High Incidence Of Venous Thrombosis Research Articles

Timing of Thrombosis with Myeloproliferative Neoplasm Diagnosis Among Veterans and Civilians

Rates of Arterial (AT) and Venous Thrombosis (VT) are increased in Veterans with Myeloproliferative Neoplasms (Vet-MPN), including Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), compared to matched controls (J Clin Oncology 2023 41:16_suppl, 7011). The timing of first AT or VT episode in Vet-MPNs remains undefined when compared to Civilians with MPN (Civ-MPN). These findings could elucidate optimal timing for risk mitigation strategies to prevent thrombotic complications and should help to determine duration of thrombotic risk and need for systemic anticoagulation prophylaxis. The Veterans Affairs Informatics and Computing Infrastructure (VINCI) database was queried from January 1, 2006 to January 26, 2023 to identify Vet-MPNs, AT, and VT through ICD-9 and -10 codes. This process yielded 2,752 Vet-MPN and 583,803 Veterans without MPN from Illinois, the state most representative of the US population. These cohorts were compared to data derived from a retrospective chart review of Civ-MPN cared for between January 1, 2019 to December 31, 2022, at MedStar Georgetown University Hospital and MedStar Washington Hospital Center. Service-Connected Exposures (SCE) to potential carcinogens among Veterans were verified through their duration and location of service. We subdivided time to first AT and VT from MPN diagnosis as follows: more than 3 months prior to MPN diagnosis, within 3 months of diagnosis, 3 months to 1 year post diagnosis, 1 to 5 years, and more than 5 years after MPN diagnosis. Mean data from various cohorts were analyzed utilizing Fisher's exact test. Vet-MPN experienced a statistically higher incidence of AT compared to Civ-MPN (p=.0019) and Civ-MPN experienced a statistically higher incidence of AT compared to Veterans without MPN (p=0.02) which served as a control. In contrast, there was a higher incidence of VT among both Vet- and Civ-MPN cohorts compared to Veterans without MPN (p<.0001) (Table 1). The mean ages at MPN diagnosis and onset of first AT were similar (≥63 years) in both Civ- and Vet-MPN. In contrast, the mean age of MPN diagnosis and age of first VT were considerably earlier for Civ-MPN (51 years) versus both Vet-MPN with VT and Veterans without MPN with VT (≥67 years). There was a higher prevalence of hypertension, hyperlipidemia, diabetes, heart failure, and smoking among Veterans with or without MPN compared to Civ-MPN with either AT or VT (Table 1). A trend toward statistical significance was observed for the presence of hypertension and hyperlipidemia (p=0.049 and p=0.02, respectively) in Vet-MPN compared to Civ-MPN, while Veterans without MPN had a statistically higher prevalence of hyperlipidemia (p=0.02) and heart failure (p=0.001) in AT. Notably, a trend toward statistical significance in VT was observed for the presence of diabetes among all Veterans with or without MPN compared to Civ-MPN (p=0.01 and p=0.007, respectively). There was a biphasic distribution in time to onset of first AT and VT in all Vet- and Civ-MPN cohorts (Figure 1). There was a higher cumulative incidence of first AT and VT in Vet-MPN at more than 3 months prior to MPN diagnosis compared to Civ-MPN with AT and VT (Figure 1). On the other hand, the Civ-MPN cohort had a late surge of first VT more than 5 years after MPN diagnosis compared to the other MPN cohorts. A biphasic distribution in time to onset of first AT and VT was also observed among the Vet-MPN cohort when stratified by SCEs from World War II, the Korean War, the Vietnam War, and the Gulf War. The vast majority of both AT and VT in Vet-MPN from all SCE examined experienced onset of thrombotic events more than 3 months prior to MPN diagnosis. Most VT in Gulf War Vet-MPN occurred within 3 months of MPN diagnosis. In conclusion, the predominant risk for developing thrombotic complications in MPN, particularly in Vet-MPN, occurs in a biphasic pattern, beginning more than 3 months prior to MPN diagnosis and becoming apparent again at more than 5 years after MPN diagnosis. These findings suggest that the MPNs convey an enduring hypercoagulability potential throughout the natural history of the disease. There appears to be an accelerated onset of thrombotic complications earlier in the course of disease in Vet-MPN, perhaps reflecting their SCE with toxic carcinogens. More work is necessary to determine epigenetic influences on MPN natural history.

A Real World, Single-Centre Study of Young Adult Patients with Philadelphia Negative Myeloproliferative Neoplasms

