss in children. Hong Kong Med J. 2011;17: 421–422. 10. Avasthi PS, Greene ER, Scholler C, et al. Noninvasive diagnosis of renal vein thrombosis by ultrasonic echo-Doppler flowmetry. Kidney Int. 1983; 23:882–887. 11. Reuther G, Wanjura D, Bauer H. Acute renal vein thrombosis in renal allografts: detection with duplex Doppler US. Radiology. 1989;170:557–558. 12. 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.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Parajuli et al
© 2015 Wolters Kluwer
13. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003;138:128–134. 14. Martinelli I, Passamonti SM, Bucciarelli P. Thrombophilic states. Handb Clin Neurol. 2014;120:1061–1071. 15. Kazory A, Ducloux D. Acquired hypercoagulable state in renal transplant recipients. Thromb Haemost. 2004;91:646–654. 16. Keller AK, Jorgensen TM, Jespersen B. Identification of risk factors for vascular thrombosis may reduce early renal graft loss: a review of recent literature. J Transplant. 2012;2012:793461. 17. Huisman MV, Rosendaal F. Thrombophilia. Curr Opin Hematol. 1999;6: 291–297. 18. Arnutti P, Nathalang O, Cowawintaweewat S, et al. Factor V Leiden and prothrombin G20210A mutations in Thai patients awaiting kidney transplant. Southeast Asian J Trop Med Public Health. 2002;33:869–871. 19. Wüthrich RP, Factor V. Leiden mutation: potential thrombogenic role in renal vein, dialysis graft and transplant vascular thrombosis. Curr Opin Nephrol Hypertens. 2001;10:409–414. 20. Kujovich JL. Thrombophilia and thrombotic problems in renal transplant patients. Transplantation. 2004;77:959–964. 21. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med. 1999;341:801–806. 22. Irish AB, Green FR, Gray DW, et al. The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients. Transplantation. 1997;64:604–607. 23. Wuthrich RP, Cicvara-Muzar S, Booy C, et al. Heterozygosity for the factor V Leiden (G1691A) mutation predisposes renal transplant recipients to thrombotic complications and graft loss. Transplantation. 2001;72: 549–550. 24. Heidenreich S, Dercken C, August C, et al. High rate of acute rejections in renal allograft recipients with thrombophilic risk factors. J Am Soc Nephrol. 1998;9:1309–1313. 25. Hocher B, Slowinski T, Hauser I, et al. Association of factor V Leiden mutation with delayed graft function, acute rejection episodes and long-term graft dysfunction in kidney transplant recipients. Thromb Haemost. 2002;87:194–198. 26. Ekmekci Y, Keven K, Akar N, et al. Thrombophilia and avascular necrosis of femoral head in kidney allograft recipients. Nephrol Dial Transplant. 2006;21:3555–3558. 27. Kujovich JL. Prothrombin-Related Thrombophilia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, et al., editors. GeneReviews(R). Seattle (WA): 1993. 28. Shen E, Uemura T, Kadry Z, et al. Successful living donor kidney transplantation in a patient with prothrombin gene mutation: Case report and literature review. J Anaesthesiol Clin Pharmacol. 2014;30: 106–108. 29. Fischereder M, Schneeberger H, Lohse P, et al. Increased rate of renal transplant failure in patients with the G20210A mutation of the prothrombin gene. Am J Kidney Dis. 2001;38:1061–1064. 30. Pherwani AD, Winter PC, McNamee PT, et al. Is screening for factor V Leiden and prothrombin G20210A mutations in renal transplantation worthwhile? Results of a large single-center U.K. study. Transplantation. 2003;76:603–605. 31. Beresford CH. Antithrombin III deficiency. Blood Rev. 1988;2:239–250. 32. Wypasek E, Undas A. Protein C and protein S deficiency - practical diagnostic issues. Adv Clin Exp Med. 2013;22:459–467. 33. Bombeli T, Basic A, Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems. Am J Hematol. 2002; 70:126–132. 34. Heijboer H, Brandjes DP, Büller HR, et al. Deficiencies of coagulationinhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med. 1990;323:1512–1516. 35. Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism—results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost. 1997;77:444–451. 36. Lewis JH, Bontempo FA, Ragni MV, et al. Antithrombin III during liver transplantation. Transplant Proc. 1989;21:3543–3544. 37. Deira J, Alberca I, Lerma JL, et al. Changes in coagulation and fibrinolysis in the postoperative period immediately after kidney transplantation in patients receiving OKT3 or cyclosporine A as induction therapy. Am J Kidney Dis. 1998;32:575–581. 38. Mitsiev I, Reinhold S, Ziemer S, et al. Combination of APC resistance and acquired protein S deficiency in a haemodialysis patient with recurrent A-V shunt thrombosis. Nephrol Dial Transplant. 1999;14:2474–2477.
