Study Unit 1.5: Cardiovascular System and Blood

Haematopoiesis

Anatomical Area Responsible
- Haematopoiesis occurs in the RED BONE MARROW.
- Location: Found within the bones of the axial skeleton and the pelvic and pectoral girdles, as well as the proximal epiphyses of the humerus and the femur.
- Composition: Red bone marrow is composed of soft reticular connective tissue that borders wide blood capillaries known as blood sinusoids.
- Cellular Content: It contains immature blood cells, macrophages, fat cells, and reticular cells.
Hormone Responsible
- ERYTHROPOIETIN (EPO): The primary hormone responsible for stimulating the production of red blood cells.
- Production Site: Produced mainly by the KIDNEY; some is also produced in the liver.
Triggers for Haematopoiesis
- A drop in normal blood oxygen levels acts as the trigger for EPO formation. Specific causes include:
  - Reduced RBC numbers: Can be caused by haemorrhage (blood loss) or excessive destruction of red blood cells.
  - Insufficient haemoglobin per RBC: For example, iron deficiency.
  - Reduced oxygen availability: Occurs in environments like high altitude or during medical conditions like pneumonia.
Mnemonic: EPO Trigger
- "LESS $O_2$ = MORE EPO": Less RBCs, less Hb, or less oxygen available all result in decreased oxygen delivery. The kidney senses this, releases EPO, and the bone marrow consequently produces more RBCs.

Changes in Sites of Blood Production After Birth

Fetal development
- Initially occurs in the yolk sac, then shifts to the liver and spleen.
- By month $7$ , red bone marrow becomes the primary site for blood production.
Infancy and Childhood
- Haematopoiesis occurs in the red marrow of nearly ALL bones, including both long bones and flat bones.
Adulthood
- Red marrow is restricted to the axial skeleton: the skull, vertebrae, ribs, sternum, and pelvis.
- It is also found in the proximal epiphyses of the humerus and femur.
- Yellow marrow (primarily fat) fills the shafts of the remaining long bones.
Severe Blood Loss (Any Age)
- The liver and spleen may resume their fetal blood-forming roles if needed.
- Yellow marrow possesses the ability to revert to active red marrow to increase blood cell production.

Formation of Red Blood Cells (Erythropoiesis) Pathway

Step-by-Step Progression
1. Pluripotent haematopoietic stem cell.
2. Proerythroblast.
3. Erythroblast: At this stage, haemoglobin ( $Hb$ ) synthesis begins.
4. Loss of nucleus and organelles: The cell transforms into a reticulocyte.
5. Reticulocyte: Spend approximately $3$ days in the marrow and $1$ day in the blood. They represent approximately $1\%$ of circulating red blood cells.
6. Loss of remaining organelles: The cell becomes a mature Erythrocyte.
Erythrocyte Lifespan: Approximately $120\,days$ .

Summarise the Three Phases of Coagulation

Events of Haemostasis (Prior to Clotting)
- Step 1: Vascular spasm: The smooth muscle in the blood vessel wall contracts, causing vasoconstriction to reduce blood flow.
- Step 2: Platelet plug formation: Exposed collagen fibers cause platelets to adhere. These platelets release chemicals that make them sticky, forming a platelet plug.
- Step 3: Coagulation: A fibrin mesh traps red blood cells and platelets to form a stable clot.
Phases of Coagulation
- Phase 1: Two pathways (intrinsic and extrinsic) converge to lead to the formation of PROTHROMBIN ACTIVATOR. This requires Factor X, $Ca^{2+}$ , and Factor V.
- Phase 2: Prothrombin activator converts Prothrombin (Factor $II$ ) into the active enzyme Thrombin (Factor $II_a$ ).
- Phase 3: Thrombin converts Fibrinogen (Factor $I$ , a soluble plasma protein) into Fibrin (an insoluble strand). $Ca^{2+}$ and Factor XIII work together to cross-link the fibrin mesh, which stabilises the clot.
Intrinsic Pathway vs. Extrinsic Pathway
- Intrinsic Pathway:
  - All clotting factors are present WITHIN the blood.
  - Triggered by negatively charged surfaces such as activated platelets, collagen, or glass.
  - SLOWER: Involves many intermediate steps.
- Extrinsic Pathway:
  - Tissue Factor (TF or Factor $III$ ) is found OUTSIDE the blood on cells surrounding the vessels.
  - Triggered by tissue trauma.
  - FASTER: Bypasses several steps; severe trauma can result in a clot in approximately $15\,seconds$ .
Mnemonic: Intrinsic vs Extrinsic
- IN-trinsic = IN the blood (slow, many steps).
- EX-trinsic = EXternal tissue damage (fast, few steps).
- Both cascade toward Factor X and the formation of Prothrombin activator.

