tacrolimus and Thrombosis

One of the key players in both hemostasis and thrombosis is von Willebrand factor (vWF), which demonstrates a duality between these two processes. Thrombus is structured by numerous elements, including endothelial cells, platelets, plasma proteins and shear stress alteration. In circulation, once a vessel wall is injured, collagen is exposed and platelets attach to the site of injury. Accordingly, vWF mediates adherence of platelets to the damaged vessel wall by binding both to the collagen and platelet receptor. A growing body of data also indicates a role for neutrophil extracellular traps (NETs) in human thrombosis as scaffolds for vWF, promoting thrombosis. VWF also mediates the protection of factor VIII, a main cofactor of the intrinsic clotting pathway. Since vWF plays a critical role in both thrombotic and bleeding events, a decreased plasma level of this factor may point to a bleeding disorder, while an elevated plasma level may predict occurrence of thrombosis. Since thrombotic events are the foremost cause of death, inhibiting the vWF activity would be a novel prophylaxis to reduce these events. Though, accumulated data have made vWF a promising focus for research on cardiovascular diseases (CVD). This chapter, however, aims to clarify the role of vWF in thrombus formation and pathogenesis of thrombosis.

Topics: ADAMTS13 Protein; Blood Platelets; Blood Vessels; Extracellular Traps; Factor VIII; Fibrinolytic Agents; Gene Expression Regulation; Hemostasis; Humans; Plasma Exchange; Platelet Adhesiveness; Purpura, Thrombotic Thrombocytopenic; Receptors, Collagen; Signal Transduction; Tacrolimus; Thrombosis; von Willebrand Factor

FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication.. We report two cases of FK506-associated TMA and review the 19 previous reported cases.. From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported.. TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patient's death.

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney; Male; Tacrolimus; Thrombosis

The aim of this multicentre, non-randomised trial was to evaluate the safety and efficacy at 180+/-14 days of a pimecrolimus eluting coronary stent based on a cobalt-chromium platform and a poly-L-lactic acid (PLLA) bioresorbable polymer.. Sixty-one patients, with single de novo coronary lesions <14 mm in length and a reference vessel diameter of 3.0 to 3.5 mm, were enrolled in five centres (Germany and Belgium). Angiography and IVUS were performed at baseline, post-procedure and 180+/-14 days later. The primary endpoint was a composite of major adverse cardiac events (MACE) at 180+/-14 days and expected to be below 20%. Patients had single vessel disease in 59%, 2-vessel disease in 28% and 3-vessel disease in 13% of cases. MACE rate at 180+/-14 days was 18.0%. Binary in-stent restenosis was 32.7% due to in-stent late lumen loss of 1.11+/-0.65 mm by QCA. Stent thrombosis rate at 30+/-7 and 180+/-14 days was 1.6% and 3.3%, respectively. Overall TLR rate at 30+/-7, 180+/-14 days and 12+/-1 months was 1.6%, 27.9% and 32.8% respectively.. The primary endpoint was met at 180+/-14 days. However, the anti-restenotic effect of the pimecrolimus eluting stent did not reach levels similar to clinically established DES.

Topics: Aged; Angioplasty, Balloon, Coronary; Belgium; Cardiovascular Agents; Chromium Alloys; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Germany; Humans; Lactic Acid; Male; Middle Aged; Myocardial Infarction; Polyesters; Polymers; Prospective Studies; Prosthesis Design; Severity of Illness Index; Tacrolimus; Thrombosis; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Subclinical inflammation is related to adverse events in patients with coronary artery disease. In the present study, we determined the changes in hemostatic parameters and inflammatory markers in a large cohort of dyslipidemic cardiac transplant recipients compared with dyslipidemic healthy controls, and the effect of cyclosporin microemulsion (CsA) vs. tacrolimus immunoprophylaxis on these parameters.. Stable cardiac transplant recipients (n=129) aged 56.7+/-10.1 years, 79+/-42 months postcardiac transplantation, and 26 mildly dyslipidemic healthy control subjects had serum measurements for lipids and lipoproteins, hemostatic parameters, and selected inflammatory markers. Transplant recipients were randomized to either continuation of CsA maintenance or conversion to tacrolimus immunoprophylaxis and were reassessed after six months.. CsA-maintained cardiac transplant recipients exhibited a significant elevation in Factor VIII, Von Willebrand factor, fibrinogen and PAI-I compared with healthy control subjects (all P<0.05). Similarly, cardiac transplant patients yielded a significantly elevated C-reactive protein (CRP) (4.11+/-6.25 [transplant group (TX)] vs. 2.09+/-2.21 mg/L [control group (CTL)]; P=0.0195), and homocysteine (19.2+/-8.8 [TX] vs. 9.70+/-2.45 microM [CTL]; P<0.001). VCAM, ICAM, E- and P-selectins were also significantly higher in transplant patients than in controls (all P<0.05). The conversion from CsA to tacrolimus resulted in a significant decrease in uric acid, total- and LDL-cholesterol, apolipoprotein B, creatinine, and homocysteine levels (all P<0.05).. Stable long-term CsA-maintained cardiac transplant patients exhibit a significant and general increase in hemostatic parameters and markers for subclinical inflammation. Tacrolimus conversion improved the patient lipid profile and decreased serum creatinine, uric acid, and homocysteine without any significant effect on the other markers.

