Blood volume expansion, normovolemia, and clinical outcomes in chronic human heart failure: more is better.

Expansion in blood volume (BV) is a well-recognized response to arterial underfilling secondary to impaired cardiac output in heart failure (HF). However, the effectiveness of this response in terms of outcomes remains inadequately understood. Prospective analysis was undertaken in 110 patients with HF hospitalized and treated for fluid overload. BVs were measured in a compensated state at the hospital discharge using the indicator-dilution methodology. Data were analyzed for composite 1-year HF-related mortality/first rehospitalization. Despite uniform standard of care, marked heterogeneity in BVs was identified across the cohort. The cohort was stratified by BV expansion greater than or equal to +25% above normal (51% of cohort), mild-moderate expansion (22%), and normal BV (27%). Kaplan-Meier (K-M) survival estimates and regression analyses revealed BV expansion (greater than or equal to +25%) to be associated with better event-free survival relative to normal BV (P = 0.038). Increased red blood cell mass (RBCm; RBC polycythemia) was identified in 43% of the overall cohort and 70% in BV expansion greater than or equal to +25%. K-M analysis demonstrated polycythemia to be associated with better outcomes compared with normal RBCm (P < 0.002). Persistent BV expansion to include RBC polycythemia is common and, importantly, associated with better clinical outcomes compared with normal total BV or normal RBCm in patients with chronic HF. However, compensatory BV expansion is not a uniform physiological response to the insult of HF with marked variability in BV profiles despite uniform standard of care diuretic therapy. Therefore, recognizing the variability in volume regulation pathophysiology has implications not only for impact on clinical outcomes and risk stratification but also potential for informing individualized volume management strategies.NEW & NOTEWORTHY The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

Global REACH 2018: volume regulation in high-altitude Andeans with and without chronic mountain sickness.

The high-altitude maladaptation syndrome known as chronic mountain sickness (CMS) is characterized by polycythemia and is associated with proteinuria despite unaltered glomerular filtration rate. However, it remains unclear if indigenous highlanders with CMS have altered volume regulatory hormones. We assessed NH2-terminal pro-B-type natriuretic peptide (NT pro-BNP), plasma aldosterone concentration, plasma renin activity, kidney function (urinary microalbumin, glomerular filtration rate), blood volume, and estimated pulmonary artery systolic pressure (ePASP) in Andean males without (n = 14; age = 39 ± 11 yr) and with (n = 10; age = 40 ± 12 yr) CMS at 4,330 m (Cerro de Pasco, Peru). Plasma renin activity (non-CMS: 15.8 ± 7.9 ng/mL vs. CMS: 8.7 ± 5.4 ng/mL; P = 0.025) and plasma aldosterone concentration (non-CMS: 77.5 ± 35.5 pg/mL vs. CMS: 54.2 ± 28.9 pg/mL; P = 0.018) were lower in highlanders with CMS compared with non-CMS, whereas NT pro-BNP was not different between groups (non-CMS: 1394.9 ± 214.3 pg/mL vs. CMS: 1451.1 ± 327.8 pg/mL; P = 0.15). Highlanders had similar total blood volume (non-CMS: 90 ± 15 mL·kg-1 vs. CMS: 103 ± 18 mL·kg-1; P = 0.071), but Andeans with CMS had greater total red blood cell volume (non-CMS: 46 ± 10 mL·kg-1 vs. CMS: 66 ± 14 mL·kg-1; P < 0.01) and smaller plasma volume (non-CMS: 43 ± 7 mL·kg-1 vs. CMS: 35 ± 5 mL·kg-1; P = 0.03) compared with non-CMS. There were no differences in ePASP between groups (non-CMS: 32 ± 9 mmHg vs. CMS: 31 ± 8 mmHg; P = 0.6). A negative correlation was found between plasma renin activity and glomerular filtration rate in both groups (group: r = -0.66; P < 0.01; non-CMS: r = -0.60; P = 0.022; CMS: r = -0.63; P = 0.049). A smaller plasma volume in Andeans with CMS may indicate an additional CMS maladaptation to high altitude, causing potentially greater polycythemia and clinical symptoms.

The influence of hemoconcentration on hypoxic pulmonary vasoconstriction in acute, prolonged, and lifelong hypoxemia.

Hemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signaling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: 1) at sea level, in normoxia and isocapnic hypoxia with and without isovolumic hemodilution (n = 10, aged 29 ± 7 yr); 2) at altitude (6 ± 2 days acclimatization at 5,050 m), before and during hypervolumic hemodilution (n = 11, aged 27 ± 5 yr) with room air and additional hypoxia [fraction of inspired oxygen ([Formula: see text])= 0.15]; and 3) at altitude (4,340 m) in Andean high-altitude natives with excessive erythrocytosis (EE; n = 6, aged 39 ± 17 yr), before and during isovolumic hemodilution with room air and hyperoxia (end-tidal Po2 = 100 mmHg). At sea level, hemodilution mildly increased pulmonary artery systolic pressure (PASP; +1.6 ± 1.5 mmHg, P = 0.01) and pulmonary vascular resistance (PVR; +0.7 ± 0.8 wu, P = 0.04). In contrast, after acclimation to 5,050 m, hemodilution did not significantly alter PASP (22.7 ± 5.2 vs. 24.5 ± 5.2 mmHg, P = 0.14) or PVR (2.2 ± 0.9 vs. 2.3 ± 1.2 wu, P = 0.77), although both remained sensitive to additional acute hypoxia. In Andeans with EE at 4,340 m, hemodilution lowered PVR in room air (2.9 ± 0.9 vs. 2.3 ± 0.8 wu, P = 0.03), but PASP remained unchanged (31.3 ± 6.7 vs. 30.9 ± 6.9 mmHg, P = 0.80) due to an increase in cardiac output. Collectively, our series of studies reveal that HPV is modified by the duration of exposure and the prevailing hematocrit level. In application, these findings emphasize the importance of accounting for hematocrit and duration of exposure when interpreting the pulmonary vascular responses to hypoxemia.NEW & NOTEWORTHY Red blood cell concentration influences the pulmonary vasculature via direct frictional force and vasoactive signaling, but whether the magnitude of the response is modified with duration of exposure is not known. By assessing the pulmonary vascular response to hemodilution in acute normobaric and prolonged hypobaric hypoxia in lowlanders and lifelong hypobaric hypoxemia in Andean natives, we demonstrated that a reduction in red cell concentration augments the vasoconstrictive effects of hypoxia in lowlanders. In high-altitude natives, hemodilution lowered pulmonary vascular resistance, but a compensatory increase in cardiac output following hemodilution rendered PASP unchanged.

Global REACH 2018: dysfunctional extracellular microvesicles in Andean highlander males with excessive erythrocytosis.

High altitude-related excessive erythrocytosis (EE) is associated with increased cardiovascular risk. The experimental aim of this study was to determine the effects of microvesicles isolated from Andean highlanders with EE on endothelial cell inflammation, oxidative stress, apoptosis, and nitric oxide (NO) production. Twenty-six male residents of Cerro de Pasco, Peru (4,340 m), were studied: 12 highlanders without EE (age: 40 ± 4 yr; BMI: 26.4 ± 1.7; Hb: 17.4 ± 0.5 g/dL, Spo2: 86.9 ± 1.0%) and 14 highlanders with EE (43 ± 4 yr; 26.2 ± 0.9; 24.4 ± 0.4 g/dL; 79.7 ± 1.6%). Microvesicles were isolated, enumerated, and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with microvesicles from highlanders without and with EE. Microvesicles from highlanders with EE induced significantly higher release of interleukin (IL)-6 (89.8 ± 2.7 vs. 77.1 ± 1.9 pg/mL) and IL-8 (62.0 ± 2.7 vs. 53.3 ± 2.2 pg/mL) compared with microvesicles from healthy highlanders. Although intracellular expression of total NF-κB p65 (65.3 ± 6.0 vs. 74.9 ± 7.8.9 AU) was not significantly affected in cells treated with microvesicles from highlanders without versus with EE, microvesicles from highlanders with EE resulted in an ∼25% higher (P < 0.05) expression of p-NF-κB p65 (173.6 ± 14.3 vs. 132.8 ± 12.2 AU). Cell reactive oxygen species production was significantly higher (76.4.7 ± 5.4 vs. 56.7 ± 1.7% of control) and endothelial nitric oxide synthase (p-eNOS) activation (231.3 ± 15.5 vs. 286.6 ± 23.0 AU) and NO production (8.3 ± 0.6 vs. 10.7 ± 0.7 µM/L) were significantly lower in cells treated with microvesicles from highlanders with versus without EE. Cell apoptotic susceptibility was not significantly affected by EE-related microvesicles. Circulating microvesicles from Andean highlanders with EE increased endothelial cell inflammation and oxidative stress and reduced NO production.NEW & NOTEWORTHY In this study, we determined the effects of microvesicles isolated from Andean highlanders with excessive erythrocytosis (EE) on endothelial cell inflammation, oxidative stress, apoptosis, and NO production. Microvesicles from highlanders with EE induced a dysfunctional response from endothelial cells characterized by increased cytokine release and expression of active nuclear factor-κB and reduced nitric oxide production. Andean highlanders with EE exhibit dysfunctional circulating extracellular microvesicles that induce a proinflammatory, proatherogenic endothelial phenotype.