Classical ‘Philadelphia negative’ myeloproliferative neoplasms (MPNs) are clonal haematopoietic disorders and include essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (MF). MPNs have a heterogenous phenotype with an inherent risk of thromboembolic and haemorrhagic complications, and risk of blastic transformation. MPNs are commonly diagnosed in the 6 th decade or later, although up to 20% of patients are diagnosed < 40 years. Current risk stratification and treatment guidance, however, is frequently extrapolated from older cohorts. Here, we present a comprehensive retrospective analysis of 107 MPN adolescent and young adult (AYA) patients diagnosed <40 years, representing 19.6% of the total outpatient MPN cohort at University College London Hospital. Median follow up was 78 months (range (r), 1 - 507). Table 1 displays clinicopathological details of the entire cohort. Median age at diagnosis was 32 years (r,13-40). There was a female preponderance (66%); 57.9% of patients were Caucasian. Most patients had a diagnosis of ET (57.9%), with 24.3% PV and 9.3% MF, respectively. The most common driver mutation was JAK2 V617F, observed in 60.7%, followed by CALR (15.9%) and MPL (1.9%); 17% of patients were classified as triple negative (TN). Where data was available (n=27), median variant allelic frequency (VAF) for JAK2 V617F was 19.7% (r, 4-75%) and for CALR 43% (r, 5.7 - 53). 9/107 (8.4%) of patients had additional pathogenic gene abnormalities, most commonly variants of NRAS (22.2%), TET2 (22.2%) and ASXL1 (22.2%). We observed a high thrombosis rate of 19.6% (21/107); the majority had a diagnosis of ET (61.9%).. In 80% of such cases, this was the heralding event leading to the MPN diagnosis. Venous thrombosis was more frequent than arterial thrombosis (68% vs 33%). In particular, there was a disproportionate number of venous thromboses at unusual sites including cerebral venous sinus and splanchnic venous thromboses, representing 40% and 33% of total events, respectively. Only 3 (2.8%) patients were found to have a co-existent thrombophilia. Younger age at diagnosis appeared to associate with a higher rate of thrombosis (60% in patients aged <20, 18.2% in patients aged 20-30, and 17.2% in patients aged 31-40). Thrombotic events were most common in those with a JAK2V617 mutation (23.4%), followed by those who were TN (20.0%). Only 5.9% of CALR mutated cases had a thrombotic event. In terms of cardiovascular risk factors, 13.0% (14/107) and 6.5% (7/107) of patients had diagnoses of hypertension and type 2 diabetes, respectively. Haemorrhagic events were reported in 8.4% (9/107) of patients; 3.7% (4/107) had grade 3 or 4 bleeding complications, requiring transfusion and/or surgical intervention. All who experienced haemorrhagic events were on treatment with an anti-platelet or anti-coagulant agent. 4.7% (5/107) were diagnosed with acquired von Willebrand's disease, of whom one experienced a grade 3 haemorrhagic event. No patients transformed during follow up. 33 patients reported pregnancies, with 7/33 (21%) reporting antenatal or perinatal medical complications. Over 50% (55/107) of patients were commenced on cytoreduction. Most common agents employed were pegylated interferon (45.5%; 25/55) and hydroxycarbamide (43.6%%; 24/55). No patients required combination therapy. 92/107 (86%) patients were treated with an antiplatelet agent and 9/107 (8.4%) were on anti-coagulant treatment with the majority (88.8%) receiving warfarin rather than a DOAC. AYA MPN patients have unique characteristics and heterogeneous clinico-biological features differentiating them from older MPN cohorts. Our data highlights a female preponderance, higher incidence of venous thrombosis (particularly atypical sites), and lower incidence of arterial thrombosis. Whilst traditionally younger patients are considered to have ‘low risk’ disease, this real-world study highlights a significant thrombosis rate of ~ 20% which may have associated morbidity considering the relatively longer duration of the disease course and need for cytoreductive therapy. Specific AYA MPN directed risk stratification and therapeutic algorithms are required to inform holistic and age-appropriate patient management.

Cerebral Venous Thrombosis and Myeloproliferative Neoplasms: A Three-Center Study of 74 Consecutive Cases

▪BackgroundThe recent association of cerebral venous thrombosis (CVT) with COVID-19 vaccinations (JAMA; 2021; 325, N Engl J Med 2021; 384) motivated the current review of CVT and MPN. Our objectives were, i) provide an estimation of the incidence of CVT in the context of MPN, followed by a description of clinical phenotype and therapeutic strategies, ii) determine long term outlook in terms of recurrent thromboses, hemorrhage, and survival, iii) identify salient features which distinguish MPN associated from COVID vaccine- related CVT.Methods74 consecutive MPN patients with CVT that underwent evaluation at the Mayo Clinic, Rochester MN, USA (n=36), Catholic University, Rome, Italy, (n=23), and University of Florence, Italy (n=15) between 1991 and 2021 were included. The cohort from a previously published multi-center study that included 42 MPN cases with CVT, which were not included in the current study, was used for comparison of observations. Diagnosis of CVT was established with computed tomography or magnetic resonance imaging with venography.Results •Patient characteristics at time of CVTAmong 74 patients with CVT and MPN (median age 44 years, range 15-85; 61% females); disease-specific frequencies were 1.3% (39/2,893), 1.2% (21/1,811) and 0.2% (3/1,888) for essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), respectively.CVT occurred prior to (n=20, 27%, median time to MPN diagnosis 16.5 months), at (n=32, 44%) or after (n=21, 29%, median time to CVT 26 months) MPN diagnosis. 72% of patients presented with headaches, 22% visual changes, 12% nausea/vomiting, 8% neurological deficits, and 6% seizures. Transverse (51%), sagittal (43%) and sigmoid (35%) sinuses were involved with central nervous system hemorrhage in 10 (14%) patients.MPN phenotype included ET (n=39, 53%), PV (n=21, 28%), pre-fibrotic MF (n=6, 8%), MPN-unclassified (n=4, 5%), PMF (n=3, 4%) and post-PV MF (n=1, 1%). Driver mutation testing was performed in 65 patients: 91% harbored JAK2V617F, 3% CALR type 1, 2% MPL, 5% triple negative; moreover, JAK2V617F was mutated in 27/33 (82%) ET patients. An underlying thrombophilia was identified in 19 (31%) cases. No patient had thrombocytopenia. (Table 1). Notably, one patient received the Ad26.COV2.S vaccine, five days prior to presenting with CVT, not associated with thrombosis in other sites, thrombocytopenia or platelet factor 4 antibodies. A history of thrombosis was documented in 10 (14%) patients with three splanchnic venous events. These observations were similar to those noted in our comparative group from a previously published report that included 42 cases; (ET (n=25, 60%), PV (n=11, 26%), PMF (n=5, 12%); median age 51 years, range 16-84; 55% females; 81% JAK2V617F mutated). Prior thrombosis occurred in 8(19%) patients with four splanchnic venous events.Treatment for CVT included systemic anticoagulation alone in 27 (36%) patients or in conjunction with aspirin (n=24, 32%), cytoreductive therapy (n=14, 19%), or both aspirin and cytoreduction (n=9, 12%). 5/21 (24%) patients with CVT post MPN diagnosis, were on anticoagulation at the time of CVT.1.Outcome following CVTAt a median follow-up of 5.1 years (range; 0.1-28.6), recurrent CVT was documented in 3 (4%) patients; incidence rates for other arterial and venous thromboses and hemorrhage were 11% (2 per 100 patient-years), 9% (1.9 per 100 patient-years) and 14% (3 per 100 patient-years), respectively. 3 of 7 (43%) venous thromboses were splanchnic events. Antithrombotic therapy was ongoing in 53% and 80% of patients with thrombotic recurrences and hemorrhage, respectively. A higher incidence of venous thrombosis was noted in the aforementioned previously published cohort (12 (29%) vs 7 (9%), p=0.01); with 5/12 (42%) splanchnic events. Incidence rates for arterial thrombosis and major hemorrhage were similar. Fibrotic and leukemic transformation occurred in 5 (8%) and 1(1%) patient, respectively, with five (7%) deaths unrelated to CVT.ConclusionsThe current study highlights close association of CVT with JAK2V617F, younger age, and female gender. Clinical features distinguishing COVID vaccine-related from MPN-associated CVT include lower likelihood of concomitant non-CVT venous thromboses with the latter; moreover, the absence of thrombocytopenia resulted in a lower rate of intracerebral hemorrhage in MPN cases; as a result, MPN-CVT was not fatal. [Display omitted] DisclosuresVannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Evaluation of totally implantable catheters in healthy horses

