Familial Hypercholesterolemia and Hemostasis

Pathogen 4.1 Vessels - Objectives

• Illustrate fluid distribution between intravascular and extravascular compartments, applying normal circulation principles.
• Distinguish oncotic and hydrostatic causes of edema, using clinical examples.
• Analyze the role of renal pathology in fluid balance disruption.
• Discuss heart pathology regarding fluid balance.
• Analyze hemorrhage and provide clinically important examples.
• Illustrate normal hemostasis, the role of endothelial cells, platelets, and coagulation proteins; addressing pathologic and medicinal implications.
• Discuss thrombus and embolus formation.
• Analyze hypercoagulability and its causes.
• Illustrate infarction and its pathogenesis.
• Illustrate shock and its pathogenesis.
• Differentiate major mechanical vascular diseases, including congenital causes.
• Illustrate arteriosclerosis.
• Illustrate aneurysm forms and their formation.
• Discuss familial hypercholesterolemia (phenotypes, inheritance, etiology, incidence, pathogenesis, etc).
• Analyze essential and secondary hypertension, relating it to pathogenesis.
• Distinguish aortic dissection types and their clinical consequences.
• List the pathogenesis types of vasculitis and vascular tumor.

Fluid Balance

• Two opposing forces drive fluid balance in the body: hydrostatic pressure and oncotic pressure (colloid osmotic pressure).
• Hydrostatic pressure typically wins, but lymphatics remove excess fluid.

Fluid Balance (IO:1)

• Opposing forces: hydrostatic and oncotic pressures
• Hydrostatic fluid pressure often wins, but lymphatics clean up extra fluid.

Causes of Edema

• Venous return issues (e.g., congestive heart failure, constrictive pericarditis, ascites).
• Venous obstruction or compression.
• Thrombosis.
• External pressure (tumors).
• Lower extremity inactivity.
• Protein-losing conditions (nephrotic syndrome, liver cirrhosis).
• Malnutrition.
• Lymphatic obstruction.
• Inflammatory diseases (inflammatory dz).
• Tumors (neoplasm).
• Post-surgical or post-irradiation issues.
• Excessive sodium intake or reduced kidney function.
• Increased Na+ uptake.
• Renal hypoperfusion.
• Increased renin-angiotensin-aldosterone secretion.

Terms

• Edema: Fluid accumulation in tissues due to net water movement into extravascular spaces.
• May manifest as swollen feet or pulmonary edema.
• Hyperemia: Increased arterial blood flow.
• Congestion: Increased venous blood flow.
• Hemostasis: Blood clotting process.
• Thrombosis: Formation of a stationary blood clot.
• Embolism: A blood clot or other matter that has moved to a different part of the body.
• Infarction: Tissues die due to ischemia.
• Effusion: Extravascular fluid collection in body tissues.

Renin, Angiotensin, Aldosterone

• Renin activates angiotensinogen, converting it to angiotensin I.
• Lungs convert angiotensin I to angiotensin II using ACE.
• Angiotensin II stimulates aldosterone release, increasing blood pressure.
• Aldosterone increases Na+ reabsorption, leading to water retention and a rise in blood volume.

BP Regulation

• Blood pressure depends on cardiac output and peripheral vascular resistance.
• Cardiac output is a function of heart rate and stroke volume, which depends on filling pressure and myocardial contractility (influenced by alpha and beta adrenergic inputs).

Hypertension

• Elevated blood pressure (consistently above 140/90 mm Hg).
• Major complications: Cardiac hypertrophy, heart failure, stroke (CVA), dissection.
• Types: Primary (essential, idiopathic) and secondary.

Hemorrhage Terms

• Hemorrhage: Blood leakage from vessels.
• Hematoma: Blood mass.
• Petechiae/Purpura: Small hemorrhages into skin, mucous membranes, or serosal surfaces (often due to low platelets).
• Ecchymoses: Bruises.
• RBCs degrade to form hemosiderin (golden-brown).
• Bilirubin (blue-green).

Clinical Tie-ins for Hemorrhage

• Massive hemorrhage leads to hypovolemic shock and exsanguination.
• Hematoma compresses tissues and may cause compartment syndrome.
• Intracranial hemorrhage results in stroke or death.

Hemostasis Review

• Arteriolar vasoconstriction reduces blood flow close to the injury site.
• Primary hemostasis involves platelet aggregation to form a plug.
• Secondary hemostasis involves activation of clotting factors and fibrin formation to create a stable clot.
• Clot stabilization, and subsequent breakdown of the clot, are regulated by counterregulatory mechanisms.

Clinical Point (IO:6)

• D-dimer is a fibrinogen breakdown byproduct.
• Its presence in the blood indicates clotting activity.
• Measured in blood tests (D-dimer test) to detect clotting.

Clotting Pathway

• PT/INR: Measures the extrinsic pathway.
• PTT: Measures the intrinsic pathway.

Clotting Inhibition

• Heparin-like molecules activate antithrombin to prevent fibrin formation.
• Endothelial cells switch between procoagulant and anticoagulant states to maintain hemostasis.
• Thrombomodulin and protein C receptor inhibit thrombin's pro-coagulant effects.
• t-PA aids in clot breakdown.

Medicinal Clotting Inhibition

• Warfarin inhibits vitamin K-dependent clotting factors.
• Heparin activates antithrombin.
• Xa inhibitors directly inhibit clotting factors.
• Aspirin is an antiplatelet drug.
• P2Y12 inhibitors block ADP receptors.

