Hematopoiesis, Leukocyte Lineages & Growth Factors

Where and how blood is made

Shifting sites. Blood formation begins in the yolk sac around week 3 and continues there until about week 8; its primitive erythroblasts make embryonic hemoglobins. From about week 6 the fetal liver takes over and dominates through midgestation, with a minor splenic contribution. Bone marrow production starts in the second trimester and is the only normal site after birth. In infants nearly all marrow is red; with age, red marrow retreats to the axial skeleton (vertebrae, pelvis, sternum, ribs, skull) and the proximal femur and humerus.

Extramedullary hematopoiesis. When marrow is replaced by fibrosis (myelofibrosis) or overwhelmed by ineffective erythropoiesis (β-thalassemia major), the liver and spleen resume blood production, producing hepatosplenomegaly.

Stem cells and progenitors. Self-renewing CD34+ hematopoietic stem cells live in a marrow niche. They give rise to a common myeloid progenitor (CFU-GEMM), which yields erythrocytes (driven by EPO), megakaryocytes and platelets (TPO), neutrophils and monocytes (G-CSF, GM-CSF, M-CSF), eosinophils (IL-5), basophils and mast cells, and a common lymphoid progenitor, which yields B cells (mature in marrow), T cells (mature in the thymus) and NK cells. CD34+ cell counts guide stem cell collection for transplant, and many leukemic blasts also express CD34.

Granulocytes

Neutrophils. Their specific granules hold lactoferrin, lysozyme, collagenase and alkaline phosphatase; azurophilic granules are lysosomes carrying myeloperoxidase, proteases and defensins. They are recruited by C5a, IL-8, LTB4 and N-formyl bacterial peptides and kill by phagocytosis, the NADPH oxidase respiratory burst (myeloperoxidase converts H₂O₂ to hypochlorite) and neutrophil extracellular traps. They circulate only hours before entering tissue. Hypersegmented neutrophils (≥6 lobes) point to B12 or folate deficiency; bilobed pince-nez nuclei suggest Pelger-Huët anomaly or myelodysplasia.

Eosinophils. Major basic protein, eosinophil cationic protein and eosinophil peroxidase kill IgE- or IgG-coated helminths by antibody-dependent cellular cytotoxicity, and eosinophils drive the late phase of allergic inflammation. IL-5 governs their production, while their histaminase and arylsulfatase dampen mast cell mediators. Charcot-Leyden crystals in sputum or stool are crystallized eosinophil protein (galectin-10).

Basophils and mast cells. Basophils circulate; mast cells arise from marrow precursors but mature and live in tissues (skin, mucosa, around vessels). Both carry FcεRI loaded with IgE. Antigen cross-linking triggers degranulation of histamine, heparin and tryptase plus synthesis of leukotrienes and prostaglandins: the type I hypersensitivity reaction. Cromolyn stabilizes mast cells.

Mononuclear cells and platelets

Monocytes and macrophages. Monocytes leave the blood to become macrophages: Kupffer cells (liver), alveolar macrophages, microglia, osteoclasts and connective-tissue histiocytes. M-CSF drives the lineage, and M-CSF plus RANKL forms osteoclasts. Macrophages phagocytose, present antigen on MHC II to CD4+ T cells, secrete IL-1, IL-6 and TNF-α (fever, acute phase) and IL-12 (Th1 differentiation), and are activated by IFN-γ. They sense LPS through CD14 and TLR4, the trigger for septic shock.

Lymphocytes. B cells mature in marrow (CD19, CD20, and CD21, the EBV receptor) and differentiate into plasma cells with clock-face chromatin and a perinuclear Golgi halo. T cells mature in the thymus (CD3 with CD4 or CD8). NK cells (CD16, CD56) kill cells lacking MHC I using perforin and granzymes.

Platelets. Megakaryocytes are large polyploid cells formed by endomitosis that shed anucleate platelets under TPO, which the liver makes constitutively. Platelets live 7–10 days, about one-third pool in the spleen, and the normal count is 150,000–400,000/μL. Dense granules hold ADP, Ca²⁺ and serotonin; α-granules hold vWF, fibrinogen, fibronectin and PF4. GpIb binds vWF and GpIIb/IIIa binds fibrinogen. Because platelets clear TPO by binding it, free TPO rises when counts fall; cirrhosis lowers TPO output, adding to splenic sequestration as a cause of thrombocytopenia.

Reactive changes in the blood count

Neutrophilia and left shift. Infection, corticosteroids, stress catecholamines and smoking raise the neutrophil count; epinephrine and steroids act partly by demargination (neutrophils leave the vessel-wall pool). Infection brings a left shift (more bands and metamyelocytes) with toxic granulation and Döhle bodies. A leukemoid reaction is a reactive count above 50,000/μL, as in C. difficile colitis, tuberculosis or brisk hemorrhage.

Eosinophilia and basophilia. Eosinophils rise with invasive helminths (Strongyloides, Toxocara, schistosomes), asthma and allergy, drug reactions (DRESS), adrenal insufficiency (loss of cortisol's eosinopenic effect), Hodgkin lymphoma (IL-5 from Reed-Sternberg cells) and EGPA (asthma, eosinophilia, p-ANCA vasculitis, often with mononeuritis multiplex; c-ANCA GPA lacks eosinophilia). Glucocorticoids and acute bacterial infection lower eosinophil counts. Basophilia points to a myeloproliferative neoplasm, classically CML.

Atypical lymphocytes. In infectious mononucleosis, EBV infects B cells via CD21, but the large atypical cells on the smear are reactive CD8+ cytotoxic T cells whose abundant pale cytoplasm scallops around neighboring RBCs (Downey cells). They also appear in CMV infection, acute HIV, toxoplasmosis and viral hepatitis.

Neutropenia. An absolute neutrophil count below 1,500/μL defines neutropenia; below 500/μL is severe, and bacterial and fungal infection risk climbs steeply.

• Chemotherapy: the most common cause.
• Idiosyncratic drug agranulocytosis: clozapine (hence ANC monitoring), methimazole and PTU, TMP-SMX, sulfasalazine.
• Immune destruction: SLE; Felty syndrome (seropositive RA, splenomegaly, neutropenia).
• Viral infection and B12 or folate deficiency.
• Benign Duffy-null-associated low counts in people of African ancestry, without infection risk.

Hematopoietic growth factors as drugs

Erythropoietin. Peritubular interstitial fibroblasts in the renal cortex make most adult EPO (the liver is the main fetal source). Hypoxia stabilizes HIF, which drives EPO transcription; the EPO receptor signals through JAK2-STAT5 to rescue erythroid progenitors from apoptosis. Epoetin alfa and longer-acting darbepoetin treat anemia of CKD and chemotherapy-associated anemia. Iron deficiency blunts the response, so iron is checked and repleted first.

Eltrombopag chelates polyvalent cations: separate doses by several hours from antacids, dairy, and iron or calcium supplements.