Histological evaluation of ischemic alterations in donors after cardiac death: A useful tool to predict post-transplant renal function.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

Donation after circulatory death and liver transplantation: a cohort study.

Donations after circulatory death (DCD) are still challenging in Italy because of prolonged ischemia time (tWIT) due to the law and logistical issues. This cohort study was primarily aimed at assessing the association between successful transplantation and DCD types in the North Italy Transplant program. Adjusted risk ratios (RR) and 95% confidence intervals (CIs) for type III versus type II DCD were estimated using a Poisson regression model with a robust error variance. All consecutive DCD between 2008 and 2020 were included. Among 142 DCD, 102 were eligible for liver donation, and 96 were proposed: 68/69 (99%) and 28/33 (85%) type III and II DCD, respectively. Sixty-nine livers were recovered, 51/68 (75%) from type III and 18/28 (64%) from type II DCD, respectively (RR: 1.18; 95% CI: 0.87-1.60). After ex-vivo perfusion, 50/68 (74%) and 14/28 (50%) livers from type III and type II DCD were transplanted (RR: 1.49; 95% CI: 1.01-2.19). The estimate decreased after further controlling for tWIT (RR: 1.11; 95% CI: 0.55-2.24). Five patients (7.8%) experienced a PNF, 3/50 and 2/14 from type III and type II DCD, respectively. Type III DCD livers were more likely to be transplanted than type II. Warm ischemia time might explain this difference.

Rationale and design of two prospective, multicenter, observational studies on reproductive outcome in women with recurrent failures after spontaneous or assisted conception: OTTILIA and FIRST registries.

BACKGROUND: Spontaneous pregnancy loss and implantation failure after assisted reproductive technologies (ART) are very common occurrences. Although 50-60% of all cases remains unexplained, various predisposing factors, including thrombophilias, have been identified. Thus, the potential benefit of a prophylaxis with low-molecular-weight heparins in improving outcomes has been often investigated over the years. However, the majority of studies are observational and results from randomized clinical trials (RCTs) are inconclusive, probably due to heterogeneity and limited sample size. To cover these unmet needs and to have further data mainly based on the real-life clinical management, we designed these multicenter registries. METHODS: OTTILIA (Observational sTudy on antiThrombotic prevention in thrombophILIA and pregnancy loss) and FIRST (recurrent Failures in assIsted Reproductive Techniques) registries are two prospective, multicenter, observational studies to evaluate pregnancy or ART outcomes in consecutive women with previous reproductive failures after spontaneous or assisted conception, respectively. All enrolled women are observed from their first visit after positive pregnancy test (OTTILIA) or before commencing a new ART cycle (FIRST) until the end of pregnancy or ART procedure (negative pregnancy test/end of pregnancy, if successful cycle), respectively. Data are collected by means of questionnaires and recorded in a central database. Follow-up investigations are performed during hospital stay, routine clinical follow-up visits or telephone interviews. Primary outcome is live birth rate in the OTTILIA register and clinical pregnancy rate in the FIRST. DISCUSSION: Although RCTs are the 'gold standard' for evaluating treatment outcomes, we believe that our registries represent a valid alternative in improving knowledge on mechanisms involved in reproductive failures and supporting future clinical decisions. TRIAL REGISTRATION: NCT02385461 , retrospectively registered 5 March 2015 (OTTILIA); NCT02685800 , registered 10 February 2016 (FIRST).

Solid Organ Transplantation in the Coronavirus Disease 2019 Era: "The Great Bet" in the North Italy Transplant Program Area.

INTRODUCTION: Solid organ transplantation is challenging for waitlist patients during the coronavirus disease 2019 (COVID-19) pandemic. AIM: This study investigates COVID-19 incidence and mortality in patients transplanted in the North Italy Transplant program (NITp) during the outbreak. MATERIALS AND METHODS: All consecutive patients transplanted from February 20 to April 3, 2020 (6 weeks), were included in our cohort and were observed for at least 4 weeks. Survival analyses were performed. RESULTS: In this study, 124 patients were transplanted with 12 (9.7%) hearts, 4 (3.2%) lungs, 39 (31.4%) livers, 67 (54%) kidneys, and 2 (1.6%) combined kidney-pancreas. Recipients' mean age was 51 years (standard deviation [SD] ± 16.6), and 76 of 124 (61%) were men. Five (4%) patients developed COVID-19 after a mean of 13 days (SD ± 6.7), with a cumulative incidence of 4.0% (95% confidence interval [CI], 0.5-7.5). During the follow-up period, 5 of 124 (4%) recipients died; overall mortality was 4.3% (95% CI, 0.6-8.0), with only 1 patient dying of COVID-19, for a COVID-19-related mortality of 0.8% (95% CI, 0-6.0). CONCLUSIONS: This study showed a low COVID-19 incidence and COVID-19-related mortality in patients transplanted during the COVID-19 pandemic. Further studies with a longer follow-up period are mandatory to confirm the safety of transplant procedures.

