Chapter 28: Structure and Function of the Hematologic System

Hematologic System (Left Side) (BLOOD AND BLOOD COMPONENTS)

• Depicts a blood vessel with red blood cells (RBCs), white blood cells (WBCs), and platelets flowing through it.

• RBCs (red, biconcave cells) are responsible for oxygen transport.

• WBCs (varied shapes and sizes) are part of the immune system, fighting infections.

• Platelets (small, disc-shaped) help in blood clotting.

• The blood circulates continuously via the heart and blood vessels, supplying oxygen, nutrients, and removing waste.

Lymphatic System (Right Side)

• Shows a human figure with major lymphatic structures labeled.

• Includes lymph nodes (cervical, axillary, intestinal, inguinal, etc.), the thymus, spleen, and tonsils—key components of immunity.

• Lymphatic vessels transport lymph (fluid containing WBCs) throughout the body.

• The thoracic duct and right lymphatic duct drain lymph into the bloodstream.

• The system helps remove toxins, waste, and unwanted materials, and plays a crucial role in immune defense.

• There is 2 components: liquid and solid component; the liquid component is the lymph(comes from interstitial fluid=outside cells, drains into superior vena cava); the solid component are the lymphatic organs(sleep and lymph nodes; secondary organs for the adaptive immune system)

Lymphoid Organs

• Primary lymphoid organs

➢ Thymus

➢ Bone marrow

• Secondary lymphoid organs

➢ Spleen

➢ Lymph nodes

➢ Tonsils

➢ Peyer patches of the small intestine

Lymphoid Organs

This image illustrates the lymphoid organs, which are essential components of the immune system. The lymphoid organs are categorized into central (primary) lymphoid organs and peripheral (secondary) lymphoid organs:

1. Central (Primary) Lymphoid Organs

These are responsible for the production and maturation of immune cells.

• Thymus (located in the chest)

  • Site of T-cell maturation, which plays a crucial role in adaptive immunity.

  • More active during childhood and shrinks with age.

• Bone Marrow (inside bones, depicted in the leg)

  • Produces all blood cells, including B-cells, which mature here before being released into circulation.

2. Peripheral (Secondary) Lymphoid Organs

These are where immune responses occur and where lymphocytes (B and T cells) become activated.

• Adenoid & Tonsils (located in the throat)

  • Help trap pathogens that enter through the mouth and nose.

• Lymph Nodes (scattered throughout the body)

  • Filter lymphatic fluid and house immune cells that fight infections.

• Spleen (left side of the abdomen)

  • Filters blood, removes old red blood cells, and helps activate immune responses.

• Peyer’s Patches (in the ileum, a part of the small intestine)

  • Monitor intestinal bacteria and prevent harmful infections in the gut.

• Lymph Nodes in Jejunum (another section of the small intestine)

  • Play a role in gut-associated immunity.

Lymphatic Vessels

• Transport lymph, a fluid containing white blood cells, throughout the body.

• Help drain excess fluid from tissues and return it to the bloodstream.

Overall Function of the Lymphoid Organs

• The central lymphoid organs generate immune cells.

• The peripheral lymphoid organs detect and respond to infections.

• Together, they help maintain immunity, filter harmful substances, and protect against pathogens.

Lymphoid Organs

• Spleen

-largest secondary lymphoid organ, composed of red(very vascularized, that’s why it appears red) and white pulp(where the T cells and B cells are developing/differentiating)

1. The left diagram (A) appears to be a histological section of the spleen stained under a microscope. It labels key structural components, including:

   • Trabeculae: These are extensions of the spleen’s connective tissue capsule that help provide structural support.

   • Trabecular vessels: Blood vessels within the trabeculae.

   • Red pulp: The region involved in filtering blood and breaking down old red blood cells.

   • White pulp: The immune-functional part of the spleen, rich in lymphocytes.

   • Capsule: The outer protective covering of the spleen.

2. The right diagram (B) is a more detailed, labeled schematic showing the histological organization of the spleen:

   • Red pulp: Contains pulp cords and venous sinusoids, which are involved in filtering blood and removing old/damaged red blood cells.

   • White pulp: Includes structures such as:

     • Germinal center: The site of active B-cell proliferation.

     • Corona of B cells: The outer region of white pulp containing mature B lymphocytes.

     • Periarterial lymphatic sheath (PALS): A T-cell-rich zone surrounding central arteries.

   • Trabecula and trabecular vein: Supportive structures that aid in blood circulation through the spleen.

Function of the Spleen

• The white pulp functions in immune surveillance, activating lymphocytes to fight infections.

• The red pulp is responsible for filtering blood, breaking down old red blood cells, and recycling iron.

• The trabecular system helps distribute blood efficiently throughout the spleen.

This image is another histological representation of the spleen, focusing on the structural and functional aspects of its red pulp and white pulp.

Key Features in the Image:

The spleen is divided into two main regions:

1. Red Pulp (Top Section)

   • Contains venous sinusoids, which help in filtering blood and store blood.

   • Penicillar arteries and their branches, including:

     • Terminal arterial capillary

     • Sheathed arteriole

     • Pulp arteriole

   • The red pulp is primarily responsible for the destruction of old red blood cells, iron recycling, and blood filtration.

2. White Pulp (Middle Section)

   • Contains lymphoid nodules with germinal centers, where B cells proliferate.

   • Corona of B cells surrounds the germinal center.

   • Periarterial lymphatic sheath (PALS), a T-cell-rich area surrounding the central artery.

   • Marginal zone (B cells) serves as the interface between the white and red pulp and is involved in antigen capture.

3. Additional Lymphoid Structures (Bottom Section)

   • Primary follicle: Contains mature B cells, particularly T-helper 2 (Th2) cells.

   • Secondary follicle(actively differentiation of b cells into plasma cells in order for them to produce antibodies): More developed, featuring a mantle zone and a germinal center.

   • The central artery is visible, running through these immune structures.

Functional Significance:

• The red pulp is involved in blood filtration, phagocytosis of old RBCs, and iron metabolism.

• The white pulp plays a role in immune responses, particularly in the activation of B and T lymphocytes.

• The marginal zone acts as a bridge between the red and white pulp, helping in the detection of bloodborne pathogens.

-when you remove the spleen there is an increased risk of infection with encapsulated bacteria because you get the primary IgM response from the spleen

Lymphoid Organs

• Lymph nodes

-site for the development and activation of lymphocytes and monocytes 

This image focuses on lymph nodes, which are essential secondary lymphoid organs that filter lymph and facilitate immune responses. The diagram provides a detailed view of the lymph node's structure and function.

Key Features of the Lymph Node in the Image:

1. Main Lymph Node Structure (Left Diagram)

   • Afferent lymphatic vessels: Carry lymph fluid into the lymph node.

   • Capsule: The outer connective tissue covering.

   • Subcapsular (Cortical) Sinus: A space beneath the capsule where lymph first enters.

   • Follicular dendritic cells: Found in secondary follicles, aiding in B-cell activation.

   • Secondary Follicle (B-cell zone): Contains germinal centers, where B cells proliferate and differentiate.

   • Paracortical Zone (T-cell zone): The region where T cells interact with dendritic cells for antigen presentation.

   • Medullary Sinus: Contains macrophages and plasma cells that filter lymph before it exits.

   • Efferent lymphatic vessel: Carries filtered lymph out of the node.

   • High Endothelial Venules (HEVs): Specialized blood vessels that allow lymphocytes (T & B cells) to enter the lymph node from the bloodstream.

2. Close-up of Lymphatic Sinuses (Top-Right Diagram)

   • Shows the fibroblastic reticular cells (FRCs) and reticular fibers, which help guide immune cells through the lymph node.

   • Dendritic cells are present for antigen presentation to lymphocytes.

   • The subcapsular sinus and trabecular sinus serve as pathways for lymph to flow through.

3. Zoomed-in View of Subcapsular Sinus (Bottom-Right Diagram)

   • Highlights subcapsular macrophages, which play a key role in trapping and processing antigens.

   • Shows lymphocytes migrating through the subcapsular sinus before entering deeper regions of the lymph node.

Functional Significance:

• Filtration of Lymph: The lymph node acts as a biological filter, removing pathogens, debris, and cancer cells.

• Immune Cell Activation: B cells and T cells encounter antigens and activate immune responses.

• Adaptive Immunity: Interaction between dendritic cells, macrophages, and lymphocytes allows for effective pathogen recognition and immune memory formation.

