Gender and Vascular Complications in the JAK2 V617F-Positive Myeloproliferative Neoplasms

We previously found that gender influenced the JAK2 V617F allele burden, but it is unknown whether this gender difference in molecular epidemiology influences complications in the myeloproliferative neoplasms (MPNs). Historically, vascular complications represented the most common cause of mortality in polycythemia vera and essential thrombocytosis and contributed to morbidity in primary myelofibrosis. To determine the influence of gender on vascular complications, we retrospectively analyzed associations between gender and vascular complications. Despite their younger age, less prevalent dyslipidemia or smoking history, lower white blood counts, and lower JAK2 V617F allele burden, women had higher rates of abdominal venous thrombosis and comparable rates of all vascular complications. Vascular risk is currently not easily stratified by MPN-disease burden or traditional risk factors. Our analysis contributes to growing literature emphasizing gender differences in the MPN and further supports the important impact of individual and host variation on MPN clinical manifestations, and especially vascular risk

Abdominal venous thrombosis presenting in myeloproliferative neoplasm with JAK2 V617F mutation: a case report

<p>Abstract</p> <p>Introduction</p> <p>An unprovoked thombotic event in a patient is cause for further evaluation of an underlying hypercoaguable state. The investigation should include a thorough search, including checking for a variety of known inherited and acquired hypercoaguble states (protein C or S deficiency, anti-phospholipid antibodies, and anti-thrombin III deficiency) and gene mutations that predispose patients to an increased risk of clotting (for example, prothrombin gene 20210 mutation, factor V Leiden, and the <it>JAK2 V617F </it>mutation).</p> <p>Case presentation</p> <p>We report the case of a 38-year-old Caucasian woman with spontaneous, unprovoked abdominal venous thrombosis and demonstrate how testing for the <it>JAK2 V617F </it>mutation was useful in unmasking an underlying hypercoaguable state.</p> <p>Conclusions</p> <p><it>JAK2 V617F</it>-positive myeloproliferative neoplasm was diagnosed. This case illustrates the importance of testing for <it>JAK2 V617F </it>in patients presenting with Budd-Chiari syndrome, even in the absence of overt hematologic abnormalities, in order to establish a diagnosis of underlying myeloproliferative neoplasm.</p

Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L), or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time, primary MPN cell samples from individual patients displayed a high degree of variability in sensitivity to these drugs. Ruxolitinib inhibited 2 major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-dependent protein kinase-mediated nonhomologous end-joining, and, when combined with olaparib, caused abundant accumulation of toxic DSBs resulting in enhanced elimination of MPN primary cells, including the disease-initiating cells from the majority of patients. Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in vivo against JAK2(V617F)+ murine MPN-like disease and also against JAK2(V617F)+, CALR(del52)+, and MPL(W515L)+ primary MPN xenografts. In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways sensitized MPN cells to synthetic lethality triggered by PARP inhibitors

The Gamma Gap and All-Cause Mortality.

The difference between total serum protein and albumin, i.e. the gamma gap, is a frequently used clinical screening measure for both latent infection and malignancy. However, there are no studies defining a positive gamma gap. Further, whether it is an independent risk factor of mortality is unknown.This study examined the association between gamma gap, all-cause mortality, and specific causes of death (cardiovascular, cancer, pulmonary, or other) in 12,260 participants of the National Health and Nutrition Examination Survey (NHANES) from 1999-2004. Participants had a comprehensive metabolic panel measured, which was linked with vital status data from the National Death Index. Cause of death was based on ICD10 codes from death certificates. Analyses were performed with Cox proportional hazards models adjusted for mortality risk factors. The mean (SE) age was 46 (0.3) years and the mean gamma gap was 3.0 (0.01) g/dl. The population was 52% women and 10% black. During a median follow-up period of 4.8 years (IQR: 3.3 to 6.2 years), there were 723 deaths. The unadjusted 5-year cumulative incidences across quartiles of the gamma gap (1.7-2.7, 2.8-3.0, 3.1-3.2, and 3.3-7.9 g/dl) were 5.7%, 4.2%, 5.5%, and 7.8%. After adjustment for risk factors, participants with a gamma gap of ≥3.1 g/dl had a 30% higher risk of death compared to participants with a gamma gap <3.1 g/dl (HR: 1.30; 95%CI: 1.08, 1.55; P = 0.006). Gamma gap (per 1.0 g/dl) was most strongly associated with death from pulmonary causes (HR 2.22; 95%CI: 1.19, 4.17; P = 0.01).The gamma gap is an independent risk factor for all-cause mortality at values as low as 3.1 g/dl (in contrast to the traditional definition of 4.0 g/dl), and is strongly associated with death from pulmonary causes. Future studies should examine the biologic pathways underlying these associations

Hypersplenism induced by splenic vein ligation.

Warm autoimmune hemolytic anemia (AIHA) is a rare clinical entity. It is usually caused by an IgG autoantibody directed against the red blood cell membrane that causes extravascular hemolysis predominantly in the spleen. As a result, disease states or procedures that result in hypersplenism would be expected to increase red cell destruction in patients with an underlying warm AIHA. We present the case of a patient with a previously undiagnosed warm AIHA, who developed worsening hemolysis after undergoing splenic vein ligation during a pancreaticoduodenectomy to remove a neuroendocrine tumor

Clinical applications of thrombopoietin silencing: A possible therapeutic role in COVID-19?

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemicThrombopoietin (TPO) is most recognized for its function as the primary regulator of megakaryocyte (MK) expansion and differentiation. MKs, in turn, are best known for their role in platelet production. Research indicates that MKs and platelets play an extensive role in the pathologic thrombosis at sites of high inflammation. TPO, therefore, is a key mediator of thromboinflammation. Silencing of TPO has been shown to decrease platelets levels and rates of pathologic thrombosis in patients with various inflammatory disorders (Barrett et al, 2020; Bunting et al, 1997; Desai et al, 2018; Kaser et al, 2001; Shirai et al, 2019). Given the high rates of thromboinflammmation in the novel coronavirus 2019 (COVID-19), as well as the well-documented aberrant MK activity in affected patients, TPO silencing offers a potential therapeutic modality in the treatment of COVID-19 and other pathologies associated with thromboinflammation. The current review explores the current clinical applications of TPO silencing and offers insight into a potential role in the treatment of COVID-19

Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression

An activating JAK2 mutation (JAK2 V617F) is present in the chronic myeloproliferative disorders (MPDs), polycythemia vera (PV), idiopathic myelofibrosis (IMF), and essential thrombocytosis (ET). JAK2 is also a chaperone for Mpl and responsible for its cell-surface expression. We observed a reciprocal relationship between neutrophil JAK2 V617F allele percentage and platelet Mpl expression in JAK2 V617F–positive PV, IMF, and ET patients. However, severely impaired platelet Mpl expression was present in JAK2 V617F–negative MPD patients. While JAK2 V617F allele status did not necessarily correlate with the clinical MPD phenotype, the degree of impaired platelet Mpl expression did. We conclude that multiple molecular abnormalities are involved in the pathogenesis of the MPDs and that aberrant Mpl expression may be a common denominator of aberrant signaling in both the JAK2 V617F–positive and JAK2 V617F–negative MPDs