10.2 Blood Composition, Hematopoiesis & Hemostasis

Blood as a Fluid Connective Tissue

Section 10.1 covered the pump and the vessels; this section covers what moves through them. Blood satisfies the AAMC definition of a connective tissue because its cells are dispersed in an abundant extracellular matrix — plasma — with the fiber component appearing only when fibrinogen polymerizes during clotting (see 8.3). Centrifuging an anticoagulated sample separates three layers:

Hematocrit is the percentage of blood volume occupied by erythrocytes: roughly $41\text{--}50%$ in adult males and $36\text{--}44%$ in adult females. Serum is plasma minus the clotting factors — what remains after a sample has clotted.

Plasma Proteins Set Oncotic Pressure

• Albumin (~60% of plasma protein) is the dominant contributor to colloid osmotic (oncotic) pressure and the major carrier for fatty acids, bilirubin, calcium and many drugs. Hepatic failure or nephrotic protein loss lowers albumin and produces edema.
• Globulins transport metals and lipids and include the immunoglobulins.
• Fibrinogen is the soluble precursor of fibrin.

Hematopoiesis

All formed elements arise from a pluripotent hematopoietic stem cell in red bone marrow — in adults, chiefly the pelvis, sternum, vertebrae, ribs and proximal femur/humerus. The stem cell gives rise to two committed progenitors:

• Myeloid lineage $\rightarrow$ erythrocytes, megakaryocytes (platelets), granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages.
• Lymphoid lineage $\rightarrow$ B lymphocytes, T lymphocytes, natural killer cells (see 10.5).

Erythrocyte Production and Destruction

• Stimulus: the kidney senses low tissue oxygen delivery and releases erythropoietin (EPO), which drives erythroid progenitor proliferation. Chronic renal failure therefore causes anemia; testing at altitude or with recombinant EPO raises hematocrit.
• Maturation: the developing erythroblast extrudes its nucleus and degrades all organelles, becoming a reticulocyte and then a biconcave, anucleate erythrocyte. Consequences the MCAT tests repeatedly: no mitochondria means anaerobic glycolysis only; no nucleus means no protein synthesis and no division; the biconcave disc maximizes surface-to-volume ratio for gas diffusion and allows deformation through capillaries.
• Lifespan and destruction: about 120 days. Senescent cells are phagocytosed by macrophages of the spleen (the "red-cell graveyard"), liver and bone marrow. Globin is degraded to amino acids; iron is recycled via transferrin and stored as ferritin; the porphyrin ring becomes biliverdin, then bilirubin, which albumin carries to the liver for glucuronide conjugation and biliary excretion. Failure at any step produces jaundice — a common passage hook.

Regulation of Plasma Volume

Plasma volume is defended by the same axes covered in Section 10.6: ADH promotes free-water reabsorption, aldosterone promotes sodium and therefore water retention, atrial natriuretic peptide opposes both, and albumin-dependent oncotic pressure holds fluid within the vasculature.

Capillary Beds: Exchange, Resistance and Heat

Capillaries are single endothelial cells thick, and they are where all gas, nutrient and waste exchange occurs. Three mechanisms operate:

1. Diffusion of $\text{O}_2$, $\text{CO}_2$ and lipid-soluble molecules directly through the endothelial membrane.
2. Bulk flow through intercellular clefts and fenestrations, governed by Starling forces:

$\text{Net filtration pressure} = (P_c - P_i) - \sigma(\pi_c - \pi_i)$

where $P_c$ is capillary hydrostatic pressure and $\pi_c$ is capillary oncotic pressure. Hydrostatic pressure falls from roughly $35\text{ mmHg}$ at the arteriolar end to about $15\text{ mmHg}$ at the venular end, while oncotic pressure stays near $25\text{ mmHg}$. Net filtration therefore occurs at the arteriolar end and net reabsorption at the venular end, with about 10–15% of filtered volume left behind for lymphatic return (see 10.4).

1. Transcytosis in vesicles for large molecules.

Peripheral resistance. Although each capillary is narrow, arterioles are the principal resistance vessels because they carry smooth muscle that can constrict or dilate; total peripheral resistance is set there, and precapillary sphincters then route flow into specific beds. Heat exchange uses the same architecture: dermal vasodilation shunts warm blood to the surface for radiative and evaporative loss, and vasoconstriction conserves core heat (see 11.5).

Hemostasis

Primary Hemostasis — the Platelet Plug

Platelets are anucleate cytoplasmic fragments shed from bone-marrow megakaryocytes, circulating 8–12 days.

1. Vascular spasm: injured smooth muscle constricts, reducing flow.
2. Adhesion: exposed subendothelial collagen binds von Willebrand factor, which bridges to platelet glycoprotein Ib.
3. Activation and secretion: platelets change shape and release ADP, thromboxane $\text{A}_2$ and serotonin, recruiting more platelets.
4. Aggregation: activated GPIIb/IIIa receptors bind fibrinogen, cross-linking platelets into a plug.

Secondary Hemostasis — the Coagulation Cascade

A proteolytic cascade of zymogens (see 1.4) converges on a common pathway.

Prothrombinase converts prothrombin (II) to thrombin (IIa); thrombin cleaves soluble fibrinogen (I) into fibrin monomers that polymerize, and activates factor XIII, which covalently cross-links the mesh. Thrombin also feeds back to activate factors V, VIII and XI, making the cascade explosively self-amplifying.

Two dependencies are heavily tested: calcium (factor IV) is required at multiple steps — which is why citrate and EDTA anticoagulate blood samples — and vitamin K is required for hepatic $\gamma$-carboxylation of factors II, VII, IX and X plus proteins C and S, the basis of warfarin's mechanism. Plasmin, generated from plasminogen by tissue plasminogen activator, later digests fibrin (fibrinolysis).

Hemophilia A is factor VIII deficiency and hemophilia B is factor IX deficiency; both are X-linked recessive, connecting this material to Section 7.2.

Blood Typing

Surface glycoprotein antigens determine compatibility.

ABO antibodies are pre-formed IgM, so a mismatched transfusion causes immediate agglutination and hemolysis.

Rh factor (D antigen). Rh-negative individuals make anti-D antibodies only after exposure. An Rh-negative mother carrying an Rh-positive fetus is typically sensitized at the first delivery; her IgG anti-D can then cross the placenta in a subsequent Rh-positive pregnancy and cause hemolytic disease of the newborn (erythroblastosis fetalis). Anti-D immunoglobulin given prophylactically prevents sensitization. Note the isotype logic: only IgG crosses the placenta, which is why the pre-formed IgM ABO antibodies do not cause the analogous problem.