725
39. Giannakopoulos B, Passam F, Rahgozar S, et al. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood. 2007;109: 422–430. 40. Sciascia S, Cuadrado MJ, Khamashta M, et al. Renal involvement in antiphospholipid syndrome. Nat Rev Nephrol. 2014;10:279–289. 41. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306. 42. Pierangeli SS, Chen PP, Raschi E, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost. 2008;34:236–250. 43. Urbanus RT, de Laat B. Antiphospholipid antibodies and the protein C pathway. Lupus. 2010;19:394–399. 44. Nojima J, Kuratsune H, Suehisa E, et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem. 2001;47: 1008–1015. 45. Lin WS, Chen PC, Yang CD, et al. Some antiphospholipid antibodies recognize conformational epitopes shared by beta2-glycoprotein I and the homologous catalytic domains of several serine proteases. Arthritis Rheum. 2007;56:1638–1647. 46. Barbour TD, Crosthwaite A, Chow K, et al. Antiphospholipid syndrome in renal transplantation. Nephrology (Carlton). 2014;19:177–185. 47. Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol. 1992;19:508–512. 48. Vaidya S, Sellers R, Kimball P, et al. Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study. Transplantation. 2000;69:1348–1352. 49. Canaud G, Bienaime F, Noël LH, et al. Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies. Am J Transplant. 2010;10:2051–2060. 50. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011;20:206–218. 51. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e326S–e350S. 52. Tsagalis G, Psimenou E, Nakopoulou L, et al. Effective treatment of antiphospholipid syndrome with plasmapheresis and rituximab. Hippokratia. 2010;14:215–216. 53. Hadaya K, Ferrari-Lacraz S, Fumeaux D, et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am J Transplant. 2011;11:2523–2527. 54. Chaturvedi S, McCrae KR. Recent advances in the antiphospholipid antibody syndrome. Curr Opin Hematol. 2014;21:371–379. 55. Canaud G, Terzi F. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:1554–1555. 56. Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010; 8:237–242. 57. Bertolaccini ML, Amengual O, Andreoli L, et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13: 917–930. 58. Aleman G, Tovar AR, Torres N. Homocysteine metabolism and risk of cardiovascular diseases: importance of the nutritional status on folic acid, vitamins B6 and B12. Rev Invest Clin. 2001;53:141–151. 59. McKinley MC. Nutritional aspects and possible pathological mechanisms of hyperhomocysteinaemia: an independent risk factor for vascular disease. Proc Nutr Soc. 2000;59:221–237. 60. Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med. 2009;60:39–54. 61. Varga EA, Kujovich JL. Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012;81:7–17. 62. van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant. 2006;21:1161–1166. 63. Ducloux D, Fournier V, Rebibou JM, et al. Hyperhomocyst(e)inemia in renal transplant recipients with and without cyclosporine. Clin Nephrol. 1998;49:232–235.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
726
Transplantation
■
April 2016
■
Volume 100
■
Number 4
64. Bostom AG, Carpenter MA, Kusek JW, et al. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation. 2011;123:1763–1770. 65. Schlanger RE, Henry ML, Sommer BG, et al. Identification and treatment of cyclosporine-associated allograft thrombosis. Surgery. 1986;100: 329–333. 66. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4:481–508. 67. Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant. 2010;10:1517–1523. 68. Saikali JA, Truong LD, Suki WN. Sirolimus may promote thrombotic microangiopathy. Am J Transplant. 2003;3:229–230. 69. Cicora F, Paz M, Mos F, et al. Use of belatacept as alternative immunosuppression in three renal transplant patients with de novo drug-induced thrombotic microangiopathy. Case Rep Med. 2013;2013:260254. 70. Ashman N, Chapagain A, Dobbie H, et al. Belatacept as maintenance immunosuppression for postrenal transplant de novo drug-induced thrombotic microangiopathy. Am J Transplant. 2009;9:424–427. 71. Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol. 1990;6:217–246. 72. Laug WE. Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Haemost. 1983;50:888–892. 73. Sartori TM, Maurizio PG, Sara P, et al. Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis and myocardial microthrombi generation. J Heart Lung Transplant. 1999;18:693–700. 74. Bertoli M, Vertolli U, Ruffatti A, Di Landro D, Romagnoli GF. Does hypercoagulability exist in CAPD patients? Perit Dial Int. 1984;4:237–239. 75. van der Vliet JA, Barendregt WB, Hoitsma AJ, et al. Increased incidence of renal allograft thrombosis after continuous ambulatory peritoneal dialysis. Clin Transplant. 1996;10(1 Pt 1):51–54. 76. Vats AN, Donaldson L, Fine RN, et al. Pretransplant dialysis status and outcome of renal transplantation in North American children: a NAPRTCS Study. North American Pediatric Renal Transplant Cooperative Study. Transplantation. 2000;69:1414–1419. 77. Ojo AO, Hanson JA, Wolfe RA, et al. Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients. Kidney Int. 1999; 55:1952–1960. 78. Dagher FJ, Ramos E, Erslev A, et al. Erythrocytosis after renal allotransplantation: treatment by removal of the native kidneys. South Med J. 1980;73:940–942. 79. Wickre CG, Norman DJ, Bennison A, et al. Postrenal transplant erythrocytosis: a review of 53 patients. Kidney Int. 1983;23:731–737. 80. Atzmony L, Halutz O, Avidor B, et al. Incidence of cytomegalovirusassociated thrombosis and its risk factors: a case-control study. Thromb Res. 2010;126:e439–e443. 81. Belli L, De Carlis L, Belli LS, et al. Thromboendarterectomy (TEA) in the recipient as a major risk of arterial complication after kidney transplantation. Int Angiol. 1989;8:206–209. 82. Englesbe MJ, Punch JD, Armstrong DR, et al. Single-center study of technical graft loss in 714 consecutive renal transplants. Transplantation. 2004;78:623–626.
www.transplantjournal.com
83. Orlando G, Gravante G, D'Angelo M, et al. A renal graft with six arteries and double pelvis. Transpl Int. 2008;21:609–611. 84. Amézquita Y, Méndez C, Fernández A, et al. Risk factors for early renal graft thrombosis: a case-controlled study in grafts from the same donor. Transplant Proc. 2008;40:2891–2893. 85. Osman Y, Shokeir A, Ali-el-Dein B, et al. Vascular complications after live donor renal transplantation: study of risk factors and effects on graft and patient survival. J Urol. 2003;169:859–862. 86. Penny MJ, Nankivell BJ, Disney AP, et al. Renal graft thrombosis. A survey of 134 consecutive cases. Transplantation. 1994;58:565–569. 87. Nagra A, Trompeter RS, Fernando ON, et al. The effect of heparin on graft thrombosis in pediatric renal allografts. Pediatr Nephrol. 2004;19: 531–535. 88. Bakir N, Sluiter WJ, Ploeg RJ, et al. Primary renal graft thrombosis. Nephrol Dial Transplant. 1996;11:140–147. 89. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant. 2011;11:2279–2296. 90. Ghisdal L, Broeders N, Wissing KM, et al. Thrombophilic factors in Stage V chronic kidney disease patients are largely corrected by renal transplantation. Nephrol Dial Transplant. 2011;26:2700–2705. 91. 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. 92. Esfandiar N, Otukesh H, Sharifian M, et al. Protective effect of heparin and aspirin against vascular thrombosis in pediatric kidney transplants. Iran J Kidney Dis. 2012;6:141–145. 93. Murphy GJ, Taha R, Windmill DC, et al. Influence of aspirin on early allograft thrombosis and chronic allograft nephropathy following renal transplantation. Br J Surg. 2001;88:261–266. 94. Ghisdal L, Broeders N, Wissing KM, et al. Thrombophilic factors do not predict outcomes in renal transplant recipients under prophylactic acetylsalicylic acid. Am J Transplant. 2010;10:99–105. 95. Kranz B, Vester U, Nadalin S, et al. Outcome after kidney transplantation in children with thrombotic risk factors. Pediatr Transplant. 2006;10: 788–793. 96. Friedman GS, Meier-Kriesche HU, Kaplan B, et al. Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis. Transplantation. 2001;72: 1073–1078. 97. Alakulppi NS, Kyllönen LE, Partanen J, et al. Lack of association between thrombosis-associated and cytokine candidate gene polymorphisms and acute rejection or vascular complications after kidney transplantation. Nephrol Dial Transplant. 2008;23:364–368. 98. Matas AJ, Humar A, Gillingham KJ, et al. Five preventable causes of kidney graft loss in the 1990s: a single-center analysis. Kidney Int. 2002;62: 704–714. 99. Alkhunaizi AM, Olyaei AJ, Barry JM, et al. Efficacy and safety of low molecular weight heparin in renal transplantation. Transplantation. 1998;66: 533–534. 100. Broyer M, Gagnadoux MF, Sierro A, et al. Prevention of vascular thromboses after renal transplantation using low molecular weight heparin. Ann Pediatr. 1991;38:397–399.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Hypercoagulability in Kidney Transplant Recipients Sandesh Parajuli, MBBS,1,2 Joseph B. Lockridge, MD,2,3 Eric D. Langewisch, MD,2,3 Douglas J. Norman, MD,2,3 and Jody L. Kujovich, MD4 Abstract: Thrombosis remains an important complication after kidney transplantation. Outcomes for graft and deep vein thrombosis are not favorable. The majority of early kidney transplant failure in adults is due to allograft thrombosis. Risk stratification, early diagnosis, and appropriate intervention are critical to the management of thrombotic complications of transplant. In patients with end-stage renal disease, the prevalence of acquired risk factors for thrombosis is significantly high. Because of hereditary and acquired risk factors, renal transplant recipients manifest features of a chronic prothrombotic state. Identification of hereditary thrombotic risk factors before transplantation may be a useful tool for selecting appropriate candidates for thrombosis prophylaxis immediately after transplantation. Short-term anticoagulation may be appropriate for all patients after kidney transplantation.