Factors That Limit Clot Growth or Formation

Swift Removal of Clotting Factors
- Rapidly flowing blood dilutes and washes away clotting factors, which prevents unnecessary clot formation.
- Thrombin is trapped within the clot, preventing it from activating further factors in other parts of the body.
Inhibition of Activated Clotting Factors
- Antithrombin III: A plasma protein that inactivates any thrombin that is NOT bound to the clot.
- Antithrombin III + Protein C: These work together to inhibit other clotting factors in the intrinsic pathway.
- Heparin: Found in basophils, mast cells, and on endothelial cell surfaces. It enhances the activity of Antithrombin III, further inhibiting thrombin and the intrinsic pathway.

Anatomical Structures Responsible for Heart Sounds

Normal Sound Pattern: Lub-dub, followed by a pause, then Lub-dub.
1st sound ("Lub"): Caused by the AV valves closing.
2nd sound ("Dub"): Caused by the SL valves snapping shut.
Pause: Represents the period of heart relaxation (quiescent period).
Murmurs: These are abnormal heart sounds caused by turbulent blood flow striking an obstruction.

Cardiac Concepts Definitions

Cardiac cycle: Includes all events associated with blood flow through the heart during ONE complete heartbeat. This includes atrial systole and diastole, and ventricular systole and diastole.
- Systole = Contraction.
- Diastole = Relaxation.
Cardiac output (CO): The volume of blood pumped by each ventricle in ONE MINUTE.
- Formula: $CO = SV \times HR$ .
- Example: $70\,ml \times 70\,bpm \approx 4\,900\,ml/min \approx 5\,L/min$ .
Stroke volume (SV): The volume of blood pumped by each ventricle in ONE BEAT. The average stroke volume is approximately $70\,ml$ .
Positive chronotropic factors: Factors that INCREASE heart rate.
Negative chronotropic factors: Factors that DECREASE heart rate.
Peripheral resistance: The amount of friction or opposition that blood encounters as it flows through the vessels. Sources include:
- Blood viscosity (thickness).
- Vessel length.
- Vessel diameter: The radius is the main determinant of resistance.

Factors Affecting Heart Rate

Vagal Stimulation
- The vagus nerve (parasympathetic) is normally slightly active to provide "vagal tone," which restrains the heart rate. If the vagal nerve is cut, the heart rate increases by approximately $25\,beats/min$ .
Exercise
- Exercise raises the heart rate via the sympathetic nervous system. This increases systemic blood pressure ( $BP$ ) and delivers more blood to the working muscles.
Epinephrine
- Produces the same cardiac effect as norepinephrine. It enhances both heart rate ( $HR$ ) and contractility.
Ions
- Low $Ca^{2+}$ : Depresses the heart.
- High $Ca^{2+}$ : Increases heart irritability and can cause spastic contractions.
- High $K^+$ : Interferes with depolarisation and may lead to heart block.
- Low $K^+$ : Results in feeble and arrhythmic heartbeats.

Role of the Autonomic Nervous System in Regulation

Sympathetic Division
- Activated by physical or emotional stressors (fright, anxiety, exercise).
- Nerve fibres release NOREPINEPHRINE at the cardiac synapse.
- Binds to $\beta_1$ -adrenergic receptors, causing the pacemaker threshold to be reached faster, thereby increasing $HR$ .
- Also enhances contractility and speeds up relaxation by boosting $Ca^{2+}$ movement in contractile cells.
Parasympathetic Division
- Opposes sympathetic effects by reducing heart rate during stressful or high-pressure situations to restore balance.
- Vagal tone keeps the resting heart rate lower than the intrinsic rate of the SA node.