The Impact of COVID-19 on Solid Organ Donation: The North Italy Transplant Program Experience.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak has unfavorably influenced solid organ donation activity. AIM: The aim of this study is to investigate the effect of COVID-19 on transplantation in the North Italy Transplant program (NITp). MATERIAL AND METHODS: This cross-sectional study included all consecutive potential deceased donors proposed in the NITp in 6 weeks after February 21, 2020 (period A) compared to all potential donors during the same time frame of the previous years (period B) and all potential donors 6 weeks before February 20, 2020 (period C). RESULTS: Fifty-eight deceased donors were proposed during period A, 95 were proposed during period B, and 128 were proposed during period C. After the evaluation process, 32 of 58 (55.2%), 60 of 95 (63.2%), and 79 of 128 (61.7%) donors were used for organ donation in periods A, B, and C, respectively (P value = .595). We observed a 47% donation reduction in period A compared to period B and a 60% reduction compared to period C. There was a reduction of 44% and 59% in transplantation comparing period A with period B and period C, respectively. CONCLUSIONS: This study showed an important reduction of donations and transplants during the COVID-19 pandemic.

Quality of Life Before and After Transplantation in Solid Organ Recipients Referred to the North Italy Transplant program (NITp): A Cross-sectional Study.

INTRODUCTION: The interest in health-related quality of life (HR-QoL) has increased in the past few years. AIM: The aim of this study was to evaluate the HR-QoL before and after transplantation in solid organ recipients referred to the North Italy Transplant program. MATERIAL AND METHODS: This cross-sectional study was performed between 2010 and 2011. All consecutive recipients on the waiting list for liver, heart, or kidney transplantation were included and compared to all consecutive transplanted patients at 6 and 24 months of follow-up after transplantation. The HR-QoL was evaluated with the 36-item Short Form Health Survey (SF-36) and the Profile of Mood States (POMS). Questionnaires were self-reported anonymously. Descriptive statistical analyses were performed. RESULTS: Four hundred eleven patients were interviewed: 146 patients (35.5%) were on the waiting list, 137 (33.3%) were transplanted 6 months before the interview, and 128 (31.1%) were transplanted 24 months before the interview. Patients on the waiting list had a lower SF-36 score for all items than did transplanted patients after both 6 and 24 months. According to POMS results, patients on the waiting list had a higher prevalence of depression, tension, anger, fatigue, and confusion than did transplanted patients. CONCLUSIONS: Patients on the waiting list showed a worse quality of life compared to patients after transplantation as demonstrated by SF-36 and POMS results. These findings should be confirmed in a cohort study.

Antithrombotic prophylaxis in a patient with nephrotic syndrome and congenital protein S deficiency.

BACKGROUND: Nephrotic syndrome confers an acquired prothrombotic phenotype due to the urinary loss of anticoagulant proteins.Patients with reactivation of nephrotic syndrome may develop thrombosis. CASE PRESENTATION: We report the case of a life-threatening cerebral venous thrombosis in a 13 year-old boy affected by a relapse of nephrotic syndrome during a P. aeruginosa otitis/mastoiditis. Due to the worsening general conditions and the severe neurological impairment, a course of systemic thrombolysis was successfully administered, followed by anticoagulant therapy. In the present case severe inherited thrombophilia (inherited dysfunctional protein S deficiency) was identified as an important additional risk factors for thrombosis. CONCLUSIONS: A careful evalutaion of risk factos for thrombosi during reactivation of nephrotic syndrome include measurement of plasma anticaogulant proteins. When low, antithrombotic prophylaxis with heparin should be considered to prevent thrombotic episodes.

Risk factors and recurrence rate of primary deep vein thrombosis of the upper extremities.

