Blood: Composition and Functions

Detailed Notes

22.1 Blood as a Connective Tissue

Blood is classified as a specialized connective tissue because, like all connective tissues, it consists of cells suspended in an extracellular matrix. What makes blood unique is that its matrix — plasma — is fluid rather than solid. Blood contains:

• Formed elements: the cellular and cell-fragment components (erythrocytes, leukocytes, platelets), which make up about 45% of whole blood volume (a value called the hematocrit).
• Plasma: the liquid extracellular matrix, accounting for roughly 55% of blood volume.

Unlike other connective tissues, blood does not contain collagen or elastic fibers in its matrix under normal conditions. However, during hemostasis, the soluble plasma protein fibrinogen is converted into insoluble fibrin strands, creating a temporary fibrous network that functions like the fiber component of other connective tissues to trap formed elements and form a clot.

22.2 Physical Characteristics of Blood

Blood is a viscous, slightly alkaline fluid with distinctive physical properties:

22.3 Functions of Blood

Blood serves three broad functional categories: transport, regulation, and protection.

22.3.1 Transport Functions

1. Gas transport: Delivers oxygen (O₂) from the lungs to tissues and carries carbon dioxide (CO₂) from tissues to the lungs for exhalation.
2. Nutrient delivery: Transports absorbed nutrients (glucose, amino acids, fatty acids, vitamins) from the gastrointestinal tract to cells throughout the body.
3. Waste removal: Carries metabolic wastes (urea, uric acid, creatinine, bilirubin) to the kidneys, liver, and other excretory organs.
4. Hormone distribution: Serves as the highway for endocrine signaling, transporting hormones from their glands of origin to target tissues.

22.3.2 Regulatory Functions

1. Thermoregulation: Absorbs and redistributes heat — vasodilation of skin blood vessels dissipates heat, while vasoconstriction conserves it.
2. pH homeostasis: Plasma proteins (albumin, hemoglobin inside RBCs, and the bicarbonate buffer system) act as buffers that resist pH changes.
3. Fluid balance: Plasma proteins (especially albumin) generate colloid osmotic pressure, which pulls interstitial fluid back into capillaries at the venous end, maintaining blood volume and preventing edema.

22.3.3 Protective Functions

1. Hemostasis: Platelets and coagulation proteins prevent excessive blood loss when vessels are damaged.
2. Immune defense: Leukocytes and plasma proteins (antibodies, complement proteins) identify and destroy pathogens, foreign cells, and debris.

22.4 Plasma Composition

Plasma is approximately 92% water by volume, with the remaining 8% consisting of dissolved solutes, dominated by plasma proteins.

Table 22.1 — Major Plasma Proteins

Other plasma solutes include:

• Electrolytes: Na⁺, K⁺, Ca²⁺, Mg²⁺, Cl⁻, HCO₃⁻, HPO₄²⁻ — maintain osmotic balance, membrane potentials, and pH.
• Nutrients: glucose, amino acids, lipids, vitamins.
• Wastes: urea, creatinine, uric acid, bilirubin.
• Dissolved gases: O₂, CO₂, N₂.
• Regulatory substances: hormones, enzymes.

Serum is plasma from which fibrinogen and other clotting factors have been removed (i.e., the fluid remaining after blood has clotted). Serum is commonly used in clinical laboratory testing because it avoids interference from clotting proteins.

22.5 Formed Elements Overview

The formed elements — the cellular and cell-fragment components of blood — are produced through hematopoiesis in the red bone marrow and constitute approximately 45% of whole blood volume.

Table 22.2 — Summary of Formed Elements

The buffy coat is the thin, whitish layer visible between the plasma and red blood cells when whole blood is centrifuged. It contains leukocytes and platelets and normally constitutes less than 1% of total blood volume.

22.6 Erythrocytes (Red Blood Cells)

Erythrocytes are the most abundant formed elements and are uniquely adapted for their primary function: gas transport.

22.6.1 Structural Adaptations

• Biconcave disc shape: Flattened with a depressed center on both sides. This shape maximizes the surface-area-to-volume ratio (about 30% more surface area than a sphere of the same volume), facilitating rapid gas diffusion into and out of the cell. It also allows the cell to deform and squeeze through narrow capillaries (as small as 3–4 µm in diameter, despite the RBC being ~7.5 µm across).
• Anucleate: Mature erythrocytes lack a nucleus and most organelles (including mitochondria and ribosomes). This creates more internal space for hemoglobin and prevents the cell from consuming the oxygen it carries — without mitochondria, RBCs rely exclusively on anaerobic glycolysis for ATP.
• Cytoskeleton: A flexible network of peripheral proteins (spectrin, ankyrin, actin) on the inner face of the plasma membrane gives the RBC its shape and deformability.