Clinical Points (IO:6)

• Using heparin before warfarin is common as warfarin inhibits Protein C and S which leads to a temporary procoagulant state.
• Other clinical conditions: Factor V Leiden mutation, Protein C and S deficiency, antithrombin III deficiency, Von Willebrand's disease.
• Medical interventions for blood clots: Anticoagulants (heparin, NOACs), Antiplatelets (ASA, P2Y12 inhibitors), Thrombolytics (tPA).

Virchow's Triad

• Endothelial injury is crucial for thrombosis.
• Abnormal blood flow (e.g., stasis, turbulence) contributes.
• Hypercoagulability predisposes to clotting.

Hypercoagulability

• Conditions increasing clotting risk: Factor V Leiden mutation, Antithrombin III deficiency, protein C and S deficiency, immobility, cancer, surgery, tissue injury, prosthetic valves, antiphospholipid antibody syndrome, smoking, atrial fibrillation, pregnancy and postpartum, oral contraceptives (especially in smokers).

Thrombi and Emboli

• Thrombi: Blood clots in blood vessels.
• Types: Arterial thrombosis (e.g., from endothelial injury or turbulent flow), venous thrombosis (often due to stasis).
• Emboli: Circulating foreign materials that block blood vessels.
• Types: Thromboemboli.

Infarct

• Infarct: Ischemic necrosis due to blocked blood supply.
• Types: White infarct (arterial blockage, pale) and red infarct (venous blockage, hemorrhagic).
• Determining factors affect outcome include vascular anatomy, rate of occlusion, collateral circulation, and tissue vulnerability.

Factor V Leiden

• Autosomal dominant genetic condition associated with a higher risk of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Two Clinically Important Conditions

• Heparin-induced thrombocytopenia (HIT): Autoantibody-mediated platelet activation, aggregation, and consumption, leading to a prothrombotic state.
• Disseminated intravascular coagulation (DIC): Widespread clotting in the microcirculation associated with activation of fibrinolysis mechanisms, leading to profuse bleeding.

Shock

• A life-threatening condition characterized by inadequate tissue perfusion.
• Types: Cardiogenic, hypovolemic, and septic shock.
• Mechanisms vary, but they all lead to insufficient blood delivery to tissues.

Stages of Shock

• Nonprogressive: Compensatory mechanisms maintain vital organ perfusion.
• Progressive: Hypoperfusion leads to worsening metabolic abnormalities (e.g., acidosis).
• Irreversible: Cellular and tissue damage is too extensive to recover.

Clinical Manifestations of Shock

• Prognosis depends on cause and response to treatment.
• Symptoms may include hypotension, weak pulse, tachypnea, altered mental status, cool clammy skin, etc.

Normal Blood Vessels

• Arteries have thicker walls with more smooth muscle.
• Veins have valves to prevent backflow.
• Organized into 3 layers: Intima, Media, Adventitia.

The Main Forms of Vascular Disease

• 1. Obstruction (Clogging)
• 2. Weakening (Weakening)
• 3. Conditionally (Pre-existing)

Congenital Anomalies of Vasculature

• Berry aneurysms: Cerebral vessel dilations.
• Arteriovenous fistulas: Abnormal connections between arteries and veins.
• Fibromuscular dysplasia: Irregular thickening of arteries.

Arteriosclerosis

• Hardening of arteries due to arterial wall thickening and loss of elasticity.
• Patterns: Arteriosclerosis, Mönckeberg medial calcific sclerosis, and Fibromuscular intimal hyperplasia.

Atherosclerosis

• Characterized by atheromas (lipid-filled plaques) that narrow artery lumens.
• Types of plaques: Vulnerable, Stable.
• Locations prone to atherosclerosis: Generalized, cerebral, coronary, aortic.

Atherosclerosis → Aneurysm

• Atherosclerosis weakens arterial walls, leading to aneurysm formation.
• Rupture risk is increased as the aneurysm grows and weakens the vessel wall.

Types of Aneurysms

• True: Saccular (focal bulge) or fusiform (circumferential dilation).
• False (Pseudoaneurysm): Vessel wall is ruptured and blood collects outside the vessel.
• Dissection: Blood dissects between the arterial layers, creating a blood-filled channel.

AAA (Abdominal Aortic Aneurysm)

• Clinical consequences of AAA include obstruction of branch vessels, compression of adjacent structures, abdominal mass and potentially fatal rupture into the peritoneal cavity.

Aortic Dissection

• Aortic dissection: Blood separates the layers of the aorta's wall, creating a blood-filled channel.
• Hypertension is a major risk factor.
• Consequences include massive hemorrhage, pericardial/pleural/peritoneal rupture.

Marfan Syndrome

• A genetic disorder affecting connective tissue due to fibrillin 1 mutation.
• Major cardiovascular effect: Weakened aorta, aneurysm risk, potentially fatal.

Familial Hypercholesterolemia

• A genetic disorder causing significantly elevated LDL cholesterol due to mutations in the LDLR gene.
• Elevated cholesterol risks coronary artery disease.

Management of Familial Hypercholesterolemia

• Aggressive dietary and pharmacological interventions (statins, bile sequestrants) are required to reduce LDL cholesterol and thereby reduce the risk of CAD.

Inheritance Risk of Familial Hypercholesterolemia

• Autosomal dominant pattern, offspring have a 50% chance of inheriting the mutated LDLR allele if one parent is affected.

Vasculitis

• Inflammation of blood vessel walls.
• Types: Giant cell arteritis, Takayasu arteritis, Polyarteritis nodosa, Kawasaki disease, thromboangitis obliterans (Buerger disease).

Vascular Tumors

• Can originate from blood or lymphatic vessels.
• Types include hemangiomas (benign), lymphangiomas (benign), angiosarcoma (malignant), Kaposi sarcoma, glomus tumor, and hemangiopericytoma.