Topics: Adult; Aged; Biomarkers; Blood Pressure; C-Reactive Protein; Cyclosporine; Dyslipidemias; Emulsions; Heart Transplantation; Hemostasis; Humans; Immunosuppressive Agents; Inflammation; Middle Aged; Postoperative Complications; Tacrolimus; Thrombosis

Pediatric donor (PD) livers have been allocated to adult transplant recipients in certain situations despite size discrepancies. We compared data on adults (age > or = 19 years) who underwent primary liver transplantation using livers from either PDs (age < 13 years; n = 70) or adult donors (ADs; age > or = 19 years; n = 1,051). We also investigated the risk factors and effect of prolonged cholestasis on survival in the PD group. In an attempt to determine the minimal graft volume requirement, we divided the PD group into 2 subgroups based on the ratio of donor liver weight (DLW) to estimated recipient liver weight (ERLW) at 2 different cutoff values: less than 0.4 (n = 5) versus 0.4 or greater (n = 56) and less than 0.5 (n = 21) versus 0.5 or greater (n = 40). The incidence of hepatic artery thrombosis (HAT) was significantly greater in the PD group (12.9%) compared with the AD group (3.8%; P =.0003). Multivariate analysis showed that preoperative prothrombin time of 16 seconds or greater (relative risk, 3.206; P =.0115) and absence of FK506 use as a primary immunosuppressant (relative risk, 4.477; P =.0078) were independent risk factors affecting 1-year graft survival in the PD group. In the PD group, transplant recipients who developed cholestasis (total bilirubin level > or = 5 mg/dL on postoperative day 7) had longer warm (WITs) and cold ischemic times (CITs). Transplant recipients with a DLW/ERLW less than 0.4 had a trend toward a greater incidence of HAT (40%; P <.06), septicemia (60%), and decreased 1- and 5-year graft survival rates (40% and 20%; P =.08 and.07 v DLW/ERLW of 0.4 or greater, respectively). In conclusion, the use of PD livers for adult recipients was associated with a greater risk for developing HAT. The outcome of small-for-size grafts is more likely to be adversely affected by longer WITs and CITs. The safe limit of graft volume appeared to be a DLW/ERLW of 0. 4 or greater.

Topics: Adolescent; Adult; Cholestasis; Graft Survival; Hepatic Artery; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Multivariate Analysis; Organ Size; Postoperative Complications; Prothrombin Time; Risk Factors; Safety; Tacrolimus; Thrombosis; Tissue Donors

Topics: Adult; Antilymphocyte Serum; Azathioprine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Male; Microcirculation; Middle Aged; Renal Circulation; Tacrolimus; Thrombosis

Despite concerns that liver transplant (LT) recipients may be at increased risk of unfavorable outcomes from COVID-19 due the high prevalence of co-morbidities, immunosuppression and ageing, a detailed analysis of their effects in large studies is lacking.. Data from adult LT recipients with laboratory confirmed SARS-CoV2 infection were collected across Europe. All consecutive patients with symptoms were included in the analysis.. Between March 1 and June 27, 2020, data from 243 adult symptomatic cases from 36 centers and 9 countries were collected. Thirty-nine (16%) were managed as outpatients while 204 (84%) required hospitalization including admission to the ICU (39 of 204, 19.1%). Forty-nine (20.2%) patients died after a median of 13.5 (10-23) days, respiratory failure was the major cause. After multivariable Cox regression analysis, age >70 (HR, 4.16; 95% CI, 1.78-9.73) had a negative effect and tacrolimus (TAC) use (HR, 0.55; 95% CI, 0.31-0.99) had a positive independent effect on survival. The role of co-morbidities was strongly influenced by the dominant effect of age where comorbidities increased with the increasing age of the recipients. In a second model excluding age, both diabetes (HR, 1.95; 95% CI, 1.06-3.58) and chronic kidney disease (HR, 1.97; 95% CI, 1.05-3.67) emerged as associated with death CONCLUSIONS: Twenty-five percent of patients requiring hospitalization for COVID-19 died, the risk being higher in patients older than 70 and with medical co-morbidities, such as impaired renal function and diabetes. Conversely, the use of TAC was associated with a better survival thus encouraging clinicians to keep TAC at the usual dose.

Topics: Adult; Age Factors; Aged; Comorbidity; COVID-19; Female; Hospitalization; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; SARS-CoV-2; Tacrolimus; Thrombosis

Tacrolimus-associated thrombotic microangiopathy (TA-TMA) is a rare complication. TA-TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage due to thrombus. We report asymptomatic TA-TMA diagnosed by laboratory tests in pig-to-rhesus corneal xenotransplantation. Corneal transplantation had been conducted from a wild-type SNU miniature pig to a rhesus macaque. The veterinary records were retrospectively reviewed in this case. The immunosuppressive regimen consisted of rituximab, basiliximab, and IVIg as inductive therapies, and steroids with tacrolimus (0.1 mg/kg/day) as maintenance therapies. Although there were no clinical symptoms, increased levels of lactate dehydrogenase, total bilirubin, blood urea nitrogen, and creatinine and decreased levels of hemoglobin and platelet were observed in laboratory tests on Day (D) 61. Systemic TA-TMA was tentatively diagnosed. Tacrolimus was discontinued starting on D71. Dalteparin, clopidogrel bisulfate (D77-D99), and IVIg (D72) were administered as a conservative treatment. Abnormal laboratory results were reversed on D99. When low-dose tacrolimus (0.07 mg/kg/day) was re-administered on D131 to prevent rejection of the graft, TMA was detected again by laboratory tests on D161, confirming the initial diagnosis. Discontinuation of tacrolimus on D162 and re-administration of Dalteparin (D161-D196) corrected the laboratory values on D161. This report shows that in pig-to-rhesus corneal xenotransplantation, clinically asymptomatic TMA can be induced by tacrolimus, and the discontinuation of tacrolimus and administration of anticoagulant seems sufficient to correct the laboratory TMA.