Evaluation of Color Difference in Placenta with Twin Anemia Polycythemia Sequence.

Twin anemia polycythemia sequence (TAPS) occurs in 5% of monochorionic twins and is characterized by large inter-twin hemoglobin differences. The postnatal diagnostic criteria for TAPS are based on hematologic parameters and placental characteristics. Placental examination after birth shows that color of the maternal side between placental territories of the anemic and polycythemic twins is remarkably different. The color difference in TAPS placentas is higher compared to monochorionic placentas with acute peripartum feto-fetal transfusion; thus, this is used as an additional diagnostic criterion for TAPS. Software such as ImageJ enables the computer-based measurement of color intensity in TAPS placentas. However, a detailed method for the calculation of color differences between anemic and polycythemic components of TAPS placentas has not yet been described. The protocol presented here provides a step-by-step method for analyzing color differences in the maternal side of TAPS placentas using ImageJ software.

Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxia.

RATIONALE: Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. OBJECTIVE: To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. METHODS AND RESULTS: We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+ß adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all P≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, P=0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (P=0.012), but this effect was not observed in the EE Andeans. CONCLUSIONS: These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.

Novel High Oxygen Affinity Hemoglobin Variant in a Patient with Polycythemia: Hb Kennisis [ß85(F1)Phe→Leu (TTT>TTG); HBB: c.258T>G].

We report the case of a 61-year-old Canadian male of Maltese descent investigated for unexplained polycythemia. Decreased p50 suggested the presence of a high oxygen affinity hemoglobin (Hb) variant. Molecular genetic testing demonstrated that he carries a novel missense mutation (HBB: c.258T>G), resulting in a Phe→Leu substitution at position 85 of the ß chain. The novel Hb variant has been designated Hb Kennisis in recognition of where the proband resides. Two other missense mutations have been reported at this position [Hb Bryn Mawr or Hb Buenos Aires, ß85(F1)Phe→Ser (HBB: c.257T>C); Hb Grantham, ß85(F1)Phe→Cys; (HBB: c.257T>G)], both of which have increased oxygen affinity.

Erythrocytosis and Performance of HbA1c in Detecting Diabetes on an Oxygen-Deficient Plateau: A Population-based Study.

CONTEXT: The hemoglobin A1c (HbA1c) test is a standard test for diabetes screening and diagnosis. OBJECTIVE: To evaluate A1c performance for diabetes screening in high-altitude polycythemia compared to a population with a high proportion of people living in an oxygen-deficient environment. DESIGN: A population-based epidemiological survey was conducted. SETTING: The cities Lhasa and Shigatse were selected. Volunteers were recruited through educational advertisements about diabetes. PARTICIPANTS: A total of 1401 Tibetan adults without known diabetes. INTERVENTIONS: Oral glucose tolerance test (OGTT), HbA1c, and complete blood cell count were performed. Hemoglobin A1c was evaluated using high-performance liquid chromatography, and serum glucose level, using the hexokinase method. MAIN OUTCOME MEASURES: World Health Organization criteria were used to define diabetes and prediabetes. Hemoglobin A1c test performance was evaluated using receiver operating characteristic analysis. RESULTS: The participants' mean age was 44.3 ± 15.0 years; 33.3% of the participants were men and 38.6% lived in urban areas. The prediabetes and diabetes prevalence rates were 7.5% and 3.6%, respectively. The optimal HbA1c cutoff for detecting diabetes was 46 mmol/mol (6.4%), with a sensitivity and specificity of 60.8% and 93.6%, respectively. The cutoff for detecting diabetes was 6.7% (50 mmol/mol) in subjects with high-altitude polycythemia (HAPC). The relationship between red blood cell (RBC) counts and HbA1c was significant (P < 0.001), while there was no correlation between hemoglobin (Hb) and HbA1c (P = 0.085). Multiple linear regression analysis showed that after adjusting for age and fasting serum glucose or 2-hour OGTT (OGTT2h) serum glucose, RBC count and not Hb level was an independent risk factor for HbA1c (ß = 0.140, P < 0.001). CONCLUSIONS: The optimal HbA1c cutoff for detecting diabetes was 46 mmol/mol (6.4%) in Tibet. Red blood cell count was an independent risk factor for elevated HbA1c, and HAPC may affect the predictive ability of HbA1c.

