Detailed Notes on Erythrocytes, Leukocytes, Vascular Diseases, and Hypertension

Erythrocytes (RBCs) and Leukocytes (WBCs)

• Erythrocytes: Red Blood Cells (RBC)
• Leukocytes: White Blood Cells (WBC)
• Granular leukocytes: Neutrophils, Eosinophils, Basophils (NEB)
• Agranular leukocytes: Lymphocytes, Monocytes (LM)
• Lymphocytes consist of: T cells, B cells, and natural killer cells
• Platelets: Special cell fragments

Bone Marrow and Hematopoiesis

• Early Embryo: Yolk sac
• Newborn: Liver and spleen
• Childhood: Axial and appendicular skeleton (both red/active marrow)
• Adult: Axial skeleton (red marrow) and appendicular skeleton (yellow marrow)
• Hematopoiesis: Blood cell formation from hematopoietic stem cells, leading to erythrocytes, thrombocytes, lymphocytes, monocytes, and granulocytes.

Conditions Affecting Blood Cells

• RBCs:
  • Anemia: Decrease in RBCs
  • Polycythemia: Excess RBCs
• WBCs:
  • Infection
  • Inflammation
  • Malignancy
  • Immunodeficiency
• Platelets/Coagulation:
  • Hypercoagulable state: Increased blood clotting
  • Hypocoagulable state: Decreased blood clotting
  • Hemophilia: Prolonged bleeding

RBC Functions

• Regulated lifespan: 120 days
• Transports: Oxygen to tissues
• Removes: CO2 from tissues
• Buffers: Blood pH
• Regulated by: Concentration of hemoglobin
• Destruction occurs in: Macrophages in spleen & liver
• Destruction process: Globin portion broken down into amino acids and recycled

Hemoglobin

• Oxygen-carrying protein in mature RBC
• Consists of two pairs of:
  • Polypeptide chains (globins)
  • Heme (Iron & Biliverdin - green pigment)
  • Globin (Iron & Protoporphyrin)
• Each hemoglobin can bind to: 4 oxygens
• Average person's hemoglobin: 15 g/100 mL of blood

Carbonic Anhydrase and Carbon Dioxide Transport

• Carbonic anhydrase: Helps form carbonic acid in RBCs
• Carbon dioxide transported in blood by:
  • Dissolved gas
  • Bicarbonate ions
  • Bound to hemoglobins

Anemia

• Hypoxia: Low oxygen carrying capacity
• Relative anemia: Normal total red cell mass with disturbance of regulation of plasma volume
• Absolute anemia: Actual decrease in the number of red cells

Polycythemia

• Increases blood: Viscosity (flow) & Volume
• Causes of polycythemia: Dehydration (reduced plasma volume)
• Absolute polycythemia: Increased total red blood cells
• Polycythemia vera:
  • EPO: Low
  • RBC/WBC/platelets: Increased
  • Symptoms: Increases red cell mass, thickened blood, slow flow
• Causes of secondary polycythemia:
  • High altitude
  • EPO-secreting tumors
  • EPO doping (high levels)
• Treatment:
  • Reduce blood volume & viscosity
  • Control platelet count

Causes of Anemia

• Blood loss
  • Increased acute/chronic trauma
• Destruction (hemolytic)
• Decreased production in RBCs
• Decreased RBC production (kidney failure): Leads to decreased EPO
• EPO stimulates: Manufacture & maturation of RBC in bone marrow

Aplastic Anemia

• Loss of hemopoietic cells by fat causes PANCYTOPENIA (decreases in RBC, WBC, platelets)
• Damage to bone marrow stem cells by: Toxins, radiation, or immune attack
• Treated by:
  • Avoiding toxins
  • Transfusions
  • Bone marrow transplant
  • Immunosuppressants
• Causes of bone marrow problems:
  • Viral: Hepatitis, Epstein-Barr virus, Cytomegalovirus
  • Autoimmune: Lupus
  • Drug: Chloramphenicol

Features of Anemia

• Tiredness
• Pallor
• Weakness
• Dyspnea (breathing issues)
• Palpitations (sensation of heartbeats)
• Heart failure (high output)