Maintenance of Blood Pressure

Short-Term Control (Minutes)
- Alters Peripheral Vascular Resistance (PVR) and Cardiac Output (CO).
Neural Control (Short-Term)
- Baroreceptors: Stretch receptors located in the carotid sinus and aortic arch. High $BP$ causes stretch, which stimulates the cardio-inhibitory centre and inhibits the vasomotor/cardio-acceleratory centres. Result: ↓ $HR$ + vasodilation = ↓ $BP$ . (The reverse occurs for low $BP$ ).
- Chemoreceptors: Located in the aortic arch and large arteries. They respond to ↑ $CO_2$ , ↓pH, or ↓ $O_2$ . These send impulses to the cardio-acceleratory and vasomotor centres to ↑ $CO$ and ↑ $BP$ . (Note: they play a larger role in respiratory rate control than $BP$ ).
- Higher brain centres: The cerebral cortex and hypothalamus relay information to medullary centres. The hypothalamus also redistributes blood during exercise and temperature changes.
Hormonal Control (Short-Term)
- Epinephrine & Norepinephrine: Released by the adrenal medulla during stress to enhance the sympathetic response (↑ $CO$ and vasoconstriction).
- Angiotensin II: Triggered when the kidneys release renin in response to low $BP$ . Renin converts angiotensinogen to Angiotensin I, which is converted to Angiotensin II. This is a potent vasoconstrictor (↑ $BP$ ). It also triggers aldosterone and ADH release.
- Atrial Natriuretic Peptide (ANP): Produced in the atria. It antagonises aldosterone, leading to ↓ $Na^+$ and water reabsorption in the kidneys (↓blood volume/pressure), and causes generalised vasodilation.
- Antidiuretic Hormone (ADH): Produced by the hypothalamus and stored in the posterior pituitary. It stimulates water conservation (long-term). However, in cases of dangerously low $BP$ , large amounts are released to cause intense vasoconstriction (short-term).
Renal Regulation (Long-Term)
- Direct Renal Mechanism: Alters blood volume independently of hormones. ↑ $BP$ /blood volume → ↑filtration rate in kidneys → less reabsorption → more urine produced → $BP$ falls.
- Indirect Renal Mechanism (Renin-Angiotensin-Aldosterone): ↓ $BP$ → ↓baroreceptor input → ↑sympathetic activity → ↑renin release → Angiotensin II formed. This stimulates aldosterone (↑ $Na^+$ /water reabsorption), ADH (↑water reabsorption), and thirst, resulting in ↑blood volume and ↑ $BP$ .

Capillary Exchange Routes

Route 1: Diffusion through the lipid bilayer
- Lipid-soluble substances pass directly through the endothelial cell membrane.
Route 2: Intercellular clefts
- Water-soluble substances move through fluid-filled gaps between endothelial cells.
Route 3: Fenestrations (pores)
- Water-soluble substances pass through specific endothelial pores.
Route 4: Pinocytotic vesicles / caveolae
- Large substances are transported via vesicles via active transport.
Mnemonic: D-I-F-V
- Diffusion (lipid), Intercellular clefts (water-soluble gaps), Fenestrations (water-soluble pores), Vesicles (large molecules, active transport).

Human Blood Groups (ABO and Rh)

ABO Blood Groups
- Group O: No antigens on RBC; Anti-A and Anti-B antibodies in plasma. Can donate to all (Universal donor); can receive from O only.
- Group A: A antigen on RBC; Anti-B antibodies in plasma. Can donate to A and AB; can receive from A and O.
- Group B: B antigen on RBC; Anti-A antibodies in plasma. Can donate to B and AB; can receive from B and O.
- Group AB: A and B antigens on RBC; no antibodies in plasma. Can donate to AB only; can receive from all (Universal recipient).
Rh Blood Group
- Rh-positive ( $Rh^+$ ): Rh (D) antigen is present on RBCs.
- Rh-negative ( $Rh^-$ ): Rh (D) antigen is absent.
- Antibodies: Unlike ABO, anti-Rh antibodies are NOT automatically present in the plasma. They only form after an $Rh^-$ person is exposed to $Rh^+$ blood (via transfusion or pregnancy).
- Clinical Importance: An $Rh^-$ mother carrying an $Rh^+$ baby may develop anti-Rh antibodies, which could lead to haemolytic disease in future $Rh^+$ pregnancies.
Mnemonic: Donors & Recipients
- $O^-$ = "gives to all, takes from none but itself" (universal donor).
- $AB^+$ = "takes from all, gives to none but itself" (universal recipient).