22.6.2 Hemoglobin — Structure and Function

Hemoglobin (Hb) is the oxygen-binding protein that fills nearly the entire cytoplasm of each erythrocyte. Each RBC contains approximately 250–300 million hemoglobin molecules.

Hemoglobin is a tetramer composed of:

• Four globin polypeptide chains: In adult hemoglobin (HbA), there are two alpha (α) chains and two beta (β) chains.
• Four heme groups: Each globin chain is associated with one heme prosthetic group. Each heme contains an iron (Fe²⁺) ion at its center.

Key principle: Each Fe²⁺ ion can reversibly bind one O₂ molecule. Since there are four heme groups per hemoglobin, a single hemoglobin molecule can carry up to four oxygen molecules. Binding is cooperative — when the first O₂ binds, it induces a conformational change in hemoglobin that increases the affinity of the remaining subunits for oxygen (positive cooperativity), giving rise to the sigmoidal (S-shaped) oxygen–hemoglobin dissociation curve.

Functions of Hemoglobin:

1. Oxygen transport: About 98.5% of O₂ in blood is bound to hemoglobin as oxyhemoglobin (HbO₂); the remaining 1.5% is dissolved directly in plasma.
2. Carbon dioxide transport: About 23% of CO₂ is transported bound to the globin portion of hemoglobin as carbaminohemoglobin. The remainder is transported as bicarbonate ions (HCO₃⁻) (~70%) or dissolved in plasma (~7%).
3. Buffering: Hemoglobin buffers H⁺ ions, helping maintain blood pH.

22.6.3 Erythrocyte Life Cycle

1. Erythropoiesis: Production of RBCs occurs in the red bone marrow under the influence of the hormone erythropoietin (EPO). EPO is produced primarily by the kidneys in response to tissue hypoxia (low oxygen levels). The process begins with a hematopoietic stem cell (HSC) and proceeds through a series of precursor stages (proerythroblast → erythroblast stages → reticulocyte → mature erythrocyte), during which the cell synthesizes massive quantities of hemoglobin, condenses and extrudes its nucleus, and sheds most organelles.
2. Circulation: A mature RBC enters the bloodstream as a reticulocyte (containing residual ribosomal RNA, which gives it a reticular or net-like appearance under certain stains). Within 1–2 days, it matures into a fully differentiated erythrocyte and circulates for approximately 120 days.
3. Destruction and Recycling: Aged or damaged RBCs are phagocytosed by macrophages in the spleen, liver, and bone marrow. The components are recycled:
   • Globin chains are broken down into amino acids for reuse.
   • Heme is split into iron (Fe²⁺) and biliverdin. Iron is transported in the blood bound to transferrin and stored in the liver bound to ferritin or hemosiderin for future erythropoiesis. Biliverdin is rapidly converted to bilirubin, which is transported to the liver, conjugated, and excreted in bile.
   • Disruption of bilirubin processing leads to jaundice (yellowing of skin and sclera).

22.7 Leukocytes (White Blood Cells)

Leukocytes are the cellular soldiers of the immune system. Unlike RBCs, they are nucleated, contain typical organelles, and are far less numerous (one WBC for every ~700 RBCs). They are classified into two broad categories based on the presence or absence of cytoplasmic granules visible under light microscopy.

Table 22.3 — Classification and Summary of Leukocytes

22.7.1 Leukocyte Functions and Movement

• Diapedesis (extravasation): WBCs can leave the bloodstream by squeezing between endothelial cells of capillary walls to enter tissues where they are needed. This is a hallmark of the immune response.
• Chemotaxis: WBCs are attracted to sites of infection or injury by chemical signals (chemotactic factors) released by damaged cells, pathogens, or other immune cells. They migrate along the chemical concentration gradient toward the source.
• Phagocytosis: Neutrophils and macrophages (derived from monocytes) are the primary phagocytes — they engulf and destroy pathogens, dead cells, and debris using enzymes contained in their lysosomes.