BACKGROUND: One third of cases of upper-extremity deep vein thrombosis (DVT) are primary, ie, they occur in the absence of central venous catheters or cancer. Risk factors for primary upper-extremity DVT are not well established, and the recurrence rate is unknown. METHODS AND RESULTS: We studied 115 primary upper-extremity DVT patients and 797 healthy controls for the presence of thrombophilia due to factor V Leiden, prothrombin G20210A, antithrombin, protein C, protein S deficiency, and hyperhomocysteinemia. Transient risk factors for venous thromboembolism were recorded. Recurrent upper-extremity DVT was evaluated prospectively over a median of 5.1 years of follow-up. The adjusted odds ratio for upper-extremity DVT was 6.2 (95% CI 2.5 to 15.7) for factor V Leiden, 5.0 (95% CI 2.0 to 12.2) for prothrombin G20210A, and 4.9 (95% CI 1.1 to 22.0) for the anticoagulant protein deficiencies. Hyperhomocysteinemia and oral contraceptives were not associated with upper-extremity DVT. However, in women with factor V Leiden or prothrombin G20210A who were taking oral contraceptives, the odds ratio for upper-extremity DVT was increased up to 13.6 (95% CI 2.7 to 67.3). The recurrence rate was 4.4% patient-years in patients with thrombophilia and 1.6% patient-years in those without thrombophilia. The hazard ratio for recurrent upper-extremity DVT in patients with thrombophilia compared with those without was 2.7 (95% CI 0.7 to 9.8). CONCLUSIONS: Inherited thrombophilia is associated with an increased risk of upper-extremity DVT. Oral contraceptives increase the risk only when combined with inherited thrombophilia. The recurrence rate of primary upper-extremity DVT is low but tends to be higher in patients with thrombophilia than in those without.

Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives.

BACKGROUND: Conflicting data are available on air travel as a risk factor for venous thromboembolism. To our knowledge, there are no studies investigating whether individuals with thrombophilia and those taking oral contraceptives are more likely to develop venous thromboembolism during flights than those without these risk factors. PARTICIPANTS AND METHODS: The study sample consisted of 210 patients with venous thromboembolism and 210 healthy controls. DNA analysis for mutations in factor V and prothrombin genes and plasma measurements of antithrombin, protein C, protein S, total homocysteine levels, and antiphsopholipid antibodies were performed. RESULTS: In the month preceding thrombosis for patients, or the visit for controls, air travel was reported by 31 patients (15%) and 16 controls (8%), with an oddsratio of 2.1 (95% confidence interval, 1.1-4.0). Thrombophilia was present in 102 patients (49%) and 26 controls (12%), and oral contraceptives were used by 48 patients and 19 controls (61% and 27% of those of reproductive age, respectively). After stratification for the presence of air travel and thrombophilia, the odds ratio for thrombosis in individuals with both risk factors was 16.1 (95% confidence interval, 3.6-70.9). Stratification for the presence of air travel and oral contraceptive use gave an odds ratio of 13.9 (95% confidence interval, 1.7-117.5) in women with both risk factors. CONCLUSIONS: Air travel is a mild risk factor for venous thromboembolism, doubling the risk of the disease. When thrombophilia or oral contraceptive use is present, the risk increases to 16-fold and 14-fold, respectively, indicating a multiplicative interaction.

Comparison between clinical indicators of transmembrane oxygenator thrombosis and multidetector computed tomographic analysis.

This study aims to assess whether multidetector computed tomography (MDCT) could accurately confirm the clinical suspicion of transmembrane oxygenator thrombosis (MOT) during extracorporeal membrane oxygenation (ECMO). Twenty-seven oxygenators were examined using MDCT at the end of patient treatment. Transmembrane oxygenator thrombosis was suspected in 15 of them according to the presence of at least 2 of the following clinical indicators: (1) increase in d-dimer, (2) decrease in platelet count, (3) decrease in oxygenator performance, and (4) presence of clots on the surface of the oxygenator. Transmembrane oxygenator thrombosis was confirmed by MDCT in 5 (33%) of them. Transmembrane oxygenator thrombosis was unexpectedly found in 5 (41%) of the remaining 12 oxygenators not suspected for MOT. Eight (80%) of these oxygenators had clots accounting for less than 1% of total volume. Clots were mainly detectable at the apical corner of the oxygenator, most likely due to greater blood stasis. We found a significant increase in d-dimer and in membrane oxygenator shunt and a decrease in platelet count from the start to the discontinuation of ECMO. Hemostatic abnormalities significantly reverted 48 hours after oxygenator removal, suggesting the role of ECMO in activation of the coagulation cascade. Multidetector computed tomographic scan could not accurately confirm the clinical suspicion of MOT.

Embryo implantation after assisted reproductive procedures and maternal thrombophilia.

