A Murine Model with JAK2V617F Expression in Both Hematopoietic Cells and Vascular Endothelial Cells Recapitulates the Key Features of Human Myeloproliferative Neoplasm

Introduction Although murine models have provided unequivocal evidence that the JAK2V617F mutation is able to cause myeloproliferative neoplasms (MPNs), there is significant heterogeneity in disease phenotypes between different murine models and none has been able to recapitulate both the myeloproliferative phenotype and cardiovascular pathology seen in patients with MPNs. In addition, these murine models were mostly followed for less than 3-9 months and how aging affects MPN disease progression has not been studied. Endothelial cells (ECs) are an essential component of the hematopoietic niche, and they have been shown to express the JAK2V617F mutation in patients with MPNs. In this study, we investigated how MPN progresses in the JAK2V617F-bearing vascular niche during aging. Methods JAK2V617F Flip-Flop (FF1) mice (which carry a Cre-inducible human JAK2V617F gene driven by the human JAK2 promoter) were crossed with Tie2-cre mice to express JAK2V617F specifically in all hematopoietic cells (including HSPCs) and vascular ECs (Tie2FF1). Results The Tie2FF1 mice developed essential thrombocythemia to primary myelofibrosisdisease transformation with extramedullary splenic hematopoiesis during 18-month follow up. No evidence of leukemia transformation was observed in the Tie2FF1 mice. (Figure 1) Hematopoietic colony formation assays, flow cytometry analysis, and in vitro culture experiments revealed that there was a loss of both HSPC number and HSPC function in the marrow of old Tie2FF1 mice during aging, mimicking the advanced phases of myelofibrosis. In contrast, the spleen of old Tie2FF1 mice was able to maintain the expansion of JAK2V617F mutant hematopoiesis during aging and MPN disease progression. (Figure 2) These differences between marrow and spleen hematopoiesis in the old Tie2FF1 mice prompted us to investigate how aging affects the JAK2V617F mutant hematopoiesis differently in the marrow and spleen. We found that, although the JAK2V617F mutant HSCs (Lin -cKit +Sca1 +CD150 +CD48 -) from old Tie2FF1 mice were more proliferative than wild-type HSCs in both the marrow and spleen, mutant marrow HSCs were more apoptotic and senescent than wild-type HSCs in the marrow while mutant spleen HSCs were relatively protected in the spleen. Examination of the hematopoietic vascular niche revealed that marrow ECs (CD45 -CD31 +) were significantly decreased in old Tie2FF1 mice compared to age-matched control mice; in contrast, spleen ECs were significantly expanded and less senescent in old Tie2FF1 mice compared to control mice. Therefore, the different vascular niche function of the marrow and spleen could contribute to the decreased marrow hematopoiesis and expanded splenic hematopoiesis we have observed in the Tie2FF1 mice during aging. (Figure 3) Previously, we reported that the Tie2FF1 mice developed spontaneous heart failure with thrombosis, vasculopathy, and cardiomyopathy at 20wk of age. Here, we followed the cardiovascular function of Tie2FF1 mice during aging. At 18mo of age, the Tie2FF1 mice continued to demonstrate a phenotype of dilated cardiomyopathy with a moderate but significant decrease in left ventricular ejection fraction and an increase in left ventricular volume and mass compared to age-matched control mice. Histology examination revealed spontaneous thrombosis in the right ventricle, pulmonary arteries, both main (epicardial) coronary arteries and scattered coronary arterioles (microvessels) in the old Tie2FF1 mice, while age-matched Tie2-cre control mice had no evidence of spontaneous thrombosis in their heart or lungs. Despite these cardiovascular dysfunctions, there was no difference in body weight nor was there any increased incidence of sudden death between the old Tie2FF1 mice and control mice. These findings suggested that there was a persistent but compensated cardiomyopathy and heart failure in the Tie2FF1 mice during aging. (Figure 4) Conclusion Compared to other MPN murine models reported so far, the Tie2FF1 mice is the first MPN murine model that faithfully recapitulated almost all the key features of the human MPN diseases. Considering the presence of the JAK2V617F mutation in microvascular ECs isolated from patients with MPNs and the recapitulation of all the key features of human MPN diseasesby the Tie2FF1 mice, the roles of endothelial dysfunction in the hematologic and cardiovascular pathogenesis of MPN shall be further investigated. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Hepatic artery pseudoaneurysm secondary to a cholangitic abscess and its spontaneous thrombosis