Composition of Blood

-The liquid component of blood is plasma(serum), and the solid is the sediments

Blood as a Percentage of Body Weight:

• Blood makes up about 8% of total body weight.

• The rest (92%) consists of other fluids and tissues.

Blood Composition by Volume:

• Plasma (55%): The liquid portion of blood.

• Formed Elements (45%): Includes red blood cells (erythrocytes), white blood cells (leukocytes), and platelets.

Plasma Composition (by weight):

• Water (91%): Major component, crucial for transport and maintaining blood volume.

• Proteins (7%): Includes:

  • Albumins (57%)(carrier proteins, transport) – Maintain osmotic pressure.

  • Globulins (38%)(antibodies) – Play roles in immunity.

  • Fibrinogen (4%) – Important for clotting.

  • Prothrombin (1%) – Also involved in clotting.

• Other Solutes (2%): Includes ions, nutrients, waste products, gases, and regulatory substances.

Formed Elements:

• Erythrocytes (Red Blood Cells, >99%): Responsible for oxygen transport.

• Leukocytes (White Blood Cells, <1%): Key components of the immune system.

• Platelets (<1%): Crucial for blood clotting.

Leukocyte Breakdown:

• Neutrophils (60-70%)(the highest proportion of leukocytes): First responders to infections.

• Lymphocytes (20-25%): Involved in adaptive immunity (T-cells, B-cells).

• Monocytes (3-8%): Become macrophages and help digest pathogens.

• Eosinophils (2-4%): Active in allergic reactions and parasitic infections.

• Basophils (0.5-1%): Release histamine and are involved in inflammatory responses.

Composition of Blood – Cells

• Erythrocytes (red blood cells)

• Leukocytes

• Platelets

Blood is composed of different cellular components, which play essential roles in oxygen transport, immune defense, and clotting. The three main types of blood cells are erythrocytes (red blood cells), leukocytes (white blood cells), and platelets.

1. Erythrocytes (Red Blood Cells – RBCs)

• Function: Transport oxygen from the lungs to tissues and carry carbon dioxide back to the lungs for exhalation.

• Structure:

  • Biconcave shape increases surface area for gas exchange.

  • Lack a nucleus to maximize hemoglobin content.

• Hemoglobin: A protein that binds oxygen, giving blood its red color.

• Lifespan: About 120 days before being broken down in the spleen and liver.

2. Leukocytes (White Blood Cells – WBCs)

• Function: Defend the body against infections, pathogens, and foreign substances.

• Types of Leukocytes:

  1. Neutrophils (60-70%) – First responders to infections; engulf bacteria through phagocytosis.

  2. Lymphocytes (20-25%) – Include B-cells (produce antibodies) and T-cells (kill infected cells).

  3. Monocytes (3-8%) – Become macrophages that digest pathogens.

  4. Eosinophils (2-4%) – Combat parasites and are involved in allergic reactions.

  5. Basophils (0.5-1%) – Release histamine, playing a role in allergic responses and inflammation.

• Lifespan: Ranges from a few hours to several years, depending on the type.

3. Platelets (Thrombocytes)

• Function: Involved in blood clotting (hemostasis) to prevent excessive bleeding from injuries.

• Structure:

  1. Small, cell fragments rather than full cells.

  2. Contain granules with clotting factors.

• Clotting Process:

  1. When a blood vessel is damaged, platelets adhere to the site.

  2. They release clotting factors to form a temporary plug.

  3. These factors activate fibrin, creating a stable clot.

• Lifespan: Around 7-10 days before being removed by the spleen

Composition of Blood-Cells

• Leukocytes= Erythrocyte

(red blood cells, most abundant cells, men have a little bit more RBCs than women, have hemoglobin(produce it), lose their nuclei and assume a biconcave shape-increases surface area to volume ratio=more room for hemoglobin=better oxygenation=easily deformed can squeeze through microcirculation to travel through tissues, oxygen-carrying cells, lives for 120 days)

Composition of Blood-Cells

• Leukocytes=neutrophil

(the granulocytes=defend the body against infection)(early phagocytes, die within 1-2 days after being at the site of infection, primary producers of pus=their death creates pus, first responders, nonspecific)

Composition of Blood-Cells

• Leukocytes=eosinophil

(the granulocytes=defend the body against infection)( show up red because they take up the dye eosin, makeup 1-4% of WBC, important in parasitic infections like protozoa, involved in type 1 reactions of asthma)

Composition of Blood-Cells

• Leukocytes=basophil

(less than 1%, contain histamine, involved in allergic reactions, also parasitic specifically ticks, local inflammatory response)

Composition of Blood-Cells

• Leukocytes=lymphocyte

(adaptive immune cells: t and b cells)

Composition of Blood-Cells

• Leukocytes=monocyte

(develop into macrophages and then they become phagocytic)(major phagocytic cell)

Composition of Blood-Cells

• Leukocytes=platelet

(clotting cells)

Composition of Blood-Cells

• Leukocytes

Erythrocytes (Red Blood Cells - RBCs) (A)

• Appear as small, round, pinkish cells with no nucleus.

• Their main function is to transport oxygen via hemoglobin.

Neutrophils (B, C)

• Characterized by a multi-lobed nucleus.

• Act as the first responders in the immune system, combating bacterial infections.

• Stained in a light purple color.

Eosinophil (D)

• Identified by a bilobed nucleus and large reddish-orange granules.

• Play a key role in allergic reactions and defense against parasites.

Basophil (E)

• Recognized by large dark purple granules that obscure the nucleus.

• Involved in inflammatory responses and allergic reactions by releasing histamine.

Lymphocyte (F)

• A small cell with a large, round nucleus and minimal cytoplasm.

• Essential for adaptive immunity, including B cells (antibody production) and T cells (cell-mediated immunity).

Monocyte (G)

• The largest of the white blood cells, with a kidney-shaped nucleus.

• Precursor to macrophages, which help in phagocytosis and immune response.

Platelets (H)

• Tiny cell fragments involved in blood clotting and wound healing.

 Question 1: A person has an infection with early inflammation. Which agranulocyte is the primary immunogenic WBC?

1. Neutrophil

2. Natural killer cell

3. Lymphocyte

4. Eosinophil

Explanation ANS: 3
Lymphocytes, which are agranulocytes, constitute approximately 36% of the total leukocyte count and are the primary cells of the immune response. Neutrophils, basophils, and eosinophils are granulocytes that act as phagocytes. Lymphocytes are the primary cells of the immune response.
1. Neutrophils are the primary granulocyte and are the chief phagocytes of early inflammation.
2. Natural killer (NK) cells, which resemble large granular lymphocytes, kill some types of tumor cells (in vitro) and some virus-infected cells without being induced by previous exposure.
4. Eosinophils are granulocytes seen in increased concentration in type I hypersensitivity, allergy, parasitic invasion, and asthma.

Composition of Blood-Cells-Platelets

-major clotting cells, end up forming blood clots in the body, anucleated, formed bt the fragmentation of megakaryocyte, essential for blood clotting and the control of bleeding, cant go through division, they have granules)

Left Image (Light Microscope View)

• Shows megakaryocytes, which are large bone marrow cells.

• These cells are responsible for producing platelets (thrombocytes) by shedding small fragments of their cytoplasm.

• The large dark-stained cell in the image is a megakaryocyte, surrounded by smaller cell fragments (platelets).

Right Image (Electron Microscope View)

• Depicts an activated platelet, with an irregular shape and extended projections.

• When platelets are activated (e.g., during injury), they change shape, adhere to the damaged vessel wall, and release clotting factors.

• The orange platelet in the image appears to be interacting with another cell (green), possibly an endothelial cell or red blood cell.

Key Takeaways

• Platelets are not actual cells but fragments of megakaryocytes.

• They play a critical role in hemostasis, forming a plug at injury sites to prevent bleeding.

• In an inactive state, platelets are small, disc-shaped cell fragments.

• When activated, they develop extensions to interact with other cells and initiate clot formation

HEMATOPOIESIS

-the process of blood cell production in the adult bone marrow

-liver and spleen is where they are produced if they aren’t produced in the bone marrow(for example in kids)

-occurs in bone marrow

-the process of blood cell formation in the bone marrow

-red bone marrow is highly vascularized and appears red because of the blood cells being produced, active hematopoises going on

-yellow bone marrow is yellow because it has fat and has adipocytes

hematopoiesis

Nutrient Arteriole

• A branch of the artery that supplies blood to the bone marrow.