BackgroundFor horses requiring prolonged daily cephalic intravenous regional limb perfusion (IVRLP), the use of a totally implantable catheter (TIC) could be indicated to reduce complications associated with frequent venipuncture or external catheterization. This study aims to evaluate the implantation technique of the TIC in the cephalic vein of horses for IVRLP, describe the complications associated with the device’s placement and use, and assess its viability up to 60 days after implantation. Totally implantable catheters, cut to 15 cm (n = 5) and 46 cm (n = 5) in length, were implanted into one cephalic vein in ten adult horses (n = 10). Twenty-four hours following placement, IVRLP with contrast was performed via the TIC and evaluated with radiography. Physical examinations, lameness evaluation, hematologic assessment, and the catheter patency tests were performed at scheduled intervals for the duration of catheterization (7–60 days).ResultsCatheters were implanted without difficulty and allowed for IVRLP 24 h post implantation. Complications resulted in removal of the catheters, with four maintained for 7 days, three in place for 15 days, and three catheters maintained for 60 days. Complications included lameness, limb swelling, catheter kinking, and venous thrombosis.ConclusionsThe implantation technique of the TIC in the cephalic vein of horses is feasible and requires minimal technical effort. Although TIC allows venous access without the need for repeated venipuncture, its long-term use presents complications. For horses requiring prolonged daily cephalic IVRLP, the use of a TIC could be indicated. However, the high incidence of venous thrombosis may limit clinical application.

Incidence and Predictors of Thrombotic Complications in 4742 Patients with COVID-19 or Other Acute Infectious Respiratory Diseases: A Propensity Score-Matched Study.

Background. A prothrombotic state, attributable to excessive inflammation, cytokine storm, hypoxia, and immobilization, is a feature of SARS-CoV-2 infection. Up to 30% of patients with severe COVID-19 remain at high risk of thromboembolic events despite anticoagulant administration, with adverse impact on in-hospital prognosis. Methods. We retrospectively studied 4742 patients with acute infectious respiratory disease (AIRD); 2579 were diagnosed to have COVID-19 and treated with heparin, whereas 2163 had other causes of AIRD. We compared the incidence and predictors of total, arterial, and venous thrombosis, both in the whole population and in a propensity score-matched subpopulation of 3036 patients (1518 in each group). Results. 271 thrombotic events occurred in the whole population: 121 (4.7%) in the COVID-19 group and 150 (6.9%) in the no-COVID-19 group (p < 0.001). No differences in the incidence of total (p = 0.11), arterial (p = 0.26), and venous (p = 0.38) thrombosis were found between the two groups after adjustment for confounding clinical variables and in the propensity score-matched subpopulation. Likewise, there were no significant differences in bleeding rates between the two groups. Clinical predictors of arterial thrombosis included age (p = 0.006), diabetes mellitus (p = 0.034), peripheral artery disease (p < 0.001), and previous stroke (p < 0.001), whereas history of solid cancer (p < 0.001) and previous deep vein thrombosis (p = 0.007) were associated with higher incidence of venous thrombosis. Conclusions. Hospitalized patients with COVID-19 treated with heparin do not seem to show significant differences in the cumulative incidence of thromboembolic events as well as in the incidence of arterial and venous thrombosis separately, compared with AIRD patients with different etiological diagnosis.

A 22-year-old COVID-19 positive male with no prior medical history presented to the emergency department with pulmonary infarction

ABSTRACT Rapidly growing evidence has now shown a high incidence of venous thrombosis in patients with severe acute respiratory syndrome secondary to novel coronavirus 2, a disease now named COVID-19. Accumulating case reports and series have also shown a higher prevalence of arterial thrombosis in these patients as well. Although the pathophysiology remains unknown but likely multifactorial – including endotheliitis from direct viral damage and an underlying hyper-inflammatory state, arterial and venous thrombosis occurrence does not appear to be linked with underlying classic risk factors for venous thromboembolism and may present in healthy patients without significant comorbidities. We present a case of a 22-year-old healthy patient with COVID-19 who developed a pulmonary embolism with a pulmonary infarction, a complication that results from arterial and venous thrombosis of the pulmonary vascular supply resulting in tissue necrosis.

High incidence of venous thrombosis in patients with moderate-to-severe COVID-19.

Increasing evidence suggests that COVID-19 may be associated with venous thromboembolism, and much data exists regarding high incidence of venous thrombosis in critical COVID-19 patients. However, evidence on this complication in less severe patients is not widely available. The aim of this study was to investigate the incidence of deep-vein thrombosis (DVT) in patients with moderate-to-severe COVID-19, to assess the prevalence of DVT with duplex ultrasound, and to compare patients with DVT and those without it using lung computerized tomography (CT), clinical information and lab data. The subjects of this study were 75 consecutive patients (aged 27–92 y, median–63 y; 36 males and 39 females) with moderate-to-severe COVID-19. DVT was found in 15 patients (20%). The vast majority of those with DVT (13 patients, 86.7%) had thrombi in calf veins and 2 (13.3%) had ileofemoral thrombosis. High incidence of DVT (20%) is observed even in patients with moderate-to-severe COVID-19. These patients require early anticoagulation therapy as part of their treatment. Such therapy may be continued after hospital discharge and these patients may also require follow-up vein ultrasonography after recovery to rule out DVT.