Hepatic artery pseudoaneurysm (HAP) is mostly encountered secondary to trauma or iatrogenic causes. HAP associated with cholangitic liver abscess is a rare complication. We present a case of gallstone disease and choledocholithiasis who developed moderate cholangitis and a liver abscess. A small HAP was detected incidentally on a biphasic CT done to evaluate the biliary system. Repeat CT after management with endoscopic retrograde cholangiopancreatography and antibiotics showed resolution of cholangitic abscess with spontaneous thrombosis of HAP.

A national cohort study on hemodialysis arteriovenous fistulas after kidney transplantation - long-term patency, use and complications

Objective To describe the long-term hemodialysis arteriovenous fistula (AVF) patency, incidence of AVF use, incidence and nature of AVF complications and surgery in patients after kidney transplantation. Patients and methods We retrospectively analysed the AVF outcome and complications in all adult kidney allograft recipients transplanted between January 1st, 2000 and December 31, 2015 with a functional AVF at the time of transplantation. Follow-up was until December 31, 2019. Results We included 626 patients. Median AVF follow-up was 4.9 years. One month after kidney transplantation estimated AVF patency rate was 90%, at 1 year it was 82%, at 3 years it was 70% and at 5 years it was 61%; median estimated AVF patency was 7.9 years. The main cause of AVF failure was spontaneous thrombosis occurring in 76% of AVF failure cases, whereas 24% of AVFs were ligated or extirpated. In a Cox multivariate model female sex and grafts were independently associated with more frequent AVF thrombosis. AVF was used in about one third of our patients. AVF-related complications occurred in 29% of patients and included: growing aneurysms, complicated thrombosis, high-flow AVF, signs of distal hypoperfusion, venous hypertension, trauma of the AVF arm, or pain in the AVF/arm. Conclusions AVFs remain functional after kidney transplantation in the majority of patients and are often re-used after graft failure. AVF-related complications are common and require proper care.

Spontaneous thrombosis of the arterial duct in a newborn with alloimmune thrombocytopaenia

We present an uncommon challenging case of spontaneous thrombosis of the arterial duct and with alloimmune thrombocytopaenia in a full-term newborn who presented with respiratory distress, hypoglycaemia dispersed petechiae on the trunk, and significant haemorrhage of the umbilical venous catheter.

Thrombophilia in obstetric practice

The rate of thromboembolic complications associated with thrombophilia is very high; therefore the detection of thrombophilia mutations in the high-risk group of patients is important for the prevention of morbidity, mortality and obstetric losses. The problem of thrombophilia is dealt with by doctors of various specialties: laboratory stuff, geneticists, vascular surgeons, hematologists, neurologists, cardiologists and obstetricians-gynecologists. At the same time, patients with spontaneous thrombosis are followed-up for years without proper examination for thrombophilia. Considering that pregnancy is a condition associated with a high probability of re-thrombosis, it is advisable to determine the cause and tactics of management and treatment of pregnant women as early as possible during the period of pregnancy.

Reoperation after Implanting a Triple-Branched Stent Graft: Case Report

Acute type A aortic dissection (ATAAD) is an aortic catastrophe with high mortality, requiring immediate surgical intervention. Recently, placement of a triple-branch stent graft has emerged as an effective technique for total arch reconstruction. Indications for this approach, however, are limited by various complications, such as endoleak, stent graft migration or kinking, and spontaneous thrombosis. Here, we report a case of Marfan syndrome in which the patient underwent a reoperation owing to frame fractures (or degradation of graft material) in a triple-branched stent graft implanted 5 years earlier.