Topics: Animals; Heterografts; Immunosuppressive Agents; Kidney Transplantation; Macaca mulatta; Male; Retrospective Studies; Swine; Tacrolimus; Thrombosis; Thrombotic Microangiopathies; Transplantation, Heterologous

The use of generic formulations of immunosuppressive drugs in renal transplantation has been and still is a controversial subject. The lack of clinical studies about safety and efficacy in transplant patients is one of the factors restricting the diffusion of generic drugs in the renal transplant field. Since March 2013, our transplant unit has incorporated generic tacrolimus (Adoport(®) ; Sandoz), replacing the one we were currently using (Prograf(®) ; Astellas). When carrying out our retrospective analysis comparing the two different formulations, we evaluated several clinical results: tacrolimus trough concentrations (C0) at 5-7 days; 1, 3, and 6 months post-transplantation; concentration/dose ratio at 6 months; acute rejection incidence; delayed graft function (DGF); renal function (as CKD-EPI); and proteinuria at 6 months in 120 patients (1:1 ratio of Prograf(®) versus Adoport(®) ), noticing no important differences. We also evaluated the results of protocol biopsies at 6 months in a subgroup of patients, thus verifying the safety and efficacy of this particular generic drug versus the reference product on a histological basis as well. No difference in the development of dnDSA (de novo donor-specific antibody) was found between the two groups.

Topics: Adult; Aged; Antibodies; Biopsy; Cohort Studies; Delayed Graft Function; Drug Administration Schedule; Drugs, Generic; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Patient Safety; Proteinuria; Reference Values; Retrospective Studies; Tacrolimus; Thrombosis; Tissue Donors; Treatment Outcome

Sirolimus should not be started within the first month after liver transplantation (LT) because of an increased risk of adverse outcomes. The evidence regarding everolimus is lacking but the manufacturer transposed the same warning. We aimed to evaluate the safety of everolimus started within the first month after LT.. A consecutive cohort 187 LT patients (2009-2013) with a tacrolimus-based immunosuppression was evaluated. Patients starting everolimus within the first month after LT (n = 33; 17.6%) were compared with those starting everolimus thereafter (n = 25; 13.4%) or not receiving everolimus (n = 129; 69%). The median follow-up after LT was 21 months (IQR 7-36). Prospective outcomes were evaluated by using Kaplan-Meier curves and Cox's regression.. The incidence of hepatic artery thrombosis was not significantly different in patients early treated with everolimus when compared with the remaining cohort (0% vs 9.1%; p = 0.12). Other vascular complications occurred in 9.1% of patients with early everolimus vs 7.3% in the remaining cohort (p = 0.72). No wound healing complications were detected with early everolimus. There were similar rates of incisional hernia (p = 0.31), infections (p = 0.15), renal impairment (p = 0.37), and histologically-proven acute rejection (p = 0.24) between groups. The rates of hyperlipidemia were increased with early everolimus (29.9% vs 16.5% at 3 years; p = 0.018). Graft loss and mortality rates were similar between groups (p = 0.34 and p = 0.94 respectively), after adjusting for possible confounding factors.. Everolimus combined with reduced tacrolimus proved to be safe within the first month after LT. Future trials may be allowed to implement everolimus early after LT.

Topics: Aged; Cohort Studies; Endothelial Cells; Everolimus; Female; Follow-Up Studies; Graft Rejection; Hepatic Artery; Humans; Liver Transplantation; Male; Middle Aged; Prospective Studies; Survival Analysis; Tacrolimus; Thrombosis; Treatment Outcome

Liver cell transplantation (LCT) is considered a new therapeutic strategy for the treatment of acute liver failure and inborn metabolic defects of the liver. Although minimally invasive, known safety risks of the method include portal vein thrombosis and pulmonary embolism. Since no systematic data on these potential side effects exist, we investigated the toxicological profile of repeated intraportal infusion of allogeneic liver cells in 30 rabbits under GLP conditions. Rabbit liver cells were administered once daily for 6 consecutive days at 3 different dose levels, followed by a 2-week recovery period. No test item-related mortality was observed. During cell infusion, clinical findings such as signs of apathy and hyperventilation, moderate elevations of liver enzymes ALT and AST and a slight decrease in AP were observed, all fully reversible. Cell therapy-related macroscopic and histological findings, especially in liver and lungs, were observed in animals of all dose groups. In conclusion, the liver and lungs were identified as potential toxicological target organs of intraportal allogeneic liver cell infusion. A NOAEL (no observed adverse effect level) was not defined because of findings observed also in the low-dose group. No unexpected reactions became apparent in this GLP study. Overall, LCT at total doses up to 12 % (2 % daily over 6 days) of the total liver cell count were tolerated in rabbits. Observed adverse effects are not considered critical for treatment in the intended patient populations provided that a thorough monitoring of safety relevant parameters is in place during the application procedure.

Topics: Animals; Cell Transplantation; Central Venous Catheters; Embolism; Female; Germany; Hepatocytes; Immunosuppressive Agents; Liver; Liver Transplantation; Lung; Male; Necrosis; Portal Vein; Pulmonary Embolism; Rabbits; Risk Assessment; Tacrolimus; Thrombosis; Transplantation, Homologous

De novo posttransplant thrombotic microangiopathy (TMA) is a complication of solid organ transplantation, which remains difficult to treat. In many cases, immunosuppressants and particularly calcineurin inhibitors, trigger TMA. Although withdrawing the offending drug may lead to resolution of TMA, graft and patient outcomes are poor. Specific treatments, including plasma exchange, have not gained widespread acceptance in those with fulminant disease and new approaches to the condition are urgently needed. We report a case of posttransplant de novo TMA presenting serially in association with ciclosporin, tacrolimus and sirolimus in a young recipient of a living donor kidney transplant. We describe a patient treated with belatacept, a novel CTLA4 Ig fusion protein, as ongoing maintenance immunosuppression to allow avoidance of conventional agents once associated with TMA. We report excellent early graft outcome, with no adverse events using this strategy. We suggest that belatacept may have a role in this traditionally difficult-to-treat group of patients.