Management and Outcome of Venous Thrombosis in Patients with Myeloproliferative Neoplasms: Data from the Israeli MPN Working Group

The BCR-ABL-negative myeloproliferative neoplasms (MPN) are associated with high incidence of venous thrombosis and a significant rate of recurrent events, but there is no consensus regarding their management. In this retrospective study, we analyzed 96 patients with MPN-related venous thrombosis. The index venous thrombosis occurred at a median age of 58 years (IQR 37–71), with 58% of the events involving unusual sites. Patients who were on antiplatelet agents at the time of index thrombosis tended to be older than patients who were not receiving antiplatelets at the time of index thrombosis. The majority of index thromboses occurring after the diagnosis of MPN had uncontrolled blood counts at the time of event and were not receiving antithrombotic agents. Following the thrombotic episode, 75% of patients received long-term anticoagulation. At a median follow-up of 3.4 years, the recurrence rate was 14%. Thrombophilia was significantly more prevalent among patients with recurrent thrombosis compared to patients without recurrence (p < 0.01). Patients who developed a recurrent event early were more likely to have thrombophilia (either inherited or antiphospholipid antibodies), and controlled blood counts, and were likely to receive anticoagulation at the time of recurrence compared to patients with later recurrences. Thrombophilia may contribute to venous thrombosis recurrence, especially early after the index venous thrombosis. Suboptimal anticoagulation and blood count control are factors associated with late venous thrombosis recurrence.

MPN-376: The Clinical Impact of the Burden of JAK2V617F Mutated Allele in Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Context: Several studies reported the impact of JAK2V617F allele burden on phenotypic properties and clinical course in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs). We aimed to analyze the association of mutated JAK2V617F allele burden with clinical phenotype and laboratory characteristics in essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. Objective: A total of 202 consecutive Philadelphia-negative MPN patients, 118 with ET and 84 with PMF, were included in this study. Methods: We used a real-time, semi-quantitative polymerase chain reaction (PCR) with JAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille, France) to screen JAK2V617 mutations and mutant allele burden. Results: According to the JAK2V617F status, ET patients were stratified into three groups: JAK2V617F mutation-negative (n=54) and JAK2V617F-positive with mutant allele burden in the lower quartile (n=59) and upper quartile (n=5) ranges. ET patients with upper quartile JAK2V617F allele burden had significantly lower Hgb levels (p=0.001), lower Htc levels (p=0.001), and higher LDH levels (p=0.008) as compared to the other two groups. Also, ET patients with upper quartile JAK2V617F allele burden had significantly increased spleen size and higher bleeding complications (p=0.034; 0.002; respectively). We observed significant association between ET patients with high JAK2V617F allele burden and higher death rates (p=0.007). There was a trend towards higher incidence of venous thrombosis in ET patients with upper quartile JAK2V617F allele burden (p=0.057). According to JAK2V617F status, PMF patients were stratified into three groups: JAK2V617F mutation-negative (n=25) and JAK2V617F-positive with mutant allele burden in the lower quartile (n=41) and upper quartile (n=18) ranges. Comparison across all three groups revealed significant associations between upper quartile allele burden and higher leukocyte counts (p=0.001). Also, PMF patients with upper quartile JAK2V617F allele burden had significantly increased spleen size compared to the other two groups (p=0.018). We observed significant association between PMF patients with low JAK2V617F allele burden and higher incidence of venous thrombosis (p=0.035). Conclusion: Our study reported that presence of higher V617F allele burden in ET is associated with defined haematological and clinical markers indicative of a more aggressive behavior while, in PMF, low allele burden was found to be associated with higher incidence of venous thrombosis.

MPN-364: The Clinical Significance of JAK2V617F Mutational Status on Phenotypic Features in Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Context: The JAK2V617F mutation is present in the majority of patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in the aforementioned diseases is still a matter of discussion. This study aims to determine differences in clinical presentation and disease outcome among PV, ET, and PMF patients with and without the JAK2V617F mutation. Objective: A total of 410 consecutive Philadelphia-negative MPN patients, 170 with ET, 135 with PV, and 105 with PMF under follow-up between 1995 and 2020 were included in this study. Methods: Two hundred twenty-eight patients (118 ET, 84 PMF, 26 PV) were genotyped for the JAK2V617F mutation with the JAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille, France). In 182 patients (109 PV, 52 ET, 21 PMF), JAK2V617F mutation was detected by LightCycler techniques, which is genotype assessment based on melting curve analysis. Results: In our study, the JAK2V617 mutation-positive PV group consisted of a significantly lower number of male patients (p=0.008). JAK2V617F mutation-positive PV patients had significantly higher leukocyte and platelet counts and lower Hgb levels (p=0.001; p=0.001 and p=0.018, respectively). Rates of total thrombosis and arterial thrombosis were significantly higher in JAK2V617F mutation-positive PV compared to JAK2V617F mutation-negative PV (42.7%, 20%; respectively; p=0.035 and 26.4%, 8%; respectively; p=0.042). In our study, JAK2V617F mutation-positive ET patients had significantly higher Hgb and Htc levels and lower platelet counts at initial diagnosis (p=0.001; p=0.001 and p=0.001, respectively). The JAK2V617 mutation-negative PMF group consisted of a significantly higher number of female patients (p=0.001). In PMF patients, the presence of JAK2V617F mutation was significantly associated with increased spleen size (p=0.042) and higher leukocyte count (p=0.019). There was a trend toward higher incidence of venous thrombosis in JAK2V617F mutation-positive PMF compared to JAK2V617F mutation-negative PMF (10%; 0; respectively; p=0.051) patients. Conclusion: We conclude that JAK2V617F-mutated ET patients express a PV-like phenotype, JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype and higher incidence of venous thrombosis, and JAK2V617F-mutated PV patients express a higher rate of total thrombosis and arterial thrombosis.

Mutations and Thrombosis in Essential Thrombocythemia and Polycythemia Vera: Mayo-Careggi Alliance Study

