Hemoglobin San Diego: A Case Report and Review of the Literature

Introduction

Erythrocytosis is characterized by an increased red blood cell mass, resulting in elevated hemoglobin (Hb) and/or hematocrit (Hct) levels. It can be classified into 2 categories based on etiology: relative and absolute. Relative erythrocytosis occurs when reduced plasma volume leads to hemoconcentration without an actual increase in red blood cell mass. Absolute erythrocytosis is further divided into primary and secondary forms. Primary erythrocytosis results from an intrinsic bone marrow defect, often driven by genetic mutations. An acquired mutation, such as Janus kinase 2 (JAK2) V617F, can lead to the myeloid clonal disorder polycythemia vera (PV). Alternatively, inherited germline mutations may cause autonomous red blood cell production. Secondary erythrocytosis arises from external factors that stimulate erythropoiesis in the bone marrow, either appropriately, as in hypoxia, or inappropriately, as with erythropoietin-producing tumors. The most common comorbid conditions linked to secondary erythrocytosis include hypoxia-related states such as tobacco smoking, chronic pulmonary disease, obstructive sleep apnea, and cardiopulmonary shunts [1]. Although many causes of erythrocytosis are well characterized, high-oxygen-affinity Hb variants represent a less common inherited cause associated with increased erythrocyte production.

High-oxygen-affinity Hb variants are a rare group of autosomal dominant disorders caused by missense mutations in globin genes. These mutations, which result in single amino acid substitutions in globin proteins, increase oxygen (O2) affinity through 3 principal mechanisms: alteration of the α1β2 interface, modification of the globin chain carboxyl terminus, or disruption of interactions with allosteric regulators [2]. Such structural changes in the Hb tetramer lead to abnormal O2 binding with increased affinity [3]. The first documented case of a high-oxygen-affinity Hb variant, Hb Chesapeake, was reported in 1966 [4]. Since then, several hundred distinct variants have been identified, including Hb San Diego [5], which was discovered in 1974 [6].

Despite their generally benign clinical course, high-oxygen-affinity Hb variants may occasionally cause symptoms related to increased blood viscosity and may be associated with an elevated risk of thrombotic events [7]. Limited clinical guidance regarding intervention reflects ongoing uncertainty about their potential complications. Although general recommendations do not advocate therapeutic intervention [8], controversy persists – some evidence suggests that phlebotomy can improve symptoms in patients with secondary erythrocytosis [9,10].

Hb variants are typically considered after common primary and secondary causes of erythrocytosis have been excluded. The vast majority of patients with JAK2-negative erythrocytosis have identifiable causes, including cardiopulmonary disease, a history of heavy smoking, or supplemental testosterone use [1]. Given their rarity, Hb variants are seldom included in the differential diagnosis unless there is a strong family history of erythrocytosis, which may raise suspicion and prompt earlier consideration during the diagnostic evaluation. Historically, diagnosis was supported by demonstrating a left-shifted p50 oxygen dissociation curve; however, the gold standard for confirmation is DNA sequencing of globin genes to identify the causative missense mutation. We present the case of a healthy young man with persistent erythrocytosis who, after comprehensive evaluation and years of diagnostic uncertainty, was confirmed to possess a high-oxygen-affinity Hb variant identified as Hb San Diego. This case highlights the diagnostic challenges and clinical uncertainty associated with high-oxygen-affinity Hb variants. It also emphasizes the importance of recognizing Hb San Diego as a rare but clinically relevant cause of persistent erythrocytosis to guide appropriate management and avoid unnecessary interventions.

Case Report

A 29-year-old otherwise healthy man was first noted to have persistent erythrocytosis several years prior to visiting our clinic, with Hb values in the 18 g/dL range and Hct approximately 51%. His initial evaluation at an outside institution included an extensive assessment for primary and secondary causes of erythrocytosis. Bone marrow biopsy showed mild hypocellularity (40%) with trilineage hematopoiesis and adequate megakaryocyte counts. Testing for primary PV, including JAK2 mutational analysis, revealed negative findings. Despite this comprehensive evaluation, no clear etiology was identified, and he was diagnosed with erythrocytosis of unclear etiology.