Eritroaféresis terapéutica: experiencia en pacientes con policitemia vera y eritrocitosis secundaria / Therapeutic erythroapheresis: Experience in patients with polycythemia vera and secondary erythrocytosis

La eritrocitaféresis terapéutica (ET) es una estrategia más eficiente que la flebotomía en la reducción del hematocrito en las eritrocitosis primarias y secundarias. Objetivo: Analizar la tasa de respuesta y seguridad de la ET en policitemia vera (PV) y eritrocitosis secundaria (ES). Pacientes y método: Revisión retrospectiva de los pacientes con PV o ES tratados con ET, ante el fracaso a flebotomías o con comorbilidades que impedían cambios importantes de volemia. Resultados: Se realizaron 127 sesiones de ET (48 PV y 79 ES) en 20 pacientes (12 ES y 8 PV). La respuesta se obtuvo en el 87,5% de PV y en el 50% de ES. La tasa de complicaciones fue del 7,08%. Conclusiones: A pesar del tamaño de nuestra muestra y la heterogeneidad clínica de nuestra serie, podemos postular que la ET reduce de manera segura los valores de hematocrito en menor tiempo que la flebotomía, especialmente en pacientes con PV y en casos seleccionados de ES en quienes se prevé intolerancia hemodinámica a la flebotomía o en quienes falla este método

Therapeutic erythrocytapheresis (TE) is a more efficient strategy compared to phlebotomy to deplete levels of haematocrit in primary and secondary erythrocytosis. Objective: To analyse response rate and safety profile of TE in polycythemia vera (PV) and secondary erythrocytosis (SE). Patients and method: Retrospective review of all patients with PV or SE treated with TE, due to phlebotomy failure, or comorbidities that prevented changes of blood volumen. Results: 217 TE sessions (48 PV and 79 SE) corresponding to 20 patients (12 ES and 8 PV). Response were achieved in 87.5% of PV patients and in 50% of SE patients. Adverse effects related to TE performance occurred in 7.08%. Conclusion: Despite our small sample size and the heterogeneous nature of the patients included, we can postulate that TE is a secure strategy that can achieve haematocrit depletion in a shorter time than phlebotomy, specifically in PV patients and in selected cases of SE with expected haemodynamic intolerance to phlebotomies or in patients who fail to respond to phlebotomies

Global Reach 2018: reduced flow-mediated dilation stimulated by sustained increases in shear stress in high-altitude excessive erythrocytosis.