• Surrounded by hematopoietic cells.

Sinusoidal Lumen

• A network of small blood vessels (sinusoids) where mature blood cells enter circulation.

Endothelial Cells

• Form a continuous lining of interconnected cells in blood vessels.

• Separated from stromal or reticular cells by a basal lamina.

Granulocyte Progeny

• Developing granulocytes are located near sinusoids.

• Mature granulocytes leave the bone marrow through diapedesis (movement of cells through blood vessel walls).

Stromal or Reticular Cells

• Provide structural support and help regulate hematopoiesis.

• Produce hematopoietic short-range regulatory molecules like colony-stimulating factors.

Megakaryocyte

• A large cell responsible for producing platelets.

• Located near venous sinusoids, it releases platelets into circulation through gaps in the endothelial lining.

Erythroid Progeny

• Precursors to red blood cells (RBCs).

• Undergo maturation before being released into circulation.

Macrophage

• Found near erythroid progenitors.

• Engulfs extruded nuclei from developing RBCs (orthonormatic erythroblasts) before they convert into reticulocytes (immature RBCs).

The image is a histological section of bone marrow, labeled to show key components involved in hematopoiesis (blood cell formation)

1. Modullary Venous Sinuses:

   • These are specialized blood vessels within the bone marrow that allow mature blood cells to enter circulation.

   • They serve as an interface between hematopoietic cells and systemic blood flow.

2. Stromal Cells:

   • Supportive cells in the bone marrow microenvironment.

   • Provide structural integrity and regulate the differentiation and proliferation of hematopoietic cells.

   • They produce cytokines and growth factors essential for hematopoiesis.

3. Endothelial Cell Lining:

   • Forms the inner lining of the venous sinuses.

   • Acts as a selective barrier, allowing mature blood cells to pass into circulation while maintaining the integrity of the marrow environment.

4. Osteoblasts:

   • Bone-forming cells found along the bone surface.

   • Play a role in bone remodeling and influence hematopoietic stem cell (HSC) regulation through signaling molecules

1. Bone Structure (Left Side)

   • Shows a cross-section of a long bone, indicating that hematopoiesis occurs within the bone marrow cavity.

2. Endosteal Area (Left Section of Bone Marrow)

   • Located near the inner bone surface.

   • Contains osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells).

   • Quiescent hematopoietic stem cells (HSCs) reside here, regulated by signals like CXCL4 and TGF-β1.

   • Megakaryocytes (platelet-producing cells) are also present.

3. Vascular Area (Right Section of Bone Marrow)

   • Contains blood vessels, including arterioles and sinusoids (specialized blood vessels).

   • Endothelial cells line the blood vessels and help regulate HSC migration.

   • Perivascular Nestin-expressing MSCs (mesenchymal stem cells) provide structural and regulatory support.

   • CAR (CXCL12-abundant reticular) cells secrete CXCL12, a critical chemokine that helps maintain stem cell quiescence and retention in the bone marrow.

4. Sympathetic Nerve Regulation

   • Sympathetic nerves and nonmyelinating Schwann cells influence the bone marrow microenvironment.

   • TGF-β1 (Transforming Growth Factor Beta 1) plays a role in maintaining stem cell dormancy.

5. Hematopoietic Stem Cell Regulation

   • Quiescent HSCs are found near osteoblasts and perivascular regions.

   • CXCL12 and SCF (Stem Cell Factor) are crucial for HSC maintenance, proliferation, and expansion.

   • Adipocytes are shown suppressing HSC numbers.

Interpretation:

• This image represents the complex bone marrow niche, illustrating the interactions between hematopoietic, stromal, endothelial, and neural components.

• Hematopoietic stem cells (HSCs) transition from quiescence to active proliferation and differentiation as they move between the endosteal and vascular niches.

• The vascular niche supports the release of mature blood cells into circulation, while the endosteal niche maintains stem cell reserves.

Hematopoiesis Process

Hematopoiesis, the process of blood cell formation

Stem Cell Pool (Left Section)

• Begins with multipotential (totipotential) stem cells, which have the ability to differentiate into various blood cell types.

• These stem cells differentiate into unipotential committed cells, which are dedicated to forming specific blood cell lineages.

Bone Marrow Pool (Middle Section)

• Committed cells undergo proliferation and maturation within the bone marrow.

• Some cells are stored in the bone marrow before being released into the bloodstream.

Peripheral Blood (Right Section)

• Blood cells enter circulation with a balance between stored and functional cells:

  • Granulocytes: 50% stored, 50% functional.

  • Thrombocytes (platelets): 30% stored, 70% functional.

  • Erythrocytes (red blood cells): 100% functional (no storage).

This image illustrates hematopoiesis, the process by which all blood cells are formed from hematopoietic stem cells (HSCs). The diagram breaks down hematopoiesis into different stages, showing the differentiation pathways and the role of various cytokines and growth factors.

Key Components of the Diagram:

1. Stem Cells (Top Section)

   • The process begins with totipotent stem cells, which differentiate into pluripotent and multipotent stem cells.

   • Hematopoietic stem cells (HSCs) give rise to all blood cells.

   • Differentiation is influenced by stem cell factors (SCF), IL-3, IL-7, and IL-11.

2. Progenitor Cells (Middle Section)

   • HSCs divide into two main progenitor lines:

     • Common Myeloid Progenitor → Forms myeloid lineage cells.

     • Common Lymphoid Progenitor → Forms lymphoid lineage cells.

   • Various cytokines drive this process:

     • SCF, IL-3, GM-CSF → Influence myeloid progenitor development.

     • SCF, IL-7 → Influence lymphoid progenitor development.

3. Committed Progenitor Cells

   • Myeloid lineage differentiates into:

     • Basophil progenitors → Develop into basophils (driven by IL-5).

     • Eosinophil progenitors → Develop into eosinophils (IL-3, GM-CSF).

     • Granulocyte/monocyte progenitors → Give rise to neutrophils, monocytes/macrophages (GM-CSF, M-CSF, G-CSF).

     • Megakaryocyte progenitors → Develop into platelets (TPO).

     • Erythroid progenitors → Develop into red blood cells (EPO, IL-3).

   • Lymphoid lineage differentiates into:

     • Pro-B cells → Develop into B cells (stimulated by IL-7).

     • Pro-NK cells → Develop into natural killer (NK) cells (IL-15).

     • Pro-T cells → Develop into T cells (IL-2, IL-7, thymus-dependent maturation).

4. Precursor Cells (Lower Section)

   • Each progenitor cell further differentiates into precursor cells (blasts), which then mature into functional blood cells.

5. Mature Blood Cells (Bottom Section)

   • Basophils – Involved in allergic responses.

   • Eosinophils – Combat parasitic infections and mediate allergic reactions.

   • Neutrophils – Key players in innate immunity and bacterial defense.

   • Monocytes/macrophages – Involved in phagocytosis and immune regulation.

   • Platelets (thrombocytes) – Essential for blood clotting.

   • Erythrocytes (red blood cells) – Transport oxygen.

   • Plasma cells (from B cells) – Produce antibodies.

   • Natural Killer (NK) cells – Involved in innate immunity.

   • T cells – Play a role in adaptive immunity.

Key Takeaways:

• Hematopoiesis is tightly regulated by cytokines and growth factors.

• The bone marrow is the primary site of blood cell production.

• Lymphoid cells mature in secondary lymphoid organs (B cells) or the thymus (T cells).

• The differentiation process ensures a balanced production of all blood cells needed for oxygen transport, clotting, and immune defense.

-mitotic(making more and more cells) and maturation(differentiation into the types of cells) stages

Question 2: Which physiologic process occurs in hematopoiesis?

1. Niches control the differentiation of hematopoietic progenitor cells.

2. The spleen as the primary adult site uses splenic pulp to develop RBCs.

3. Peyer patches in the bone marrow stimulate the growth process.

4. Mesenchymal stem cells differentiate into hematologic cells.

Explanation: ANS: 1
The hematologic compartment of the bone marrow consists of a variety of cellular microenvironments, called niches, that control differentiation of hematopoietic progenitor cells.
2. The spleen compartments contain masses of lymphoid tissue called splenic pulp. It is a site of fetal hematopoiesis.
3. The secondary lymphoid organs consist of the spleen, lymph nodes, tonsils, and Peyer patches of the small intestine. Hematopoiesis occurs in the red bone marrow.
4. Mesenchymal stem cells (MSC) are stromal cells that can differentiate into a variety of cells, including osteoblasts, adipocytes, and chondrocytes (produce cartilage). Hematopoietic stem cells (HSC) are progenitors of all hematologic cells.