22.7.2 Leukocyte Disorders in Brief

• Leukocytosis: An abnormally high WBC count (>11,000/µL), typically indicative of infection, inflammation, or leukemia.
• Leukopenia: An abnormally low WBC count (<4,000/µL), which may result from chemotherapy, radiation, autoimmune disease, or certain viral infections, and increases susceptibility to infection.

22.8 Platelets (Thrombocytes)

Platelets are not true cells — they are small, anucleate cytoplasmic fragments shed from large, multinucleated bone marrow cells called megakaryocytes.

• Size: 2–4 µm in diameter (smallest formed element).
• Lifespan: Approximately 8–10 days in circulation.
• Count: 150,000–400,000 per µL of blood.
• Structure: Platelets contain granules packed with clotting factors, serotonin (a vasoconstrictor), ADP (promotes platelet aggregation), thromboxane A₂ (stimulates platelet aggregation and vasoconstriction), and platelet-derived growth factor (PDGF) (stimulates wound healing). They also possess surface receptors that allow them to adhere to exposed collagen at injury sites.

Primary function: Platelets are essential for hemostasis — the process of stopping bleeding. They form a temporary platelet plug, provide a phospholipid surface for the coagulation cascade, and secrete chemicals that promote vasoconstriction and attract more platelets.

22.9 Hematopoiesis

Hematopoiesis (or hemopoiesis) is the lifelong process of blood cell formation. In adults, it occurs exclusively in the red bone marrow, which is found in the proximal epiphyses of the humerus and femur, the sternum, ribs, vertebrae, pelvis, and skull. In children, red marrow is also present in the medullary cavities of long bones, but with age much of it is replaced by yellow marrow (fat).

22.9.1 The Hematopoietic Stem Cell (HSC)

All blood cells arise from a common ancestor: the pluripotent hematopoietic stem cell (HSC). HSCs are rare (~1 in 10,000 bone marrow cells), self-renewing, and give rise to two progressively more restricted progenitor lineages:

1. Myeloid stem cell → gives rise to erythrocytes, platelets (via megakaryocytes), neutrophils, eosinophils, basophils, and monocytes.
2. Lymphoid stem cell → gives rise to lymphocytes (B cells, T cells, and NK cells).

Figure 22.1 — Hematopoietic Lineage Overview (Simplified)

                        Pluripotent HSC
                       /                \
              Myeloid Stem Cell       Lymphoid Stem Cell
             /    /     |     \           |       \
    Erythrocyte  Megakaryocyte  Myeloblast   B Cell  T Cell  NK Cell
       (RBC)         |        /   |    \       (Antibodies) (Cell-mediated)
                 Platelets  Neutrophil  Monocyte
                            Eosinophil     |
                            Basophil    Macrophage

22.9.2 Regulation of Hematopoiesis

Hematopoiesis is controlled by a family of hematopoietic growth factors (cytokines):

• Erythropoietin (EPO) — produced by kidneys; stimulates RBC production.
• Thrombopoietin (TPO) — produced by liver and kidneys; stimulates platelet production from megakaryocytes.
• Colony-stimulating factors (CSFs) and interleukins (ILs) — stimulate production of specific WBC lineages.

22.10 Hemostasis

Hemostasis is the sequence of events that stops bleeding when a blood vessel is damaged. It unfolds in three major phases, with the coagulation cascade representing the third and most complex.

22.10.1 Phase 1: Vascular Spasm

Immediately upon injury, the smooth muscle in the damaged vessel wall contracts reflexively. This vascular spasm (vasoconstriction) reduces blood flow to the damaged area and limits blood loss. It is triggered by:

• Direct mechanical stimulation of smooth muscle.
• Release of endothelin from damaged endothelial cells.
• Serotonin and thromboxane A₂ released by activated platelets.
• Pain reflexes mediated by the nervous system.

22.10.2 Phase 2: Platelet Plug Formation

1. Platelet adhesion: Exposed collagen fibers in the damaged vessel wall cause platelets to adhere via von Willebrand factor (vWF) , which bridges platelet surface receptors (GPIb) to collagen.
2. Platelet activation: Adherent platelets swell, extend spiky processes, degranulate (release ADP, serotonin, thromboxane A₂), and express activated GPIIb/IIIa receptors on their surface.
3. Platelet aggregation: Released ADP and thromboxane A₂ attract and activate additional circulating platelets, which bind to one another via fibrinogen bridges between GPIIb/IIIa receptors. A rapidly growing platelet plug forms over the injury site.