Background:Thrombosis is a characteristic feature in essential thrombocythemia (ET) and polycythemia vera (PV). Previous studies had focused on thrombotic events occurring after diagnosis and did not always distinguish between arterial and venous thrombosis. Arterial thrombosis in ET has been associated with age >60 years, JAK2 mutations, leukocyte count >11 x 109/l, history of thrombosis and cardiovascular risk factors, and venous thrombosis with male sex (Blood 2011;117:5857). In the current two-enter study, we looked for associations between both driver and other mutations, with first incidences of arterial and venous thrombosis in ET and PV, analyzed together and separately.Methods:Study patients were recruited from the Mayo Clinic, Rochester, MN, USA and the University of Florence, Florence, Italy, based on availability of next-generation sequencing-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). Conventional statistics was employed to examine significance of associations, with separate analysis of arterial vs venous thrombosis, occurring at any time before or after formal diagnosis of ET or PV. For the purposes of the current study, only first events were considered.Results:906 molecularly-annotated patients (416 from Mayo and 490 from Florence), including 502 ET and 404 PV cases, were included in the current study. The Mayo/Florence cohorts included 270/232 ET (median age 57/54 years, 60%/59% females) and 146/258 PV (median age 63/58 years, 52%/44% females) patients; median follow-up was 9.9/12.9 years for ET and 10.7/12.4 years for PV. Driver mutation distribution in ET was 55% JAK2, 27% CALR, 5% MPL and 13% triple-negative. Most frequent mutations, other than JAK2/CALR/MPL, were TET2 (14%; 11% in ET and 18% in PV) and ASXL1 (13%; 13% in ET and 13% in PV).301 (33%) patients experienced first time thrombosis, before or after diagnosis, including 152 (30%) in ET and 149 (37%) in PV (p=0.03); arterial events occurred in 174 (19%) patients, including 96 (19%) in ET and 78 (19%) in PV (p=0.9); venous events occurred in 177 (20%) patients, including 82 (16%) in ET and 95 (24%) in PV (p=0.007). The number of vascular events after diagnosis was 174 (19%) for arterial and 154 (17%) for venous thrombosis, with no significant difference between ET and PV.Associations with arterial thrombosis:In multivariable logistic regression analysis that included both ET and PV (n=906), age >60 years (23% vs 16%; OR, 1.6, 95% CI 1.1-2.2) and absence of ASXL1 and RUNX1 mutations (21% vs 9%; OR 2.6, 95% CI 1.4-4.8) were associated with arterial thrombosis; these associations remained significant (or near significant) when ET and PV were analyzed separately; in addition, JAK2 mutations in ET displayed borderline significance (p=0.05). Overall incidence of arterial events in ET was estimated at 27% in the presence of all three risk factors (i.e. older age, presence of JAK2 mutations and absence of ASXL1/RUNX1 mutations), 21% with two risk factors, 13% with one risk factor and 9% in the absence of all three risk factors (p=0.01).Associations with venous thrombosis:In multivariable analysis, including both ET and PV (n=906), JAK2 mutations (p<0.001), higher leukocyte count (p=0.03) and younger age (p=0.04) were identified as being significant. Analysis of ET patients only (n=502) identified JAK2 mutations (p<0.001; OR 2.4, 95% CI 1.4-4.1), absence of SRSF2 mutations (p=0.03) and younger age (p=0.04) as independent risk factors and in PV patients (n=404), higher leukocyte count (p=0.06).Prognostic interaction between JAK2 mutations and age:In ET, the overall frequency of venous events was 27% for young patients with JAK2 mutations vs 13% for older JAK2 mutated cases vs 10% for JAK2 unmutated young patients vs 13% for JAK2 unmutated older patients (p<0.001). The corresponding percentages for arterial events were 20%, 24%, 14% and 19%, respectively (p=0.1).Conclusions:JAK2 mutations contribute to the risk of both venous (younger patients) and arterial (young and older patients) thrombosis, in an age-dependent manner; the association with venous thrombosis might explain the higher incidence of venous thrombosis in PV, compared to ET. Additional studies are required to confirm the observed lower risk of thrombosis in patients with ASXL1, RUNX1 and SRSF2 mutations and provide insight into the underlying biological explanation. DisclosuresNo relevant conflicts of interest to declare.

Myeloproliferative neoplasms in the young: Mayo Clinic experience with 361 patients age 40 years or younger.

Between 1967 and 2017, 361 patients with myeloproliferative neoplasms (MPN), age ≤ 40 years, were seen at our institution, constituting 12% of all MPN patients (n = 3023) seen during the same time period; disease-specific incidences were 12% in polycythemia vera (PV; n = 79), 20% in essential thrombocythemia (ET; n = 219) and 5% in primary myelofibrosis (PMF; n = 63). Compared to their older counterparts, younger patients were more likely to present with low risk disease (P < .001) and display female preponderance in ET (P = .04), lower incidence of arterial events overall (P < .001), and higher incidence of venous thrombosis in PV (P = .01). Younger patients were also more likely to express CALR mutations, in ET and PMF, normal karyotype, in PV and PMF, and lower incidence of high molecular risk mutations in PMF (P significant in all instances). Over median follow-up of 11.3, 13, and 7.1 years for PV, ET, and PMF, leukemic transformations were respectively documented in 4%, 2%, and 10% (P values 0.1-0.9) while incidences of fibrotic progression in PV (22%) and ET (16%) were expectedly higher in young patients, because of their longer survival (P < .001). Median survival in young patients was 37 years for PV, 35 for ET and 20 for PMF; the corresponding values were 22, 22, and 8 years for ages 41-60 years and 10, 11, and 3 years for ages >60 years (P < .001). Young MPN patients comprise a unique disease subset defined by an attenuated-risk cytogenetic and mutational backdrop and conspicuously longer survival compared to their older counterparts, which requires assertion during patient counseling.

Pediatric En Bloc Kidney Transplants: Clinical and Immediate Postoperative US Factors Associated with Vascular Thrombosis.

Purpose To evaluate clinical and immediate postoperative ultrasonographic (US) risk factors associated with vascular thrombosis of pediatric en bloc kidney grafts. Materials and Methods This institutional review board-approved HIPAA-compliant retrospective study consisted of 195 recipients of pediatric en bloc kidney grafts throughout a 10-year period. The average recipient and donor age was 45 years (range, 7-74 years) and 9 months (range, 0-84 months), respectively. Clinical factors and immediate postoperative US findings were assessed. Categorical variables were evaluated by using the Fisher exact test and linear models with generalized estimating equations. Results Seventeen patients (23 kidneys) experienced thrombotic events. In six patients (eight kidneys), thrombosis occurred intraoperatively. The remaining 11 patients (15 kidneys) received a diagnosis of thrombosis on postoperative days 1-13. Recipients more than 40 years old had a higher incidence of arterial thrombosis than did younger recipients (eight of 62 vs three of 133, respectively; P < .01). Recipients were more likely to develop thrombosis with donor weight less than 5 kg (10 of 52 vs seven of 140 with donor weight of ≥ 5 kg; P < .01), with intraoperative perfusional concern (10 of 21 vs seven of 174 without; P < .01), or with right-sided allograft placement (10 of 64 vs seven of 131 left sided; P = .03). At US of the 15 postoperative thrombotic events, the incidence of thrombosis was greater when donor arterial velocity was less than 100 cm/sec (seven of 56 vs four of 126 with velocity ≥ 100 cm/sec; P = .04). An intrarenal arterial resistive index of less than 0.6 was associated with higher incidence of arterial thrombosis (nine of 123 vs zero of 217, respectively; P = .01). A resistive index greater than 0.8 was associated with a higher incidence of venous thrombosis (four of 13 vs one of 217, respectively; P = .04). Conclusion Clinical factors and immediate US findings can help stratify patients receiving pediatric en bloc kidneys into risk categories for vascular thrombosis that, if proven in prospective studies, could affect immediate postoperative treatment. (©) RSNA, 2015.