Excessive erythrocytosis [EE; hemoglobin concentration (Hb) ≥ 21 g/dL in adult men] is a maladaptive high-altitude pathology associated with increased cardiovascular risk and reduced reactive hyperemia flow-mediated dilation (FMD); however, whether a similar impairment occurs in response to more commonly encountered sustained increases in shear stress [sustained stimulus (SS)-FMD] over a range of overlapping stimuli is unknown. We characterized SS-FMD in response to handgrip exercise in Andeans with and without EE in Cerro de Pasco, Peru (4,330 m). Andean highlanders with EE (n = 17, Hb = 23.2 ± 1.2 g/dL) and without EE (n = 23, Hb = 18.7 ± 1.9 g/dL) performed 3 min of rhythmic handgrip exercise at 20, 35, and 50% of maximum voluntary contraction (MVC). Duplex ultrasound was used to continuously record blood velocity and diameter in the brachial artery, and blood viscosity was measured to accurately calculate shear stress. Although baseline shear stress did not differ, Andeans with EE had 22% lower shear stress than Andeans without at 50% MVC (P = 0.004). At 35 and 50% MVC, SS-FMD was 2.1 ± 2.0 and 2.8 ± 2.7% in Andeans with EE compared with 4.1 ± 3.4 and 7.5 ± 4.5% in those without (P = 0.048 and P < 0.001). The stimulus-response slope (∆shear stress vs. ∆diameter) was lower in Andeans with EE compared with Andeans without (P = 0.028). This slope was inversely related to Hb in Andeans with EE (r2 = 0.396, P = 0.007). A reduced SS-FMD in response to small muscle mass exercise in Andeans with EE indicates a generalized reduction in endothelial sensitivity to shear stress, which may contribute to increased cardiovascular risk in this population.NEW & NOTEWORTHY High-altitude excessive erythrocytosis (EE; hemoglobin concentration ≥ 21 g/dL) is a maladaptation to chronic hypoxia exposure and is associated with increased cardiovascular risk. We examined flow-mediated dilation (FMD) in response to sustained elevations in shear stress achieved using progressive handgrip exercise [sustained stimulus (SS)-FMD] in Andean highlanders with and without EE at 4,330 m. Andeans with EE demonstrated lower SS-FMD compared with those without. Heightened hemoglobin concentration was related to lower SS-FMD in Andeans with EE.

Global REACH 2018: High Blood Viscosity and Hemoglobin Concentration Contribute to Reduced Flow-Mediated Dilation in High-Altitude Excessive Erythrocytosis

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P<0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P=0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r2=0.303; P<0.001) and Hb ( r2=0.230; P=0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P<0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P=0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.

In utero Partial Exchange Transfusion Combined with in utero Blood Transfusion for Prenatal Management of Twin Anemia-Polycythemia Sequence.

Monochorionic twin pregnancies are at risk of unique complications due to placental sharing and vascular connections between placental territories assigned for each twin. Twin anemia-polycythemia sequence (TAPS) is an infrequent but potentially dangerous complication of abnormal placental vascular connections. TAPS occurs due to very-small-caliber (< 1 mm) abnormal placental vascular connections which lead to chronic anemia in the donor twin and polycythemia in the recipient twin. TAPS may occur spontaneously or following fetoscopic laser photocoagulation of communicating placental vessels for twin-twin transfusion syndrome. One of the hallmarks of TAPS is the absence of polyhydramnios and oligohydramnios. The postnatal diagnosis is based on significant hemoglobin discrepancy between the twins. Middle cerebral artery peak systolic velocity Doppler ultrasound allows for the prenatal diagnosis of TAPS. The optimal prenatal treatment and intervention timing has not been established. Here, we report 3 spontaneous TAPS cases diagnosed and managed in the prenatal period with a combination of in utero blood transfusion for the anemic twin (donor) and in utero partial exchange transfusion for the polycythemic twin (recipient). These cases contribute to the limited outcome data of this underutilized method for the management of TAPS.

Incidence of and Risk Factors for Residual Anastomoses in Twin-Twin Transfusion Syndrome Treated with Laser Surgery: A 15-Year Single-Center Experience.

OBJECTIVES: To evaluate the incidence of residual anastomoses (RA) after laser therapy for twin-twin transfusion syndrome (TTS) and investigate risk factors for incomplete laser surgery. MATERIAL AND METHODS: All available TTS placentas treated with laser at our center between 2002 and 2016 were injected with color dye to assess the presence of RA. We evaluated the incidence of RA over the past 15 years by dividing the cohort into three time periods, and studied the association with risk factors and neonatal outcome. RESULTS: Overall, RA were detected in 21.0% (78/371) of placentas. The incidence of RA decreased from 38.8% (26/67) in the initial period to 11.7% (16/137) in the most recent period (p < 0.001). On multivariate analysis, several risk factors were independently associated with the risk of RA, including Solomon laser technique (odds ratio [OR] 0.17, 95% CI 0.09-0.33) and estimation of surgical success (OR 19.28, 95% CI 8.17-45.49). Premature delivery and neonatal morbidity occurred more often in TTS cases with RA. CONCLUSIONS: The incidence of RA after laser therapy for TTS decreased significantly in the past 15 years and is now below 15% due to the use of the Solomon technique.