Note: The platelet plug is effective for small vessel injuries but requires reinforcement by the coagulation cascade for larger or higher-pressure injuries.

22.10.3 Phase 3: The Coagulation Cascade

The coagulation cascade is a series of enzymatic reactions in which inactive plasma proteins (clotting factors, designated by Roman numerals I–XIII) are sequentially activated, culminating in the conversion of soluble fibrinogen (Factor I) into insoluble fibrin (Factor Ia). The cascade operates through two pathways that converge on a common pathway.

Table 22.4 — Key Clotting Factors

The Three Coagulation Pathways:

1. Extrinsic pathway (the "tissue factor" pathway — rapid, triggered externally):
   • Tissue damage exposes tissue factor (Factor III) from subendothelial cells.
   • Tissue factor forms a complex with Factor VII, which activates Factor X.
   • This pathway is fast (seconds) and provides the initial burst of thrombin.

1. Intrinsic pathway (the "contact activation" pathway — slower, triggered internally):
   • Begins when Factor XII contacts exposed collagen or other negatively charged surfaces at the injury site.
   • Sequential activation: XII → XI → IX → VIII. Factor VIII serves as a cofactor to Factor IX in activating Factor X.
   • This pathway is slower (minutes) but amplifies the response.

1. Common pathway (where both intrinsic and extrinsic pathways converge):
   • Factor Xa (activated Factor X) combines with Factor V and Ca²⁺ to form the prothrombinase complex, which converts prothrombin (Factor II) to thrombin (Factor IIa).
   • Thrombin catalyzes the conversion of fibrinogen (Factor I) to fibrin (Factor Ia).
   • Thrombin also activates Factor XIII, which cross-links fibrin monomers into a stable, insoluble fibrin mesh that traps RBCs, WBCs, and platelets — forming the definitive clot.

Calcium ions (Ca²⁺), designated as Factor IV, are an essential cofactor at multiple steps in the cascade. Without Ca²⁺, coagulation cannot proceed — this is the basis for using calcium chelators (citrate, EDTA) in blood collection tubes to prevent clotting.

22.10.4 Clot Retraction and Fibrinolysis

• Clot retraction: Within 30–60 minutes after clot formation, platelets contract via their actin-myosin cytoskeleton, pulling on the fibrin strands and squeezing serum out of the clot. This compacts the clot, drawing the edges of the damaged vessel closer together and facilitating repair.
• Fibrinolysis: Once the vessel is repaired, the clot must be dissolved to restore normal blood flow. The inactive plasma protein plasminogen is converted to the active enzyme plasmin by tissue plasminogen activator (tPA) released from endothelial cells. Plasmin digests the fibrin mesh, breaking the clot into fragments.

22.10.5 Hemostasis — Summary of Sequence

1. Vascular spasm — injured vessel constricts to limit blood flow.
2. Platelet adhesion — platelets stick to exposed collagen via vWF.
3. Platelet activation and aggregation — platelets degranulate, attract more platelets, and form a temporary platelet plug.
4. Coagulation cascade — intrinsic and extrinsic pathways converge to generate thrombin, which converts fibrinogen to fibrin.
5. Fibrin mesh formation — Factor XIII cross-links fibrin, creating a stable clot.
6. Clot retraction — platelets contract, compacting the clot and drawing wound edges together.
7. Fibrinolysis — plasmin dissolves the fibrin clot after vessel repair is complete.

22.11 Blood Typing

Blood typing is determined by the presence or absence of specific antigens (also called agglutinogens) on the surface of RBCs. These antigens are genetically determined and trigger immune responses if "foreign" blood is transfused.

22.11.1 The ABO Blood Group System

The ABO system is based on two antigens: antigen A and antigen B. An individual's RBCs may display antigen A, antigen B, both (AB), or neither (O). The immune system produces antibodies (agglutinins) against the antigens NOT present on the individual's own RBCs — these preformed antibodies circulate in the plasma from early infancy.

Table 22.5 — ABO Blood Groups

Transfusion reaction: If a recipient receives blood containing antigens against which they have antibodies, those antibodies bind to the transfused RBCs, causing agglutination (clumping) and hemolysis (rupture). This can be fatal. For example, a Type A individual has anti-B antibodies — if they receive Type B blood, the anti-B antibodies attack the transfused B RBCs, causing a hemolytic transfusion reaction.