(Transplantation 2016;100: 719–726)
T
hrombotic disease is a well-known complication after kidney transplantation. As early as 1970, Clarke et al1 reported a case of allograft renal vein thrombosis requiring thrombectomy. Graft-specific complications, including renal artery thrombosis, renal artery stenosis, and renal vein thrombosis, represent 0.5% to 6.0% of postoperative complications.2,3 Though uncommon, these complications may lead to allograft loss, usually in the early postoperative period,3 or require surgical intervention. The need for early surgical intervention is an independent predictor of graft survival.4 In the North American Pediatric Renal Transplant Cooperative Study, graft thrombosis represented the main cause of graft failure in the first year.5 In a recent large retrospective study of 2381 patients by Phelan et al,6 the incidence of early graft failure in adults within 30 days after Received 17 March 2015. Revision requested 27 May 2015. Accepted 1 June 2015. 1
Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI.
2
Division of Nephrology, Department of Medicine, Oregon Health and Science University, Portland, OR.
3
Portland VA Medical Center, Portland, Oregon.
4
Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR. The authors declare no funding or conflicts of interest. S.P. participated in design, data collection, analysis, manuscript preparation, editing. J.B.L. participated design, data collection, analysis, manuscript preparation, editing. E.L. participated in data collection, analysis, manuscript preparation, editing. D.J.N. design, data collection, analysis, manuscript preparation, editing. J.L.K. participated in design, data collection, analysis, manuscript preparation, editing. Correspondence: Douglas J Norman, MD, Division of Nephrology, Department of Medicine, Oregon Health and Science University, 2611 SW 3rd Ave, Ste 360, Portland, OR 97201. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/16/10004–719 DOI: 10.1097/TP.0000000000000887
Transplantation
■
April 2016
■
Volume 100
■
Number 4
transplantation was 4.6%; 44% of these were due to allograft thrombosis, whereas 17.4% were due to acute rejection. Prompt and accurate diagnoses along with timely management of graft vascular thrombosis after kidney transplant are essential. A delay in the diagnosis or management of these complications can result in serious recipient morbidity with a risk of graft loss and death.7 The initial clinical presentation of vascular allograft thrombosis includes sudden oliguria or anuria, graft tenderness, and swelling, and lower extremity edema that is more pronounced in the ipsilateral limb.8 A high index of clinical suspicion is required for diagnosis because other common conditions, including acute tubular necrosis and acute severe rejection, may have a similar clinical presentation.9 Ultrasound with Doppler is the initial study of choice to exclude graft thrombosis. In the acute setting, ultrasound may reveal an edematous and enlarged kidney with decreased echogenicity caused by diffuse edema, as well as focal or diffuse disruption of parenchymal architecture and/or thrombus in the renal vessels. Duplex Doppler ultrasound demonstrates peaked, abruptly decreasing systolic frequency shifts and retrograde plateau-like shifts during diastole at the level of the main renal artery and its proximal branches, with an absent venous signal.10,11 There is evidence suggesting an association between kidney transplantation and a prothrombotic state. An analysis of long-term renal transplant patients found evidence of a chronic prothrombotic and persistent inflammatory state. Renal transplant recipients (RTRs) had significantly higher levels of fibrinogen, d-dimer, the prothrombin activation fragment F 1 + 2, and IL-6 than controls. These changes reflect activation of coagulation and thrombin generation and may involve interactions between common genetic and environmental factors.12 Thrombophilic disorders may be inherited or acquired. This is outlined in Table 1. Inherited thrombophilic disorders including factor V Leiden (FVL), prothrombin 20210G > A mutation and deficiencies of protein C, protein S, and www.transplantjournal.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
719
720
Transplantation
■
April 2016
■
Volume 100
■
Number 4
TABLE 1.
Inherited and acquired risk factors for thrombosis in renal transplant recipients Inherited
Factor V Leiden mutation Prothrombin 20210G > A mutation Antithrombin deficiency Protein C deficiency Protein S deficiency
Mutation in the tissue plasminogen activator inhibitor-1promoter Mutation of MTHFR Increased lipoprotein
Acquired
Antiphospholipid syndrome and/or antibodies Hyperhomocysteinemia Cryoglobulins Cryofibrinogenemia Acquired deficiencies of protein C, S and antithrombin- sepsis, DIC, liver disease, nephrotic syndrome Malignancy
DIC indicates disseminated intravascular coagulation.
