Pathology: Haemodynamic Disorders and Hemostasis

Introduction to Pathology and Haemodynamic Disorders

Definition of Haemodynamic Disorders: These are medical disorders specifically relating to the flow of blood within the body's organs and tissues. This includes the movement and balance of water, minerals, and the components of whole blood.
Discipline Context: Presented within the Faculty of Dentistry, Basic Sciences (Pathology) at İstanbul Gelişim University by Prof. Dr. Halit Hami ÖZ.

Water Balance and Distribution

Sources of Water Input:
- Ingested liquids.
- Foods (specifically fruits and vegetables).
- Endogenous metabolic water production.
Sources of Water Output:
- Sensible Losses: Urine, stools, and sweat. The body's ability to dilute or concentrate urine allows for a wide range of flexibility in output.
- Insensible Losses: Skin loss through insensible perspiration and air exhaled from the respiratory tract.
Osmolality: Defined as the ratio of total body solute in total body water. The total solute concentration (tonicity) of body fluids is kept constant, regulated between $280-295\,mOsm/kg$ .
Body Water Distribution by Gender:
- Men: Water accounts for $60\%$ of total body weight.
- Women: Water accounts for $50\%$ of total body weight.
Compartmental Distribution:
- Intracellular Fluid (ICF).
- Extracellular Fluid (ECF).
- The proportion of intracellular water to extracellular water is $2:1$ .
ECF Components:
- Intra-vascular: Plasma.
- Extra-vascular: Interstitial tissue fluid and lymph.
- The proportion of interstitial to intracellular water is $3:1$ .
Mass Example: For a male weighing $72\,kg$ , total body water is estimated at $42\,liters$ .
Transcellular Fluids: A subset of extracellular fluid separated from plasma by an additional epithelial layer. Examples include:
- Intra-ocular fluid.
- Pericardial, peritoneal, and pleural fluids.
- Synovial fluids.
- Cerebro-spinal fluid (CSF).
- Glandular secretions.
Table: Distribution of Body Water (70 kg basis):
- Total Body Weight: $100\%$ ( $70\,kg$ ).
- Total Body Water: $60\%$ ( $42\,L$ ).
- Intra cellular water: $40\%$ ( $28\,L$ ).
- Extra cellular water: $20\%$ ( $14\,L$ ).

Regulation of Water and ECF Assessment

Clinical Assessment of ECF Volume: Status is assessed via level of consciousness, thirst, moistness of mucosal surfaces, skin turgor, heart rate, blood pressure, and urine output.
Regulatory Mechanisms:
- Renal System: Utilizes urine concentrating mechanisms.
- Osmoreceptors: Hypothalamic sensors that monitor plasma osmolality.
- Arginine Vasopressin (ADH): Activated by pain, stress, volume receptors, and thirst sensors.
Renal Regulation Details:
- Reabsorption of $65\%$ to $75\%$ of water occurs in the proximal convoluted tubule, accompanying sodium.
- Further reabsorption occurs in the descending limb of the loop of Henle and the collecting ducts, mediated by ADH.
ADH Stimulation Factors:
- Osmolality: Increased plasma tonicity/osmolarity.
- Plasma Volume: Reduced plasma volume detected by cardiovascular volume receptors.
- Blood Pressure: Fall in arterial blood pressure detected by cardiovascular baroreceptors.
- Hormonal: Adrenaline, angiotensin II, hypothyroidism, and hypoadrenalism.
- Drugs: Nicotine, barbiturates, and vincristine.
- Miscellaneous: Nausea, vomiting, hypoglycemia, stress, and heat.
ADH Inhibition Factors: The inverse of stimulation factors, including decreased osmolality, volume expansion, rise in blood pressure, alpha-adrenergic stimulation, cold, and ethanol (alcohol).

Disorders of Water Balance (Dehydration and Overhydration)

Dehydration (Water Loss):
- Sequence of loss: Fluids are lost first from the extracellular space, followed by the intracellular space.
- Isotonic (Isonatremic) Dehydration: Dehydration that does not affect the sodium concentration in the ECF. Also called iso-osmolar dehydration.
- Hypertonic (Hypernatremic) Dehydration: Resulting in an increased sodium concentration in the ECF. Also called hyperosmolar dehydration.
- Hypotonic (Hyponatremic) Dehydration: Resulting in a decreased sodium concentration in the ECF. Also called hypoosmolar dehydration.
Overhydration (Water Excess):
- Types: Increased water intake (faster than kidneys can excrete) or water retention due to medical conditions (specifically inappropriate ADH secretion).
- Risks: Can lead to water intoxication and fatal low sodium levels (hyponatremia).