Hematopoiesis occurs primarily in the bone marrow, where niches (specialized microenvironments) regulate the differentiation and proliferation of hematopoietic progenitor cells. These niches provide signaling molecules, cytokines, and growth factors that influence the development of different blood cell lineages.

Why the other options are incorrect:

• Option 2: The spleen is not the primary site of hematopoiesis in adults; it mainly functions in blood filtration and immune responses. The bone marrow is the primary site for blood cell production in adults.

• Option 3: Peyer’s patches are lymphoid tissue found in the small intestine and are involved in immune responses, not hematopoiesis.

• Option 4: Mesenchymal stem cells (MSCs) give rise to bone, cartilage, and fat cells, but not directly to hematopoietic (blood) cells. Instead, hematopoietic stem cells (HSCs) are responsible for blood cell formation.

Erythropoiesis

• Development of RBCs from erythroblasts

• Stimulated by erythropoietin

erythropoiesis, the process of red blood cell (RBC) formation, which occurs in the bone marrow and is stimulated by erythropoietin (EPO), a hormone primarily produced by the kidneys.

Key Stages of Erythropoiesis:

1. Erythroid Progenitor

   • A precursor stem cell in the bone marrow that has the potential to develop into an erythrocyte (RBC).

   • Requires stimulation by erythropoietin (EPO) to commit to erythropoiesis.

2. Committed Proerythroblast

   • The first recognizable cell in RBC development.

   • It undergoes multiple divisions and begins hemoglobin synthesis.

3. Normoblast

   • The cell continues to produce hemoglobin.

   • Nucleus shrinks and is reabsorbed, a key step in erythrocyte maturation.

4. Reticulocyte

   • An immature RBC that lacks a nucleus but still contains residual RNA.

   • It leaves the bone marrow and enters the bloodstream.

   • Reticulocytes typically mature into erythrocytes within 1-2 days.

5. Erythrocyte (Mature RBC)

   • Fully developed RBC that achieves its final shape and size.

   • Hemoglobin synthesis ceases as it no longer has a nucleus or organelles.

   • Functions primarily to transport oxygen and carbon dioxide

Erythropoiesis

erythropoiesis, the process of red blood cell formation. It consists of two main sections:

1. Left Image (Electron Microscopy of Bone Marrow)

   • Depicts the bone marrow environment where red blood cells develop.

   • Labels indicate:

     • Developing blood cells in the bone marrow.

     • Medullary venous sinuses, which are blood vessels within the marrow where mature cells enter circulation.

     • Mature blood cells are entering the venous sinus, signifying their transition into the bloodstream.

     • Endothelial cell lining, which forms the barrier of the sinuses.

2. Right Image (Cross-section of Bone Marrow)

   • Highlights different stages of red blood cell maturation:

     • Proerythroblast – an early precursor of red blood cells.

     • Orthochromatic erythroblast – a later stage before becoming a reticulocyte.

     • Reticulocyte – an immature red blood cell that eventually matures into a functional erythrocyte.

Erythropoiesis

• Regulation

The image explains the regulation of erythropoiesis, which is the process of red blood cell (RBC) production. It highlights the role of the kidneys and erythropoietin (EPO) in response to low oxygen levels.

Key Components in the Image:

1. Triggers for Erythropoiesis (Top right box)

   • Conditions that lead to increased RBC production:

     • Decreased RBC count

     • Decreased hemoglobin synthesis

     • Decreased blood flow

     • Hemorrhage (blood loss)

     • Increased oxygen consumption by tissues

   • These factors cause a reduction in oxygen (O₂) levels in the blood.

2. Kidney’s Role (Center of the Image)

   • The kidney detects low oxygen levels (hypoxia).

   • In response, it releases erythropoietin (EPO) into the bloodstream.

   • EPO signals the bone marrow to produce more RBCs.

3. Bone Marrow Stimulation (Left Side)

   • EPO stimulates erythropoiesis in the bone marrow.

   • More RBCs are produced and released into circulation.

4. Increased Oxygen Delivery (Bottom Right)

   • Newly produced RBCs increase the oxygen-carrying capacity of the blood.

   • This restores normal oxygen levels.

   • The kidney then reduces EPO production in response to improved oxygenation.

Overall Concept:

This image illustrates a negative feedback loop that regulates RBC production. When oxygen levels drop, the kidney releases EPO, stimulating RBC production. Once oxygen levels normalize, EPO secretion decreases to maintain balance.

Hemoglobin

• Oxygen-carrying protein in RBCs

• Each RBC has up to 300 molecules

• Hemoglobin A: 2 α-(alpha), 2 β-chains(beta)

• Heme group contains iron, syntheszied in the mitochondria

Nutritional Requirements for Erythropoiesis

• Proteins (amino acids)

• Vitamins

➢ B12

➢ B6 and E and pantothenic acid

➢ Folic acid

➢ C

➢ Riboflavin

➢ Niacin

➢ E

1. Proteins (Amino Acids)

• Essential for globin synthesis, a key component of hemoglobin.

2. Vitamins and Their Roles in Erythropoiesis:

• Vitamin B12:

  • Required for DNA synthesis and maturation of RBCs.

  • Deficiency leads to megaloblastic anemia (large, immature RBCs).

• Vitamin B6 (Pyridoxine):

  • Essential for hemoglobin production.

  • Aids in iron metabolism and RBC formation.

• Vitamin E:

  • Protects RBC membranes from oxidative damage.

• Pantothenic Acid (Vitamin B5):

  • Involved in heme synthesis (a key part of hemoglobin).

• Folic Acid (Vitamin B9):

  • Required for DNA replication and cell division.

  • Deficiency causes megaloblastic anemia, leading to large, dysfunctional RBCs.

• Vitamin C (Ascorbic Acid):

  • Enhances iron absorption in the intestines.

  • Helps maintain the stability of RBCs.

• Riboflavin (Vitamin B2):

  • Important for RBC energy metabolism.

  • Deficiency may cause normocytic anemia (normal-sized but reduced RBCs).

• Niacin (Vitamin B3):

  • Aids in NAD/NADP synthesis, which is vital for RBC metabolism.

Question 3: A person has an inadequate intake of folic acid (folate). What will happen to this person’s RBCs?

1. Impaired iron metabolism

2. Impaired DNA synthesis

3. Impaired hemoglobin synthesis

4. Impaired heme metabolism

Explanation: ANS: 2
Folate is the second most important vitamin for erythrocyte production and maturation. Folate is necessary for DNA synthesis, being a component of three of the four DNA bases (thymine, adenine, and guanine), and RNA synthesis.
1. Vitamin C is needed for proper iron metabolism.
3. Iron is necessary for hemoglobin synthesis.
4. Vitamin B6, E, and pantothenic acid are needed for heme synthesis.

Erythrocyte Senescence/Destruction

• Spleen macrophages remove from circulation

            ➢ Kupffer cells in liver can also remove

• Sequence

           ➢ Heme: porphyrin broken down to bilirubin and excreted

           ➢ Globin: broken down to amino acids

           ➢ Iron recycled

As red blood cells (RBCs) age (approximately 120 days in circulation), they undergo senescence (aging) and are removed by the body through specialized cells and processes.

1. Removal of Aged RBCs

• Spleen macrophages (major site):

  • The spleen acts as a "filter," trapping and breaking down old or damaged RBCs.

• Kupffer cells in the liver:

  • These specialized macrophages in the liver can also remove old RBCs, especially if the spleen is not functioning properly.

2. Breakdown & Recycling Sequence

1. Heme Breakdown:

   • The porphyrin ring in heme is broken down into bilirubin.

   • Bilirubin is transported to the liver, where it is conjugated and excreted in bile.

   • It is ultimately eliminated through the feces (as stercobilin) and urine (as urobilin).

2. Globin Breakdown:

   • The protein portion (globin) of hemoglobin is broken down into amino acids, which can be reused by the body for protein synthesis.

3. Iron Recycling:

   • Iron from hemoglobin is recycled and transported by transferrin to the bone marrow for new RBC production.

   • Some iron is stored in the liver and spleen as ferritin or hemosiderin.