antithrombin affect different sites in the coagulation pathway (Figure 1). Acquired disorders include antiphospholipid antibodies (APLA) and hyperhomocysteinemia.13,14 Additional risk factors for graft thrombosis include immunosuppressive agents, pretransplant dialysis modality mainly peritoneal dialysis (PD), and posttransplant erythrocytosis (PTE). Recurrent proteinuria and acute cytomegalovirus (CMV) infection may also increase the risk of graft thrombosis.15 Other potentially important donor or recipient factors include extreme donor age, cold ischemia time longer than 24 hours, renal vessel atherosclerosis, right kidney compared to left, recipient age, technical surgical problems, hemodynamic instability, delayed graft function (DGF), and a history of thrombosis.16 FVL Mutation
The FVL refers to a specific G-to-A substitution in F5 that predicts a single amino acid replacement (Arg506Gln) that destroys a cleavage site for activated protein C (APC). Activated protein C with its cofactor protein S normally proteolytically inactivates procoagulant factors Va and VIIIa, thereby downregulating further thrombin generation.17 Because of this single amino acid substitution, factor Va is resistant to APC and is inactivated at a 10-fold slower rate than normal. The impaired anticoagulant response to APC results in increased thrombin generation and a prothrombotic state leading to increased thrombin generation.18,19 The FVL is the most common inherited thrombophilic disorder, found in 5% to 8% of the general population, primarily in whites of European descent, in 20% of patients with a first venous thrombosis, and in up to 50% of patients with a personal or family history of recurrent thrombosis.20 The clinical expression of FVL is influenced by coexisting genetic and acquired thrombophilic disorders and circumstantial risk factors. The combination of FVL heterozygosity and most thrombophilic disorders (for example, prothrombin 20210G > A mutation) has a superadditive effect on overall thrombotic risk.21 Several studies reported a significantly higher incidence of venous thromboembolism in RTRs with FVL compared to those without the mutation. The FVL was associated with an overall 4-fold increased risk of graft vein thrombosis and venous thromboembolism.22,23 Heidenreich et al24 reported
www.transplantjournal.com
a higher prevalence of acute rejection and other vascular complications in patients with thrombophilic disorders including FVL. The authors hypothesized that adhesion and chemotaxis of lymphocytes in response to clotting in the allograft vascular bed may trigger acute rejection or aggravate incipient rejection. The FVL has also been associated with increased risk for DGF, acute rejection, and chronic graft dysfunction.25 Renal transplant recipients with FVL had a high incidence of avascular necrosis of the femoral head.26 Prothrombin G20210A Mutation
A single nucleotide substitution (20210G > A) in the 3′ untranslated region of the prothrombin gene (F2) is associated with elevated prothrombin levels and an increased risk of venous thromboembolism. Evidence suggests that the G > A transition increases the efficiency and accuracy of processing of the 3′ end of the mRNA resulting in an accumulation of mRNA and increased prothrombin protein synthesis.27 The prothrombin 20210G > A mutation is found in 2% to 3% of the general population and also occurs primarily in whites.20,28 The evidence implicating prothrombin 20210G > A in complications after renal transplantation is more limited and conflicting. Fischereder et al29 demonstrated that a prothrombin G20210A mutation conferred a 2.95-fold increased risk of graft loss. Median graft survival for 20210G > A heterozygotes was 65.9 months versus 149 months in those without the mutation. Graft failure was due to arterial, venous, or microvascular thrombosis in the majority of carriers. However, another single-center study of 562 transplant recipients found no association between FVL or prothrombin 20210G > A and renal allograft loss.30 Anticoagulant Protein Deficiencies
Inherited thrombophilia also includes deficiencies of the natural anticoagulant proteins C, S, and antithrombin. Antithrombin inhibits serine proteases involved in coagulation including thrombin and activated factors X, IX, and XI.31 Protein C and protein S are vitamin K-dependent anticoagulant proteins. Activated protein C requires free protein S as a cofactor to inhibit activated factors V and VIII.32 Anticoagulant protein deficiencies are approximately 10-fold less common than FVL and prothrombin 20210G > A with a combined prevalence of less than 1% of the population.33 They are found in 2% to 5% of individuals with a first venous thromboembolism.34,35 Acquired deficiencies of protein C, S, and antithrombin are far more common and occur during sepsis, disseminated intravascular coagulation,
FIGURE 1. Coagulation pathway affected at different sites in inherited thrombophilic disorders.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Parajuli et al
© 2015 Wolters Kluwer
liver disease, major surgery, and acute thrombosis.36 Protein C and protein S levels are reduced by vitamin K deficiency. Antithrombin levels fall in nephrotic syndrome and are lowered up to 30% by heparin. One study found a marked fall in antithrombin, protein C, and thrombomodulin levels during the first 24 hours after transplantation.37 Protein S levels are often low in RTRs and may reflect acute or chronic inflammation.38 Another study identified a small group of patients with antithrombin deficiency and a high (80%) rejection rate in first 6 months after transplantation.24 It is unknown whether an acquired temporary fall in anticoagulant protein levels contributes to the thrombotic risk in renal transplant patients. Antiphospholipid Antibodies
Antiphospholipid antibodies comprise a heterogeneous group of autoantibodies directed against phospholipids and phospholipid-binding proteins including B2-glycoprotein-I and prothrombin.39 The prevalence of APLA varies with the population studied. Low titer APLA are found in 1% to 3% of the general population and are usually clinically insignificant. The prevalence is higher in patients with thrombotic manifestations (10-26%) and in women with recurrent miscarriage (10-40%).40 Diagnosis of the APLA syndrome (APLS) requires a history of arterial or venous thromboembolism or unexplained pregnancy morbidity and laboratory evidence of persistent APLA: anticardiolipin antibodies (aCL), anti-β2GP I antibodies, and/or a lupus anticoagulant (LAC).41 The APLS can manifest as a primary disease or occur in association with other autoimmune diseases, such as systemic lupus erythematosus (SLE) (secondary APLS).40 The APLA are found in nearly 50% of patients with SLE and nearly 40% of these develop thrombotic complications.40 The APLA predispose to thrombosis by a variety of different mechanisms. The APLA have effects on platelets, endothelial cells (ECs), and monocytes and have been shown to interfere with the protein C pathway, fibrinolysis and complement activation.42 Acquired APC resistance and the