Introduction to Normal Bone Marrow and Blood Cells

Haematology: The study of blood and its forming organs, primarily focusing on health and diseases related to blood and haematopoietic (blood-forming) tissues.

This field of medicine studies various disorders, including:

• Anaemia: A condition characterised by a deficiency of red blood cells (RBCs) or haemoglobin, leading to decreased oxygen transport and fatigue.

• Sickle Cell Disease: A genetic disorder that results in abnormal haemoglobin, causing distorted, sickle-shaped red blood cells that can block blood flow.

• Haemophilia: A genetic disorder affecting the body’s ability to clot blood, often leading to excessive bleeding.

• Leukaemia: A type of cancer that affects blood-forming tissues, leading to the overproduction of abnormal white blood cells.

• Infections: Blood disorders can also be a consequence of infections that affect the blood or bone marrow directly.

Components of Blood

Blood consists of various components, each with specific functions:

• Plasma: The liquid component of blood that carries cells, nutrients, hormones, and waste products. It also plays a role in regulating body temperature and maintaining blood pressure.

• Red Blood Cells (Erythrocytes):

  • Function: Transport oxygen from the lungs to the rest of the body and carbon dioxide back to the lungs.

  • Normal range:$4-5.5 imes 10^{12}/L .

  • Diameter: Approximately 8 µm; capable of passing through capillaries as small as 3 µm due to their biconcave shape, which also allows them to deform without causing damage.

• White Blood Cells (Leukocytes):

  • Function: Crucial for fighting infections and involved in immune responses.

  • Norange:range4-11 imes 10^{9}/L.

• Platelets (Thrombocytes):

  • Role: Essential for clotting and preventing bleeding.

  • Normal range:150-400 imes 10^{9}/L$$.

• Blood Volume: An average adult has approximately 9-12 pints of blood, equating to roughly 6 kg.

Hematopoiesis

Haematopoiesis is the complex physiological process through which all blood cells are formed from haematopoietic stem cells (HSCs).

• Stages of Haematopoiesis:

  • Before Birth: Initial blood cell formation occurs in the yolk sac, liver, and spleen. These organs produce blood cells to support the developing embryo until the bone marrow takes over.

  • After Birth: The primary site for haematopoiesis transitions to the bone marrow, where HSCs proliferate and differentiate into various blood cell lineages.

  • In Disease: In pathological circumstances, haematopoiesis can occur outside of the bone marrow (extramedullary) in organs such as the liver or spleen.

Bone Marrow

Bone marrow is a specialised tissue responsible for the generation of blood cells. It has two primary types:

• Red Bone Marrow: Contains the stem cells responsible for producing around 500 billion new blood cells each day. It is essential for the creation of red blood cells, white blood cells, and platelets.

• Yellow Bone Marrow: Contains adipocytes (fat cells) and mesenchymal stem cells, which can differentiate into cartilage, fat, and bone.

• Transition: All bone marrow is red at birth. By age seven, it transitions to a mix of red (active haematopoietic tissue) and yellow (adipose tissue).

Differentiation and Growth Factors

The differentiation of haematopoietic stem cells into various blood cell lineages is tightly regulated by cytokines:

• Colony-Stimulating Factors (CSFs): Promote the growth and differentiation of blood cells.

• Interleukins (ILs): A family of cytokines that facilitate communication between cells and regulate immune responses.

  • Important examples include erythropoietin (EPO) for red blood cell formation, IL-3 for multiple cell types, and thrombopoietin (TPO) for platelet production.

Erythropoiesis

Erythropoiesis is the specific process of red blood cell production:

• Process Overview:

  • A haematopoietic stem cell differentiates into a common myeloid progenitor, which then becomes a megakaryocyte/erythroid progenitor.

  • It progresses through several stages: Proerythroblast ➔ Erythroblast ➔ Normoblast ➔ Reticulocyte ➔ Erythrocyte.

• Maturation: Erythrocytes take about one week to mature and have an average lifespan of 120 days.

• Hormonal Regulation: Erythropoiesis is stimulated by EPO, produced by the kidneys in response to hypoxia (low oxygen levels). Factors such as renal failure, nutritional deficiencies (iron, vitamin B12, and folate), and high altitudes can significantly impact this process.