Hemoglobin San Diego: An Uncommon Cause of Hereditary Erythrocytosis Discovered Incidentally in a Military Trainee.

High-affinity hemoglobinopathies are a rare clinical entity that commonly presents as an isolated erythrocytosis in asymptomatic individuals. We report such a case involving an 18-year-old active duty military trainee who presented to the hematology clinic after an isolated erythrocytosis was incidentally discovered during a flight physical. The patient was asymptomatic but did report a family history of erythrocytosis in his mother and maternal grandmother which intermittently required venesection. Initial history and physical exam were unremarkable. P50 RBC Oxygen Dissociation showed a left-shifted oxygen dissociation curve, although hemoglobin electrophoresis did not reveal an abnormal hemoglobin variant. A ß-globin variant was identified via mass spectrometry and sequencing that was consistent with the rare high-oxygen affinity hemoglobin variant designated hemoglobin San Diego. This patient was medically cleared to return to training without limitations and counseled regarding the potential significance of being a carrier of this rare hemoglobin variant. This case represents the first observation of hemoglobin San Diego in the U.S. military population.

Improved prediction of twin anemia-polycythemia sequence by delta middle cerebral artery peak systolic velocity: new antenatal classification system.

OBJECTIVES: To investigate the diagnostic accuracy of delta middle cerebral artery peak systolic velocity (MCA-PSV) > 0.5 multiples of the median (MoM) and compare its predictive value with that of the current MCA-PSV cut-off values of > 1.5 MoM in the donor and < 1.0 MoM in the recipient, for the diagnosis of twin anemia-polycythemia sequence (TAPS) in monochorionic twin pregnancy. METHODS: This was a retrospective consecutive cohort study comprising all uncomplicated monochorionic twin pregnancies and twin pregnancies with a postnatal diagnosis of TAPS managed between 2003 and 2017 in the Dutch national referral center for fetal therapy. Cases with incomplete MCA-PSV Doppler measurements 1 week prior to delivery or with incomplete hemoglobin measurements within 1 day after birth were excluded. The postnatal diagnosis of TAPS was based on an intertwin hemoglobin difference > 8 g/dL and at least one of the following: reticulocyte count ratio > 1.7 or presence of minuscule anastomoses on the placental surface. We compared the predictive accuracy of the current diagnostic method using MCA-PSV cut-off values of > 1.5 MoM in the donor and < 1.0 MoM in the recipient with that of a new method based on intertwin difference in MCA-PSV > 0.5 MoM for prediction of TAPS. RESULTS: In total, 45 uncomplicated and 35 TAPS monochorionic twin pregnancies were analyzed. The sensitivity and specificity of the cut-off MCA-PSV values (donor > 1.5 MoM, recipient < 1.0 MoM) to predict TAPS was 46% (95% CI, 30-62%) and 100% (95% CI, 92-100%), respectively; positive predictive value was 100% (95% CI, 81-100%) and negative predictive value 70% (95% CI, 58-80%). Delta MCA-PSV showed a sensitivity of 83% (95% CI, 67-92%) and a specificity of 100% (95% CI, 92-100%); the positive and negative predictive values were 100% (95% CI, 88-100%) and 88% (95% CI, 77-94%), respectively. Of the 35 cases with TAPS diagnosed postnatally, 13 twin pairs showed a delta MCA-PSV > 0.5 MoM but did not fulfill the cut-off MCA-PSV criteria. Of these 13 TAPS twins, nine donors and four recipients had normal MCA-PSV values. There was a high correlation between delta MCA-PSV and intertwin difference in hemoglobin level (R = 0.725, P < 0.01). CONCLUSION: Delta MCA-PSV > 0.5 MoM has a greater diagnostic accuracy for predicting TAPS compared to the current MCA-PSV cut-off criteria. We therefore propose a new antenatal classification system for TAPS. In monochorionic twin pregnancies with delta MCA-PSV > 0.5 MoM on Doppler ultrasound, but normal MCA-PSV values in the donor or recipient, obstetricians should be aware of the therapeutic implications and neonatal morbidities associated with TAPS. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Role of fetal intertwin difference in middle cerebral artery peak systolic velocity in predicting neonatal twin anemia-polycythemia sequence.

