My primary care physician orders a routine complete blood count (CBC) every year or so at my annual physical exam, a common experience for most adult patients. On a recent review of the medical records in my online patient portal, I’ve noted that my hemoglobin values continue to show little variation, ranging over the years from 12.8 to 13 g/dL, with a reference interval for my age and gender of 12 to 16 g/dL. Reference intervals for CBC indices are ideally established based on the distribution of values in a healthy and relevant population.1 However, even with age- and gender-specific CBC reference intervals, population-based normal ranges, based on interpatient variation, remain wide.
Brody H. Foy, DPhil, and colleagues recently studied the intrapatient variation in CBC indices in a large cohort of 12,407 healthy patients under stable conditions over a 20-year period. The CBC indices measured hematocrit (HCT), hemoglobin, mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), mean corpuscular volume (MCV), mean platelet volume, platelet, red blood cell (RBC), red cell distribution width (RDW), and white blood cell (WBC). As shown in Figure 1, the authors found that the long-term (20-year) intrapatient variation in CBC indices was smaller than the interpatient variation in the study cohort, with coefficients of variation (CVs) ranging from 2% to 15% versus 5% to 30%, respectively. Compared to short-term (weeks or months) intrapatient CVs derived from the preestablished European Federation of Clinical Chemistry and Laboratory Medicine database, the authors noted only a slightly larger long-term intrapatient variation. This data supports the presence of an individual hematologic setpoint that remains stable over decades in states of health. The authors demonstrated that this setpoint shows very small age-related changes and modest shift following normal physiologic changes of pregnancy and menopause, after the development of chronic hypothyroidism or hepatitis, and after splenectomy.
Both long-term and short-term intrapatient variation is notably less than interpatient variation
Abbreviations: CV, coefficient of variation; HCT, hematocrit; HGB, hemoglobin; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MPV, mean platelet volume; PLT, platelet; RBC, red blood cell; RDW, red cell distribution width; WBC, white blood cell.
Both long-term and short-term intrapatient variation is notably less than interpatient variation
Abbreviations: CV, coefficient of variation; HCT, hematocrit; HGB, hemoglobin; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MPV, mean platelet volume; PLT, platelet; RBC, red blood cell; RDW, red cell distribution width; WBC, white blood cell.
All CBC setpoints except MCHC showed strong heritability as estimated from electronic health record-derived relationship data. Genome-wide association studies suggested CBC setpoints are partially genetically determined, with as-yet-identified acquired factors contributing.
Additional patient cohorts were used to study setpoint associations. In a cohort of individuals with 15 years of follow-up after setpoint estimation (and with confirmation in two independent cohorts), CBC setpoints showed an association with all-cause mortality and onset of major illness. An HCT setpoint in the lowest quartile was associated with chronic kidney disease, a lowest-quartile MCHC setpoint with major adverse cardiovascular events, a highest-quartile MCV setpoint with osteoporosis, a lowest-quartile RBC setpoint with myelodysplastic syndromes, a highest-quartile RDW setpoint with atrial fibrillation, and a highest-quartile WBC setpoint with type 2 diabetes (Figure 2). The association between CBC parameters and the risk of myeloid neoplasm has been noted previously, with select parameters included in models for the prediction of myeloid neoplasm in patients with clonal hematopoiesis.2,3
Hematologic setpoints are associated with disease risk
Abbreviations: HCT, hematocrit; MACE, major adverse cardiovascular events; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MDS, myelodysplastic syndromes; RBC, red blood cell; RDW, red cell distribution width; WBC, white blood cell.
Hematologic setpoints are associated with disease risk
Abbreviations: HCT, hematocrit; MACE, major adverse cardiovascular events; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MDS, myelodysplastic syndromes; RBC, red blood cell; RDW, red cell distribution width; WBC, white blood cell.
In Brief
The work of Dr. Foy and his colleagues provides intriguing insight into long-term intrapatient variation, an area with limited literature.4 Their data support unique and stable hematologic setpoints for each individual based on nine CBC indices. Associations between hematologic setpoints and disease risk may allow for targeted screening in select individuals. Monitoring variation from individual setpoints could aid in short-term clinical management (e.g., variations from baseline due to acute pathophysiologic disruption), as well as disease prediction.
Perhaps in the future, my patient portal will compare my current hemoglobin to a personalized hemoglobin setpoint in addition to a population-based reference range.
Disclosure Statement
Dr. Courville indicated no relevant conflicts of interest.