Erythrocyte Destruction

1. ​​Erythrocyte Formation in Bone Marrow

• Red blood cells (erythrocytes) are produced in the bone marrow and circulate in the bloodstream for about 120 days.

2. Erythrocyte Destruction in Macrophages (Mononuclear Phagocyte System - MPS)

   • Old or damaged RBCs are engulfed by macrophages, primarily in the spleen, liver, and bone marrow.

   • Hemoglobin is broken down into:

     • Heme → Further degraded into bilirubin.

     • Globin → Broken down into amino acids for reuse.

3. Bilirubin Processing in the Liver

   • Unconjugated (free) bilirubin binds to albumin in the blood.

   • The liver uptakes this bilirubin and conjugates it with glucuronic acid via glucuronyl transferase, making it water-soluble.

4. Excretion of Bilirubin

   • Conjugated bilirubin is excreted into the gut via bile.

   • In the intestine, bacteria convert bilirubin into urobilinogen.

     • Some urobilinogen is reabsorbed into the bloodstream and excreted by the kidneys as urobilin in urine.

     • The rest is converted into stercobilin and excreted in feces, giving stool its brown color.

Key Points:

• RBC lifespan is about 120 days before destruction.

• The liver plays a key role in bilirubin metabolism and excretion.

• Kidney excretes urobilinogen, contributing to urine color.

• The gut flora helps process bilirubin into its final excretory forms.

Iron Cycle

Iron Cycle, which describes how iron is conserved and reused in the body, particularly in red blood cell (erythrocyte) turnover.

Key Steps in the Iron Cycle:

1. Erythropoiesis (Red Blood Cell Production) in Bone Marrow

   • The bone marrow produces erythrocytes (RBCs) containing hemoglobin, which is rich in iron.

   • These RBCs circulate in the bloodstream.

2. Aging and Breakdown of Erythrocytes

   • Aged, abnormal, or damaged erythrocytes are engulfed by macrophages in the spleen, liver, and bone marrow.

   • Hemoglobin is broken down into:

     • Heme → Further processed into bilirubin and iron.

     • Globin → Broken down into amino acids for reuse.

3. Iron Recycling

   • Iron released from hemoglobin is bound to transferrin, a transport protein, for distribution.

   • It can be:

     • Directly released into the bloodstream to be reused.

     • Stored in the spleen for future use.

     • Stored in the liver and later released when needed.

4. Reutilization for Hemoglobin Synthesis

   • Iron is transported back to the bone marrow for the synthesis of new hemoglobin in developing erythrocytes.

   • This ensures a continuous and efficient recycling process, minimizing iron loss.

Key Takeaways:

• The body efficiently recycles iron to reduce dependency on dietary intake.

• The spleen and liver serve as major iron storage sites.

• The bone marrow reuses iron for new RBC production.

• Transferrin is essential for iron transport in the blood.

Leukopoiesis

​​1. Myeloid Progenitor Pathway (Left Purple Section)

Common Myeloid Progenitor (CMP) gives rise to:

• Granulocyte-Monocyte Progenitor → Further differentiates into:

  • Granulocyte Progenitor → Myeloblast → Neutrophils (first responders in infections).

  • Monocyte Progenitor → Monoblast → Monocytes → Macrophages/Dendritic Cells (involved in antigen presentation and phagocytosis).

• Basophil Progenitor → Basophiloblast → Basophils (inflammatory response, histamine release).

• Eosinophil Progenitor → Eosinophiloblast → Eosinophils (allergic reactions and parasitic infections).

Regulated by:

• SCF, IL-3, GM-CSF → Early myeloid differentiation.

• IL-5 → Eosinophil development.

• M-CSF, G-CSF → Stimulate monocyte and granulocyte formation.

2. Lymphoid Progenitor Pathway (Right Purple Section)

Common Lymphoid Progenitor (CLP) gives rise to:

• Pro-B Cell → B Cell → Plasma Cell (produces antibodies in secondary lymphoid organs).

• Pro-NK Cell → NK Cell (natural killer cells, involved in immune surveillance).

• Pro-T Cell → T Cell (matures in the thymus into CD4+ helper T cells and CD8+ cytotoxic T cells).

Regulated by:

• SCF, IL-7 → Lymphoid differentiation.

• IL-2, IL-15 → NK cell activation.

• IL-4, Antigen Exposure → B cell differentiation into plasma cells.

Key Takeaways from the Purple Sections:

• Myeloid pathway → Produces granulocytes and monocytes, involved in innate immunity and phagocytosis.

• Lymphoid pathway → Produces B cells, T cells, and NK cells, involved in adaptive immunity.

• Cytokines regulate differentiation at various stages, ensuring immune system balance.

Leukopoiesis

• Arise from stem cells in the bone marrow

            ➢ Common lymphoid progenitors

            ➢ Common myeloid progenitors

• Granulocytes mature in the bone marrow

• Agranulocytes and monocytes released into bloodstream before fully mature

• Increase in infection, with steroids, and reduced reserves in bone marrow.

Leukopoiesis (White Blood Cell Formation)

Leukopoiesis is the process of forming white blood cells (leukocytes) from stem cells in the bone marrow. These cells play a crucial role in immune defense.

1. Lineages of White Blood Cells

White blood cells arise from two major progenitor pathways:

• Common Lymphoid Progenitors → Give rise to:

  • Lymphocytes (B cells, T cells, and Natural Killer (NK) cells)

• Common Myeloid Progenitors → Give rise to:

  • Granulocytes (Neutrophils, Eosinophils, Basophils)

  • Monocytes (which later differentiate into macrophages and dendritic cells)

2. Maturation and Release

• Granulocytes (Neutrophils, Eosinophils, Basophils) → Fully mature in the bone marrow before entering circulation.

• Agranulocytes (Lymphocytes) & Monocytes → Released into the bloodstream before fully maturing and continue development in peripheral tissues.

3. Factors Affecting Leukopoiesis

• Increased production during infections → The immune system ramps up WBC production to fight pathogens.

• Stimulated by steroids → Corticosteroids can increase white blood cell count by preventing apoptosis of neutrophils.

• Reduced reserves in bone marrow → Conditions like bone marrow suppression (e.g., chemotherapy, radiation, or certain diseases) can lower WBC production, leading to immunodeficiency.

Development of Platelets

• Endomitosis (anaphase and cytokinesis blocked)

• Thrombopoietin

Common myeloid progenitor→megakryocyte progenitor(TPO) → megakaryoblast→ platelets

The development of platelets, also known as thrombopoiesis, occurs in the bone marrow and is primarily regulated by thrombopoietin (TPO). Here’s a breakdown of the process:

1. Lineage Commitment

• Common Myeloid Progenitor (CMP): Gives rise to various myeloid cells, including megakaryocytes.

• Megakaryocyte Progenitor (MkP): Differentiates into megakaryoblasts under the influence of thrombopoietin (TPO).

2. Megakaryopoiesis and Endomitosis

• Megakaryoblast: The first recognizable megakaryocyte precursor, undergoes a unique process called endomitosis.

• Endomitosis: A modified cell cycle where anaphase and cytokinesis are blocked, leading to DNA replication without cell division. This results in large, polyploid megakaryocytes (with multiple copies of DNA in a single nucleus).

3. Platelet Formation

• Mature Megakaryocytes: These large, multinucleated cells extend proplatelet projections into the bone marrow sinusoids.

• Platelet Shedding: The proplatelets fragment into thousands of platelets, which enter circulation.

Key Regulator: Thrombopoietin (TPO)

• Produced mainly by the liver and kidney.

• Stimulates megakaryocyte proliferation, maturation, and platelet production.

• Regulated via a negative feedback loop—higher platelet levels lead to decreased free TPO

Mechanisms of Hemostasis(control of bleeding)

• Blood vessels

            ➢ Regulate blood flow

            ➢ Prevents spontaneous activation of platelets and clotting

            ➢ Inhibit platelet adhesion and aggregation (NO, prostacyclin)

1. Regulation of Blood Flow: Blood vessels control the flow of blood, ensuring a balance between clot formation and circulation.

2. Prevention of Spontaneous Platelet Activation: The endothelium (inner lining of blood vessels) prevents unnecessary platelet activation to avoid excessive clotting.

3. Inhibition of Platelet Adhesion and Aggregation: The endothelium releases nitric oxide (NO) and prostacyclin (PGI₂) to prevent platelets from sticking together and forming a clot inappropriately.