Sodium Balance and Regulation

General Principle: Sodium is regulated by water, and water is regulated by sodium. Serum level is normally $135-145\,mmol/l$ .
Physiological Roles of Sodium:
- Osmolality: Principal osmotically active solute in plasma and ECF.
- Fluid Volume: Total body sodium directly influences ECF and plasma volume.
- Nerve Excitation: Essential for transmembrane potential differences and excitability in nerve and muscle fibers.
- Cell Volume: Na+ permits water movement to the intracellular compartment.
- Co-transport: Facilitates renal reabsorption and enteric uptake of solutes (glucose, amino acids).
- Na-K Pump: Major metabolic gate affecting various pathways via Na-K-ATPase.
Regulation of Sodium:
- Sensors: Pressure receptors (baroreceptors) in the carotid sinus and renal juxtaglomerular apparatus; osmoreceptors and volume receptors in the atria, hypothalamus, and hepatic vasculature.
- Renal Mechanism: Sodium and water reabsorption in the proximal tubule; aldosterone increases sodium reabsorption and potassium excretion in the distal convoluted tubules via the Renin-Angiotensin-Aldosterone System (RAAS).

Disorders of Sodium

Hyponatremia: Serum sodium level under $130\,mmol/l$ or defined as less than $150\,mEq/L$ in specific contexts. Signs include lethargy, headache, confusion, seizures, and coma.
- Pseudo-hyponatremia: Sample errors with normal osmolality, caused by severe hyperproteinemia, hypertriglyceridemia, or samples taken near an IV infusion.
- True Hyponatremia Types:
- Hypovolemic: Greater reduction in sodium than water (e.g., diuretics, GI loss, skin loss).
- Euvolemic: Increased body water with normal total sodium (e.g., ADH excess).
- Hypervolemic: Greater increase in water than sodium (e.g., heart failure, cirrhosis, renal failure).
- Redistribution: Water shift from ICF to ECF due to high osmolality (e.g., severe hyperglycemia).
Hypernatremia: Serum sodium level greater than $150\,mmol/l$ . Indicates a relative water deficit.
- Hypovolemic: Water deficit greater than sodium deficit (e.g., osmotic diuresis, secretory diarrhea).
- Hypervolemic: Sodium increase greater than water increase (e.g., iatrogenic hypertonic saline, primary hyperaldosteronism).
- Euvolemic: Renal water loss (Diabetes Insipidus) or insensible loss with normal total sodium.

Potassium Balance

Distribution: Major cation in the Intracellular Fluid ( $ICF$ ). Normal serum level: $3.5-5\,mmol/l$ . $90\%$ of body potassium is available for exchange.
Functions:
- Generation of transmembrane potentials (electrical excitability).
- Enzymatic cofactor.
- Maintenance of cell volume and polarity.
- Acid-base balance maintenance.
Movement Factors:
- Into Cells: Alkalosis (metabolic), insulin, beta-adrenergic agonists, high extracellular K+ concentration, and hyperosmolarity.
- Out of Cells: Acidosis (respiratory), low osmolarity, glucagon, beta-adrenergic blockade, alpha-adrenergic agonists, and cell injury.
Renal Control: Depends on Na-K and H-K pumps in the tubule under the Renin-Angiotensin System.
Hypokalemia (<3.5\,mmol/l):
- Redistributional: Shifts into cells due to alkalosis, insulin, or rapid cell growth.
- True: Renal loss (diuretics, high aldosterone, osmotic diuresis) or GI loss (secretory diarrhea, laxative abuse).
Hyperkalemia (Increase in serum K+):
- Pseudo: Hemolysis during blood collection, marked leukocytosis, or thrombocytosis.
- True: Reduced excretion (renal failure, potassium-sparing diuretics), increased intake, or release from cells (rhabdomyolysis, tumor lysis, acidosis, beta-blockers).

Mechanisms of Haemostasis

Definition: The mechanism used by the body to control bleeding and prevent thrombosis.
Components:
- Intact Blood Vessel: Endothelium has a negative charge to repel platelets; constricts when injured.
- Normal Platelets: Form the primary haemostatic plug. Normal count: $150,000-400,000\,cu.mm$ . Functions include adhesion (via GpIb receptors to von Willebrand factor/VWF), aggregation (via GpIIb-IIIa to fibrinogen), and release (ADP, TXA2).
- Normal Coagulation Factors: Inactive circulating proteins (I to XIII) that activate in a cascade. Factor X to Xa, then Prothrombin (II) to Thrombin (IIa).
- Normal Fibrinolytic System: Prevents thrombus propagation. Plasminogen (main factor) converts to Plasmin via t-PA to dissolve fibrin.
- Natural Inhibitors: Protein S, Protein C, and Antithrombin III; these inactivate factors to prevent excessive thrombosis.

