Pathogen 4.1 Vessels PDF

Objectives 1. Illustrate the distribution of fluid between the intravascular and extravascular compartments and apply the basic aspects of normal circulation. 2. Distinguish both oncotic and hydrostatic causes of edema and debate clinical examples. 3. Analyze the role renal pathology in di...

Objectives 1. Illustrate the distribution of fluid between the intravascular and extravascular compartments and apply the basic aspects of normal circulation. 2. Distinguish both oncotic and hydrostatic causes of edema and debate clinical examples. 3. Analyze the role renal pathology in disrupting fluid balance 4. Discuss the pathology of the heart with regard to fluid balance 5. Analyze hemorrhage and give clinically important examples of this pathologic process. 6. Illustrate normal hemostasis and the role of endothelial cells, platelets, and the coagulation proteins in this process and address pathologic and medicinal implications. 7. Discuss the formation of thrombus and embolus. 8. Analyze the concept of hypercoagulability and its causes. 9. Illustrate infarction and relate its pathogenesis. 10. Illustrate shock and relate its pathogenesis. 11. Differentiate major mechanical illnesses of vascular disease, including congenital causes 12. Illustrate arteriosclerosis. 13. Illustrate the different forms of aneurysm and their formation. 14. Debate the major phenotypic features, inheritance, etiology, incidence, pathogenesis, and phenotype of familial hypercholeste rolemia. 15. Analyze essential and secondary hypertension and relate its pathogenesis. 16. Distinguish the types of aortic dissections and their clinical consequences. 17. Inventory the pathogenesis types of vasculitis and vascular tumor. Fluid Balance Terms Edema – the accumulation of fluid in tissues resulting from net movement of water into extravascular spaces May be swollen feet, might be flash pulmonary edema Hyperemia – too much arterial blood Congestion – too much venous blood Hemostasis – process of blood clotting Thrombosis – bad clot Embolism – bad clot that moved Infarction – ischemia → cell death Congested tissues sometimes take on cyanotic appearance due to deoxygenated blood Effusion- extravascular fluid collected in body tissues Fluid Balance (IO:1) Two opposing forces Hydrostatic pressure Oncotic pressure (colloid osmotic pressure) Hydrostatic “wins” But only a little bit Lymphatics clean up the extra fluid Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Causes of Edema (IO:2) Venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (mass/cancer) Lower extremity inactivity – dependency Oncotic pressure Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (albumin!) Malnutrition Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory dz Neoplasm Post surgical Postirradiation Sodium Retention Too much salt – too little kidney function Increased Na+ uptake Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation  Renin, Angiotensin, Aldosterone Thirsty Kidneys: What follows is the pathway whereby hypoperfused kidneys attempt to increase renal blood supply Renin, once secreted, activates angiotensinogen and turns into angiotensin I (Angiotensinogen is a plasma protein that is already, always present in plasma) Angiotensin I activated in lungs via pulmonary circulation and turned into angiotensin II by angiotensin-converting enzyme (ACE) which is abundant in pulmonary capillaries Angiotensin II stimulates aldosterone release from adrenal cortex Angiotensin II is also a potent vasoconstrictor, increasing BP [Stimulates thirst (increase fluid intake) and vasopressin (which increases H2O retention from kidneys] Aldosterone increases Na+ reabsorption which results in H2O retention → rise in blood volume → and rise in arterial blood pressure Rise in these factors will alleviate renin triggers Renin, Angiotensin, Aldosterone Renin, Angiotensin, Aldosterone BP regulation: Kidneys, adrenals, and Heart Kidneys Regulate salt Renin- angiotensin- aldosterone Myocardium Release natriuretic peptides Inhibit Na+ reabsorption when volume expansion is sensed BP regulation: Kidneys, adrenals, and Heart Kidneys Regulate salt Renin- angiotensin- aldosterone Myocardium Release natriuretic peptides Inhibit Na+ reabsorption when volume expansion is sensed One thing leads to another (IO: 3, 4) Watch out for the combination of heart and kidney failure! Heart failure Decreased flow to kidneys Renal failure Increased fluid on the heart Another contributing factor is change in oncotic force: This is an issue with albumin One thing leads to another (IO: 3, 4) Watch out for the combination of heart and kidney failure! Heart failure Decreased flow to kidneys Renal failure Increased fluid on