A Novel ß-Globin Variant, Hb Raklev [ß 75(E19) HBB:c.227T > A (Leu→Gln)].

We present a new hemoglobin variant, Hb Raklev, characterized by the substitution of leucine with glutamine at position 75 in the ß-globin chain. This variant was discovered inadvertently during an HbA1c evaluation using high performance liquid chromatography in a symptomless 54-year-old Caucasian woman, with the same variant also identified in her 16-year-old daughter. Purification of the hemoglobin revealed possibly diminished 2,3-bisphosphoglycerate (2,3-BPG) sensitivity, which may result in heightened oxygen affinity. Notably, two variants have been previously documented at this location: the unstable Hb Atlanta and the high-affinity Hb Pasadena.

Symptomatic Erythrocytosis Due to Homozygosity for Hb Luton [HBA2: c.269A>T (or HBA1)] and α-Thalassemia: A Clinical Update.

A female proband homozygous for both Hb Luton [α89(FG1)His→Leu (CAC>CTC), HBA2: c.269A>T (or HBA1)], a high oxygen affinity hemoglobin (Hb), and for α(+)-thalassemia (α-thal), (-α(4.2), leftward deletion) was first described in 2012. This is a follow-up report of the same case. At the age of 18, the described patient presented with progressively worsening lethargy, headaches, dizziness, syncope and Raynaud's phenomenon. Following extensive cardiological and neurological investigation, it was felt that significant erythrocytosis was the most likely cause. Venesection followed by regular exchange transfusions were arranged with marked amelioration in symptomatology. In the vast majority of cases of high oxygen affinity Hbs, venesection is not recommended due to the asymptomatic phenotype and reduced oxygen delivery resulting from venesection. This update describes the evolving phenotype of this unique proband and, to the best of our knowledge, the first use of regular, long-term therapeutic red cell exchange transfusions in a case of high affinity Hb.

Influence of High Hemoglobin-Oxygen Affinity on Humans During Hypoxia.

Humans elicit a robust series of physiological responses to maintain adequate oxygen delivery during hypoxia, including a transient reduction in hemoglobin-oxygen (Hb-O2) affinity. However, high Hb-O2 affinity has been identified as a beneficial adaptation in several species that have been exposed to high altitude for generations. The observed differences in Hb-O2 affinity between humans and species adapted to high altitude pose a central question: is higher or lower Hb-O2 affinity in humans more advantageous when O2 availability is limited? Humans with genetic mutations in hemoglobin structure resulting in high Hb-O2 affinity have shown attenuated cardiorespiratory adjustments during hypoxia both at rest and during exercise, providing unique insight into this central question. Therefore, the purpose of this review is to examine the influence of high Hb-O2 affinity during hypoxia through comparison of cardiovascular and respiratory adjustments elicited by humans with high Hb-O2 affinity compared to those with normal Hb-O2 affinity.

Dissociating the effects of oxygen pressure and content on the control of breathing and acute hypoxic response.

Arterial oxygen tension and oxyhemoglobin saturation (SaO2) decrease in parallel during hypoxia. Distinguishing between changes in oxygen tension and oxygen content as the relevant physiological stimulus for cardiorespiratory alterations remains challenging. To overcome this, we recruited nine individuals with hemoglobinopathy manifesting as high-affinity hemoglobin [HAH; partial pressure at 50% SaO2 (P50) = 16 ± 0.4 mmHg] causing greater SaO2 at a given oxygen partial pressure compared with control subjects (n = 12, P50 = 26 ± 0.4 mmHg). We assessed ventilatory and cardiovascular responses to acute isocapnic hypoxia, iso-oxic hypercapnia, and 20 min of isocapnic hypoxia (arterial Po2 = 50 mmHg). Blood gas alterations were achieved with dynamic end-tidal forcing. When expressed as a function of the logarithm of oxygen partial pressure, ventilatory sensitivity to hypoxia was not different between groups. However, there was a significant difference when expressed as a function of SaO2. Conversely, the rise in heart rate was blunted in HAH subjects when expressed as a function of partial pressure but similar when expressed as a function of SaO2. Ventilatory sensitivity to hypercapnia was not different between groups. During sustained isocapnic hypoxia, the rise in minute ventilation was similar between groups; however, heart rate was significantly greater in the controls during 3 to 9 min of exposure. Our results support the notion that oxygen tension, not content, alters cellular Po2 in the chemosensors and drives the hypoxic ventilatory response. Our study suggests that in addition to oxygen partial pressure, oxygen content may also influence the heart rate response to hypoxia.NEW & NOTEWORTHY We dissociated the effects of oxygen content and pressure of cardiorespiratory regulation studying individuals with high-affinity hemoglobin (HAH). During hypoxia, the ventilatory response, expressed as a function of oxygen tension, was similar between HAH variants and controls; however, the rise in heart rate was blunted in the variants. Our work supports the notion that the hypoxic ventilatory response is regulated by oxygen tension, whereas cardiovascular regulation may be influenced by arterial oxygen content and tension.