Microcytic Anemia

• Iron Deficiency, Thalassemia, Chronic Diseases
• Iron deficiency:
  • Ferritin levels are: Low
  • TIBC is: Increased
  • Pica: Craving non-food items (ice)
  • Also HYPOCHROMIC (small/pale RBCs)
  • DECREASED lab values: MCV, MCH, MCHC
  • Treatment: Oral ferrous sulfate or IV ferric gluconate
  • Common causes:
    • Men: GI bleeding
    • Women (menstruating): Menorrhagia (heavy menstrual bleeding)
    • Women (post-menopause): GI bleeding
• Thalassemia:
  • Doesn't produce: Enough hemoglobin
  • Peripheral smear finding: Target-shaped RBCs (bullseye appearance)
  • Value: <80 fL
• Chronic diseases:
  • Ferritin levels are: High
  • TIBC is: Decreased
• Lead poisoning:
  • Peripheral smear finding: Basophilic stippling (small blue dots in RBCs)
• Treat autoimmune-related anemia by: Treating the primary autoimmune disease
• Serum iron:
  • LOW in: Iron deficiency and chronic diseases
• Key tests to evaluate microcytic anemia:
  • Serum ferritin
  • TIBC
  • RBC count
  • Peripheral smear

Macrocytosis

• B12 Deficiency, Folate Deficiency
• RBCs released from bone marrow too early
• Low RBC, WBC, platelets, and High MCV
• WBC nuclei are also affected, resulting in HYPERSEGMENTED PMNs
  • Neutrophils have too many nuclei (5-6 lobes)
• Value: > 100 fL
• Caused by: Disruption of DNA synthesis in blast cells → MEGABLAST formation
  • Megablasts: Large, immature cells
• Symptoms of B12 deficiency:
  • Numbness
  • Tingling
  • Which spinal tract is affected: Dorsal column medial lemniscus
• Dietary habits: Alcoholism and strict vegetarian diets
• Treated by: Replacing the missing nutrient
• Conditions increase demand for folate/ deficiency: Pregnancy and malignancy
• Treatment for megablastic anemia: Supplement folate or Vitamin B12

Normocytic Anemia

• Aplastic Anemia & Chronic Renal Failure
• Aplastic anemia
• Chronic renal failure
• Treatment: Dialysis and EPO administration

Diagnostic Terms

• Ferritin: An intracellular protein that stores iron
• TIBC: Available binding sites for iron on transferrin
• Peripheral smear: Microscopic visualization of blood
• Reticulocyte count measures: Young RBC %
• Low retic count: DECREASED production from bone marrow
• High retic count: RBC destruction vs bleeding
• Schistocytes:
  • Mechanical damage to RBCs
  • Fragmented/ destroyed RBCs

Vitamin B12 Absorption

• Vitamin B12 absorbed in: The terminal ileum
• First step in vitamin B12 absorption: Consumed in the diet
• What binds to vitamin B12 in stomach: Intrinsic factors
• What produces intrinsic factor?: Parietal cells in stomach
• B12 binding steps:
  • B12 → intrinsic factor → complex → receptors in terminal ileum
• What tests diagnose B12 absorption problems: SCHILLING TEST
  • IM injection of B12
  • Oral radioactive B12 is given
  • Normal absorption → no deficiency or intrinsic factor problem
• Repeat injection of radioactive B12 + intrinsic factor
• If B12 appears in urine after repeated steps: Intrinsic factor deficiency (pernicious anemia)
  • Common cause
• If B12 doesn't appear after repeated steps: Terminal ileum disease, preventing absorption
• Other conditions impacting parietal cells: Chronic gastritis

Vascular Diseases

• Investigation of Microcytic Anemia
• Blockage in blood vessels ← NARROWING of the blood vessels
• Rupture of blood vessels ← WEAKENING of the blood vessels
• Two main vascular diseases: Atherosclerosis & Hypertension

Blood Vessel Layers

• Three layers of blood vessels:
  • Innermost: Intima
    • Cell that makes up this layer: Endothelial cells
  • Middle: Media
    • What is found in this layer: Smooth muscle
  • Outermost: Adventitia
    • Composed of: Connective tissue

High vs Low Pressure Vessels

• Vessels that experience high pressure & thick walls:
  • Aorta
  • Arteries
  • Muscular arteries
• Layers found in high-pressure vessels:
  • Intima
  • Internal elastic lamina
  • Media
  • Adventitia
• Low-pressure vessels:
  • Large veins
  • Medium veins
  • Venules
  • Postcapillary venules

Capillaries

• Blood vessels specialized for gas and nutrient exchange:
  • capillaries
• Structures founded in them:
  • Endothelial cells
  • Intima
  • Media
  • Adventitia
  • Pericytes

Arteriosclerosis

• Hardening of arteries
• Commonly associated with:
  • Hypertension
  • Diabetes
• Three types:
  • Atherosclerosis (most common)
  • Monckeberg medial calcific sclerosis
    • Calcification of: The medial layer of arteries
  • Arteriolar sclerosis