BACKGROUND AND OBJECTIVES: Women undergoing assisted reproductive procedures, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), fail to achieve pregnancy in approximately 70% of cases. Postulating that among the possible causes of failure of embryo implantation might be an impairment of the uteroplacental circulation due to hypercoagulability in the mother, we investigated the association between thrombophilia and failure to achieve pregnancy after IVF or ICSI. DESIGN AND METHODS: A case-control study was carried out in 234 women undergoing IVF or ICSI and in 234 women who, in the same period, conceived naturally. Thrombophilia due to mutations in genes encoding coagulation factor V (G1691A), prothrombin (G20210A), methylene-tetrahydrofolate reductase (C677T) and the presence of antiphospholipid antibodies was searched for. RESULTS: The prevalence of factor V, prothrombin and methylene-tetrahydrofolate reductase mutations was similar in the 162 women who failed to achieve pregnancy after IVF or ICSI and in control women (5% and 2% for factor V G1691A, odd ratio 2.4, 95% CI 0.8-7.4; 3% and 6% for prothrombin G20210A, odds ratio 0.5, 95% CI 0.2-1.5; 19% and 20% for homozygous methylene-tetrahydrofolate reductase C677T, odds ratio 1.0, 95% CI 0.6-1.6). Nor was any association found when women who failed to achieve pregnancy were divided according to the total number of assisted reproductive procedures, age, type of procedure and cause of infertility. Antiphospholipid antibodies were not detected in any of the women. INTERPRETATION AND CONCLUSIONS: This study provides no evidence for an association between maternal thrombophilia and failure to achieve pregnancy after assisted reproductive procedures. Routine anticoagulant treatment in women undergoing assisted reproductive procedures is not warranted.

Thrombophilic states.

Cerebral venous sinus thrombosis (CVST) is a rare life-threatening disease with an estimated annual incidence of three to four cases per million in adults and seven cases per million in neonates. Brain tumors, cerebral infections or traumas, oral contraceptive use, pregnancy, and puerperium are established risk factors for CVST but in 15-20% of patients the disease is apparently unprovoked, i.e., occurring in the absence of predisposing factors. In the last decade there has been increasing evidence that early diagnosis and anticoagulant treatment reduce morbidity of CVST and improve survival. However, the optimal duration of anticoagulant treatment is not well established, because limited information is available on the rate of CVST recurrence after anticoagulant discontinuation. Thrombophilia is a hypercoagulable state leading to a thrombotic tendency, and young patients with CVST, either provoked or unprovoked, deserve investigation. Thrombophilic abnormalities can be inherited (deficiency of the natural anticoagulant proteins antithrombin, protein C, or protein S, mutations in the factor V gene (factor V Leiden) or prothrombin gene (prothrombin G20210A)), acquired (antiphospholipid antibodies), or "mixed," i.e., either congenital or acquired (hyperhomocysteinemia). The risk of thrombosis is different according to each abnormality. The aim of this chapter is to review the literature about the role of thrombophilia in CVST and to give suggestions for management of the disease.

Cerebral sinus-venous thrombosis.

Cerebral sinus-venous thrombosis (CSVT) is a rare life-threatening disease with an estimated annual incidence of 3-4 cases per million in adults and 7 cases per million in neonates. Brain tumors, cerebral infections and traumas are local risk factors for CSVT, but the commonest encountered risk factors are oral contraceptive use, pregnancy and puerperium that make the disease predominant in female sex. In 15-20 % of patients, the disease remains unprovoked, i.e., occurring in the absence of predisposing factors. Thrombophilic abnormalities either inherited [deficiency of the natural anticoagulant proteins antithrombin, protein C or protein S, mutations in the factor V gene (factor V Leiden) or prothrombin gene (prothrombin G20210A)] or acquired (antiphospholipid antibodies) are worthy to be investigated in patients with CSVT, as well as hyperhomocysteinemia. In a small proportion of patients, CSVT is the first manifestation of a myeloproliferative neoplasm. The proportion of patients with recurrent CSVT is low, but venous thromboembolism (deep vein thrombosis in the lower limbs or pulmonary embolism) can develop particularly in patients with a first idiopathic CSVT. In the past decade, there has been increasing evidence that early diagnosis and anticoagulant treatment reduce morbidity of CSVT and improve survival. However, the optimal duration of anticoagulant treatment is not well established, because limited information is available on the rate of CSVT recurrence after anticoagulant discontinuation.

Influence of anticoagulant therapy with vitamin K antagonists on plasma levels of coagulation factor VIII.

Vitamin K-antagonists (VKA) decreases vitamin K coagulation factors. To counterbalance this effect, it has been postulated that non-vitamin K proteins increase during VKA treatment. To investigate if VKA affect FVIII, a cohort of 1772 patients referred from Jan 1997 to Oct 2008 to our Thrombosis Center for a thrombophilia screening after at least 3 months from diagnosis of first venous thrombosis was studied. At the time of blood sampling, 1303 patients had discontinued VKA for at least one month, whereas the remaining 469 were still taking VKA. FVIII was significantly higher in patients on VKA than in those who had discontinued VKA (mean+/-SD: 144+/-41 IU/dL and 134+/-40 IU/dL, respectively, p<0.0001), also after adjustment for sex, age, body mass index, thrombophilia and time elapsed from thrombosis in a multiple linear regression analysis. In order to avoid overestimation of FVIII levels, patients should be preferentially tested after VKA discontinuation.