presence of anti-protein C and antiprotein S antibodies are reported in patients with APLS43,44. One study found that APLA directed against β2GPI cross-react with APC.45 Renal manifestations of APLA include renal vein thrombosis, renal artery stenosis and thrombosis and thrombotic microangiopathy (TMA). Other renal complications include preeclampsia, glomerulonephritis, renal infarct, and renovascular hypertension.46 Catastrophic antiphospholipid syndrome is a severe form of TMA involving kidneys, lungs, brain and other organs which leads to acute multiorgan failure.47 The APLS is well known to cause graft thrombosis without appropriate thromboembolic prophylaxis. Vaidya et al reported thrombosis leading to graft loss in all 7 patients with APLS who did not receive anticoagulation.48 Patients with APLA have poor renal allograft outcomes. A retrospective study found that RTRs with a lupus inhibitor (+/− other APLA) had a significantly higher overall frequency of thrombotic complications. Graft thrombosis occurred in 27% of patients with APLA compared to 6.9% of those who were APLA negative. The characteristic lesions of APLA associated nephropathy were found in the majority of screening biopsies at 3 and 12 months in recipients with APLA but only rarely in those without APLA.49 Long-term therapeutic anticoagulation is recommended in APLS patients with
721
thrombosis.44 Management of perioperative anticoagulation requires an individualized assessment of the risk of both thrombosis and bleeding.50,51 Rituximab has been used in combination with other therapies in patients with APLS and renal limited TMA.52 Eculizumab is a humanized monoclonal antibody to C5 that blocks the terminal complement cascade. Eculizumab was effective in the treatment of a fulminant recurrence of APLA-related TMA after kidney transplantation.53 A phase 2 clinical trial is currently investigating the effectiveness of eculizumab in patients with pretransplant catastrophic antiphospholipid syndrome.46 The APLA are hypothesized to cause thrombosis by a variety of different mechanisms. Potential pathogenic mechanisms include APLA-mediated activation of platelets, ECs and monocytes, activation of complement and inhibition of natural anticoagulant and fibrinolytic pathways.54 Recent evidence suggests that the mechanistic target of rapamycin complex (mTORC) pathway is involved in the development of the renal vascular lesions associated with APLS nephropathy. Renal transplant patient with APLS who received the mTOR inhibitor, sirolimus had no evidence of recurrent vascular lesions on biopsy compared to APLA-positive patients not receiving sirolimus, suggesting inhibition of the mTORC pathway may prevent graft loss in this group.55 It remains difficult to predict thrombotic risk in asymptomatic patients with APLA. Lupus anticoagulants are more strongly associated with thrombotic risk than anticardiolipin or anti-B2GP1 antibodies. Increasing evidence that “triple positive” profile of APLA (LAC plus aB2gPI and aCL antibodies) confers the highest thrombotic risk.56 A subset of anti-B2GP1 antibodies directed against B2GP1 domain 1 (anti-D1 antibodies) may also be associated with a high thrombotic risk. However, it is still unclear whether testing for anti-D1 antibodies will enable identification of patients at highest risk for thrombosis.57 Hyperhomocysteinemia
Homocysteine is an amino acid generated during methionine metabolism. It is metabolized by 2 enzymatic pathways that require vitamin B12, vitamin B6, and/or folic acid as essential cofactors.58,59 Hyperhomocysteinemia may result from defects or deficiencies of the enzymes involved in homocysteine metabolism or deficiencies of their vitamin cofactors. The most common polymorphism in the N5, N10 methylenetetrahydrofolate reductase (MTHFR) gene, the C677T variant, results in a thermolabile enzyme with reduced activity for homocysteine metabolism.60 Approximately 12% of the general population is homozygous for this variant. The A1298C variant has a prevalence of 9% to 20% in most ethnic groups. Homozygosity (677TT) and compound heterozygosity (C677T/A1298C) for MTHFR polymorphisms predispose to mild elevations in homocysteine levels in the setting of suboptimal folate levels.61 Deficiencies of folate, vitamin B12, and/or vitamin B6 are the most common acquired causes of hyperhomocysteinemia. Patients with chronic kidney disease exhibit various protein and amino acid abnormalities, including hyperhomocysteinemia. Plasma homocysteine levels are inversely related to glomerular filtration rate, with a prevalence of hyperhomocysteinemia in end stage renal disease (ESRD) as high as 85% to 100%.62 Elevated plasma levels of homocysteine are associated with an increased risk of venous and arterial thrombosis.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
722
Transplantation
■
April 2016
■
Volume 100
■
Number 4
Hyperhomocysteinemia was identified as an independent risk factor for cardiovascular disease and thromboembolic events in RTRs.63 To date, there is no evidence that homocysteine-lowering treatment with folic acid at doses greater than 1 mg per day lowers the risk of vascular events or mortality in patients with ESRD.62 Treatment of stable kidney transplant recipients with increased levels of homocysteine and reduced glomerular filtration rate, with vitamins containing high doses of folic acid, vitamin B6, vitamin B12, did not reduce cardiovascular disease or all-cause mortality compared to a low dose multivitamin without folic acid.64 It is possible that homocysteine levels do not have a direct causal effect on thrombosis and cardiovascular disease but instead may act as a marker for disease. Environmental and Other Factors
Various environmental and other factors are associated with vascular thrombosis in RTRs. This is outlined in Table 2. Immunosuppressive agents used to prevent rejection may predispose to thrombosis of small vessels leading to TMA. Calcineurin inhibitors may increase the expression of plasminogen activator inhibitor resulting in hypofibrinolysis.5 Cyclosporine is associated with endothelial injury resulting in irreversible intrarenal allograft thrombosis and allograft loss even without rejection.65 Cyclosporine and tacrolimus increase the risk of TMA due to endothelial injury secondary to vasoconstriction associated ischemia and possibly increased platelet aggregation and other prothrombotic effects.66 Dose reduction or discontinuation of calcineurin inhibitors or substitution of mTOR inhibitors to limit drug-related nephrotoxic insults has been attempted without improved outcomes.67 Thrombotic microangiopathy has also been reported with mTOR inhibitors.68 Belatacept a novel CTLA4 Ig fusion protein was used as an alternative to calcineurin inhibitors in several cases of drug-induced TMA.69,70 The monoclonal antibody OKT3 has prothrombotic effects and is associated with an increased risk of allograft thrombosis, especially in patients treated with high dose steroids.5 Glucocorticoids may have hypofibrinolytic effects by inhibiting EC production of plasminogen activator.71,72 TABLE 2.
