The case of a diabetic patient who developed portal vein thrombosis after islet transplantation, leading to the diagnosis of Factor V Leiden (FVL) mutation, was recently reported by Brennan et al. (1). Because of the high prevalence of this mutation in the general population, the authors propose systematic screening of prospective islet transplant recipients for thrombophilia, and optimized islet preparation (high purity and low volume) in case of positive findings. Herein we present the case of a 30-year-old white female patient with a 27-year history of type 1 diabetes, and a heterozygous FVL mutation diagnosed after a transient ischemic attack in December 1998. The patient underwent simultaneous kidney-pancreas transplantation in April 1999. On postoperative day 7, the pancreas was removed due to complete thrombosis of the artery and vein. Acenocoumarol anticoagulation was introduced. She received two intraportal islet infusions by a percutaneous approach in 2003 (Table 1). Anticoagulation was reversed with 2,400 units of a preparation of coagulation factors (Prothromplex; Baxter, Volketswil, Switzerland) just prior to islet infusion. Full-dose intravenous heparin therapy was started immediately upon completion of the procedure.TABLE 1: Characteristics of islet infusionsNo adverse event occurred after the first infusion. On the day after the second infusion, a mild intraperitoneal hematoma was seen on routine ultrasound. Her hemoglobin level decreased only slightly from 8.2 mg/dl preoperatively to 7.8 mg/dl. She was transfused with 3 units of packed red blood cells. Heparin infusion was switched to a prophylactic dose and bleeding stopped spontaneously. Liver ultrasound follow-up revealed no portal vein thrombosis. Acenocoumarol was resumed on postoperative day 7. Patient became insulin-independent shortly after the second infusion. As of October 2004, she was still free of insulin with normalized HbA1c (6%) and oral glucose tolerance test. Heterozygosity for FVL is a common occurrence in the general population (2). In case of islet transplantation, the further issue of hypercoagulability associated with type 1 diabetes must also be considered (3). In the case of portal vein thrombosis reported by Brennan et al., two additional risk factors were present. First, the patient was on oral contraception. This type of birth control should be discontinued in FVL patients because of the increased risk of thrombosis (4). Second, the islet preparation contained a large tissue volume (9 ml) with a purity at the limit of release criteria (30%). A large tissue volume is the consequence of the addition to the final preparation of the islet fractions of lower purity. This big expansion in total volume is accompanied by only a marginal increase in transplanted islet mass, and is thought to increase the risk of portal thrombosis. In our patient, the second preparation contained 6 ml of tissue with low-purity fractions corresponding to half the volume of the final preparation and 15% of the infused islets. In our experience, although tissue volume was strongly correlated with the rise in portal pressure during islet transplantation, we could not find a relationship between tissue volume infused and occurrence of portal vein thrombosis in a series of 93 intraportal islet infusions (5). There are no clear guidelines as to the need for long-term anticoagulation in the presence of thrombophilic disorders. The discovery of a thrombophilic disorder during a screening workup, in the absence of spontaneous thrombotic events, does not require indefinite anticoagulation as a rule. However, there is a consensus in recommending vigorous anticoagulation in high-risk settings, such as intraportal islet infusion (6). Immediate anticoagulation carries a higher risk of bleeding, which could be prevented by performing the intraportal infusion through an open surgical approach at the cost of losing the benefits of a minimally invasive procedure (5). This case report shows that FVL per se is not an absolute contraindication for islet transplantation. It requires tight coagulation control in order to balance the risks of developing portal vein thrombosis or intraperitoneal bleeding, which are the two most common complications of percutaneous intraportal islet infusion. In accordance with Brennan et al. (1), we recommend that all candidates for islet transplantation be screened for thrombophilia and all thrombogenic stimuli (oral contraceptives, smoking) be discontinued whenever possible. Effective anticoagulation by intravenous heparin should be started immediately upon completion of the procedure, at the risk of developing intraperitoneal bleeding. Infusing the islet preparation with an open approach should be considered. Axel Andres Domenico Bosco Philippe Morel Christian Toso Reto Baertschiger Pietro E. Majno Leo Buhler Thierry Berney Cell Isolation and Transplantation Center Department of Surgery Geneva University Hospitals Geneva, Switzerland
Up to now, liver resections have been the initial treatment of almost all cancers and benign tumors limited to a liver lobe. This retrospective review assesses the results of a consecutive series of 113 major elective hepatic resections during a ten-year period. Major hepatectomy was defined by the resection of at least 3 Couinaud segments. Mean age was 52 years (20 to 79 years). There were 62 women and 51 men. 35 resections were performed for colorectal metastases, 22 for a benign tumor, 20 for non-colorectal metastases, 11 for hydatid disease, 10 for hepatocarcinoma, 7 for cholangiocarcinoma and 8 for other indications. The resections performed were 86 right hepatectomies with 18 extended right hepatectomies, 24 left hepatectomies with 4 extended left hepatectomies and 3 trisegmentectomies. Total vascular exclusion was used in 22 patients (19%). Mortality rate was zero. Significant morbidity was encountered in 24 patients (21%). These results suggest that the mortality rate may be independent of the extent of liver resection, provided that hepatic function is normal and preoperative selection adequate. With improving surgical management and techniques, and the use of intra-operative sonography, extensive liver surgery can now be performed with a very low mortality rate.
