What cell types are normally present in peripheral blood besides erythrocytes, leukocytes, and platelets?

Cells Normally Circulating in the Bloodstream Beyond Blood Cells

Besides erythrocytes, leukocytes, and platelets, the peripheral blood normally contains circulating endothelial cells (CECs), endothelial progenitor cells including endothelial colony-forming cells (ECFCs), and extracellular vesicles (EVs), though these are present in extremely low concentrations compared to traditional blood cells. 1

Circulating Endothelial Cells (CECs)

Mature circulating endothelial cells are shed from the vasculature and represent a distinct population from endothelial progenitor cells. These cells are present in measurably higher concentrations than their progenitor counterparts. 1

• In patients with pulmonary arterial hypertension, CECs are found at a mean concentration of approximately 80 cells per milliliter of blood, which is substantially higher than progenitor cell counts 1
• CECs can be distinguished from progenitor cells by their immediate presence in blood samples and lack of colony-forming capacity in culture 1

Endothelial Colony-Forming Cells (ECFCs)

ECFCs are endothelial progenitor cells that circulate at very low concentrations but represent a physiologically important cell population. 1

• These cells are present at approximately 1 colony per 10^7 mononuclear cells, which translates to roughly 2.5 ECFC colonies per milliliter of blood in normal individuals 1
• ECFCs express endothelial markers (CD31, CD144, CD146, VEGFR2) and lack hematopoietic markers (CD45, CD14) 1
• They are distinct from mature CECs because they appear in culture only after 7-20 days of plating and form highly proliferative colonies 1
• Success rates for isolating ECFCs from peripheral blood of healthy subjects range from 70-75%, meaning some individuals may have undetectable levels 1

Extracellular Vesicles (EVs)

Extracellular vesicles are membrane-bound particles released by various cell types that circulate in blood plasma at concentrations estimated around 1 × 10^9 per milliliter. 1

• EVs range in diameter from 30 nm to 1 μm and have densities between 1.02-1.19 g/mL 1
• Blood plasma contains EVs alongside proteins, lipoproteins, residual platelets, and cell fragments such as red blood cell "ghosts" 1
• The physiological functions of blood EVs include cellular homeostasis and hemostasis, with early observations showing they remove redundant transmembrane receptors and support coagulation 1

Rare Circulating Cells in Pathological States

While not normally present in healthy adults, certain cells may appear in peripheral blood under specific circumstances:

Nucleated Red Blood Cells (nRBCs)

• nRBCs are not identified in peripheral blood of healthy individuals beyond the neonatal period 2
• Contemporary analyzers can detect very low levels, with updated reference intervals suggesting an upper limit of 0.10 × 10^6/μL may be acceptable 2

Plasma Cells

• A low proportion of plasma cells can occasionally be detected across the spectrum of plasma cell dyscrasias, and exceptionally even in monoclonal gammopathy of undetermined significance 1
• Peripheral blood flow cytometry is important to demonstrate clonality and exclude reactive polyclonal plasma cells that can appear transiently in non-malignant conditions like severe sepsis or infectious mononucleosis 1

Clinical Significance

The detection and quantification of these non-traditional circulating cells has important clinical applications:

• ECFCs serve as liquid biopsies to investigate endothelial dysfunction and have been instrumental in studying cellular defects in von Willebrand disease and hereditary hemorrhagic telangiectasia 1
• Careful peripheral blood smear examination by experienced laboratory professionals remains essential for identifying abnormal circulating cells 3, 4
• At least 200 circulating nucleated cells per smear should be systematically analyzed 4