Topics: Abatacept; Adult; Cyclosporine; Female; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus; Tacrolimus; Thrombosis; Tumor Necrosis Factor-alpha

Early central nervous complications (CNS) are significant after allogeneic stem cell transplantation; however, the clinical characteristics of early CNS complications have not yet been well described. The medical record of 77 patients who underwent cord blood transplantation (CBT) between March 2001 and November 2005, at 8 centers of the Nagoya Blood and Marrow Transplantation Group were retrospectively reviewed. The preparative regimen included myeloablative CBT (n = 31) or reduced-intensity (RI)-CBT (n = 46). Of the 77 patients, 10 (13%) developed early CNS complications. Causes included Cyclosporine encephalopathy (n = 5), tacrolimus encephalopathy (n = 2), thrombocytic microangiopathy (n = 1), and unknown (n = 3). The median time of onset was 19 days (range: 2-58 days). All of the 10 patients developed impaired consciousness. Seizures developed in 6 patients. Early CNS complications spontaneously subsided in 3 patients. Three patients responded to cyclosporine or tacrolimus discontinuation. The remaining 4 patients died within 30 days of developing of early CNS complications. No relationship was detected between the preparative regimen and the onset of early CNS complications, while an HLA disparity showed borderline significance (hazard ratio, 3.24; 95% confidential interval, 0.94-11.20; P = .06). Early CNS complications are a significant problem after CBT, and the clinician has to be aware of the possibility of these complications.

Topics: Adolescent; Adult; Aged; Central Nervous System Diseases; Consciousness Disorders; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Histocompatibility; Humans; Male; Middle Aged; Retrospective Studies; Seizures; Tacrolimus; Thrombosis; Transplantation Conditioning; Transplantation, Homologous; Young Adult

To report the 4-month angiographic and 6-month clinical follow-up in first-in-man study using the tacrolimus-eluting bioabsorbable polymer-coated cobalt-chromium MAHOROBA stent.. A total of 47 patients with either stable angina or unstable angina, or silent myocardial ischaemia, based on a de novo coronary stenosis that could be covered by a single 18 mm stent in a native coronary artery with a diameter between 3.0 and 3.5 mm were enrolled at three sites. The primary endpoint was in-stent late loss at 4 months. The secondary endpoints include %volume obstruction of the stents assessed by intravascular ultrasound (IVUS) at 4 months and major adverse cardiac events (MACE) at 6 months. Forty-seven patients were enrolled. Procedural success was achieved in 97.9%. At 4-month follow-up, in-stent late loss was 0.99 +/- 0.46 mm, whereas in-stent %volume obstruction in IVUS was 34.8 +/- 15.8%. At 6 months, there were no deaths, but 2 patients suffered from a myocardial infarction and 11 patients required ischaemia-driven repeat revascularization. The composite MACE rate was 23.4%.. This tacrolimus-eluting stent failed to prevent neointimal hyperplasia, despite the theoretical advantages of the tacrolimus, which has less inhibitory effects on endothelial cells than smooth muscle cells.

Topics: Absorbable Implants; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Stenosis; Drug-Eluting Stents; Feasibility Studies; Female; Humans; Hyperplasia; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus; Thrombosis; Time Factors; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

To evaluate the degree of endothelialization of the nonapposed struts located at the ostia of side branches.. Endothelialization of coronary stents has got considerable relevance because of the phenomenon of late thrombosis. Bifurcation location and incomplete stent apposition have been linked to this complication.. Domestic pigs (n = 11; weight: 25 +/- 3 kg) were anesthetized and had one stent per coronary artery implanted: one stainless steel (Tecnic), one cobalt-chromium (Chrono), and one tacrolimus-eluting stent (Janus), all of them being Carbofilm-coated (Sorin). One, three, or seven days postprocedure, the pigs were sacrificed, the hearts explanted, and longitudinal sections examined by surface electron microscopy to quantify the percentage of the strut endothelialized over the branches and in the total surface.. Forty-four side branches (25 stents) that had stent struts over their origin were evaluated. Different patterns of endothelialization were observed, from the total absence to the complete endothelialization. There were no significant differences in relation to type of stent or to the artery treated. The predictors of higher percentage of endothelialization were the ratio of metal to branch diameter (P = 0.04) and better endothelialization in the rest of the stent (P = 0.0002), only this parameter maintaining significant correlation (P = 0.03) in multivariate analysis.. Carbofilm-coated stent struts located over the origin of side branches follow the pattern of endothelialization for the rest of the stent, even in the case of tacrolimus-eluting stent.

Topics: Analysis of Variance; Animals; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Endothelium; Humans; Immunosuppressive Agents; Risk Factors; Statistics as Topic; Swine; Tacrolimus; Thrombosis

Thrombotic microangiopathy has been reported in association with calcineurin inhibitors and less frequently with sirolimus in renal transplant patients. The diagnosis of thrombotic microangiopathy is typically made by diagnostic biopsy in the setting of allograft dysfunction. The finding of thrombotic microangiopathy on surveillance biopsy without a significant elevation of baseline serum creatinine is unusual. The optimal treatment of this disorder remains controversial. Treatment strategies have included dose adjustment, drug substitution, plasmapheresis, and intravenous immunoglobulin G. We report a case of de novo thrombotic microangiopathy diagnosed by surveillance biopsy in a patient without hematologic abnormalities or elevated serum creatinine. This patient had resolution of the renal lesion following conversion from tacrolimus to sirolimus-based immunosuppression.