Black-White Differences In Venous Thrombosis Risk: the Longitudinal Investigation of Thromboembolism Etiology (LITE)

AbstractAbstract 478Black-White Differences in Venous Thrombosis Risk: The Longitudinal Investigation of Thromboembolism Etiology (LITE).Neil A. Zakai, Pamela L. Lutsey, Aaron R. Folsom, Mary Cushman. Introduction:Venous thrombosis (VT) is more common in blacks than whites. The reasons for this difference and whether it is explained by racial differences in VT risk factors is not known. Methods:VT was ascertained by physician review of medical records in the Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective observational study of 21,680 men and women age 45–100 years participating in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) cohorts. VT was classified as provoked if preceded within 90 days by major surgery, trauma, immobility, or associated with active cancer or chemotherapy. We used age- and sex-adjusted Cox models to evaluate whether certain VT risk factors explained the increased risk of VT in blacks vs whites. We also tested if the impact of VT risk factors differed by race using interaction terms. Most risk factors were assessed in both ARIC and CHS cohorts (body mass index (BMI), diabetes, hypertension, chronic kidney disease (CKD), factor VIII, and education) except the activated partial thromboplastin time (aPTT), von Willebrand factor (vWF), and protein C were measured in ARIC only and C-reactive protein was measured in CHS only. Results:With up to 15 years of follow up, among 20,964 participants (5,054 blacks) without VT at baseline, 648 developed new VT (200 blacks). The age- and sex-standardized incidence of VT per 1000 person-years was higher in blacks than whites for all VT (3.18 vs 1.96), whether the VT was provoked (2.11 vs. 1.24) or unprovoked (1.12 vs. 0.74), all p <0.01. Blacks and whites had a similar incidence of pulmonary embolism (PE) (0.83 vs. 0.76, p = 0.56). Blacks had more adverse levels of many VT risk factors except CKD and a lower aPTT: BMI (29.3 vs. 26.8 kg/m2), diabetes (21 vs 11%), hypertension (59 vs 38%), CKD (5 vs. 12%), high school graduation (58 vs 80%), factor VIII (146 vs 124%), vWF (134 vs 113%), CRP (2.4 vs 1.8 mg/L) protein C (3.13 vs. 3.18 mg/L), all p <0.01. In age- and sex-adjusted Cox models, the relative risk of total VT for blacks vs. whites was 1.67 (95% CI 1.41, 1.97). When risk factors were added to age-, sex- and race-adjusted Cox models, BMI explained 36% of the excess risk of VT in blacks, factor VIII 58%, and vWF 54%. The other risk factors had a minimal impact on the HR for race. When all risk factors measured in both cohorts were considered in the same model, the association of black race with VT was attenuated (HR 1.15; 95% CI 0.94, 1.42). Of the risk factors evaluated, there were significant interactions between race and hypertension, CKD, and aPTT below the median (29s). The table lists the HR for each of these risk factors stratified by race; hypertension and CKD were stronger risk factors for VT in blacks while an aPTT less than the median was a stronger risk factor for VT in whites. Conclusions:Blacks have a higher incidence of VT than whites, whether provoked or unprovoked. The increased risk in blacks was largely explained by a greater prevalence of VT risk factors among blacks, particularly obesity, higher factor VIII and higher vWF. Further, CKD and hypertension were stronger risk factors for VT in blacks, while a shorter aPTT was a weaker risk factor for VT in blacks. Larger studies of VT in blacks addressing environmental and genetic risk factors and health-care disparities are needed to fully understand reasons for these ethnic differences in VT incidence.Table:Age- and Sex-Adjusted Hazard Ratio for VT Stratified by RaceBlacksWhitesp-interactionFollow-up time:69,908 person-years223,831 person-yearsHypertension2.12 (1.53, 2.94)1.07 (0.88, 1.31)0.0005Chronic kidney disease2.37 (1.37, 4.10)1.00 (0.88, 1.63)0.02aPTT < median (29s)1.40 (1.01, 1.95)2.14 (1.66, 2.75)0.04 Disclosure:No relevant conflicts of interest to declare.

Is Platelet Aggregation a Useful Investigation in Assessing the Risk of Thrombosis in Patients With JAK-Positive Chronic Myeloproliferative Disorders? Brief Report: A Study on 14 Patients

