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Blood and hemostasis


Introduction

Blood is a specialized type of connective tissue that performs several key functions required for the viability of all other organs:

  • Major transportation route via the circulatory system.

  • Brings oxygen and nutrients (i.e., glucose), as well as endocrine hormones.

  • Removes carbon dioxide and waste products for disposal.

  • Maintains body temperature.

  • Provides defense against infection.

System structure

The structure of blood differs in two important aspects from that of other organ systems:

  • 1.

    Blood is liquid under normal conditions rather than solid.

  • 2.

    Blood circulates throughout the body.

These features are essential to the functions blood performs, and loss of either can result in serious pathophysiology.

Gross anatomy of the circulatory system

A healthy adult normally has approximately 5 liters (female) to 6 liters (male) of blood within the circulatory system. In brief, the circulatory system is constructed as follows ( Fig. 7.1 ):

  • Blood cells are produced in bone marrow.

  • Blood circulates via blood vessels.

  • The heart serves as the central pump of the circulatory system.

  • Arteries carry blood from the heart to capillary beds of peripheral tissues and organs, where it exerts its main effects.

  • Veins return blood to the heart.

  • Lymphatic vessels return extracellular fluid to the circulatory system.

Fig. 7.1, Simplified diagram of the circulatory system. While the volumes of blood in the arterial and venous systems appear roughly equal, the greater capacitance of the venous system compared to the arterial system results in a greater volume of blood being in the veins than in the arteries. Note the lymphatic system is not pictured. LA , Left atrium; LV , left ventricle; RA , right atrium; RV , right ventricle.

Components of blood

Blood consists of two components:

  • 1.

    Formed elements: includes red blood cells, white blood cells, and platelets.

  • 2.

    Plasma: the aqueous medium that contains a variety of proteins, small molecules, and ions.

These two components can be separated by centrifugation ( Fig. 7.2 ).

  • The hematocrit, or percentage of blood volume consisting of red blood cells, is calculated by measuring the height of the packed red cells and dividing by the height of the total blood in the tube. If a small volume of blood is prevented from clotting and the red blood cells are allowed to sediment on their own based on their density, one can both calculate the hematocrit and the rate at which the cells sediment in mm/hr. This rate is known as the erythrocyte sedimentation rate (ESR) and is a general measure of inflammation. The increased ESR in inflammatory states is due to increased erythrocyte density due to the adhesion of proinflammatory proteins to the red blood cells. The blood is also less viscous in inflammatory states, allowing erythrocytes to sediment faster. A commonly used formula is that the ESR = 200 − (2*hematocrit).

  • The hematocrit constitutes 40% to 50% of the blood volume in a normal adult.

Fig. 7.2, Hematocrit tubes before and after centrifugation. Blood from a patient is collected in a test tube. Before centrifugation ( left ), the blood appears to be homogeneously red from the abundance of erythrocytes. After centrifugation ( right ), the red cells fall to the bottom of the tube, the white cells form a small band called the buffy coat, and the plasma remains on top.

Blood cells and organelles

Blood cells are produced in bone marrow by hematopoietic stem cells (HSCs).

  • HSCs are undifferentiated cells.

  • They can either divide (via mitosis) to produce additional stem cells or differentiate into specialized cells.

When differentiated cells reach a sufficient degree of maturity, they exit the bone marrow to circulate in the vasculature. The number and morphology of different blood cells within the circulatory system may be assessed by peripheral blood smears ( Fig. 7.3 ).

Fig. 7.3, A peripheral blood smear. A drop of normal blood is smeared onto a glass slide, dried, stained, and examined under a light microscope. Note the shapes, relative numbers, and relative sizes of erythrocytes ( E) , neutrophils ( N ), lymphocytes (L), and platelets ( P ).

There are several different blood cell types found in peripheral blood ( Table 7.1 ), each specialized for different functions.

TABLE 7.1
The Formed Elements of Blood
Cell Diameter (µm) Number a
Erythrocytes 6.5–8 Males: 4.1–6 × 10 6 /µL
Females: 3.9–5.5 × 10 6 /µL
Leukocytes 4,000–10,000/µL
Neutrophils 12–15 60%–70%
Eosinophils 12–15 2%–4%
Basophils 12–15 0%–1%
Lymphocytes 6–18 20%–30%
Monocytes 12–20 3%–8%
Platelets 2–4 1.5–4.5×10 5 /µL

a Some sources give these values per cubic millimeter (mm 3 ). Microliters and cubic millimeters are identical units.

Erythrocytes (red blood cells)

  • Most numerous of the formed elements with about 4 to 6 million erythrocytes per µL of blood.

  • Biconcave discs with no nucleus, mitochondria, or ribosomes ( Fig. 7.4 ).

    • Lack of organelles facilitates transit through circulatory system.

    • Large surface-to-volume ratio facilitates gas exchange.

    Fig. 7.4, A scanning electron micrograph of typical erythrocytes. Note especially the biconcave-disc shape of the cells and their lack of a nucleus. During development, red cell precursors eject their nucleus, making them lighter and thus easier for the heart to pump throughout the circulatory system. The cytoplasm is filled largely with hemoglobin for carrying oxygen.

  • Eosinophilic (pink) staining on peripheral smears because of high protein content.

    • Contain mainly hemoglobin.

  • Immature erythrocytes, or reticulocytes, normally comprise around 1% of circulating red blood cells (RBCs).

    • Also lack nuclei.

    • Basophilic (blue) staining because of ↑ ribonucleic acid (RNA) content reflecting ongoing protein synthesis.