Red Cells and Hemoglobin

Haemoglobin, the molecule within erythrocytes responsible for oxygen transport, possesses:

• Structure: A quaternary structure consisting of four polypeptide chains (two alpha and two beta in adults, HbA) and one heme group that binds oxygen.

  • Foetal Haemoglobin (HbF): Contains two gamma chains and has a greater affinity for oxygen compared to HbA, facilitating oxygen transfer from mother to foetus during pregnancy. The switch from HbF to HbA typically occurs around six months postpartum.

• Competitive Inhibitors: Haemoglobin function can be impaired by molecules such as NO, CO, and CN⁻ that compete with oxygen for binding sites on the heme group.

Heme Biosynthesis

Heme is produced primarily in the mitochondria of developing erythrocytes:

• Key Steps: The biosynthesis begins with the production of ALA (aminolevulinic acid) from glycine and succinyl-CoA, catalysed by ALA synthase, followed by a series of enzymatic reactions that culminate in heme formation.

• Regulation: The enzyme ALA synthase is inhibited by heme levels to prevent overproduction.

Nutritional Requirements for Erythropoiesis

Several essential nutrients are critical for optimal red blood cell formation:

• Copper: Important for iron metabolism.

• Iron: Crucial for haemoglobin synthesis; deficiency leads to iron deficiency anaemia.

• Folate and Vitamin B12: Necessary for DNA synthesis in rapidly dividing cells; deficiencies cause megaloblastic anaemia.

• Vitamin B6: Plays an integral role in haemoglobin production; deficiency can lead to sideroblastic anaemia.

Gas Exchange and Transport

Red blood cells function primarily in gas exchange:

• Oxygen Transport: Haemoglobin has the capacity to bind up to four oxygen molecules, with binding dynamics influenced by the partial pressure of oxygen, which is highest in the lungs and lower in peripheral tissues.

Red Cell Membrane

The red blood cell membrane is intricately structured:

• Composition: Comprised of three layers, including an external carbohydrate layer, lipid bilayer, and an internal protein network. This architecture helps maintain the flexibility and integrity of blood cells.

  • Key Components: Includes glycoproteins and glycolipids that contain blood group antigens, as well as membrane proteins that facilitate transport and signalling.

• Cytoskeletal Elements: Maintains the biconcave shape of red blood cells, primarily made of spectrin and ankyrin, which allow for deformation and resilience when navigating through microvasculature.

White Blood Cells (Leukocytes)

Leukocytes are essential for the immune system and are categorised into several types:

• Types: Neutrophils, eosinophils, basophils, monocytes, and lymphocytes.

• Function: They play a critical role in combating infections and contribute to the regulation of immune responses. Variations in white cell counts can indicate health conditions ranging from infections to blood cancers.

Neutrophils

Neutrophils are the most abundant type of white blood cells:

• Characteristics: They typically have a polylobulated nucleus with 3-5 lobes and constitute approximately 40-70% of total WBCs.

• Functions: Involved in phagocytosis of pathogens, release of cytokines that mediate inflammatory responses, and formation of neutrophil extracellular traps (NETs) that immobilise pathogens.

Eosinophils and Basophils

These cells are involved in allergic responses and fighting parasitic infections:

• Eosinophils: Characterised by 2-3 lobes and primarily respond to parasitic infections and allergens.

• Basophils: Containing granules filled with histamine, they play a role in allergic reactions and asthma responses.

Monocytes

Monocytes are a type of white blood cell with distinct features:

• Characteristics: Possess an irregular nucleus and are larger than other WBC types (15-22 µm in diameter).

• Function: Act as phagocytic cells and serve as antigen-presenting cells, activating lymphocyte responses.

Platelets (Thrombocytes)

Platelets play a crucial role in haemostasis:

• Origin: Derived from megakaryocytes in the bone marrow, they are vital for blood clotting mechanisms.

• Conditions: Variations in platelet counts can result in conditions like thrombocytopenia (low platelet count, leading to increased bleeding risk) or thrombocytosis (high platelet count, associated with trauma or bone marrow disorders).

• Functions: Platelets contribute to clot formation by adhering to site injuries and aggregating into a plug, releasing signalling molecules that promote further clotting and wound healing.