Potential important recipient and donor factors for graft Thrombosis Recipient
Previous history of thromboembolism Extreme of recipient age Diabetes Systemic lupus erythematosus Peritoneal dialysis Renal vessel atherosclerosis Technical surgical problem Delayed graft function Hemodynamic instability—hypotension Cytomegalovirus infection Posttransplant erythrocytosis Use of calcineurin inhibitor, high dose steroid, and OKT3
Donor
Extreme of donor age ( >60 or A, and MTHFR C677T mutations). Patients with thrombophilia received intravenous heparin adjusted to achieve an activated partial thromboplastin time (PTT) of 50 to 60 seconds for 14 days and were then switched to low-molecular-weight heparin for
FIGURE 2. Hypercoagulability screening and anticoagulation protocol.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
724
Transplantation
■
April 2016
■
Volume 100
■
Number 4
8 weeks, followed by aspirin for the first year. Patients without thrombophilia received low dose heparin for 14 days followed by aspirin. There were no thromboembolic events in either group. One serious bleeding complication occurred in the setting of activated PTT >180 seconds and required surgical intervention.95 Friedman et al96 demonstrated a 2.6-fold reduction in expected incidence of allograft thrombosis in patients with thrombophilic disorders states who received prophylactic anticoagulation with unfractionated heparin followed by warfarin after transplantation. Identifying patients at high risk for thrombosis is difficult and still requires an individual risk assessment. Outside of the renal transplant setting thrombosis occurs in the absence of identifiable risk factors or thrombophilia. Renal transplant recipients carry a unique combination of surgical, donor, and recipient predisposing factors. Thrombophilia testing does not reliably predict graft thrombosis post transplantation and different transplant centers vary in their strategies for identifying high risk patients. Alakulppi et al97 investigated whether detection of polymorphisms in candidate genes with a role in thrombosis or cytokine mediated vascular inflammation would facilitate identification of patients at high risk for vascular complications or acute rejection after renal transplantation. There was no association between any of the genetic polymorphisms and venous thrombosis, rejection or graft survival. Screening for genetic and acquired thrombophilic disorders before transplantation remains controversial. Some programs screen all patients, while others selectively screen high risk of patients with a personal or family history of thrombosis.98 At our institution, all patients are screened at the time of transplant with the following tests: INR, PTT, prothrombin, 20210G > A mutation, APC resistance assay, antithrombin III activity, protein C activity, free protein S antigen, aCL, and LAC panel. Patients considered at high risk for thrombosis are those with a history of deep vein thrombosis (DVT) and/or pulmonary embolism, ESRD due to lupus, previous allograft loss due to a vascular complication or early rejection, history of recurrent miscarriage, and pancreas transplant recipients. All kidney transplant recipients receive prophylaxis with low molecular weight heparin (enoxaparin) beginning on the second postoperative day and continuing until discharge, in the absence of contraindications. After discharge, patients start low-dose aspirin. Patients who required a complex arterial or venous anastomosis receive low-dose intravenous heparin (500 units/hour) until enoxaparin is begun on the second postoperative day. Patients with abnormal thrombophilia screening tests are discharged on a 4- to 6-week course of prophylactic dose (30 mg/day) enoxaparin. Our protocol is outlined in Figure 2. From July 1, 2009, through June 30, 2014, there were no cases of graft loss due to thrombosis in 444 kidney transplants performed at our center. In the same timeframe, there were 11 (2.5%) cases of DVT during the 3 month posttransplant period. Of these, 45% of the patients who developed DVT had abnormal thrombophilia testing and/or a high-risk clinical risk factor identified at the time of transplant. Postoperative anticoagulation after renal transplantation remains controversial, and there are no evidence-based guidelines for its use. Despite concerns about the safety of low molecular weight heparin in immediate postoperative period, we previously reported that dalteparin was safe as well as effective for preventing graft thrombosis and DVT during
www.transplantjournal.com
the perioperative period.99 Low-risk patients with a normal thrombophilia panel received a single 2500 U dose of dalteparin subcutaneously immediately after surgery and then daily during their hospitalization. Those with an abnormal thrombophilia screen and/or a medical history suggestive of a hypercoagulable state received a single daily dose of 5000 U of dalteparin for 1 month after transplantation followed by warfarin for 4 weeks. There were no cases of allograft arterial or venous thrombosis among the 120 patients transplanted between December 1996 and November 1997. One patient developed a right subclavian vein thrombosis. Importantly, there were no significant bleeding complications during the treatment period.99 Similarly, prophylactic enoxaparin was effective for preventing renal graft thrombosis without severe complications among pediatric recipients with multiple risk factors for graft thrombosis.100
CONCLUSIONS To date, there has been no established method to predict thrombotic events in RTRs. Patients with ESRD have specific acquired risk factors for thrombosis, some of which are ameliorated after successful transplantation. Other risk factors and comorbid conditions include a previous history of thrombosis, inherited disorder of coagulation, donor and recipient age, diabetes, SLE, DGF, and many more. Outcomes of graft thrombosis are not favorable, and preventive strategies are recommended. When evaluating patients for transplantation, a proper history and identification of risk factors for thrombosis is important. With proper use of prophylactic anticoagulation, graft and patient survival may increase. Further studies are needed to identify a proper therapeutic strategy to reduce thrombosis in the transplant population.