Thrombosis

Definition: A coagulated solid mass composed of blood constituents (platelets, fibrin, WBCs, RBCs) developing in an artery, vein, capillary, or heart chamber.
Virchow’s Triad (Pathogenesis):
- Damage to endothelial lining.
- Abnormal blood flow (stasis or turbulence).
- Hypercoagulability of blood.
Endothelial Injury Mechanisms: Release of procoagulants (thromboplastin, VWF, PAF), reduced secretion of anticoagulants (thrombomodulin, NO, t-PA), and exposure of collagen for platelet binding.
Venous Thrombosis Predisposing Factors: Varicose veins, prolonged immobility, tissue damage (trauma/burns), pregnancy/obstetrical complications (forceps, oral contraceptives), circulatory disturbances (MI, stroke), and tumors.
Thrombi Macro-features:
- Lines of Zahn: Alternating white (platelets/fibrin) and red (RBCs) layers.
- Friability: Thrombi crumble along cleavage lines.
- Attachment: Firmly attached to the vessel wall.
- Molding: Typically takes the shape of the vessel.
Postmortem Clots (Comparison): Pliable, not friable, not attached to the wall, exhibits a "currant jelly" (red) and "chicken fat" (yellow) appearance due to gravity sedimentation.
Comparison: Venous vs. Arterial Thrombi:
- Venous: Arise at areas of stasis; grow in direction of flow; loose attachment (embolism risk); partially occlusive; rapid lysis.
- Arterial: Arise at site of injury; grow retrograde; firm attachment; usually occlude flow completely; slow lysis.
Outcomes of Thrombosis: Resolution (fibrinolysis), Propagation (growth), Embolization (detachment), Organization (fibrous scar), Recanalization (re-establishing blood flow channels).

Hemorrhage

Definition: The escape of blood from blood vessels due to trauma, inflammation, neoplasia, or abnormal haemostasis.
Classification by Organ/Site:
- Cardiac: Ventricle rupture (MI) or wounds.
- Arterial: Trauma or aneurysm rupture.
- Capillary: Trauma, surgery, or collagen disorders (Ehlers-Danlos).
- Venous: Trauma.
Terminology by Size:
- Petechiae: Pinpoint hemorrhages <1\,mm.
- Purpura: $1\,mm$ to $1\,cm$ in diameter.
- Ecchymoses: Larger than $1\,cm$ .
Hematoma Progression: Initially red, then bluish (deoxygenation), greenish (biliverdin), yellowish (bilirubin), and finally brownish (hemosiderin/iron pigment).
Body Cavity Bleeding:
- Hemopericardium / Hemothorax / Hemarthrosis.
- Hematocephalus: Blood in brain ventricles.
- Hematocolpos: Blood in the vagina (imperforate hymen).
Secretory Terms:
- Hematuria: Blood in urine.
- Hematemesis: Vomiting blood (ruptured varices, ulcers).
- Hemoptysis: Blood-stained sputum associated with cough.

Edema

Definition: Abnormal accumulation of fluid in interstitial spaces or body cavities (also called dropsy or hydropsy).
: Increased hydrostatic pressure, reduced plasma oncotic pressure (hypoproteinemia), increased tissue oncotic pressure, increased vessel permeability (inflammation), or lymphatic obstruction.

Starling’s Law: Accumulation is regulated by the balance between hydrostatic pressure (filtering out) and oncotic pressure (drawing in).
Clinical Classification:
- Pitting Edema: Indentation persists after pressure; caused by water retention/heart failure.
- Non-pitting Edema: Indentation does not persist; associated with lymphedema and myxedema.
Organ-Specific Edema:
- Cerebral: Causes drowsiness/unconsciousness.
- Pulmonary: From left ventricle failure; produces shortness of breath.
- Corneal: Occurs with glaucoma or surgery.
- Lymphedema: Obstruction due to cancer, radiotherapy, or parasites (Elephantiasis).
- Laryngeal: Emergency condition, often from hair-dye poisoning.
- Hydrops Fetalis: Severe generalized edema in a fetus.