OBJECTIVES: To evaluate the relationship between the fetal intertwin difference in middle cerebral artery peak systolic velocity (MCA-PSV) and intertwin difference in hemoglobin (Hb) concentration at birth in monochorionic diamniotic (MCDA) twin pregnancies in order to assess its potential role in the prediction of twin anemia-polycythemia sequence (TAPS). METHODS: This was a retrospective cohort study of MCDA twin pregnancies delivered between January 2012 and January 2018. All pregnancies with measurements of MCA-PSV within 7 days prior to delivery and in which neonatal Hb concentration was available were included. The correlation between fetal intertwin difference in MCA-PSV, expressed in multiples of the median (MoM), and neonatal intertwin difference in Hb concentration was investigated. Receiver-operating characteristics (ROC) curve analysis was used to assess the performance of fetal intertwin difference in MCA-PSV for predicting intertwin difference in Hb > 90th centile at birth. RESULTS: A total of 154 out of 256 MC twin pregnancies fulfilled the inclusion criteria. Fetal intertwin difference in MCA-PSV MoM correlated positively with neonatal intertwin difference in Hb concentration (r = 0.79; P < 0.001). The 90th centile for intertwin difference in Hb was 7.25 g/dL. There were 15 (9.7%) cases with a Hb difference ≥ 7.25 g/dL at birth. ROC curve analysis showed a high accuracy of fetal intertwin MCA-PSV MoM difference for the prediction of neonatal intertwin Hb difference ≥ 7.25 g/dL at birth (area under the ROC curve, 0.976 (95% CI, 0.935-0.993); P = 0.012). The optimal cut-off for intertwin MCA-PSV MoM difference was 0.373, with a sensitivity of 93.3% (95% CI, 68.1-99.8%) and a specificity of 95.7% (95% CI, 90.8-98.4%). The positive predictive value was 70% (95% CI, 45.7-88.1%) and the negative predictive value was 99.3% (95% CI, 95.9-100%). CONCLUSION: Our findings show that fetal intertwin MCA-PSV MoM difference is a good predictor of neonatal intertwin Hb concentration difference > 90th centile and potentially of TAPS. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Serum Iron Status of Children with Cyanotic Congenital Heart Disease in Lagos, Nigeria.

OBJECTIVES: Cyanotic congenital heart disease (CCHD) predisposes patients to iron deficiency due to compensatory secondary erythrocytosis. This study aimed to determine the serum iron status and prevalence of iron deficiency among children with cyanotic congenital heart disease attending the Paediatric Cardiology outpatient clinic of Lagos State University Teaching Hospital, Lagos, Nigeria. METHODS: This cross-sectional case-control study took place between May and October 2015 at the Lagos State University Teaching Hospital. A total of 75 children with cyanotic congenital heart disease and 75 apparently healthy age-, gender- and socioeconomically-matched controls were analysed to determine serum iron status and the prevalence of iron deficiency as defined by the World Health Organization criteria. RESULTS: The mean age of the children was 47.5 ± 2.9 months (range: 6-144 months old). Iron deficiency was significantly more frequent among CCHD patients compared to control subjects (9.3% versus 0%; P = 0.006). While latent iron deficiency was more prevalent among children in the control group compared to those with CCHD, this difference was not statistically significant (13.3% versus 9.3%; P = 0.303). No cases of iron deficiency anaemia were observed in the studied sample. CONCLUSION: Neither the children in the control group nor those with CCHD had iron deficiency anaemia. However, iron deficiency was significantly more prevalent among children with CCHD in Lagos. Periodic serum iron status screening is therefore recommended for this population.

Hypodipsic-hypernatremia syndrome in an adult with polycythemia: a case report.