REFERENCES 1. Clarke SD, Kennedy JA, Hewitt JC, et al. Successful removal of thrombus from renal vein after renal transplantation. Br Med J. 1970;1:154–155. 2. Kocak T, Nane I, Ander H, et al. Urological and surgical complications in 362 consecutive living related donor kidney transplantations. Urol Int. 2004;72:252–256. 3. Zilinska Z, Chrastina M, Trebaticky B, et al. Vascular complications after renal transplantation. Bratisl Lek Listy. 2010;111:586–589. 4. Barba Abad J, Rincón Mayans A, Tolosa Eizaguirre E, et al. Surgical complications in kidney transplantation and their influence on graft survival. Actas Urol Esp. 2010;34:266–273. 5. Ponticelli C, Moia M, Montagnino G. Renal allograft thrombosis. Nephrol Dial Transplant. 2009;24:1388–1393. 6. Phelan PJ, O'Kelly P, Tarazi M, et al. Renal allograft loss in the first postoperative month: causes and consequences. Clin Transplant. 2012;26: 544–549. 7. Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial. 2005;18:505–510. 8. Winsett F RP, Martin J, Reed L, Bateman C. Kidney Transplantation 2002. Available at: http://www.medscape.com/viewarticle/443490_14. Published 2002. Accessed April 8, 2014. 9. Chu WP. Ultrasonography diagnosis of renal arterial thrombosis: an important cause of renal allograft loss in children. Hong Kong Med J. 2011;17: 421–422. 10. Avasthi PS, Greene ER, Scholler C, et al. Noninvasive diagnosis of renal vein thrombosis by ultrasonic echo-Doppler flowmetry. Kidney Int. 1983; 23:882–887. 11. Reuther G, Wanjura D, Bauer H. Acute renal vein thrombosis in renal allografts: detection with duplex Doppler US. Radiology. 1989;170:557–558. 12. 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.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Parajuli et al
© 2015 Wolters Kluwer
13. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003;138:128–134. 14. Martinelli I, Passamonti SM, Bucciarelli P. Thrombophilic states. Handb Clin Neurol. 2014;120:1061–1071. 15. Kazory A, Ducloux D. Acquired hypercoagulable state in renal transplant recipients. Thromb Haemost. 2004;91:646–654. 16. Keller AK, Jorgensen TM, Jespersen B. Identification of risk factors for vascular thrombosis may reduce early renal graft loss: a review of recent literature. J Transplant. 2012;2012:793461. 17. Huisman MV, Rosendaal F. Thrombophilia. Curr Opin Hematol. 1999;6: 291–297. 18. Arnutti P, Nathalang O, Cowawintaweewat S, et al. Factor V Leiden and prothrombin G20210A mutations in Thai patients awaiting kidney transplant. Southeast Asian J Trop Med Public Health. 2002;33:869–871. 19. Wüthrich RP, Factor V. Leiden mutation: potential thrombogenic role in renal vein, dialysis graft and transplant vascular thrombosis. Curr Opin Nephrol Hypertens. 2001;10:409–414. 20. Kujovich JL. Thrombophilia and thrombotic problems in renal transplant patients. Transplantation. 2004;77:959–964. 21. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med. 1999;341:801–806. 22. Irish AB, Green FR, Gray DW, et al. The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients. Transplantation. 1997;64:604–607. 23. Wuthrich RP, Cicvara-Muzar S, Booy C, et al. Heterozygosity for the factor V Leiden (G1691A) mutation predisposes renal transplant recipients to thrombotic complications and graft loss. Transplantation. 2001;72: 549–550. 24. Heidenreich S, Dercken C, August C, et al. High rate of acute rejections in renal allograft recipients with thrombophilic risk factors. J Am Soc Nephrol. 1998;9:1309–1313. 25. Hocher B, Slowinski T, Hauser I, et al. Association of factor V Leiden mutation with delayed graft function, acute rejection episodes and long-term graft dysfunction in kidney transplant recipients. Thromb Haemost. 2002;87:194–198. 26. Ekmekci Y, Keven K, Akar N, et al. Thrombophilia and avascular necrosis of femoral head in kidney allograft recipients. Nephrol Dial Transplant. 2006;21:3555–3558. 27. Kujovich JL. Prothrombin-Related Thrombophilia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, et al., editors. GeneReviews(R). Seattle (WA): 1993. 28. Shen E, Uemura T, Kadry Z, et al. Successful living donor kidney transplantation in a patient with prothrombin gene mutation: Case report and literature review. J Anaesthesiol Clin Pharmacol. 2014;30: 106–108. 29. Fischereder M, Schneeberger H, Lohse P, et al. Increased rate of renal transplant failure in patients with the G20210A mutation of the prothrombin gene. Am J Kidney Dis. 2001;38:1061–1064. 30. Pherwani AD, Winter PC, McNamee PT, et al. Is screening for factor V Leiden and prothrombin G20210A mutations in renal transplantation worthwhile? Results of a large single-center U.K. study. Transplantation. 2003;76:603–605. 31. Beresford CH. Antithrombin III deficiency. Blood Rev. 1988;2:239–250. 32. Wypasek E, Undas A. Protein C and protein S deficiency - practical diagnostic issues. Adv Clin Exp Med. 2013;22:459–467. 33. Bombeli T, Basic A, Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems. Am J Hematol. 2002; 70:126–132. 34. Heijboer H, Brandjes DP, Büller HR, et al. Deficiencies of coagulationinhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med. 1990;323:1512–1516. 35. Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism—results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost. 1997;77:444–451. 36. Lewis JH, Bontempo FA, Ragni MV, et al. Antithrombin III during liver transplantation. Transplant Proc. 1989;21:3543–3544. 37. Deira J, Alberca I, Lerma JL, et al. Changes in coagulation and fibrinolysis in the postoperative period immediately after kidney transplantation in patients receiving OKT3 or cyclosporine A as induction therapy. Am J Kidney Dis. 1998;32:575–581. 38. Mitsiev I, Reinhold S, Ziemer S, et al. Combination of APC resistance and acquired protein S deficiency in a haemodialysis patient with recurrent A-V shunt thrombosis. Nephrol Dial Transplant. 1999;14:2474–2477.
725
39. Giannakopoulos B, Passam F, Rahgozar S, et al. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood. 2007;109: 422–430. 40. Sciascia S, Cuadrado MJ, Khamashta M, et al. Renal involvement in antiphospholipid syndrome. Nat Rev Nephrol. 2014;10:279–289. 41. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306. 42. Pierangeli SS, Chen PP, Raschi E, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost. 2008;34:236–250. 43. Urbanus RT, de Laat B. Antiphospholipid antibodies and the protein C pathway. Lupus. 2010;19:394–399. 44. Nojima J, Kuratsune H, Suehisa E, et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem. 2001;47: 1008–1015. 45. Lin WS, Chen PC, Yang CD, et al. Some antiphospholipid antibodies recognize conformational epitopes shared by beta2-glycoprotein I and the homologous catalytic domains of several serine proteases. Arthritis Rheum. 2007;56:1638–1647. 46. Barbour TD, Crosthwaite A, Chow K, et al. Antiphospholipid syndrome in renal transplantation. Nephrology (Carlton). 2014;19:177–185. 47. Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol. 1992;19:508–512. 48. Vaidya S, Sellers R, Kimball P, et al. Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study. Transplantation. 2000;69:1348–1352. 49. Canaud G, Bienaime F, Noël LH, et al. Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies. Am J Transplant. 2010;10:2051–2060. 50. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011;20:206–218. 51. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e326S–e350S. 52. Tsagalis G, Psimenou E, Nakopoulou L, et al. Effective treatment of antiphospholipid syndrome with plasmapheresis and rituximab. Hippokratia. 2010;14:215–216. 53. Hadaya K, Ferrari-Lacraz S, Fumeaux D, et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am J Transplant. 2011;11:2523–2527. 54. Chaturvedi S, McCrae KR. Recent advances in the antiphospholipid antibody syndrome. Curr Opin Hematol. 