Atherosclerosis Plaque Composition

• Necrotic center of a plaque contains:
  • Cell debris
  • Cholesterol crystals
  • Foam cells
  • Calcium
• Found beneath the plaque in the vessel wall:
  • Media
  • Composed of: Smooth muscle cells

Atherosclerosis Pathogenesis

• Chronic inflammatory response of the arterial wall initiated by endothelial injury
• Initiated by: Injury to the endothelium
• Early changes in the intima: Thickening
• Key morphologic changes:
  • Lipid accumulation
  • Fatty streaks
  • Atheroma formation
  • Smooth muscle proliferation
  • Fibrous
  • Calcification
  • Aneurysm
  • Thrombosis
• Common geographic locations: US and Western Europe

Risk Factors for Atherosclerosis

• Non-modifiable risk factors:
  • Increasing age
  • Male gender
  • Family history
  • Genetic abnormalities
• Modifiable risk factors:
  • Obesity
  • Physical inactivity
  • Stress
  • Estrogen deficiency (postmenopausal)
  • High carbs
  • Hyperlipidemia
  • Hypertension
  • Smoking (extremely significant)
  • Diabetes
  • Lipoprotein Lp(a)
  • Trans fat intake

Fibrous Cap Components

• Components of the fibrous cap in an atherosclerotic plaque:
  • Smooth muscle cells
  • Macrophages
  • Foam cells
  • Lymphocytes
  • Collagen
  • Elastin
  • Proteoglycans
  • Neovascularization

Atherosclerosis Progression

• Follows endothelial damage:
  • Inflammation
  • LDL entry into the intima
  • Monocyte adhesion and migration
  • Foam cell formation
  • Platelet activation
  • PDGF release
    • Function: Stimulates smooth muscle proliferation
  • To plaque formation
  • Smooth muscle proliferation
• Chronic endothelial injury:
  • Hyperlipidemia
  • Hypertension
  • Smoking
  • Toxins
  • Hemodynamic stress
  • Immune reactions
  • Stress
  • Viruses
  • Homocysteine
• Characterized mild stage: Fatty streaks
• Advanced plaques:
  • Rupture
  • Ulceration
  • Erosion
  • Atheroboli
  • Hemorrhage
  • Thrombosis
  • Aneurysm

Atherosclerosis Treatment

• Weight loss
• Smoking cessation
• Drug therapy
• Balloon or laser angioplasty
• Coronary artery bypass grafting

Hypertension and Atherosclerosis

• Chronic high pressure damages: The endothelial lining
• Promotes: Plaque formation and vessel stiffness

Blood Pressure

• Pressure gradient drives blood flow:
  • The left heart pumps at High pressure
  • The right heart at Low pressure
  • Blood flows from High to Low.
• What generates arterial blood pressure:
  • The left ventricle CONTRACTS → BUILDS PRESSURE →
  • OPENS the aortic valve → blood ENTERS the arteries
• Equation for blood pressure: BP = Cardiac Output \times Peripheral Resistance

Factors Influencing Blood Volume

• Factors influencing blood volume:
  • Sodium
  • Atrial natriuretic peptide (ANP)
  • Mineralocorticoids

Vasoconstrictors

• Signals that cause blood vessels to Narrow
  • Smooth muscle: Contracts
• Examples of humoral vasoconstrictors:
  • Catecholamines
  • Angiotensin II
  • Thromboxane
  • Leukotrienes
  • Endothelin

Vasodilators

• Signals that cause blood vessels to widen (dilate)
  • Smooth muscle: Relaxes
• Examples of humoral vasodilators:
  • Prostaglandins
  • Nitric oxide
  • Kikins

Cardiac Output and Peripheral Resistance

• Determines cardiac output:
  • Heart rate
  • Contractility
• Peripheral resistance:
  • Constrictors: α-adrenergic stimulation
  • Dilators: β-adrenergic stimulation

Blood Pressure Regulation

• Local factors regulate blood pressure:
  • Autoregulation via:
    • pH
    • Hypoxia
    • Low-oxygen carrying
• Regulates systemic blood pressure:
  • Neural
  • Humoral
  • Renal mechanism

Short-Term BP Regulation

• Mediates short-term changes in blood pressure:
  • sympathetic nervous system
• Receptors activated:
  • α1 receptors in arteriole Smooth Muscle (VASOCONSTRICTION)
  • β1 receptors in the Heart (Increased heart rate and contractility)
• Neurotransmitters released in short-term BP regulation:
  • Epinephrine
  • Norepinephrine
• Activates the vasomotor center: Baroreceptors