Brief Abstract Patients with chronic myeloproliferative disorders have frequently thrombosis, especially for JAK2-positive patients. The aim of this study is to identify and correlate abnormalities of platelet aggregation for 14 JAK-positive patients, with thrombosis incidence. Thromboses were present more frequently in the JAK-positive group than the JAK-negative group. Patients with JAK2 genotype have more diminished platelet response for ADP, epinephrine, and collagen than the JAK-negative group and normal response for ristocetin, but these results do not have statistical significance to correlate with a higher risk of thrombosis Full Abstract Background Patients with chronic myeloproliferative disorders (CMPD) have a variety of structural and functional abnormalities of platelets. JAK2, which is constitutively activated in most patients with CMPD, might be involved in signal transduction for thrombopoietin-induced aggregation of platelets in these disorders. The patients with JAK2-positive CMPD have a higher incidence of venous thrombosis compared with noncarriers; these are more frequent in patients with the wild-type JAK2 genotype. Aim We aim to identify abnormalities of platelet aggregation for CMPD patients with JAK present and to correlate these findings with increased risk of thrombosis. Materials and Methods We present a retrospective study on 14 cases with JAK2-positive CMPD compared with 6 cases with JAK2-negative CMPD admitted in University Emergency Hospital Bucharest. We analyzed the clinical and laboratory parameters for both groups. Platelet function was investigated by platelet aggregation on Chrono-log aggregometer. As stimuli, we used ADP, collagen, epinephrine, and ristocetin. Results and Discussion We studied 14 JAK2-positive patients (5 patients, ET; 6, PV; 1, IMF; and 2, unclassifiable CMPD), 9 men and 5 women, with a median age of 58.35 years; and 6 JAK2-negative patients (1 patient, ET; 2, PV; 3, IMF), 4 men and 2 women, with a median age of 67.16 years. Thrombosis was present in 69.12% of the JAK2-positive patients. Of these, 3 patients presented with portal vein thrombosis as the first clinical manifestation; all 3 patients were young (median age, 33 years). Ischemic stroke was presented in 5 patients (median age, 74.75 years), arterial or venal thrombosis in 2 patients. Patients who were JAK negative rarely presented with thrombosis (1 patient in our study). Platelet aggregation studies showed decreased response to ADP (49.75 vs. 50.92), epinephrine (23.05 vs. 11.53), and collagen (42.93 vs. 66.51). For ristocetin, we obtained normal value for JAK2-positive patients (60.67 vs. 44). We also obtained higher duration of collagen lag phase for JAK2-positive patients (153.97 vs. 61.57) and no differences for amplitude or duration of ADP lag phase (4.27 vs. 5.1; 8.14 vs. 9.46) or amplitude of collagen lag phase (6.21 vs. 7.61). Deaggregation is more frequent for JAK2-positive patients: 6 cases (42.85%) versus 5 cases (83.33%) for ADP; 4 cases (28.57%) versus 2 cases (33.33%) for collagen. Conclusion Patients with CMPD frequently present with venal thrombosis (portal/suprahepatic veins) or ischemic strokes. In patients with JAK2-positive CMPD, platelet aggregation is diminished for ADP, epinephrine, and collagen; also, the lag phase was longer for collagen in JAK2-positive patients. Platelet aggregation is not enough of a technique for the investigation of platelet function in order to correctly establish the risk of thrombosis. In our study, the low number of cases does not allow obtaining statistically significant results.

High incidence of venous thrombosis after surgery for abdominal aortic aneurysm

The incidence of venous thromboembolism (VT) after aortic abdominal aneurysm (AAA) surgery is imprecisely reported. On one hand, thromboprophylaxis has improved, on the other hand, AAA patients have become older and/or present worse comorbidities. Herein, we prospectively analyzed the incidence of VT in a continuous series of patients operated on for AAA repair and looked for predictive factors. Between January 1, 2005, and December, 31, 2006, 193 consecutive patients (177 men and 16 women), mean age 73 (range, 47-93) underwent elective AAA repair, 137 open (71%) and 56 endovascular (29%), in our institution. Thromboprophylaxis consisted of thigh-length compression bandages or stockings, early mobilization, and a daily subcutaneous injection of low-molecular-weight heparin (enoxaparin 40 mg per day). Patients with renal insufficiency or aged over 80 were given unfractionated heparin (5000 IU twice a day). Heparin was started between day 1 and day 5 (median = day 1) after surgery, according to the prescription of the surgeon. A bilateral lower limb duplex venous compression ultrasonography scan using 3 to 7.5 MHz transducers was systematically done before and after surgery in each patient. Two groups were considered: group 1 with postoperative VT (n = 17) and group 2 without (n = 176). The 17 patients with VT were compared with 51 patients randomly chosen among the 176 patients without VT. Different characteristics such as venous risk factors, preoperative antithrombotic treatment, anatomical features of the AAA, and perioperative data were studied. Seventeen patients (8.1%) were diagnosed with postoperative VT (15 asymptomatic deep vein thrombosis [DVT] and 2 symptomatic pulmonary embolisms [PE]). VTE tended to be more frequent in open (10.2%) than endovascular (5.3%) repair (P = .28). Among perioperative data, delay to thromboprophylaxis was related to bleeding complication (P = .05) and blood transfusion (P = .02), and tended to be longer in VT patients (1.7 +/- 1.4 vs 0.9 +/- 0.9 day; P = .09). Despite systematic prevention with heparin, surgery for AAA repair induces a high incidence of postoperative VT. This series mandates for vigilance about VT, with particular attention to the patients who received transfusion with fresh frozen plasma. Even though this series is one of the largest ever published on this topic, the rarity of the events calls for confirmation with a larger prospective study.

Predicting Thrombosis in Factor VLeiden Heterozygotes.

Factor VLeiden (G1691A;R506Q) is an autosomal dominant allele displaying high prevalence (3–7%) in the United States Caucasian population and a high incidence of venous thrombosis in homozygotes (50% lifetime risk) but reduced penetrance in heterozygote carriers (<10% lifetime risk). Factors that precipitate or suppress the expression of the thrombotic phenotype in factor VLeiden heterozygotes are not well defined except for relatively infrequent instances of coexpression of other thrombophilic risk factors, e.g. the prothrombin G20210A mutant. Our goal is to mathematically evaluate the effect of factor VLeiden on tissue factor-initiated thrombin generation and determine whether concentration variations within the normal range of antithrombin (86–128%), prothrombin (60–140%) or protein C (77–183%) modulate the factor VLeiden effect when all other factor levels are at mean physiologic concentrations. Our mathematical model (Hockin et al. (2002) JBC 277:18322) was extended to incorporate the protein C pathway by including descriptions of thrombin binding to thrombomodulin, activation of protein C and factor Va inactivation by activated protein C. Simulations were conducted with 100% factor V, 50% factor V/50% factor VLeiden (heterozygote), and 100% factor VLeiden (homozygote). Heterozygous expression of factor VLeiden increases the maximum level of thrombin by 25% and the maximum rate of thrombin generation by a factor of 1.6 over that seen with 100% factor V. Homozygous factor VLeiden yields a 2.6-fold increase in maximum rate and a 60% increase in maximum thrombin level compared to 100% factor V. Decreasing the protein C concentration to 77% in a factor VLeiden heterozygote results in a thrombin generation profile with maximum levels and rates comparable to the factor VLeiden homozygote. At 150% protein C, thrombin generation is suppressed to levels similar to those seen with 100% factor V. When the effect of variable prothrombin levels in a factor VLeiden heterozygote is examined, a 60% level of prothrombin decreases the maximum level of thrombin generation below that seen with 100% factor V. When prothrombin levels are at 140% in the factor VLeiden heterozygote, the thrombin generation profile is similar to that observed with 100% factor VLeiden . When the effect of variable antithrombin levels was tested in a factor VLeiden heterozygote, a 14% decrease in antithrombin resulted in maximum thrombin levels approaching those of the factor VLeiden homozygote. In contrast, 128% antithrombin in a factor VLeiden heterozygote resulted in the suppression of thrombin generation to levels consistent with those seen with 100% factor V. Our results predict that the thrombotic effect of heterogenous expression of factor VLeiden can be reduced when prothrombin levels are at the low extreme of the normal range or when antithrombin or protein C levels are at the high extreme of the normal range. Conversely, the thrombotic effect of the heterozygous expression of factor VLeiden is intensified when prothrombin levels are at the high extreme of normal values or when antithrombin or protein C levels at the low extreme of normal. These results may contribute to the understanding of phenotypic variation within factor VLeiden heterozygotes.