the heart Another contributing factor is change in oncotic force: This is an issue with albumin One thing leads to another (IO: 3, 4) Watch out for the combination of heart and kidney failure! Heart failure Decreased flow to kidneys Renal failure Increased fluid on the heart Another contributing factor is change in oncotic force: This is an issue with albumin Hemorrhage Terms (IO:5) Hemorrhage – extravasation of blood Hematoma – blood mass, may be trivial or life-threatening depending on location Petechia (3mm) / Purpura – small hemorrhages into skin, mucous membranes, serosal surfaces Caused by low platelets! defective platelet function! Ecchymoses – bruises Under sub q RBCs are degraded by macrophages Hemoglobin goes from blue → bilirubin (blue-green) → hemosiderin (golden- brown) Hemorrhages Clinical Tie-ins for hemorrhage (IO:5) Massive hemorrhage – blood loss, hypovolemic shock, exsanguination, death Hematoma – compression of tissues/compartments Compartment syndrome, (worst case scenario) Intracerebral hemorrhage – stroke, death Chronic hemorrhage – slow blood loss → iron deficiency anemia Hemorrhages Hemostasis Hemostasis Review 1. Arteriolar vasoconstriction Stop the flow! Local response (endothelin) Won’t last long Hemostasis Review 2. Primary hemostasis: platelet plug When the endothelium is broken → von Willebrand factor (vWF) is released This promotes platelet activation → shape change! Platelets release granules that recruit more platelets This leads to platelet aggregation → primary hemostatic plug Hemostasis Review 3. Secondary hemostasis: fibrin clot Tissue factor is exposed from basement membrane → clotting cascade Thrombin turns fibrinogen into a fibrin clot Hemostasis Review 4. Clot stabilization and resorption Fibrin makes a solid, permanent scaffolding that stops further clotting Counterregulatory mechanisms come into play to limit too much clotting Tissue plasminogen activator t-PA Plasmin breaks down fibrin Resorption and repair – mediated by interactions with endothelial cells Hemostasis Review (IO:6) 1. Arteriolar vasoconstriction Stop the flow! Local response (endothelin) Won’t last long 2. Primary hemostasis: platelet plug When the endothelium is broken → von Willebrand factor (vWF) is released This promotes platelet activation → shape change! Platelets release granules that recruit more platelets This leads to platelet aggregation → primary hemostatic plug 3. Secondary hemostasis: fibrin clot Tissue factor is exposed from basement membrane → clotting cascade Thrombin turns fibrinogen into a fibrin clot 4. Clot stabilization and resorption Fibrin makes a solid, permanent scaffolding that stops further clotting Counterregulatory mechanisms come into play to limit too much clotting Tissue plasminogen activator t-PA Plasmin breaks down fibrin Resorption and repair – mediated by interactions with endothelial cells  Clinical Point (IO:6) Clinical Testing A sign that clotting has been going on occurs when breakdown products of fibrinogen appear in the blood “fibrin-split products” One of these products, called D-dimer, is measurable This is what the “D-dimer” blood test is looking for Clotting Pathway PT/INR addresses extrinsic pathway PTT addresses the intrinsic pathway *Note there are several “feedback loops” that amplify the sequence Clotting Pathway PT/INR addresses extrinsic pathway PTT addresses the intrinsic pathway *Note there are several “feedback loops” that amplify the sequence Clotting Inhibition Heparin-Like Molecule Activates antithrombin! Binds to thrombin → No more turning fibrinogen into a fibrin clot! Endothelial Cells In their passive state are anticoagulant in the factors they emit After endothelial injury, they become procoagulant – for a time Then they revert to anticoagulant in order to keep a balance They become anticoagulant by releasing tissue factor VIIa complexes that block VII activity Clotting Inhibition Thrombomodulin and endothelial protein C receptor Together, these bind thrombin and protein C in a complex on the endothelial surface This robs thrombin of the ability to “feedback” and activate coagulation factors and platelets – also keeps thrombin from forming clot Instead, thrombin activates Protein C Protein C and its cofactor protein S are anticoagulants that disrupt the clotting pathway (Inhibits Va and VIIIa which are secondarily Vitamin K dependent) Clinical point: Answer this question for yourself → What would deficiency of protein C and protein S do? Clotting Inhibition t-PA made by endothelium Becomes active when bound to fibrin Given as medicine to break up clot Comes with risk of bleeding Other endothelial products Prostacyclin (PGI2), nitric oxide, (both inhibit platlets) adenosine