The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006–1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of ≥1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15–11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort.

To learn more about controlling renal interstitial hydrostatic pressure (RIHP), we assessed its response to renal medullary direct interstitial volume expansion (rmDIVE = 100 μL bolus infusion/30 sec). Three experimental series (S) were performed in hydropenic, anesthetized, right‐nephrectomized, acute left renal‐denervated and renal perfusion pressure‐controlled rats randomly assigned to groups in each S. S1: Rats without hormonal clamp were contrasted before and after rmDIVE induced via 0.9% saline solution bolus (SS group) or 2% albumin in SS bolus (2% ALB + SS group). Subcapsular ΔRIHP rose slowly, progressively and similarly in both groups by ~3 mmHg. S2: Rats under hormonal clamp were contrasted before and after sham rmDIVE (time CTR group) and real rmDIVE induced via either SS bolus (SS group) or SS bolus containing the subcutaneous tissue fibroblast relaxant dibutyryl‐cAMP (SS + db‐cAMP group). ΔRIHP showed time, group, and time*group interaction effects with a biphasic response (early: ~1 mmHg; late: ~4 mmHg) in the SS group that was absent in the SS + db‐cAMP group. S3: Two groups of rats (SS and SS + db‐cAMP) under hormonal clamp were contrasted as in S2, producing similar ΔRIHP results to those of S2 but showing a slow, progressive, and indistinct decrease in renal outer medullary blood flow in both groups. These results provide highly suggestive preliminary evidence that the renal interstitium is capable of contracting reactively in vivo in response to rmDIVE with SS and demonstrate that such a response is abolished when db‐cAMP is interstitially and concomitantly infused.

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For chronic myeloid leukemia (CML) patients with a known risk of cardiovascular events (CVE), imatinib is often recommended for first-line tyrosine kinase inhibitor (TKI) treatment rather than a second-generation TKI (2G-TKI) such as nilotinib or dasatinib. To date, very few studies have evaluated the genetic predisposition associated with CVE development on TKI treatment. In this retrospective study of 102 CML patients, 26 CVEs were reported during an average follow-up of over 10 years. Next-generation sequencing identified pathogenic/likely pathogenic mutations in genes associated with myeloid malignancies in 24.5% of the diagnostic samples analyzed. Patients with a recorded CVE had more myeloid mutations (0.48 vs. 0.14, p = 0.019) and were older (65.1 vs. 55.7 years, p = 0.016). Age ≥ 60 years and receiving a 2G-TKI in first-line were CVE risk factors. The presence of a pathogenic somatic myeloid mutation was an independent risk factor for CVE on any TKI (HR 2.79, p = 0.01), and significantly shortened the CV event-free survival of patients who received first-line imatinib (by 70 months, p = 0.011). Indeed, 62% of patients on imatinib with mutations had a CVE vs. the 19% on imatinib with a mutation and no CVE. In conclusion, myeloid mutations detectable at diagnosis increase CVE risk, particularly for patients on imatinib, and might be considered for first-line TKI choice.

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To assess the determinants of Renal Interstitial Hydrostatic Pressure (RIHP) amplification during saline volume expansion (E), [Pr]p, Ht, renal perfusion pressure (RPP), renal medullary blood flow (RMBF) and RIHP were measured in two groups of anesthetized, left renal denervated, hormonally clamped and RPP controlled rats, with or without medullary interstitial infusion of L‐NAME (LNA group or VHC group, respectively ) during both hydropenia (H) and E (0.58 ml/min, i.v., 2.5% of bw). RMBF was measured by laser‐Doppler flowmetry and RIHP by sub‐capsular catheter. Under RPP control (100 mmHg), LNA group showed a decrease in %ΔRMBF (−24.7 ± 7 %) vs VHC group (−8 ± 4%, p=0.05) during H, however, during E both group rose similarly their %ΔRMBF (49.8 ± 13% LNA group vs 33.7 ± 5% VHC group). Delta (Δ= E ‐ H) of [Pr]p was of −1.7 ± 0.08 g/dl in LNA group vs −1.6 ± 0.07 g/dl in VHC group (ns). ΔHt was of −10.3 ± 0.6% in LNA group vs −8.0 ± 0.7% in VHC group (p=0.03). ΔRIHP was of 4.2 ± 0.7 mmHg in LNA group vs 3.6 ± 0.4 mmHg in VHC group (ns). Both groups showed a similar upper shift of %ΔRMBF/RPP relationship from H to E, however, whereas LNA group showed autoregulation of %ΔRMBF during E, VHC group did not. Both groups showed similar flat ΔRIHP/RPP relationships during H, which were amplified similarly during E. Conclusion: Data modeling indicated that RIHP amplification during E in the rat is independent of hemodilution and autoregulatory and non‐autoregulatory changes in RMBF. Supported by: C07‐FAI‐11‐14.50.