Protein Z Dependent Protease Inhibitor Inhibition of Factor XIa Is Accelerated by Unfractionated Heparin in the Presence and Absence of Protein Z: Further Evidence of the Potential Significance of XIa Inhibitory Activity.

Protein Z dependent protease inhibitor (ZPI) is a human plasma serpin that inhibits factors Xa and XIa in the coagulation pathway. Kinetic studies have shown that ZPI is an efficient inhibitor of factor Xa. This interaction is accelerated by protein Z in the presence of calcium and phospholipid. The inhibition of factor XIa is by an alternative mechanism that does not require phospholipid but is influenced by both heparin and protein Z; heparin increases inhibition whereas protein Z /calcium delays inhibition. The latter maybe physiologically relevant to XIa inhibitory activity as ZPI and protein Z circulate in complex in plasma, with ZPI in slight excess. The kinetics of ZPI/XIa/heparin interactions have not been fully characterised. In this study we report the kinetic analysis of the interaction between factor XIa and recombinant ZPI expressed in Escherichia coli, in the presence of unfractionated heparin, pentasaccharide and protein Z.Results: Recombinant ZPI (rZPI) had characteristics similar to native protein as previously described; serpin-protease complexes were non-covalent, and reactive centre loop proteolytic cleavage of ZPI was noted during this reaction. On SDS gel rZPI had a molecular weight of 50kDa. Circular dichroism of rZPI showed an unfolding transition on thermal denaturation typical of a serpin in native conformation with a Tm of 58.8°C. In contrast loop cleaved rZPI had increased thermal stability as expected for a serpin. A discontinuous method was used to measure the rate of inhibition of target proteases by rZPI; the first order rate constant was measured over time under pseudo first order conditions, and was used to derive the second order rate constant (ka) as shown in Table 1.Table 1: Second order rate constants (ka)Xa (Ms−1)XIa (Ms−1)ZPI1.9 x 1039.0 x 104ZPI + protein Z*6.6 x 1051.8 x 104ZPI + unfractionated heparin (1IU/mL)-1.0 x 106ZPI + pentasaccharide (500nM)-1.0 x 105ZPI + protein Z* + unfractionated heparin (1IU/mL)-6.0 x 105* And calcium/phospholipid vesiclesIn the presence of calcium and phospholipid vesicles the ka for Xa in the absence and presence of protein Z was similar to previous reports. The ka for ZPI inhibition of XIa increased 11 fold in the presence of unfractionated heparin. Heparin titration curves suggest that a template mechanism is likely; the heparin pentasaccharide had no impact on inhibition rate consistent with this observation. It has previously been reported that protein Z impedes the ZPI inhibition of XIa; our results support this with a 5-fold reduction in ka. However the addition of heparin to ZPI in the presence of Protein Z leads to a significant 33-fold increase in inhibitory activity with a rate similar to the inhibitory activity of ZPI against Xa in the presence of protein Z.Conclusions: There are several physiological inhibitors of factor XIa. In previous reports ZPI inhibition only increased 2-fold in the presence of heparin. Our results confirm that heparin increases the ZPI inhibition of XIa but with a significantly higher increase than previously reported. The increase in activity is even more marked in the presence of protein Z. Although protein Z alone inhibits ZPI activity against XIa the combination with heparin achieves a 33 fold increase in activity. Of all the serpin inhibitors of XIa, antithrombin is considered a major inhibitor in the presence of heparin. Our results show that the ka for FXIa inhibition in the presence of ZPI, protein Z and heparin is more than 20 fold higher than the ka reported for the antithrombin/heparin inhibition of XIa (2-3x104Ms−1). We have previously reported a higher incidence of venous thrombosis in patients with nonsense mutations in the ZPI gene suggesting the clinical significance of this protein. The suggestion that the inhibition of XIa maybe more relevant than that of Xa has been raised in recent murine work where ZPI knockouts have a more severe phenotype than protein Z knockouts. ZPI inhibition of XIa in the presence of endogenous heparins maybe an important contributor to its physiological significance.

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Surgical techniques in right laparoscopic donor nephrectomy.

The benefits of laparoscopic donor nephrectomy (LDN) have been well described, but limitations in the technical performance of LDN of the right kidney have isolated its performance to only a few advanced laparoscopic centers. Laparoscopic harvesting of the right kidney is technically more challenging than that of the left kidney because of the short right renal vein and the need to retract the liver away from the right kidney. Also, early experience with right LDN was marked by a high incidence of venous thrombosis and graft loss. Because of the challenge and complications associated with right LDN, most laparoscopic surgeons favor left LDN and many avoid right LDN. Also, not all potential donors have anatomy conducive to left nephrectomy. The majority of groups performing right LDN have used the presence of multiple left renal arteries ( 3), a dominant left kidney, or a cystic lesion of unknown histology in the right kidney as relative contraindications to left LDN. Despite prior reports from the Maryland group indicating the feasibility of left LDN in donors with multiple arteries numbering more than three, this and other groups have deferred this option for the performance of right LDN in the setting of either singleor doublevessel donors on the right side. Technical shortcomings of the original LDN procedure, when applied to procurement of the right kidney, required modifications to improve outcomes. Several authors postulated that the increased risk of thrombosis after right LDN was because of shortening of the right renal vein necessitated by the use of standard endoscopic vascular staplers. The Johns Hopkins group was the first to address these technical difficulties via the open division of the renal vein and the more proximal placement of the extraction port. In an alternative approach, we have reported the use of the hand-assist extraction port to facilitate renal vein division. This article reviews the technical challenges of right LDN and offers several approaches for improving the right LDN technique.