Hypercoagulable state and graft rejection—is there a link?

Stefan Heidenreich1, Ulricke Nowak-Göttl2 and Christian August3

1 Departments of Medicine, 2 Pediatrics and 3 Pathology, University of Münster, Münster, Germany

Correspondence and offprint requests to: Stefan Heidenreich, MD, Department of Medicine D, University Münster Medical School, Albert-Schweitzer-Str. 33, D-48129 Münster, Germany.

Keywords: acute rejection; coagulation; haemostasis; thrombophilia; transplant

Introduction

Although renal allografting has become a standard procedure in transplant medicine, 10–20% of kidney grafts are lost during the first year. Acute rejection episodes are the most common cause of early transplant failure, but early graft loss due to venous or arterial thrombosis is also a well-known complication with an incidence of 1–5% [1]. More drastically, in paediatric renal transplantation vascular thrombosis is still a major issue accounting for about 12% of failed transplants and 20% of failed repeat transplants [2]. Since genetic prothrombotic risk factors have been shown to play a major role in the occurrence of various thromboembolic diseases, the relevance of hypercoagulable states in the setting of organ transplantation has attracted attention as well.

The first patient with inherited thrombophilia caused by antithrombin (AT) deficiency was described in 1965. In the 1980s, knowledge about thrombotic disorders was extended by the identification of prothrombotic risk factors within the protein C (PC) pathway, i.e. PC deficiency or deficiency of its cofactor protein S (PS) [3]. In 1993 a large Swedish group of patients with venous thrombosis was studied. It was observed that in these patients activated factor Va was resistant against the anticoagulant action of activated PC (APC) [4]. The basis for the APC resistance observed in the Swedish patients was a single point mutation in the factor V gene with an Arg to Gln transition at position 506 [5]. This so-called factor V Leiden mutation, first described by Bertina et al. in its heterozygous state, is the most frequent genetic prothrombotic risk factor with a prevalence of approximately 6% in Caucasian populations. A deficiency of the natural anticoagulants AT, PC and PS has been mainly associated with thrombosis of deep veins of the legs; besides its established role for venous thromboembolism the factor V Leiden mutation has also been discussed in association with cryptogenic stroke or myocardial infarciton in young adults. Recently, a further variant in the prothrombin gene located at position G20210A has been described by Poort et al. in adult patients with venous thrombosis [6]. Polymorphisms encoding for the genes of fibrinogen or factor VII have also been discussed in connection with arterial vascular accidents. Furthermore, homocystinuria and elevated fasting homocysteine concentrations associated with a thermolabile variant of the gene encoding for methylenetetrahydrofolate reductase (MTHFR) at position C677T, are well documented prothrombotic risk factors in arterial vascular disease, i.e. myocardial infarction or stroke [7].

Prothrombotic defects in chronic renal failure

Patients with uraemia or on maintenance haemodialysis are endangered by haemorrhage as well as by thromboembolism. A bleeding diathesis of uraemic patients had been observed a long time before renal replacement modalities were available. Typical manifestations are ecchymosis, epistaxis or purpura. The coagulation defect has been attributed to vascular, endothelial and platelet abnormalities. Bleeding becomes a major problem in the setting of dialysis inadequacy, or is due to overdosage of heparin.

Patients with chronic renal insufficiency are mainly burdened by a substantial mortality and morbidity as a consequence of thromboembolic disease [8]. The prothrombotic state of uraemia presents as venous thromboembolism, vascular access thrombosis, skin necrosis or atherothrombotic disease [9]. Laboratory studies have indicated a variety of haemostasis abnormalities in uraemia explaining hypercoagulation and contributing to thrombotic disease, such as high plasma levels of fibrinogen, von Willebrand factor (vWF), factor VII acitvity, factor VIII and XIII. On the other hand, low plasma concentrations of several anticoagulatory compounds have been found such as AT, thrombomodulin, PC and PS [10]. In renal patients, deficiency of AT may be caused by various mutations or be acquired as a consequence of a pronounced proteinuria. This well-established abnormality may lead to venous thrombosis, particularly of the renal veins.

Thrombophilia as a consequence of immunosuppression or virus infection

Deep vein and renal vein thrombosis in the first weeks post transplantation are quite frequently observed in patients receiving a kidney allograft. Histological evidence of a hypercoagulable state, e.g. glomerular capillary thrombus formation or thrombotic microangiopathy, have been reported in renal allograft biopsies in the early days of kidney transplantation [11]. It has been shown that surgical stress and anaesthesia as well as the type of immunosuppressive regimen were responsible for hypercoagulation and thrombotic complications. When the monoclonal antibody OKT3 was used as induction therapy, graft thromboses, microangiopathic haemolysis and glomerular capillary occlusion have been described in conjunction with systemic procoagulant activation [12]. However, most of these studies used high OKT3 doses of 10 mg/day. Generally OKT3 induction therapy is no longer recommended today. More importantly, immunosuppression with cyclosporin A and cyclosporin A toxicity is associated with an imbalance of haemostasis and thrombotic diathesis in renal transplant patients. In a retrospective study on 90 transplant patients treated with cyclosporin A, Vanrenterghem noted a high incidence of thrombotic complications, particularly pulmonary embolism, compared to a group of patients with cyclosporin free immunosuppression [13]. When transplant patients on cyclosporin A were compared with healthy volunteers, examination of the haemostasis system revealed evidence of impaired fibrinolysis and endothelial damage with an enhanced plasminogen activator inhibitor (PAI) and vWF, and reduced tissue-type plasminogen activator activity [14]. Recent in vitro experiments have shown that cyclosporin A also enhances platelet aggregation by affecting the prostanoid metabolism and endothelial NO generation.