The diagram illustrates multiple mechanisms that prevent unwanted clotting:

• Prostacyclin (PGI₂) and cAMP Production (Left Section)

  • Cyclooxygenase-1 (COX-1) in endothelial cells produces prostacyclin (PGI₂).

  • PGI₂ increases cAMP levels in platelets, which inhibits activation and aggregation.

• Nitric Oxide (NO) and cGMP Pathway (Left Section)

  • Endothelial cells release NO, stimulating the production of cGMP.

  • This leads to vascular smooth muscle relaxation and further inhibition of platelet activation.

• ADPase Activity (Middle Section)

  • The enzyme ADPase degrades ADP, reducing platelet activation since ADP is a key activator of platelets.

• Thrombin Inhibition (Middle Section)

  • Antithrombin III (AT-III), with the help of heparan sulfate (HS), neutralizes thrombin to prevent excessive clot formation.

• Tissue Factor Pathway Inhibition (Right Section)

  • Tissue Factor Pathway Inhibitor (TFPI) prevents activation of Factor Xa, a crucial enzyme in the clotting cascade.

• Protein C and S System (Right Section)

  Activated Protein C (APC), along with Protein S, degrades clotting factors (Factor Va and VIIIa), reducing excessive coagulation.

Mechanisms of Hemostasis

• Hemostasis: arrest of bleeding

• Components

           ➢ Vasculature (endothelial cells, subendothelial matrix

           ➢ Platelets

           ➢ Blood proteins

• Sequence

           ➢ Vascular injury leads to vasoconstriction.

           ➢ Formation of a hemostatic plug

           ➢ Tissue factor activates coagulation cascade.

           ➢ Secondary hemostasis

           ➢ Clot retraction and clot dissolution (fibrinolysis)

Hemostasis refers to the process of stopping bleeding (arrest of bleeding) and involves a well-regulated sequence of events to maintain vascular integrity while preventing excessive clotting.

Key Components of Hemostasis

1. Vasculature (Blood Vessels)

   • Endothelial cells: Regulate clotting by producing anticoagulants (e.g., prostacyclin, nitric oxide).

   • Subendothelial matrix: Contains collagen and von Willebrand factor (vWF), which activate platelets when exposed.

2. Platelets

   • Form the primary hemostatic plug by adhering to the injury site.

   • Release granules containing ADP, thromboxane A₂ (TXA₂), and serotonin, promoting aggregation.

3. Blood Proteins (Coagulation Factors)

   • Form the secondary hemostatic plug via the coagulation cascade.

   • Includes tissue factor (TF), thrombin, fibrinogen, and fibrin.

Sequence of Hemostasis

1. Vascular Injury → Vasoconstriction

   • Immediate reflex to reduce blood loss.

   • Endothelin-1 (ET-1) released by endothelial cells enhances vasoconstriction.

2. Formation of Hemostatic Plug (Primary Hemostasis)

   • Platelets adhere to exposed collagen and vWF in the damaged vessel.

   • Platelets activate, changing shape and releasing granules (ADP, TXA₂).

   • Platelets aggregate, forming a temporary plug.

3. Tissue Factor Activation of Coagulation Cascade

   • Tissue Factor (TF) from damaged cells activates Factor VII, initiating the extrinsic pathway.

   • Leads to thrombin generation.

4. Secondary Hemostasis

   • Thrombin converts fibrinogen to fibrin, stabilizing the platelet plug.

   • The coagulation cascade (intrinsic + extrinsic) forms a strong, stable clot.

5. Clot Retraction and Fibrinolysis

   • Clot retraction: Platelets contract via actin and myosin, strengthening the clot.

   • Fibrinolysis (Clot Dissolution):

     • Plasmin (activated from plasminogen) breaks down fibrin.

     • Prevents excessive clotting and allows tissue repair.

Mechanisms of Hemostasis

First Image Breakdown (Early Hemostasis)

This image explains the initial steps of hemostasis: subendothelial exposure, adhesion, and activation of platelets.

1. Subendothelial Exposure

• Occurs when the endothelium (inner lining of blood vessels) is damaged.

• Platelets start filling the gaps.

• This process is promoted by thromboxane A₂ (TXA₂) and inhibited by prostacyclin I₂ (PGI₂).

• Platelet function depends on calcium.

2. Adhesion

• When endothelial cells are lost (due to injury or erosion of atherosclerotic plaque), it exposes collagen and von Willebrand factor (vWF).

• vWF helps platelets adhere to the subendothelium.

• Platelet adhesion occurs through glycoprotein receptors:

  • GPIb (binds vWF),

  • GPIa/IIa (binds collagen),

  • GPIIb/IIIa (binds fibrinogen).

3. Activation

• Once adhered, platelets undergo activation, changing shape and forming pseudopods.

• GPIIb/IIIa receptors become activated, allowing platelets to bind to fibrinogen and vWF.

• Arachidonic acid pathway is activated, leading to the release of TXA₂.

Second Image Breakdown (Late Hemostasis)

This image describes the later stages of hemostasis: platelet aggregation, plug formation, and clot dissolution.

4. Aggregation

• Platelets stick together via GPIIb/IIIa receptors, binding to fibrinogen and forming a stable clot.

• TXA₂ plays a major role in aggregation.

• The coagulation cascade is activated, producing thrombin, which converts fibrinogen to fibrin.

• Heparin neutralizing factor enhances clot formation.

5. Platelet Plug Formation

• Red blood cells (RBCs) and platelets become trapped in a fibrin mesh, stabilizing the clot.

• The platelet plug (also known as a thrombus or blood clot) fully forms.

6. Clot Retraction and Dissolution

• Clot retraction: Platelets contract (via actin and myosin) to pull the edges of the wound together.

• Clot dissolution (fibrinolysis):

  • Plasminogen activators convert plasminogen into plasmin, which breaks down fibrin.

  • This process is regulated to prevent excessive clotting or premature clot breakdown.

Summary

These images illustrate the stepwise process of hemostasis, balancing clot formation and clot dissolution:

1. Injury → Vasoconstriction.

2. Platelet adhesion and activation (via collagen, vWF, TXA₂).

3. Platelet aggregation via fibrinogen and GPIIb/IIIa receptors.

4. Coagulation cascade activation, forming a stable fibrin clot.

5. Clot retraction to stabilize healing.

6. Fibrinolysis (clot breakdown) to restore normal blood flow.

Mechanisms of Hemostasis – Platelets

• Normal count is 140,000–340,000/mm3

           ➢ Thrombocytopenia: below 100,000/mm3

           ➢ Spontaneous bleeding can occur if below 20,000/mm3

           ➢ Thrombocytosis: risk increases for spontaneous blood clots (thrombosis), stroke, or heart attack

• Functions

          ➢ Induce vasoconstriction

          ➢ Initiate platelet-to-platelet interactions to form platelet plug

          ➢ Activate the clotting cascade to stabilize the platelet plug

          ➢ Initiate repair processes (clot retraction and fibrinolysis)

• Adhesion (platelet plug formation)

          ➢ Platelet glycoprotein-Ib binds to vWF

• Activation

          ➢ Platelet-release reaction – become spiny and degranulate

          ➢ vWF released from endothelial cell Weibel-Palade bodies

• Aggregation

          ➢ Facilitated by fibrinogen bridges between platelets

Platelet Count and Abnormalities

• Normal platelet count: 140,000–340,000/mm³.

• Thrombocytopenia (low platelets):

  • Below 100,000/mm³: Increased risk of bleeding.

  • Below 20,000/mm³: Risk of spontaneous bleeding (dangerous).

• Thrombocytosis (high platelets):

  • Increases risk of thrombosis (clots forming in vessels).

  • Can lead to stroke or heart attack.

Functions of Platelets in Hemostasis

1. Vasoconstriction: Platelets release vasoactive substances (e.g., TXA₂) to narrow the blood vessel and reduce bleeding.

2. Platelet-to-platelet interaction: Helps form a platelet plug at the injury site.

3. Clotting cascade activation: Platelets release factors to stabilize the clot with fibrin.

4. Initiate repair: Involved in clot retraction and fibrinolysis to restore normal blood flow.

Key Steps in Platelet Action

1. Adhesion (Platelet Plug Formation)

• Glycoprotein Ib (GPIb) binds to von Willebrand factor (vWF) on the damaged endothelium.