Topics: Adolescent; Biopsy; Capillaries; Creatinine; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Circulation; Sirolimus; Tacrolimus; Thrombosis; Treatment Outcome

Thrombotic microangiopathy (TMA) is one of the severe complications after stem cell transplantation (SCT) and is associated with graft-versus-host disease (GVHD) prophylaxis including FK506. In this study, we experimented on rats using FK506 to demonstrate the occurrence of intestinal TMA. FK506 was administrated into Wistar/ST rats intraperitoneally for 7 days. Rats were examined histopathologically after FK506 injection using light and electron microscopy and immunohistochemistry. FK506 concentrations in whole blood were measured by enzyme immunoassay. In the acute phase, hemorrhagic lesions with multifocal erosions and crypt loss were found in the small intestines of all treated rats. Capillary vessels were dilated, and a few platelet thrombi were found. Electron microscopy demonstrated degenerative swelling of endothelial cells and platelet aggregates adhering to the vessel walls. In the later phase, epithelial regenerative failure, characterized by crypt ghosts, was found in the affected mucosa. Apoptotic epithelial cells were increased in number. The extent of intestinal injury was proportional to the whole blood levels of FK506. The intestinal lesions in rats were consistent with TMA and induced by the injection of FK506 alone. Apoptotic enteropathy was also observed and similar to intestinal GVHD. In this study, we established an intestinal TMA model induced by immunosuppressant (Tacrolimus) only without irradiation.

Topics: Animals; Apoptosis; Capillaries; Disease Models, Animal; Dose-Response Relationship, Drug; Histocytochemistry; Immunosuppressive Agents; Intestinal Mucosa; Male; Peripheral Vascular Diseases; Rats; Rats, Wistar; Tacrolimus; Thrombosis

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II-IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II-IV for TMA were 8.7 (95% CI 2.0-37), 5.7 (95% CI 1.5-21), and 3.4 (95% CI 1.3-9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that high-dose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents.

Topics: Adolescent; Adult; Aged; Busulfan; Disease-Free Survival; Evaluation Studies as Topic; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Myeloablative Agonists; Retrospective Studies; Risk Factors; Tacrolimus; Thrombosis; Transplantation Conditioning; Transplantation, Homologous

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.

Topics: Animals; Animals, Genetically Modified; Anticoagulants; Antigens, CD; Factor Xa; Heart Transplantation; Heparin, Low-Molecular-Weight; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; International Normalized Ratio; Ischemia; Membrane Cofactor Protein; Membrane Glycoproteins; Microcirculation; Myocardium; Papio; Primates; Prothrombin; Sirolimus; Swine; Tacrolimus; Thrombosis; Time Factors; Transplantation, Heterologous; Treatment Outcome; Vitamin K; Warfarin

Acute overdose of tacrolimus appears to cause no or minimal adverse clinical consequences. We encountered a pediatric case who underwent liver transplantation associated with hepatic artery thrombosis (HAT), which recurred following acute tacrolimus overdose. A 10-month-old girl underwent living-related liver transplantation because of biliary atresia. To reconstruct the hepatic artery, the right gastroepiploic artery of the donor was interposed between the right hepatic artery of the recipient (2.5 mm in diameter) and the left hepatic graft artery (1 mm in diameter) under microscopy. On postoperative day 4, Doppler ultrasonography showed a remarkable reduction in hepatic arterial flow, which was consistent with HAT. The patient underwent immediate hepatic arteriography and balloon angioplasty. The stenotic sites were dilated by the procedure. Tacrolimus was infused intravenously after transplantation and the infusion rate was adjusted to achieve a target concentration of 18-22 ng/mL, which remained stable until the morning of day 6. An unexpectedly high blood concentration of tacrolimus (57.4 ng/mL) was detected at 6:00 PM on day 6, and tacrolimus was discontinued at 9:00 PM; however, the tacrolimus level reached 119.5 ng/mL at 0:00 h on day 7. While the concentration decreased to 55.2 ng/mL on the morning of day 7, the hepatic arterial flow could not be observed by Doppler ultrasonography. Emergent hepatic arteriography showed stenosis of the artery at the proximal site of the anastomosis. Balloon angioplasty was again performed and the stenotic site was successfully dilated. High level of tacrolimus exposure to the hepatic artery with injured endothelium by preceding angioplasty may have been related to the recurrence of HAT in the present case.

Topics: Blood Urea Nitrogen; Child; Cholangitis; Creatinine; Drainage; Drug Monitoring; Drug Overdose; Female; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intravenous; Liver Transplantation; Postoperative Complications; Recurrence; Tacrolimus; Thrombosis; Treatment Outcome; Ultrasonography

Calcineurin inhibitor-induced thrombotic microangiopathy (TMA) has been described in up to 14% of solid-organ transplant recipients. Sirolimus has recently been described in two reports in association with TMA. Sirolimus is known to potentiate cyclosporine-induced nephrotoxicity, but such effect has not been shown with tacrolimus. We report two intestinal transplant patients who developed TMA while on a tacrolimus and sirolimus immunosuppressive regimen. This syndrome appeared soon after institution of or increase in sirolimus dosage and improved only after this medication was discontinued.