22.11.2 The Rh Blood Group System

The Rh system is based on the presence or absence of the Rh antigen (specifically the D antigen) on RBC surfaces:

• Rh-positive (Rh⁺) : RBCs carry the D antigen (~85% of the population).
• Rh-negative (Rh⁻) : RBCs lack the D antigen (~15% of the population).

Unlike the ABO system, anti-Rh antibodies are NOT preformed. An Rh⁻ individual develops anti-Rh antibodies only after sensitization — exposure to Rh⁺ blood (via transfusion or pregnancy).

Hemolytic disease of the newborn (HDN) / Erythroblastosis fetalis:

This is the most clinically significant consequence of Rh incompatibility:

1. An Rh⁻ mother carries an Rh⁺ fetus (inherited from an Rh⁺ father).
2. During delivery (or any event causing fetal-maternal hemorrhage), fetal Rh⁺ RBCs enter the maternal circulation.
3. The mother's immune system is exposed to the Rh antigen and produces anti-Rh antibodies (IgG class, which can cross the placenta).
4. In a subsequent pregnancy with another Rh⁺ fetus, maternal anti-Rh antibodies cross the placenta and attack fetal RBCs, causing hemolysis, severe anemia, jaundice, and potentially fetal death.
5. Prevention: Administration of RhoGAM (anti-Rh immunoglobulin) to the Rh⁻ mother at 28 weeks of gestation and within 72 hours after delivery. RhoGAM binds and neutralizes any fetal Rh⁺ RBCs before the maternal immune system can mount a lasting antibody response, preventing sensitization.

22.12 Common Blood Disorders

22.12.1 Anemia

Anemia is defined as a reduction in the oxygen-carrying capacity of blood, typically due to a decrease in the number of RBCs or a decrease in hemoglobin content. Common symptoms include fatigue, pallor, shortness of breath, and tachycardia.

Table 22.6 — Major Types of Anemia

22.12.2 Polycythemia

Polycythemia is an abnormally high RBC count, which increases blood viscosity and places greater strain on the heart.

• Polycythemia vera: A bone marrow disorder characterized by uncontrolled RBC production (a myeloproliferative neoplasm).
• Secondary polycythemia: A physiological response to chronic hypoxia (e.g., living at high altitude, chronic lung disease) in which the kidneys produce excess EPO.
• Relative polycythemia: Results from a decrease in plasma volume (dehydration) without an absolute increase in RBCs.

22.12.3 Leukemia

Leukemia is a group of cancers of the hematopoietic tissue in which abnormal, non-functional leukocytes proliferate uncontrollably in the bone marrow and spill into the peripheral blood.

• Acute leukemia: Rapid progression; characterized by large numbers of immature, non-functional blast cells. Requires prompt treatment.
• Chronic leukemia: Slower progression; accumulation of more mature (but still abnormal) WBCs. May be asymptomatic for years.
• Both forms crowd out normal hematopoietic activity, leading to anemia (low RBCs), thrombocytopenia (low platelets → bleeding risk), and increased susceptibility to infection despite high WBC counts (because the WBCs are non-functional).

22.12.4 Hemophilia

Hemophilia is a group of hereditary bleeding disorders caused by a deficiency of specific clotting factors.

• Hemophilia A (most common, ~80% of cases): Deficiency of Factor VIII (antihemophilic factor).
• Hemophilia B (Christmas disease): Deficiency of Factor IX.
• Both are X-linked recessive disorders, affecting primarily males; females are typically carriers.
• Characterized by excessive bleeding after minor trauma, spontaneous bleeding into joints (hemarthrosis), and easy bruising.
• Treatment involves replacement of the missing clotting factor via intravenous infusion.

22.12.5 Thrombocytopenia

Thrombocytopenia is an abnormally low platelet count (<150,000/µL). It can result from decreased platelet production (bone marrow failure, leukemia, chemotherapy), increased platelet destruction (autoimmune disorders like immune thrombocytopenic purpura/ITP , viral infections), or sequestration in an enlarged spleen (hypersplenism). Patients present with petechiae (pinpoint skin hemorrhages), easy bruising, and prolonged bleeding from minor cuts.