• This step anchors platelets to the site of injury.

2. Activation

• Platelets undergo shape change (become spiny).

• Degranulation: Platelets release clotting mediators.

• vWF is released from endothelial Weibel-Palade bodies, reinforcing adhesion.

3. Aggregation

• Fibrinogen bridges bind to platelet GPIIb/IIIa receptors, linking platelets together.

• This step solidifies the platelet plug, making it strong enough to stop bleeding.

Summary

Platelets play a critical role in hemostasis by:

1. Adhering to the injury site (via vWF).

2. Activating and releasing clotting factors.

3. Aggregating to form a stable platelet plug (via fibrinogen bridges).

4. Stabilizing the clot with fibrin and later aiding in clot retraction and dissolution.

Any imbalance in platelet function can lead to bleeding disorders (thrombocytopenia) or excessive clotting (thrombocytosis), increasing the risk of stroke or heart attack.

Vasoconstriction:

• Refers to the narrowing of blood vessels.

• Reduces blood flow and increases blood pressure.

• Important for reducing blood loss after injury.

• Increases blood pressure in response to shock or cold exposure.

• Key mediators: Thromboxane A₂ (TXA₂), Endothelin, Norepinephrine.

• Helps improve oxygen delivery and prevent excessive bleeding.

Vasodilation:

• Refers to the widening of blood vessels.

• Increases blood flow and decreases blood pressure.

• Not directly involved in hemostasis but aids circulation and heat dissipation.

• Key mediators: Nitric Oxide (NO), Prostacyclin (PGI₂), Histamine.

• Helps cool the body, especially during heat exposure or exercise, and increases blood flow to tissues.

• Excessive vasodilation can cause hypotension (low blood pressure) and shock.

Summary:

• Vasoconstriction reduces blood flow and raises blood pressure.

• Vasodilation increases blood flow and lowers blood pressure.

Mechanisms of Hemostasis – Clotting Factors

• Fibrin production

• Intrinsic pathway

• Extrinsic pathway

• Common pathway

The image presents an overview of the mechanisms of hemostasis with a focus on clotting factors involved in the coagulation cascade. It includes a diagram of clotting in vivo, highlighting the pathways involved in blood clot formation.

Key Components:

1. Fibrin Production

   • The ultimate goal of the clotting cascade is to convert fibrinogen into fibrin, which forms a stable blood clot.

2. Intrinsic Pathway

   • Triggered by damage to the vascular surface.

   • Involves Factor XI (XI) being activated to Factor XIa (XIa).

   • Leads to the activation of Factor IX (IX), which then forms a complex with Factor VIIIa (VIIIa).

3. Extrinsic Pathway

   • Initiated by tissue factor (TF) released due to vascular damage.

   • Factor VII (VII) binds to TF, becoming activated (VIIa).

   • This complex activates Factor X (X), leading to the common pathway.

4. Common Pathway

   • Both pathways converge at Factor X (X), which gets activated to Factor Xa (Xa).

   • Xa converts prothrombin into thrombin.

   • Thrombin(enzyme that can cleave fibrinogen to produce fibrin) converts fibrinogen into fibrin(sticky fibers that form the fibrin clot), leading to clot formation.

Regulatory Components:

• TFPI (Tissue Factor Pathway Inhibitor): Inhibits the extrinsic pathway.

• AT (Antithrombin): Inhibits thrombin and Factor Xa to prevent excessive clotting.

Question 4: von Willebrand factor is:

1. essential for platelet activation.

2. necessary for platelet adhesion.

3. needed to stimulate platelet aggregation.

4. required for Hageman factor to degrade platelets.

Explanation: ANS: 2
Platelet adhesion is mostly mediated by the binding of platelet surface receptor glycoprotein-Ib (GPIb) (in a complex with clotting factors IX and V) to von Willebrand factor (vWF). The vWF protein is found in the subendothelial matrix and is released by endothelial cells and platelets.
1. Platelet activation results in reorganization of the platelet cytoskeleton leading to dynamic changes in platelet shape from smooth spheres to those with spiny projections and degranulation (also called the platelet-release reaction) resulting in the release of various potent biochemicals.
3. Platelet aggregation is stimulated primarily by TXA2 and ADP, which induce functional fibrinogen receptors on the platelet.
4. The intrinsic pathway for clotting is activated when Hageman factor (factor XII) in plasma contacts negatively charged subendothelial substances exposed by vascular injury.

Von Willebrand factor (vWF) is a glycoprotein essential for platelet adhesion to the site of vascular injury. It binds to exposed collagen in the damaged blood vessel wall and interacts with platelet glycoprotein Ib (GPIb) to facilitate the initial attachment of platelets to the injured site.

• Option 1 (Platelet activation): Incorrect. vWF is more involved in adhesion rather than activation. Platelet activation is primarily driven by thrombin, ADP, and thromboxane A₂.

• Option 3 (Platelet aggregation): Incorrect. Platelet aggregation is mainly mediated by fibrinogen linking platelets via the GPIIb/IIIa receptor.

• Option 4 (Hageman factor degradation of platelets): Incorrect. Hageman factor (Factor XII) is involved in the intrinsic coagulation pathway, not in degrading platelets.

Control of Hemostasis

• Prevention

           ➢ Antithrombin(prevent activation of thrombin→which then prevent the production of fibrin)

           ➢ TFPI(tissue factor pathway inhibitor that is produed in vasculature that prevents the tissue factor pathway from being activated)

           ➢ Thrombomodulin(modulates thrombus production)

           ➢ Protein C (+ protein S)

• Lysis(limit the size of the clot and remove the clot after the bleeding has ceased)

          ➢ Plasminogen/plasmin(promote resolution of the fibrin clot of break down of fibrin)(plasminogen system where you get activation of the proteins that are going to degrade fibrin)

          ➢ t-PA, u-PA

          ➢ D-Dimer

This content outlines the control mechanisms of hemostasis, focusing on two main aspects: prevention of excessive clot formation and lysis (breakdown) of clots once hemostasis is achieved.

1. Prevention of Excessive Clotting

These mechanisms help regulate the coagulation process and prevent unnecessary clot formation:

• Antithrombin: Inhibits thrombin activation, preventing the conversion of fibrinogen into fibrin (a key step in clot formation).

• TFPI (Tissue Factor Pathway Inhibitor): Produced in the vasculature, it blocks the tissue factor pathway, reducing clot initiation.

• Thrombomodulin: A receptor on endothelial cells that binds thrombin, reducing its ability to generate clots.

• Protein C & Protein S: These work together to inhibit clotting factors Va and VIIIa, reducing thrombin formation and slowing the clotting cascade.

2. Clot Lysis (Fibrinolysis)

Once a clot has served its purpose, it must be broken down to restore normal blood flow:

• Plasminogen/Plasmin System:

  • Plasminogen is an inactive precursor that gets activated to plasmin, which degrades fibrin, breaking down clots.

• t-PA (Tissue Plasminogen Activator) & u-PA (Urokinase Plasminogen Activator):

  • These enzymes help convert plasminogen into plasmin, initiating fibrinolysis.

• D-Dimer:

  • A breakdown product of fibrin, used clinically as a marker of clot breakdown (elevated levels indicate active clot degradation, such as in DVT or pulmonary embolism).

Clinical Evaluation of the Hematologic System

• Bone marrow function

          ➢ Aspiration(less invasion) or biopses from sternum or pelvis

          ➢ Biopsy

          ➢ Marrow iron stores

          ➢ Differential cell count

• Blood tests

         ➢ Cell differential

         ➢ Justify marrow aspiration

         ➢ Many available

1. Bone Marrow Function Evaluation

Bone marrow plays a crucial role in producing blood cells (erythrocytes, leukocytes, and platelets). Evaluating bone marrow function helps diagnose conditions such as anemia, leukemia, and bone marrow failure syndromes.

• Aspiration (Less Invasive) or Biopsy

  • Samples are taken from the sternum or pelvis (usually the iliac crest).

  • Aspiration: Extracts liquid bone marrow for cell examination.

  • Biopsy: Removes a solid core of marrow to assess overall marrow structure.

• Marrow Iron Stores

  • Evaluates iron levels in the bone marrow to detect conditions like iron-deficiency anemia or iron overload (e.g., hemochromatosis).

• Differential Cell Count

  • Determines the proportions of different hematopoietic cells (e.g., myeloid vs. lymphoid cells) to diagnose conditions like leukemia or aplastic anemia.