On the other hand, further studies concerning transplant patients on cyclosporin A therapy pointed to inhibition of monocytic tissue factor expression, i.e. the initiator of the extrinsic pathway of blood coagulation [15]. Apparently immunosuppressive drugs, particularly cyclosporin A, up- or down-regulate different procoagulant and anticoagulant factors in a distinct and specific fashion. Reduction of immunosuppression per se is not a useful measure to counteract hypercoagulation in allograft recipients.

Cytomegalovirus (CMV) infection is a notorious complication after organ transplantation that is responsible for high morbidity [16]. Injury of the endothelial cell layer by direct viral attack can provoke hypercoagulable states. Recently, it could be shown that CMV and herpes simplex virus type 1 and 2 can initiate thrombin generation by providing viral phospholipids into the prothrombinase complex. Also, tissue factor antigen could be demonstrated locally on herpes viruses [17]. This finding provides new arguments that vascular pathology may be mediated by viruses.

Renal transplant loss and rejection—links to prothrombotic risk factors

Since chronic renal failure and renal transplantation are associated with a high risk of thrombosis and accelerated arteriosclerosis, the implications of the factor V Leiden mutation for thrombotic complications were first investigated in 300 kidney allograft recipients by the Oxford transplant group [18]. The prevalence of this genetic thrombophilic risk factor was 6%, and heterozygous carriers had a significantly increased risk of developing venous thrombosis including primary graft thrombosis (39 vs 15% in patients without the mutation). Since patients with the factor V Leiden mutation did not have a higher incidence of arterial thrombosis, it was suggested that other acquired or genetic prothrombotic risk factors must contribute to the development of this complication. The Munich transplant group calculated 1-year graft survival rates of 132 renal transplant recipients depending on the presence of one of the following thrombophilic risk factors: factor V Leiden mutation, PC or PS deficiency, and lupus anticoagulant [19]. Thrombophilia was detected in 13.6% of recruited patients. They had a 3.5-fold increased risk for graft loss at 1 year. These results must be interpreted with caution because no histological data were presented to document which complications led to early graft loss.

In a retrospective survey our group studied the significance of the prothrombotic risk factors factor V Leiden mutation, PC, PS as well as AT on the occurrence of acute rejections within the first 6 months post transplantation [20]. The prevalence of acute rejection was significantly higher in patients with a thrombophilic disorder as compared with patients without thrombophilia (71 vs 41%). In eight of the 15 patients with an acute rejection and a hypercoagulable state, rejection was confirmed by histomorphological evaluation which demonstrated acute vascular rejection in four patients. In two further biopsies vascular involvement was suspected on the basis of occlusive vasculopathy and glomerulitis. Figure 1Go gives an example of a transplant biopsy section showing acute vascular rejection in conjunction with vascular clotting and thrombus formation. The corresponding patient had a heterozygous factor V Leiden mutation, unknown so far, and lost this allograft 6 weeks post transplantation.



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Fig. 1. Renal transplant biopsy section of a patient with factor V Leiden mutation showing acute vascular rejection with endothelialitis and lymphocytic infiltration of the intimal wall as well as vascular obliteration by a fibrinoid thrombus. Periodic acid-Schiff stain; magnification: x200.

 
These previous studies suggest that genetic thrombophilia might act together with acquired procoagulant risk factors, e.g. as a consequence of immunosuppression or endothelial injury secondary to the surgical anastomosis, to induce venous graft thrombosis or even arterial occlusion. As to the putative link between prothrombotic states and acute rejection, one might speculate that vascular clotting is the first event to occur, causing subsequently lymphocyte activation and adherence to the affected endothelium. In our view, a sequence of events in the opposite direction is more likely. Incipient rejections, clinically subthreshold, may be aggravated by a primary haemostasis defect.

Conclusions and perspectives

Haemostasis abnormalities are well-established clinical problems in renal patients. The focus of interest has recently shifted from bleeding diathesis to hypercoagulable states. Hypercoagulability can be due to congenital and acquired defects. It is associated with the risk of venous thrombosis and atherothrombotic disease. It is known that distinct prothrombotic risk factors affect haemostasis in a characteristic vascular-bed-specific fashion. This means that heart, brain or peripheral vascular trees are specifically targeted by different hypercoagulable defects [21].

Recently, hypercoagulable states have been recognized as risk factors not only of graft thrombosis but also of early renal allograft rejection. Some issues concerning coagulatory abnormalities in graft recipients require clarification.

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