2014;21:371–379. 55. Canaud G, Terzi F. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:1554–1555. 56. Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010; 8:237–242. 57. Bertolaccini ML, Amengual O, Andreoli L, et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13: 917–930. 58. Aleman G, Tovar AR, Torres N. Homocysteine metabolism and risk of cardiovascular diseases: importance of the nutritional status on folic acid, vitamins B6 and B12. Rev Invest Clin. 2001;53:141–151. 59. McKinley MC. Nutritional aspects and possible pathological mechanisms of hyperhomocysteinaemia: an independent risk factor for vascular disease. Proc Nutr Soc. 2000;59:221–237. 60. Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med. 2009;60:39–54. 61. Varga EA, Kujovich JL. Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012;81:7–17. 62. van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant. 2006;21:1161–1166. 63. Ducloux D, Fournier V, Rebibou JM, et al. Hyperhomocyst(e)inemia in renal transplant recipients with and without cyclosporine. Clin Nephrol. 1998;49:232–235.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
726
Transplantation
■
April 2016
■
Volume 100
■
Number 4
64. Bostom AG, Carpenter MA, Kusek JW, et al. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation. 2011;123:1763–1770. 65. Schlanger RE, Henry ML, Sommer BG, et al. Identification and treatment of cyclosporine-associated allograft thrombosis. Surgery. 1986;100: 329–333. 66. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4:481–508. 67. Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant. 2010;10:1517–1523. 68. Saikali JA, Truong LD, Suki WN. Sirolimus may promote thrombotic microangiopathy. Am J Transplant. 2003;3:229–230. 69. Cicora F, Paz M, Mos F, et al. Use of belatacept as alternative immunosuppression in three renal transplant patients with de novo drug-induced thrombotic microangiopathy. Case Rep Med. 2013;2013:260254. 70. Ashman N, Chapagain A, Dobbie H, et al. Belatacept as maintenance immunosuppression for postrenal transplant de novo drug-induced thrombotic microangiopathy. Am J Transplant. 2009;9:424–427. 71. Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol. 1990;6:217–246. 72. Laug WE. Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Haemost. 1983;50:888–892. 73. Sartori TM, Maurizio PG, Sara P, et al. Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis and myocardial microthrombi generation. J Heart Lung Transplant. 1999;18:693–700. 74. Bertoli M, Vertolli U, Ruffatti A, Di Landro D, Romagnoli GF. Does hypercoagulability exist in CAPD patients? Perit Dial Int. 1984;4:237–239. 75. van der Vliet JA, Barendregt WB, Hoitsma AJ, et al. Increased incidence of renal allograft thrombosis after continuous ambulatory peritoneal dialysis. Clin Transplant. 1996;10(1 Pt 1):51–54. 76. Vats AN, Donaldson L, Fine RN, et al. Pretransplant dialysis status and outcome of renal transplantation in North American children: a NAPRTCS Study. North American Pediatric Renal Transplant Cooperative Study. Transplantation. 2000;69:1414–1419. 77. Ojo AO, Hanson JA, Wolfe RA, et al. Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients. Kidney Int. 1999; 55:1952–1960. 78. Dagher FJ, Ramos E, Erslev A, et al. Erythrocytosis after renal allotransplantation: treatment by removal of the native kidneys. South Med J. 1980;73:940–942. 79. Wickre CG, Norman DJ, Bennison A, et al. Postrenal transplant erythrocytosis: a review of 53 patients. Kidney Int. 1983;23:731–737. 80. Atzmony L, Halutz O, Avidor B, et al. Incidence of cytomegalovirusassociated thrombosis and its risk factors: a case-control study. Thromb Res. 2010;126:e439–e443. 81. Belli L, De Carlis L, Belli LS, et al. Thromboendarterectomy (TEA) in the recipient as a major risk of arterial complication after kidney transplantation. Int Angiol. 1989;8:206–209. 82. Englesbe MJ, Punch JD, Armstrong DR, et al. Single-center study of technical graft loss in 714 consecutive renal transplants. Transplantation. 2004;78:623–626.
www.transplantjournal.com
83. Orlando G, Gravante G, D'Angelo M, et al. A renal graft with six arteries and double pelvis. Transpl Int. 2008;21:609–611. 84. Amézquita Y, Méndez C, Fernández A, et al. Risk factors for early renal graft thrombosis: a case-controlled study in grafts from the same donor. Transplant Proc. 2008;40:2891–2893. 85. Osman Y, Shokeir A, Ali-el-Dein B, et al. Vascular complications after live donor renal transplantation: study of risk factors and effects on graft and patient survival. J Urol. 2003;169:859–862. 86. Penny MJ, Nankivell BJ, Disney AP, et al. Renal graft thrombosis. A survey of 134 consecutive cases. Transplantation. 1994;58:565–569. 87. Nagra A, Trompeter RS, Fernando ON, et al. The effect of heparin on graft thrombosis in pediatric renal allografts. Pediatr Nephrol. 2004;19: 531–535. 88. Bakir N, Sluiter WJ, Ploeg RJ, et al. Primary renal graft thrombosis. Nephrol Dial Transplant. 1996;11:140–147. 89. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant. 2011;11:2279–2296. 90. Ghisdal L, Broeders N, Wissing KM, et al. Thrombophilic factors in Stage V chronic kidney disease patients are largely corrected by renal transplantation. Nephrol Dial Transplant. 2011;26:2700–2705. 91. 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. 92. Esfandiar N, Otukesh H, Sharifian M, et al. Protective effect of heparin and aspirin against vascular thrombosis in pediatric kidney transplants. Iran J Kidney Dis. 2012;6:141–145. 93. Murphy GJ, Taha R, Windmill DC, et al. Influence of aspirin on early allograft thrombosis and chronic allograft nephropathy following renal transplantation. Br J Surg. 2001;88:261–266. 94. Ghisdal L, Broeders N, Wissing KM, et al. Thrombophilic factors do not predict outcomes in renal transplant recipients under prophylactic acetylsalicylic acid. Am J Transplant. 2010;10:99–105. 95. Kranz B, Vester U, Nadalin S, et al. Outcome after kidney transplantation in children with thrombotic risk factors. Pediatr Transplant. 2006;10: 788–793. 96. Friedman GS, Meier-Kriesche HU, Kaplan B, et al. Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis. Transplantation. 2001;72: 1073–1078. 97. Alakulppi NS, Kyllönen LE, Partanen J, et al. Lack of association between thrombosis-associated and cytokine candidate gene polymorphisms and acute rejection or vascular complications after kidney transplantation. Nephrol Dial Transplant. 2008;23:364–368. 98. Matas AJ, Humar A, Gillingham KJ, et al. Five preventable causes of kidney graft loss in the 1990s: a single-center analysis. Kidney Int. 2002;62: 704–714. 99. Alkhunaizi AM, Olyaei AJ, Barry JM, et al. Efficacy and safety of low molecular weight heparin in renal transplantation. Transplantation. 1998;66: 533–534. 100. Broyer M, Gagnadoux MF, Sierro A, et al. Prevention of vascular thromboses after renal transplantation using low molecular weight heparin. Ann Pediatr. 1991;38:397–399.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