Long-Term BP Regulation

• Serum sodium:
  • How does it affect long-term BP:
    • Increase sodium → raises osmolality → triggers ADH release and water retention
• Remember: water follows solutes
  • If osmolality is high:
    • More solutes
  • Water moves toward that area
• If osmolality is low:
  • Fewer solutes
  • Water moves away.
• Hormone plays key role: Renin-Angiotensin-Aldosterone System (RAAS).
• Regulates:
  • Body water volume
  • Sodium levels
• Effect activation on water and sodium:
  • Increases water volume
  • Increases sodium reabsorption
• What organ produces angiotensinogen?: LIVER
• When and where is renin released?
  • KIDNEYS
  • Response to LOW RENAL PRESSURE or LOW SODIUM
• What does renin do: Converts Angiotensinogen into Angiotensin I (ONE)
• Where is angiotensin I converted to angiotensin II?
  • LUNGS by ACE
• What does angiotensin II stimulate?
  • Aldosterone release from the Adrenal Glands
• What is the role of Aldosterone?
  • Promotes sodium and water reabsorption
  • By what organs?: KIDNEYS
  • It raises: Blood Volume and BP

ANP

• Atrial natriuretic peptide (ANP) function:
  • Causes: Vasodilation
  • Promotes: Excretion of sodium and water
  • Lowers: BP

Blood Pressure Classifications

• Normal BP:
  • Systolic: <120
  • Diastolic: <80
• Elevated BP:
  • Systolic: 120-129
  • Diastolic: <80
• Stage 1 hypertension:
  • Systolic: 130-139
  • Diastolic: 80-89
• Stage 2 hypertension:
  • Systolic: 140+
  • Diastolic: 90+
• Hypertensive crisis:
  • Systolic: 180+
  • Diastolic: 120+

Hypertension

• "The silent killer":
  • No symptoms
  • Leads to an increased risk of diseases in the:
    • Heart
    • Kidney
    • Vascular
    • Brain
• Two main types of hypertension:
  • Primary: Idiopathic (most common)
    • Means: Unknown
  • Secondary: Due to an identifiable cause
    • Such as: Specific condition or disease

Primary Hypertension

• Subtypes of primary hypertension:
  • Isolated systolic
  • Isolated diastolic
  • Combined systolic and diastolic
• Uncontrolled risk factors for primary:
  • Genetics
  • Family history
  • Age
• Controllable factors for primary:
  • Diet
  • Stress
  • Inactivity
  • Obesity
  • Metabolic syndrome
  • Sodium intake

Complications of Untreated Hypertension

• Heart:
  • LV hypertrophy
  • Heart failure
  • Myocardial Infarction
  • Angina
• Kidneys:
  • Glomerular damage
  • Atrophy
  • End Stage Renal Disease
• Brain:
  • Stroke
  • Transient ischemic attack
  • Hemorrhage
• Eyes:
  • Retinal hemorrhage
  • Detachment
  • Blindness

Hypertension Treatment

• Treatment: Lifestyle modifications
• Stage 1 medications:
  • Thiazide diuretics
  • ACEI
  • ARB
  • CCB
  • BB
• Stage 2 medications:
  • Two-drug combination therapy
  • Thiazide + ACEI/ARB/CCB/BB

Hypertension Drugs Mechanisms

• Drugs reduce heart rate:
  • β-blockers
  • β/α-blockers
• Drugs reduce stroke volume:
  • Diuretics (thiazide, loop, K-sparing)
  • ACE inhibitors
  • ARBs
  • Venodilators
  • Aldosterone antagonists
• Drugs reduce systemic vascular resistance:
  • ACE inhibitors
  • ARBs
  • CCBs
  • α1-blockers
  • β/α-blockers
  • Central α2 agonists
  • Arterial vasodilators

Secondary Hypertension

• Common causes:
  • Renal disease
  • Coarctation of the aorta
  • Pregnancy
  • Obstructive sleep apnea
  • Endocrine disorders
    • Examples:
      • Cushing's syndrome
      • Hyperthyroidism

Hypotension (Orthostatic)

• A drop in blood pressure when you stand up from sitting or lying down
• Symptoms: Dizziness or fainting
• After 3 minutes of standing:
  • Decrease in systolic BP by: 20+
  • Decrease in diastolic BP by: 10+
• Causes:
  • Baroreceptor/vasomotor dysfunction
  • Dehydration
  • Blood loss (volume depletion)
• Medications such as:
  • Diuretics
  • Vasodilators
  • Antihypertensive
• Nervous system disorders:
  • Such as: Parkinson's Disease
  • Arterial stiffness
• Treatments for hypotension:
  • Review med history
  • Slow posture changes
  • Avoid heat
  • Avoid heavy meals
  • Physical maneuvers (squat, leg crossing)