Topics: Adult; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Intestines; Male; Microcirculation; Sirolimus; Tacrolimus; Thrombosis

Topics: Adult; Angiography; Angioplasty, Balloon; Cyclosporine; Female; Fibrinolytic Agents; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Recombinant Proteins; Renal Artery; Renal Artery Obstruction; Retreatment; Tacrolimus; Thrombosis; Tissue Plasminogen Activator

Thrombotic microangiopathy is a well-known problem in patients following renal transplantation. In postrenal transplantation, thrombotic microangiopathy is often a reflection of hemolytic uremic syndrome. We aimed to determine the causes of thrombotic microangiopathy in a population of renal transplantation recipients and discuss the literature.. We investigated the causes of thrombotic microangiopathy during a 1-year period, from June 2003 to June 2004, at the King Fahad National Guard Hospital in Riyadh, Saudi Arabia, by reviewing the slides of all transplant biopsies (n=25) performed during this interval. Pre- and posttransplant crossmatching was done when possible.. Five cases of thrombotic microangiopathy were found. Three of these cases were from the 25 transplantations performed at King Fahad National Guard Hospital, while the other 2 transplantations had been performed abroad and were referred to us for follow-up. Three cases were related to cyclosporine, and 1 case was secondary to both cyclosporine and tacrolimus. The fifth case had features of thrombotic microangiopathy related to an antiphospholipid syndrome in a patient with systemic lupus erythematosus.. In the literature, the most-frequent cause of hemolytic uremic syndrome in patients following renal transplantation is recurrence of the hemolytic uremic syndrome. Other causes include drug-related (cyclosporine, tacrolimus) toxicity, procoagulant status, and antibody-mediated rejection. We found that the most-frequent cause of thrombotic microangiopathy was drug related, secondary mainly to cyclosporine. In the current study, the frequency of thrombotic microangiopathy was similar to the percentage reported in the literature (20%).

Topics: Acute Disease; Adult; Antiphospholipid Syndrome; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Microcirculation; Middle Aged; Postoperative Period; Retrospective Studies; Tacrolimus; Thrombosis

Cyclosporine A (CSA) and tacrolimus (FK-506) are both associated with thrombotic microangiopathy (TMA) in allogeneic BMT recipients, although it is not known which drug is more likely to cause the syndrome. The optimal treatment of BMT-associated TMA is also not known.. To estimate the risks, predisposing factors, and outcomes of TMA, data were analyzed from two cohorts of BMT patients who had received CSA or FK-506 in our institution with the same clinical definition for TMA. TMA was diagnosed in 11 of 55 patients (CSA, 3 of 24; FK-506, 8 of 31).. The daily risk of developing TMA was 0.12 percent for patients receiving CSA and 0.26 percent for those receiving FK-506 (p = 0.16, chi-square). Among patients receiving FK-506, sibling donor BMT recipients were as likely to develop TMA as matched unrelated donor recipients. Serum CSA and FK-506 concentrations were not elevated above the therapeutic range in most patients with TMA. The blood urea nitrogen to serum creatinine ratio was elevated in patients with TMA. Despite daily plasmapheresis, 9 of 11 patients died without resolution of TMA; however, the causes of death were multifactorial, including GVHD. Histologic evidence for TMA was absent in 1 patient who died with persistent clinical signs attributed to microangiopathy.. In this study, a high incidence of TMA was found in patients receiving either CSA or FK-506 following BMT, with uniform diagnostic criteria and strict monitoring. Neither drug showed elevated levels in most patients with TMA. Plasmapheresis was unsuccessful in reversing most cases of TMA.

Topics: Adult; Bone Marrow Transplantation; Cyclosporine; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Plasmapheresis; Retrospective Studies; Tacrolimus; Thrombosis

Topics: Adult; Black People; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Tacrolimus; Thrombosis; Treatment Outcome

Topics: ABO Blood-Group System; Blood Group Incompatibility; Cyclosporine; Humans; Incidence; Kidney Transplantation; Microcirculation; Postoperative Complications; Prospective Studies; Tacrolimus; Thrombosis

Topics: Adult; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Recurrence; Renal Veins; Tacrolimus; Thrombosis

A woman on daclizumab developed thrombotic microangiopathy secondary to cyclosporine after a living-unrelated kidney transplant. Despite cyclosporine discontinuation, hemolysis persisted. The second dose of daclizumab was postponed 24 h, and after a maximum of two sessions of plasmapheresis (to avoid further modifications in daclizumab schedule) with plasma exchange, daclizumab was administered. Plasma infusions were prescribed until D-dimer and fibrinogen-degradation products normalized; thereafter, FK-506 was started without recurrence of the hemolytic picture and renal function restored. This observation suggests that in patients on daclizumab who develop thrombotic microangiopathy secondary to immunosuppressants, if discontinuation of the offending drug is unsuccessful, plasmapheresis with plasma exchange can be performed when the lowest levels of daclizumab exist, followed by daclizumab infusion. Plasma prescription must be continued thereafter until D-dimer and figrinogen-degradation products normalize. However, if hemolysis persists when daclizumab levels are high, plasma infusions are useful and plasmapheresis avoided. FK-506 administration did not result in recurrence of hemolysis during daclizumab induction.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers; Blood Component Transfusion; Cyclosporine; Daclizumab; Drug Therapy, Combination; Female; Fibrin Fibrinogen Degradation Products; Hemolysis; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Microcirculation; Middle Aged; Plasmapheresis; Polycystic Kidney Diseases; Tacrolimus; Thrombosis

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Therapy, Combination; Humans; Ileum; Immunoglobulin G; Immunosuppressive Agents; Infarction; Intestine, Small; Jejunum; Mesenteric Veins; Middle Aged; Retrospective Studies; Tacrolimus; Thrombosis; Transplantation, Homologous; Wounds, Gunshot

The development of thrombotic microangiopathy (TMA) associated with the use of cyclosporine has been well documented. Treatments have included discontinuation or reduction of cyclosporine dose with or without concurrent plasma exchange, plasma infusion, anticoagulation, and intravenous immunoglobulin G infusion. However, for recipients of organ transplantation, removing the inciting agent is not without the attendant risk of precipitating acute rejection and graft loss. The last decade has seen the emergence of tacrolimus as a potent immunosuppressive agent with mechanisms of action virtually identical to those of cyclosporine. As a result, switching to tacrolimus has been reported to be a viable therapeutic option in the setting of cyclosporine-induced TMA. With the more widespread application of tacrolimus in organ transplantation, tacrolimus-associated TMA has also been recognized. However, literature regarding the incidence of the recurrence of TMA in patients exposed sequentially to cyclosporine and tacrolimus is limited. We report a case of a living donor renal transplant recipient who developed cyclosporine-induced TMA that responded to the withdrawal of cyclosporine in conjunction with plasmapheresis and fresh frozen plasma replacement therapy. Introduction of tacrolimus as an alternative immunosuppressive agent resulted in the recurrence of TMA and the subsequent loss of the renal allograft. Patients who are switched from cyclosporine to tacrolimus or vice versa should be closely monitored for the signs and symptoms of recurrent TMA.