BACKGROUND: Hypernatremia is a very common electrolyte disorder and is frequently encountered in out-patient as well as in-hospital settings. We describe an adult who was found to have unexplained relative polycythemia and episodic hypernatremia. A diagnosis of idiopathic hypodipsic-hypernatremia syndrome was made and the patient was managed with a water-drinking schedule. CASE PRESENTATION: A 24-year-old South African-Indian man was found to have polycythemia in association with episodes of hypernatremia. Investigations indicated that he had relative polycythemia. He experienced no thirst at a time when his serum sodium concentration was found to be 151 mmol/L. Further testing indicated that his renal response to arginine vasopressin was intact and magnetic resonance imaging of his brain revealed no hypothalamic lesions. A diagnosis of idiopathic hypodipsic-hypernatremia syndrome was made and he was managed with a water-drinking schedule that corrected his hypernatremia. CONCLUSION: Hypodipsia should always be considered when a patient without physical or cognitive disability presents with unexplained episodic hypernatremia or with relative polycythemia.

Associations of high-altitude polycythemia with polymorphisms in PIK3CD and COL4A3 in Tibetan populations.

BACKGROUND: High-altitude polycythemia (HAPC) is a chronic high-altitude disease that can lead to an increase in the production of red blood cells in the people who live in the plateau, a hypoxia environment, for a long time. The most frequent symptoms of HAPC include headache, dizziness, breathlessness, sleep disorders, and dilation of veins. Although chronic hypoxia is the main cause of HAPC, the fundamental pathophysiologic process and related molecular mechanisms responsible for its development remain largely unclear yet. AIM/METHODS: This study aimed to explore the related hereditary factors of HAPC in the Chinese Han and Tibetan populations. A total of 140 patients (70 Han and 70 Tibetan) with HAPC and 60 healthy control subjects (30 Han and 30 Tibetan) were recruited for a case-control association study. To explore the genetic basis of HAPC, we investigated the association between HAPC and both phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit delta gene (PIK3CD) and collagen type IV α3 chain gene (COL4A3) in Chinese Han and Tibetan populations. RESULTS/CONCLUSION: Using the unconditional logistic regression analysis and the false discovery rate (FDR) calculation, we found that eight SNPs in PIK3CD and one SNP in COL4A3 were associated with HAPC in the Tibetan population. However, in the Han population, we did not find any significant association. Our study suggested that polymorphisms in the PIK3CD and COL4A3 were correlated with susceptibility to HAPC in the Tibetan population.

Excessive Erythrocytosis and Cardiovascular Risk in Andean Highlanders.

Corante, Noemí, Cecilia Anza-Ramírez, Rómulo Figueroa-Mujíca, José Luis Macarlupú, Gustavo Vizcardo-Galindo, Grzegorz Bilo, Gianfranco Parati, Jorge L. Gamboa, Fabiola León-Velarde, and Francisco C. Villafuerte. Excessive erythrocytosis and cardiovascular risk in Andean highlanders. High Alt Med Biol. 19:221-231, 2018.-Cardiovascular diseases are the main cause of death worldwide. Life under high-altitude (HA) hypoxic conditions is believed to provide highlanders with a natural protection against cardiovascular and metabolic diseases compared with sea-level inhabitants. However, some HA dwellers become intolerant to chronic hypoxia and develop a progressive incapacitating syndrome known as chronic mountain sickness (CMS), characterized by excessive erythrocytosis (EE; Hb ≥21 g/dL in men, Hb ≥19 g/dL in women). Evidence from HA studies suggests that, in addition to CMS typical signs and symptoms, these highlanders may also suffer from metabolic and cardiovascular disorders. Thus, we hypothesize that this syndrome is also associated to the loss of the cardiometabolic protection observed in healthy highlanders (HH), and therefore to a higher cardiovascular risk (CVR). The aim of the present work was to evaluate the association between EE and CVR calculated using the Framingham General CVR Score and between EE and CVR factors in male highlanders. This cross-sectional study included 342 males from Cerro de Pasco, Peru at 4340 m (HH = 209, CMS = 133). Associations were assessed by multiple logistic regressions adjusted for potential confounders (BMI, pulse oxygen saturation and age). The adjusted models show that the odds of high CVR (>20%) in highlanders with EE was 3.63 times the odds in HH (CI 95%:1.22-10.78; p = 0.020), and that EE is associated to hypertension, elevated fasting serum glucose, insulin resistance, and elevated fasting serum triglycerides. Our results suggest that individuals who suffer from EE are at increased risk of developing cardiovascular events compared with their healthy counterparts.