The ability to transplant pig organs into humans would resolve the current crisis in the supply of cadaveric human organs for the treatment of end stage disease. Several immunologic barriers need to be overcome if pig-to-primate transplantation is to be successful. The presence of preformed antibodies in humans, apes and Old World monkeys directed against galactose epitopes on pig vascular endothelium provides the major barrier, as binding of antibody to antigen leads to graft destruction by complement activation and other mechanisms. Hyperacute rejection can result from the action of complement. If this is prevented, delayed antibody-mediated rejection develops, which can be associated with a state of consumptive coagulopathy (disseminated intravascular coagulation, DIC). Efforts being made to overcome antibody-mediated rejection include depletion of antibody by extracorporeal immunoadsorption, prevention of an induced antibody response by co-stimulatory blockade, B-cell and/or plasma cell depletion, depletion or inhibition of complement, or the use of organs from pigs transgenic for a human complement regulatory protein, such as hDAF. The ultimate solution would be the induction of both B- and T-cell tolerance to the transplanted pig organ, which is being explored by attempting to induce haematopoietic cell chimerism. One complication of this is a thrombotic microangiopathy, similar to thrombotic thrombocytopenic purpura. The many and diverse roles in which pharmacotherapy is involved in attempts to overcome the barriers of xenotransplantation are reviewed and current progress, particularly in our own laboratory, is discussed.
Background: Recent data have suggested that a population of CD4+
CD25high T cells, phenotypically characterized by the expression of
CD45RO and CD127, is significantly expanded in stable liver and
kidney transplant recipients and represents alloreactive T cells. We
analyzed this putative new alloreactive cellular marker in various
groups of kidney transplant recipients.
Patients and methods: Flow cytometry was used to analyze the
expression of CD25, CD45RO and CD127 on peripheral CD4+ T cells.
Of 73 kidney recipients, 59 had a stable graft function under standard
immunosuppressive therapy (IS), 5 had biopsy-proven chronic
humoral rejection (CHR), 8 were stable under minimal IS and one was
an operationally tolerant patient who had discontinued IS for more
than 3 years. Sixty-six healthy subjects (HS) were studied as controls.
Results: Overall, the alloreactive T cell population was found to be
significantly increased in the 73 kidney recipients (mean ± SE: 15.03 ±
1.04% of CD4+ CD25high T cells) compared to HS (5.93 ± 0.39%)
(p <0.001). In the 5 patients with CHR, this population was highly
expanded (31.33 ± 4.16%), whereas it was comparable to HS in the
8 stable recipients receiving minimal IS (6.12 ± 0.86%), in 4 patients
who had been switched to sirolimus (4.21 ± 0.53%) as well as in
the unique tolerant recipient (4.69%). Intermediate levels (15.84 ±
0.93%) were found in the 55 recipients with stable graft function
on standard CNI-based IS. Regulatory T cells, defined as CD4+
CD25high FoxP3+ CD127low, were found to be significantly reduced
in all recipients except in those with minimal or no IS, and this
reduction was particularly striking in recipients with CHR.
Conclusion: After kidney transplantation, an alloreactive T cell
population was found to be significantly expanded and it correlates
with the clinical status of the recipients. Interestingly, in stable
patients with minimal (or no) IS as well as in patients on sirolimus,
alloreactive T cells were comparable the healthy controls. Measuring
circulating CD4+ CD25high CD45RO+ CD127high T cells may
become a useful monitoring tool after transplantation.
Background and Objectives Loss of liver tissue leading to impairment of liver function represents a major cause of mortality. Understanding the mechanism of liver regeneration and developing therapies to sustain liver regeneration are of high therapeutic relevance. In this regard, platelets are considered as potential candidates for stimulating liver regeneration. Methods We aim to review the most recent evidence regarding the role of platelets in liver regeneration. Results Platelets stimulate liver regeneration in animal models of liver resection. In humans, platelets are independent predictors of postoperative mortality, liver function and volume recovery. One proposed mechanism by which platelets stimulate liver regeneration relies on their direct effect on hepatocytes. Following partial hepatectomy, platelets accumulate in the residual liver and release their granule content. Platelet‐containing molecules, such as HGF , VEGF , IGF ‐1 and serotonin, stimulate hepatocyte proliferation. A putative additional mechanism involves the transfer of platelet mRNA to hepatocytes following platelet internalization. Recent studies have suggested that the effect of platelets relies on their interactions with LSEC . Platelets induce the secretion of IL ‐6 from LSEC , a strong initiator of hepatocyte proliferation. Additionally, platelets convey molecules that may impact LSEC function and, by extension, liver regeneration. Platelets potentially interact with Kupffer cells, but the effect of that interaction on liver regeneration remains to be determined. Conclusion Platelets stimulate liver regeneration. Several mechanisms seem to be involved, acting on the level of hepatocytes, LSEC and potentially Kupffer cells. Identification of the platelet‐molecule(s) involved may lead to targeted therapies for patients with impairment of liver function.