Topics: Adult; Colon; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Microcirculation; Tacrolimus; Thrombosis

The association between cyclosporine (CsA) and thrombotic microangiopathy (TMA) in renal allografts is well documented. However, predisposing factors and therapy guidelines are not adequately characterized.. We reviewed 188 patients with kidney or kidney-pancreas transplants who were treated between January 1994 and December 1996 with prednisone, CsA, or tacrolimus, and azathioprine or mycophenolate. We analyzed 50 patients who had graft biopsies: 26 with TMA and 24 with no TMA, as well as 19 patients with well-functioning grafts who never required biopsy.. TMA was observed in 26 of 188 renal graft recipients (14%). TMA was confined to the allograft kidney without any systemic evidence in 24 of the 26 patients. At the time of the diagnosis of TMA, 24 of the patients were on CsA, with 19 on the microemulsion form. Conversely, 5 of 18 control patients with no graft dysfunction were on the microemulsion form of CsA (P = 0.0026). Graft loss was seen in 8 of 26 patients with TMA. Conversion from CsA to tacrolimus resulted in a one-year salvage of graft function in 13 of 16 (81%) patients.. TMA was the cause of renal graft dysfunction in 14% of renal graft recipients and was associated with the use of the microemulsion form of CsA. Systemic signs of TMA were rare, underscoring the importance of the graft biopsy in making the diagnosis. The most successful strategy was switching from CsA to tacrolimus, with good graft function in 81% of the recipients one year after the TMA episode.

Topics: Adolescent; Adult; Case-Control Studies; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Thrombosis

Thrombotic microangiopathy is an uncommon complication of cyclosporin immunosuppression following renal transplantation. We present a 15-year-old girl who developed clinical features of acute rejection, but in whom an early biopsy revealed thrombotic microangiopathy, allowing a change to FK506 immunosuppression resulting in excellent graft recovery.

Topics: Adolescent; Biopsy; Capillaries; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Retreatment; Tacrolimus; Thrombosis

An activated coagulation system has been implicated as a potential initiating or inciting factor in the development and progression of cardiac allograft vasculopathy (CAV).. By performing ex vivo perfusion studies of blood thrombogenicity under constant rheologic conditions and with a constant substrate, we sought to determine the relative effects on the coagulation system of FK506 vs cyclosporine in patients who have undergone cardiac transplantation.. Compared with cyclosporine, FK506 significantly decreased the propensity to form thrombus; this suggests that FK506 may have a favorable impact on the development of CAV.

Topics: Blood Coagulation; Cyclosporine; Female; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Tacrolimus; Thrombosis

A murine paratopic model of intestinal transplantation was developed and used to study the immune response to allografts in normal C57BL/6 recipients (H2(b)) and C57BL/6 recipients treated with tacrolimus (1 mg/kg, Days 0-7). B6C3F1 mice (C57BL/6 x C3H/HeJ, H2(bxk)) were used as donors. The paratopic model differed from the standard heterotopic model in that continuity of the intestine graft with the recipient intestine was established by anastomosing the graft ileum to the side of the recipient jejunum. The success rate of this modified procedure was 82% (94/114). Major complications included hypovolemic shock and/or anesthetic-related deaths (8%), infection (8%), and vascular thrombosis (2%). Rejection was assessed using both clinical features (i.e., edema and closure of the stoma, mucous discharge, and a palpable mass) and histologic features (apoptosis of crypt cells, crypt destruction, lymphocytic infiltrate, and mucosal ulceration). Syngeneic grafts appeared clinically and histologically normal throughout the study period. Untreated recipients of allografts developed clinical and histologic evidence of rejection by Day 4 which progressed to severe rejection and graft destruction by Day 18. After initially developing evidence of mild to moderate graft rejection on Day 8, the severity of allograft rejection decreased significantly by Days 10 to 14 in tacrolimus-treated mice. By Day 28 evidence of moderate rejection had recurred in mice treated with an 8-day course of tacrolimus. Consistent with these observations, graft function, as assessed by maltose absorption, was impaired in rejecting allografts when compared with syngeneic grafts. Allografts in mice treated with tacrolimus demonstrated improved maltose absorption relative to allografts from untreated mice. These studies describe a modified technique for intestinal transplantation in mice and provide a detailed analysis of complications as well as an assessment of rejection and its functional consequences. Based on these results, we conclude that the paratopic model of intestinal transplantation in mice is a useful tool for studying the host immune response to intestinal allografts.