After relocating, he established care at our clinic. He remained asymptomatic and otherwise healthy. He was a lifelong nonsmoker with no history of cardiopulmonary disease and no use of supplemental testosterone, exogenous erythropoietin, or anabolic steroids. His Epworth Sleepiness Scale and STOP-BANG scores for obstructive sleep apnea were unremarkable. Vital signs were within normal limits: he was normotensive, with a heart rate of 55 beats/minute, O2 saturation of 98% on room air, and respiratory rate of 12 breaths/minute. Cardiopulmonary examination findings were unremarkable, without facial or palmar plethora. No clinical signs of dehydration were noted. Comprehensive laboratory testing was performed as part of the erythrocytosis evaluation (Table 1). Complete blood count confirmed persistent erythrocytosis, with an Hb level of 18.7 g/dL (reference range: 14.3–18.1 g/dL) and Hct of 53.9% (reference range: 39.2%–50.2%). Chronic, stable thrombocytopenia was also noted (platelet count of 96×109/L; reference range: 150–400×109/L). Other causes of thrombocytopenia were evaluated and excluded, including an extensive panel for rare familial thrombocytopenia. Given prior bone marrow analyses demonstrating adequate megakaryopoiesis and negative molecular test results, the patient’s findings were not consistent with a primary hematologic disorder. Although mild immune thrombocytopenia cannot be entirely excluded, its long-term stability made such a diagnosis less likely. In the context of splenomegaly on imaging, splenic sequestration may represent a contributing factor. A repeat evaluation for primary erythrocytosis was performed, including mutation analysis for JAK2 V617F and JAK2 exon 12; both analyses showed negative results. The erythropoietin level was within the normal range at 22 mU/mL (reference range: 4–27 mU/mL), effectively excluding primary PV.

The clinical presentation and laboratory findings confirmed true erythrocytosis, prompting a systematic evaluation for secondary causes. Transthoracic echocardiography with a shunt study showed no abnormalities. Imaging studies in search of an autonomous erythropoietin-secreting tumor revealed no clinically significant findings. Abdominal ultrasound demonstrated splenomegaly and raised concern for a potential hemangioma; however, liver magnetic resonance imaging subsequently excluded this possibility. Additionally, there was no evidence of renal pathology. Given the patient’s young age and overall good health, the persistence of unexplained erythrocytosis raised suspicion for a rare underlying etiology, prompting evaluation for atypical etiologies such as abnormal Hb variants [11]. Bidirectional sequencing of the beta-globin gene identified a β109 (GTG→ATG) valine (Val) to methionine (Met) substitution, consistent with Hb San Diego. The management plan included biannual laboratory monitoring and regular assessment for symptoms potentially related to hyperviscosity.

Discussion

High-oxygen-affinity Hb variants alter O2 affinity, disrupt Hb allosteric regulation, and impair normal O2 delivery. These variants often arise from mutations affecting key structural regions, leading to stabilization of the R state (relaxed, high-affinity, oxygenated) and reduced O2 release to tissues. The allosteric transition of Hb involves a structural shift between the T state (tense, low-affinity, deoxygenated) and the R state, initiated by O2 binding and accompanied by extensive reorganization at the subunit interfaces. The α1β2 interface plays a critical role in stabilizing Hb allosteric states, and mutations at this interface frequently disrupt cooperativity [12]. Under normal conditions, O2 binding to an Hb subunit destabilizes α1β2 interactions, facilitating the transition from the T to the R state and promoting cooperative O2 binding [2,12]. Mutations that interfere with these interactions preferentially stabilize the R state and impair transition back to the deoxygenated T state in peripheral tissues [13]. In Hb San Diego, the mutation occurs in the β-globin chain at position G11, where valine is replaced by methionine. The β109(G11) Val→Met substitution indirectly alters the αβ interface by disrupting the G helix [6]. Similar indirect effects have been described in other Hb variants. Some variants arise from mutations affecting the carboxyl terminus of globin chains, which disrupt salt bridges that stabilize the T state. Others involve mutations that alter interactions with allosteric regulators, including binding sites for hydrogen ions or 2,3-bisphosphoglycerate, thereby impairing Hb responsiveness to environmental stimuli.