2. Blood Tests for Hematologic Evaluation

Blood tests provide a less invasive way to assess hematologic function and determine if further bone marrow testing is necessary.

• Cell Differential

  • Measures the proportions of different types of white blood cells (e.g., neutrophils, lymphocytes, monocytes, eosinophils, basophils).

  • Helps diagnose infections, immune disorders, and blood cancers.

• Justify Marrow Aspiration

  • If blood test results show abnormal cell counts, bone marrow aspiration may be needed to investigate conditions like leukemia, lymphoma, or myelodysplastic syndromes.

• Many Available Tests

  • Complete Blood Count (CBC): Measures RBCs, WBCs, hemoglobin, hematocrit, and platelets.

  • Coagulation Tests: Assess clotting function (e.g., PT, aPTT, INR).

  • Peripheral Blood Smear: Examines blood cell morphology for conditions like sickle cell disease or hemolytic anemia.

Blood consists of cells suspended in a solution of about 91% water and 8% solutes. In adults the total blood volume is approximately 5.5 L.

Plasma, the liquid portion of the blood (50% to 55% of blood volume), contains two major groups of proteins: albumins and globulins.

The cellular elements of blood are the erythrocytes (red blood cells), leukocytes (white blood cells), and platelets (thrombocytes).

Erythrocytes are the most abundant cells of the blood, occupying approximately 48% of the blood volume in men and approximately 42% in women. Erythrocytes are responsible for tissue oxygenation.

 Leukocytes are fewer in number than erythrocytes and constitute approximately 5000 to 10,000 mm3 of blood. Leukocytes defend the body against infection and remove dead or injured host cells.

Leukocytes are classified as either granulocytes (neutrophils, basophils, eosinophils) or agranulocytes (monocytes, macrophages, lymphocytes).

 Macrophages remove old and damaged cells and large molecular substances from the blood by phagocytosis.

The neutrophil is the most abundant leukocyte (approximately 55% of the leukocytes) and is the primary granulocyte that defends against infections.

Lymphocytes are the primary cells of the immune response.

Platelets are not cells—they are disk-shaped cytoplasmic fragments. Platelets are essential for blood coagulation and control of bleeding.

The lymphoid organs are classified as primary (thymus and bone marrow) or secondary (spleen, lymph nodes, tonsils, and Peyer patches of the small intestine).

The lymphoid organs are sites of residence, proliferation, differentiation, and function of lymphocytes and mononuclear phagocytes.

The spleen is the largest of the secondary lymphoid organs and functions as the site of hematopoiesis in the fetus, filters and cleanses the blood, and is a reservoir for lymphocytes and other blood cells

The lymph nodes are the site of development or activity of large numbers of lymphocytes, monocytes, and macrophages. 15. The MPS is composed of macrophages in tissue and lymphoid organs

The MPS is the main line of defense against bacteria in the bloodstream and cleanses the blood by…

removing old, injured, or dead blood cells; antigen-antibody complexes; and macromolecules.

Hematopoiesis, or blood cell production, occurs in the liver and spleen of the fetus and in the bone marrow after birth.

Hematopoiesis involves two stages: (a) proliferation and (b) maturation.

Hematopoiesis continues throughout life to replace blood cells that grow old and die, are killed by disease, or are lost through bleeding.

 Bone marrow consists of red (hematopoietic) marrow (blood vessels, mononuclear phagocytes, stem cells, blood cells in various stages of differentiation, stromal cells) and yellow marrow (fatty tissue).

The bone marrow contains multiple populations of stem cells; mesenchymal stem cells develop into fibroblasts, osteoclasts, and adipocytes; and hematopoietic stem cells develop into blood cells.

Regulation of hematopoiesis occurs in specialized microenvironments (niches) in the bone marrow (an osteoblastic niche and a vascular niche) in which hematopoietic stem cells are signaled to undergo differentiation through the effects of multiple cytokines and chemokines and through direct contact with osteoblasts (osteoblastic niche) or vascular endothelial cells (vascular niche), as well as several other specialized cells, including CAR cells and nestin-expressing cells.

Specific hematopoietic growth factors (e.g., colony-stimulating factors) are necessary for the adequate production of myeloid, erythroid, lymphoid, and megakaryocytic lineages.

Erythropoiesis (production of erythrocytes) is regulated by erythropoietin. Erythropoietin is secreted by the kidneys in response to tissue hypoxia and causes a compensatory increase in erythrocyte production if the oxygen content of the blood decreases because of anemia, high altitude, or pulmonary disease.

Hemoglobin, the oxygen-carrying protein of the erythrocyte, enables the blood to transport 100 times more oxygen than could be transported dissolved in plasma alone.

The iron cycle reutilizes iron released from old or damaged erythrocytes. Iron binds to transferrin in the blood, is transported to macrophages of the MPS, and is stored in the cytoplasm as ferritin.

Iron homeostasis is controlled by hepcidin, a small hormone produced by hepatocytes, which regulates ferroportin, the principal transporter of iron from stores in hepatocytes and macrophages and from intestinal cells that take up dietary iron.

Granulocytes and monocytes in the blood develop from common myeloid progenitor cells in the bone marrow under the direction of several growth factors, including stem cell factor, IL-3, and GM-CSF.

Platelets develop from megakaryocytes by a process called endomitosis, which is controlled by thrombopoietin.

During endomitosis the megakaryocytes undergo mitosis but not cell division and the cytoplasm and plasma membrane fragment into platelets.

Hemostasis, or arrest of bleeding in damaged vessels, involves (a) vasoconstriction, (b) damage to the endothelium and exposure of connective tissue resulting in formation of a platelet plug, (c) activation of the clotting cascade, (d) formation of a blood clot, and (e) activation of fibrinolysis for clot retraction and clot dissolution.

Platelet activation involves three linked processes: (a) adhesion, (b) activation, and (c) aggregation.

A blood clot is a meshwork of protein strands that stabilizes the platelet plug. The strands are made of fibrin. Fibrin is the end product of the coagulation cascade.

The pathways of hemostasis include the intrinsic pathway (also known as the contact pathway) and extrinsic pathway. The extrinsic pathway is the major pathway of normal hemostasis initiated by TF that forms a complex with the TF/VIIa complex. The intrinsic (contact) pathway is activated by artificial negative surfaces and also functions in thrombotic states.

The endothelium prevents the formation of spontaneous clots in normal vessels by several anticoagulant mechanisms, including production of NO and PGI2, thrombin inhibitors (antithrombin III), and tissue factor inhibitors (tissue factor pathway inhibitors); and degradation of activated clotting factors (thrombomodulin–protein C).

Fibrinolysis (breakdown of blood clots) is the function of the plasminogen-plasmin system. Plasmin is a degrading enzyme of fibrin clots. It is produced from plasminogen by activation of plasminogen activators (t-PA, u-PA), thrombin, fibrin, factor XIIa, factor XIa, and kallikrein. Products of fibrinolysis include fibrin degradation products, such as D-dimer.

Tests of bone marrow function include bone marrow aspiration and bone marrow biopsy.

Cells contained in the marrow specimen are assessed with respect to (a) relative numbers of stem cells and their developing daughter cells, and (b) morphologic structure.

Blood cell counts rise above adult levels at birth and then gradually decline throughout childhood.

The average blood volume of an infant is 75 to 77 mL/kg, which is similar to that of older children and adults.

In response to the change from a placental to a pulmonary oxygen supply during the first few days of life, levels of erythropoietin and the rate of blood cell formation decrease.

The normal erythrocyte life span is 60 to 80 days in full-term infants, 20 to 30 days in premature infants, and 120 days in children, adolescents, and adults.

The lymphocyte count is high at birth, rises further during the first year of life, and steadily declines until lower adult volumes are reached.

The neutrophil count is very high at birth, falls to adult ranges after 2 weeks, and is the same as that for adults by 4 years of age.

The eosinophil count is high in the first year of life and is higher in children than in adolescents and adults. Monocyte counts are high in the first year of life and decrease to adult levels.

Platelet counts in full-term infants are comparable with those in adults and remain so throughout childhood.

Blood composition changes little with age. A delay in erythrocyte replenishment may occur after bleeding, presumably because of iron deficiency.

Lymphocyte function appears to decrease with age. Particularly affected is a decrease in cellular immunity. Platelet adhesiveness probably increases with age, as do clotting factors increasing risk for thromboembolism.