    • Marker of ↑ erythroid proliferation (see Fast Fact Box 7.1 ). FLOAT NOT FOUND

Fast Fact Box 7.1

During tissue staining, pathologists employ the dyes hematoxylin and eosin for a basic H&E stain. Hematoxylin, which is a base and positively charged, binds to negatively charged/acidic substrates, such as DNA/RNA. It stains them blue/violet. Eosin, which is acidic and negatively charged, stains positively charged/basic substrates, such as positively-charged amino acid side chains (lysine, arginine). It stains them pink/red.

Basic Binds Basophilic Becoming Blue

Acidic Attaches Acidophilic Appearing Auburn

DNA , Deoxyribonucleic acid; H&E , hematoxylin and eosin; RNA , ribonucleic acid.

Leukocytes (white blood cells)

  • White blood cells (WBCs) are roughly twice the size of RBCs.

  • Less numerous with 4000 to 10,000 per µL of peripheral blood.

  • There are several different types of leukocytes, classified according to their nuclear shape and the presence and type of granules in their cytoplasm ( Fig. 7.5 ):

    • Granulocytes (contain cytoplasmic granules).

      • Neutrophils (polymorphonuclear leukocytes [PMNs]).

        • Account for 60% to 70% circulating WBCs.

        • Nuclei with 2 to 5 lobes linked by fine chromatin threads.

        • Larger primary granules (lysosomes) and smaller secondary granules containing several mediators.

        • Immature neutrophils (“band forms”) have a nonsegmented nucleus and serve as a marker for ↑ myeloid proliferation.

      • Eosinophils

        • 2% to 4% of circulating WBCs.

        • Bilobed nuclei that appear as “sunglasses.”

        • Numerous large, eosinophilic granules containing major basic protein (MBP), histamine, and other mediators.

      • Basophils

        • Less than 1% of leukocytes.

        • Irregular multilobulated nuclei.

        • Numerous large, basophilic granules containing histamine, heparin, and leukotrienes.

      • Mononuclear granulocytes (nongranule containing, nonlobulated nuclei).

      • Monocytes.

        • Largest blood cell diameter (12–20 µm).

        • Kidney-shaped nucleus.

        • Precursors of macrophages in peripheral tissues.

          • May also develop into mast cells when they enter tissues such as the skin and gastrointestinal (GI) tract.

      • Lymphocytes.

        • Approximately the size of an erythrocyte but grow when activated.

        • Characterized by a spherical, deeply basophilic nucleus surrounded by a very thin rim of cytoplasm.

        • The different subclasses of lymphocytes, including B cells and T cells, are described in Chapter 8 .

    Fig. 7.5, Five types of leukocytes (white blood cells). Neutrophils, eosinophils, and basophils collectively form the granulocytes, or granule-containing leukocytes. Monocytes can transform into macrophages and travel to sites of inflammation. Lymphocytes circulate between the blood, peripheral tissues, and the lymphatic and lymph node system. There are two subtypes of lymphocytes, T cells and B cells, but they cannot be differentiated from one another by light microscopy alone. NK , Natural killer; RBC , red blood cell.

Platelets (thrombocytes)

  • 150,000 to 450,000 per µL in normal blood.

    • Note: One-third of total platelet pool is stored in the spleen!

  • Small, anucleate cell fragments with a diameter of 2 to 4 µm.

  • Essentially membrane-enclosed sacs of cytoplasm that pinch off from large cells called megakaryocytes, which remain in the bone marrow.

  • Contain dense granules (calcium, adenosine diphosphate) and alpha-granules (von Willebrand factor, fibrinogen).

  • Possess a number of cell surface glycoprotein adhesion molecules called “integrins” that mediate attachment to a blood vessel wall when endothelium is damaged or dysfunctional. The role of platelets in hemostasis, the control of bleeding, is described later in this Chapter.

Blood molecules

Plasma contains over 100 different proteins, as well as numerous other molecules, listed in Table 7.2 . Blood proteins can be classified as extracellular or intracellular.

TABLE 7.2
The Molecular Constituents of Plasma
Proteins 6.0–8.0
Albumin (g/dL) 3.4–5.0
Total globulin (g/dL) 2.2–4.0
Transferrin (mg/dL) 250
Haptoglobin (mg/dL) 30–205
Hemopexin (mg/dL) 50–100
Ceruloplasmin (mg/dL) 25–45
Ferritin (mcg/L) 15–300
Nonproteins
Cholesterol (mg/dL) 140–250
Glucose (mg/dL) 70–110
Urea nitrogen (mg/dL) 6–23
Uric acid (mg/dL) 4.1–85
Creatinine (mg/dL) 0.7–1.4
Iron (mcg/dL) 50–150

Extracellular (plasma)

  • Total plasma protein.

    • Normal range of 6.0 to 8.0 g/dL.

    • Functions of numerous proteins as carriers, clotting factors, immunoproteins, hormones, or enzymes are detailed below for the coagulation cascade and in subsequent chapters for the immunoproteins and hormones.

  • Albumin is the principal plasma protein.

    • Normal range of 3.4 to 5.0 g/dL of plasma protein.

    • Accounts for nearly two-thirds of total plasma protein mass.

  • Globulin consists of several groups of proteins (α-, β-, and γ-globulin).

Fast Fact Box 7.2

The proteins in plasma can be separated using a technique known as protein electrophoresis, in which proteins exposed to an electrical field move through a solid gel based on their size and charge. Different proteins are distinguished by their respective mobility in the gel.

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