The clinical presentations, laboratory findings, family histories, and interventions reported for individuals with Hb San Diego have varied among cases (Table 2). Notably, 25% of patients in those cases exhibited nonspecific symptoms, most commonly headaches and dizziness [6,14–16]. Optimal management of Hb San Diego remains unclear. The approach to erythrocytosis, regardless of etiology, is often modeled after the management of JAK2-positive PV, despite a lack of data indicating whether this strategy is appropriate. PV has a well-established association with symptoms such as headaches, dizziness, and microcirculatory disturbances, which can lead to neurologic complications [17]. Thrombotic risk is also increased. Although these complications may be partly related to increased blood viscosity resulting from erythrocytosis, additional factors likely contribute, including the JAK2 mutation itself. Indeed, there is some evidence that up to one-third of patients with PV experience a thrombotic event before hematologic abnormalities (eg, erythrocytosis) become apparent [18]. Patients with PV undergo phlebotomy to maintain an Hct level below 45%, which improves symptoms and reduces thrombotic risk [19]. However, there are currently no substantial data or adequately powered studies clearly linking thrombotic complications to other causes of erythrocytosis, including high-oxygen-affinity Hb variants, or demonstrating that phlebotomy improves outcomes in these populations.

A study of 41 patients with high-oxygen-affinity hemoglobinopathy-associated erythrocytosis revealed that 25% experienced thrombotic events. Among these 41 patients, 3 had Hb San Diego; 1 patient with Hb San Diego developed thrombosis. However, the study did not identify associations of Hb or Hct levels with thrombotic or nonthrombotic events [20]. A Spanish study of 34 individuals with various Hb variants showed no cases of thrombosis before or at the time of diagnosis [21]. These findings suggest that phlebotomy in patients with high-oxygen-affinity Hb variants may not confer the same thrombosis-prevention benefit observed in JAK2-positive PV. However, the small sample sizes limit the precision of thrombotic risk estimates and preclude definitive conclusions regarding management. Current understanding of thrombotic risk in high-oxygen-affinity hemoglobinopathies is constrained by the absence of large-scale population data and reliance on small case series and isolated reports. This evidence gap hinders accurate risk stratification and the development of standardized management recommendations. Future research should prioritize multicenter collaborations and the establishment of dedicated registries to collect longitudinal clinical and molecular data. Such efforts may clarify true risk profiles and guide optimal management. Until more robust data are available, we recommend annual follow-up with a hematologist to monitor blood counts and screen for signs or symptoms suggestive of thrombosis or other variant-related complications. Interventions such as phlebotomy should be reserved for cases in which there is compelling evidence that symptoms are attributable to erythrocytosis. Even then, such interventions should be used with caution given the absence of evidence-based guidelines.

Conclusions

High-oxygen-affinity Hb variants, although rare, represent an important cause of erythrocytosis that is frequently overlooked during the initial diagnostic evaluation, leading to delayed diagnosis and unnecessary interventions. Persistent erythrocytosis unexplained by standard testing warrants targeted genetic analysis – sequencing of globin genes is essential to identify rare Hb variants. These hemoglobinopathies, including Hb San Diego, result from mutations in globin genes that alter O2 binding affinity and disrupt tissue O2 delivery, thereby stimulating erythropoiesis. Although typically benign, they may be associated with nonspecific symptoms such as headaches and dizziness, which are often difficult to attribute directly to the underlying hemoglobinopathy.

Management remains uncertain due to limited evidence regarding long-term outcomes. Although phlebotomy has been reported to improve hyperviscosity-related symptoms in selected cases, its role is not well established, and no evidence-based guidelines exist. Further research is needed to better define the clinical significance of these Hb variants, clarify associated risks, and establish appropriate management strategies, particularly given ongoing controversy regarding the benefit of phlebotomy for symptom control and thrombosis prevention in patients with high-oxygen-affinity hemoglobinopathies.