Embolism

Definition: Passage of solid, liquid, or gaseous material in blood vessels capable of obstructing flow distal to the site of insertion.
Composition Type:
- Solid: Thrombus ( $99\%$ of cases), tumor, cholesterol debris.
- Liquid: Fat embolism (bone fractures), amniotic fluid embolism (labor), lipid embolism.
- Gaseous: Air embolism (thoracic trauma, diving accidents).
Migration Pathways:
- Venous: Peripheral veins → right heart → lungs.
- Arterial: Left heart → aorta → brain, kidney, or lower limbs.
- Portal: Mesenteric veins → liver.
- Paradoxical (Crossed): Venous embolus transfers to arterial system via patent foramen ovale.
Pulmonary Embolism (PTE): $95\%$ arise from deep leg veins. Large "saddle embolus" can cause sudden death; small emboli ( $60-80\%$ ) may be clinically silent.
Systemic Embolism Sites: Lower extremities ( $75\%$ ), brain ( $10\%$ ), intestines, kidney, and spleen.

Infarction

Definition: Ischemic necrosis in an area after occlusion or rupture of an artery via embolus, thrombus, spasm, or torsion.
Susceptibility to Hypoxia:
- Neurons: Irreversible damage in $3-4\,minutes$ .
- Myocardial cells: Death after $20-30\,minutes$ .
- Fibroblasts: Most resistant.
Types of Infarcts:
- Red (Hemorrhagic): Occurs in venous occlusions (torsion), loose tissues (intestine), or dual-circulation organs (lung, liver).
- White (Anemic): Occurs in arterial occlusion in solid organs with single blood supply (heart, spleen, kidney).
Morphology: Usually wedge-shaped with the occluded vessel at the apex.

Shock

Definition: Systemic hypoperfusion resulting from progressive cardiovascular collapse and reduced cardiac output.
Hemodynamic Equation: $(CO) = \text{Stroke Volume} \times \text{Heart Rate}$ .
Types:
- Hypovolemic: Loss of blood/fluid volume (hemorrhage/diarrhea). Significant at $25\%$ volume loss ( $1.2\,liters$ ).
- Cardiogenic: Pump failure (MI involving >40\% of ventricular mass).
- Distributive: Peripheral vasodilation (Septic, Anaphylactic, Neurogenic).
Stages:
- Initial: Hypoperfusion, anaerobic metabolism, lactic acid.
- Compensatory: Reversible sympathetic activation.
- Progressive: Development of metabolic acidosis.
- Irreversible (Refractory): Cellular necrosis and multi-organ failure.

Hyperemia and Congestion

Hyperemia: Active process; arteriolar dilation (e.g., exercise, inflammation); tissue is red and oxygenated.
Congestion: Passive process; venous obstruction; tissue is blue-red (cyanosed) and deoxygenated.
Nutmeg Liver: Chronic passive hepatic congestion where the central zone is red-brown and the portal zone is tan, resembling a nutmeg seed.

Arteriosclerosis and Atherosclerosis

Arteriolosclerosis: Hypertrophy/fibrosis of the media in arterioles causing narrowing.
Atherosclerosis: Most common form. Complications cause half of all US mortality.
Lesion Stages:
1. Intimal thickening.
2. Fatty streaks: Lipid in foam cells.
3. Fibrofatty plaques: Raised lesions with collagen and calcification.
4. Complicated lesions: Ulceration, thrombosis, or aneurysm.
Hard Risk Factors: Hyperlipidemia (cholesterol/LDL over $3.9\,mmol/L$ ), hypertension, diabetes, and smoking.

Questions & Discussion

Question regarding Dehydration Types: Why is it important to differentiate between iso-, hyper-, and hypotonic dehydration?
Answer: This suggests the specific etiology of the dehydration and dictates the clinical management approach.
Numerical Clarification: Normal healthy adults can lose $0.5\,liters$ ( $10\%$ blood volume) without significant symptoms.
Numerical Clarification: Mortality from cardiogenic shock can reach $80\%$ when >40\% of the ventricle is damaged.

Define Haemodynamic Disorders
What are the primary sources of water input in the body?
Differentiate between sensible and insensible water losses.
What is osmolality and what is its normal range in the body?
Describe the body water distribution by gender.
What are the compartments of body water distribution?
How is the extracellular fluid (ECF) compartment divided?
What is the significance of transcellular fluids?
List the factors assessed for ECF volume clinical assessment.
What regulatory mechanisms control water balance in the body?
Define isotonic, hypertonic, and hypotonic dehydration.
What are the risks associated with overhydration?
What is the normal serum sodium level and its physiological roles?
Differentiate between true hyponatremia and pseudo-hyponatremia.
Explain the factors affecting potassium movement in the body.
Describe the definitions and components of haemostasis.
What are the factors in Virchow’s triad?
Differentiate between venous and arterial thrombi.
What are the classifications of hemorrhage by size and organ/site?
What are the secretory terms used to classify hemorrhage?