Topics: Animals; Digestive System Surgical Procedures; Graft Rejection; Immunosuppressive Agents; Intestinal Absorption; Intestine, Small; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Models, Biological; Shock; Surgical Wound Infection; Tacrolimus; Thrombosis; Transplantation, Homologous; Transplantation, Isogeneic

FK506 (Tacrolimus) recently has been shown to be an effective immunosuppressant after renal transplantation. It is associated with less hypertension, hypercholesterolemia and steroid use compared with cyclosporine. We report 10 patients on FK506 who showed fibrin thrombi within the glomerular capillaries and/or arterioles at renal allograft biopsy. These biopsies were generally performed to assess increasing serum creatinine levels; laboratory evidence of hemolytic uremic syndrome was present in one instance. Plasma or whole blood FK506 levels were elevated in eight of 10 cases. Reduction of immunosuppression led to clinical improvement or biopsy-proven resolution of thrombi in all cases. These observations suggest that FK506 may occasionally produce microvascular changes in the renal allograft. The estimated incidence of this occurrence (1%) is comparable with that reported with cyclosporine (3%).

Topics: Adult; Aged; Arterioles; Capillaries; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Care; Renal Circulation; Tacrolimus; Thrombosis

The aim of this study was to investigate the mechanism of hypertension and thromboembolic events induced by cyclosporin (CyA) and tacrolimus (FK506) in respect to their action on the serotonergic blood system. The study was carried out on healthy rats and those with experimental chronic renal failure. CyA injected into healthy and uremic rats caused an increase in serotonin (5-HT) concentration levels in whole blood and platelets. Concomitantly a rise in systolic blood pressure was observed. Platelet aggregation values were significantly higher in uremic rats given CyA. FK506 had no influence on 5-HT blood content, blood pressure or platelet aggregation values. It is concluded that 5-HT may play a role in the development of hypertension and thrombotic events caused by CyA. Furthermore, lower incidence of these complications during FK506 treatment could be the result of this drug's limited effect on the serotonergic blood system.

Topics: Animals; Cyclosporine; Hypertension; Immunosuppressive Agents; Male; Rats; Rats, Wistar; Serotonin; Tacrolimus; Thrombosis; Uremia

Topics: Animals; Arterial Occlusive Diseases; Cyclosporine; Disease Models, Animal; Male; Platelet Aggregation; Rats; Rats, Wistar; Tacrolimus; Thrombin; Thrombosis

We investigated the effect of the potent immunosuppressive agent, FK506, on experimental glomerular thrombosis in rats by combined injections of nephrotoxic serum (NTS) and lipopolysaccharide (LPS). Either FK506 or placebo was administered intramuscularly three hours prior to injection of NTS that was followed one hour later by LPS. Rats were killed five hours after the LPS injection. Compared with placebo, FK506 pretreatment significantly reduced thrombosis formation, in a dose-dependent manner. FK506 also reduced proteinuria and the rise of serum creatinine level. Early infiltration of polymorphonuclear leukocytes into the glomeruli after LPS injection was significantly suppressed in the FK506 group compared with the placebo group. We also measured serum tumor necrosis factor (TNF) activity by using an L929 fibroblast cytotoxicity assay. Peak serum TNF activity was observed one hour after LPS injection, and FK506 significantly suppressed the elevation. Thrombosis was also developed in athymic nude rats, suggesting thrombosis formation is T cell independent. These data suggest that the FK506 has inhibitory effects on non-lymphocytes and possesses an anti-inflammatory effect in vivo.

Topics: Acute Disease; Animals; Basement Membrane; Dose-Response Relationship, Immunologic; Immunoglobulins; Kidney Glomerulus; Lipopolysaccharides; Male; Rabbits; Rats; Rats, Wistar; Tacrolimus; Thrombosis; Tumor Necrosis Factor-alpha

Topics: Adult; Female; Humans; Hypertension, Renal; Kidney; Kidney Diseases; Liver Failure; Liver Transplantation; Renal Dialysis; Tacrolimus; Thrombosis

A step-wise method of freezing cutaneous soft tissue containing vessels to -196 degrees C for permanent preservation was developed. The methods of embryo cryopreservation were modified for soft-tissue preservation. Cutaneous tissue obtained from the abdominal wall of a Lewis rat was preserved for more than 3 weeks by this method and was then transplanted to a Brown Norway rat with the largest difference in major histocompatibility complex. Rejection reaction against the epidermal layer was markedly delayed, followed by a decrease in antigenicity of the dermis, with survival of the majority of the tissue for more than 6 months. A concept of artificial skin was formed based on these experimental results. A skin flap from the abdominal wall with a vascular pedicle consisting of the femoral artery and vein was similarly preserved and transplanted by vascular anastomosis. This transplant was made viable over a long period through the additional use of an immunosuppressant. Replantation of a rat hindleg also was successfully accomplished by using a skin flap from the abdominal wall with a vascular pedicle consisting of the femoral artery and vein, which had been cryopreserved for more than 3 weeks. These results with 65 pieces in five different treatment groups indicate the reliability of this method of preservation in maintaining the tissue in a state adequate for transfer without loss of viability over a long period. The applicability of this method of allograft preservation to the field of free-tissue transfer combined with microsurgical technique may introduce a new concept to the field of reconstructive surgery in the future. According to the results of the present experiment, the great potential for clinical application is described for the deepithelialized cryopreserved allocutaneous flap transfer.

Topics: Abdominal Muscles; Anastomosis, Surgical; Animals; Blood Vessels; Cryopreservation; Femoral Artery; Femoral Vein; Glycerol; Graft Rejection; Graft Survival; Hindlimb; Male; Microsurgery; Rats; Rats, Inbred Lew; Skin; Skin Transplantation; Surgical Flaps; Tacrolimus; Thrombosis; Time Factors; Tissue Preservation; Transplantation, Heterologous

Topics: Animals; Anti-Bacterial Agents; Body Weight; Dogs; Duodenum; Graft Rejection; Immunosuppressive Agents; Injections, Intramuscular; Injections, Intravenous; Pancreas Transplantation; Postoperative Complications; Tacrolimus; Thrombosis; Transplantation, Homologous