diphosphatase (degrades ADP: this affects clotting because ADP promotes platelet aggregation) Clotting Inhibition Medicinal Clotting Inhibition (IO:6) Warfarin (anticoagulant) Acts by inhibiting vitamin K and depletes its reserves in the body The Liver uses vitamin K to synthesize factors II, VII, IX, and X This inhibits the extrinsic pathway and its effect is measured by PT/INR It is a notoriously unstable steady state and is often “tinkered with” in clinic Reversed, as you can imagine, by giving vitamin K Heparin (anticoagulant) Made by the liver Activates antithrombin Inhibits thrombin Also given as medicine to prevent clotting It can be quickly reversed by giving Protamine Sulfate, which is soluble in the blood – binds to heparin Xa inhibitors: Novel Oral AntiCoagulants (anticoagulant) Act directly on Xa clotting factor Some reversal agents have been developed Aspirin (antiplatelet) Binds irreversibly to platelets and inactivates them P2Y12 inhibitors (antiplatelet) Block the receptor for ADP on platelets This inhibits the ability of ADP to promote clot Clinical Point (IO:6) Why “bridge to Warfarin?” by giving Heparin Because warfarin inhibits production of Protein C and S, causing a temporary procoagulant state, before the clotting cascade is fully blocked Clinical Points (IO:6) What can go wrong? Factor V Leiden Mutation Protein C and S deficiency Antithrombin III deficiency Von Willebrand's disease How do we intervene on other pathology with medicines that act on hemostasis? Blood Clots and Cardiovascular Disease Anticoagulate with heparin or NOAC now called (DOAC) Use ASA or P2Y12 inhibitors for antiplatelet therapy Lyse clot with tPA What makes you clot? Virchow’s Triad (IO:8) Endothelial injury is most important Abnormal blood flow? Turbulent flow irritates endothelium and leads to...... Endothelial injury Hypercoagulability! Well yeah... See next slide Hypercoagulability (IO:8) Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability (IO:8) Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Hypercoagulability (IO:8) Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35) Thrombi and Emboli Thrombi (IO:7) Morphology Arterial or cardiac thrombi Think endothelial injury or turbulent flow “Mural thrombi” – those occurring in aortic lumen and heart chambers Thrombi on heart valves are called “vegetations” Venous thrombi – think stasis When deep these are called DVT When superficial they are called superficial thrombophlebitis Venous thrombi – almost invariably occlusive Thrombus growth Attach to underlying vascular surface and grow toward the heart Arterial thrombi grow retrograde and venous extend with blood flow Propagating portion is poorly attached and prone to fragmentation → embolus Embolism (IO:7) Embolism (IO:7) Embolism (IO:7) Embolism: Other types (IO:7) Fate of the thrombus (IO:7) Risk: Propagation It enlarges through addition of platelets and fibrin Risk: Embolization It may move elsewhere in part or whole Dissolution Fibrinolytic factors may lead to its shrinkage Heparin will prevent spread Organization and recanalization Old thrombi become organized by new endothelial cells, smooth muscle, and fibroblasts Capillary channels are formed The original lumen is restored (at least in part) Infarct (IO:9) Infarct (IO:9) White Infarct (anemic) Arterial occlusion Solid tissues Red infarct (hemorrhagic) Venous occlusion Infarct (IO:9) Anatomy of the vascular supply Factors that affect the outcome Is there an alternative path? →→→ Rate of occlusion Did this develop abruptly? Is there time to divert to collateral blood supply? Tissue vulnerability for hypoxia Ex: Is this the brain or skeletal muscle? Factor V Leiden Factor V Leiden Autosomal dominant with incomplete penetrance Exacerbated by environmental factors Low incidence in Black and Asian and higher among Whites Physical exam DVT Possible PE Factor V accelerates clotting Inheritance Risk One parent carries mutant allele 50% risk of child getting it 10% penetrance 5% lifetime risk Two clinically important conditions 1. Heparin induced thrombocytopenia (HIT) Up to 5% of patients who get heparin Autoantibodies bind to complexes of heparin and platelet membrane protein and endothelial surfaces This results in platelet activation, aggregation, and consumption → also causes endothelial injury This leads to a PROTHROMBOTIC state! For this reason: PT/INR PTT always required for baseline before starting heparin Two clinically important conditions 2. Disseminated Intravascular Coagulation (DIC) It occurs in some severe sepsis / shock, obstetric complications, advanced malignancy This is wide-spread clotting in the microcirculation all over the body At the same time, fibrinolytic mechanisms are activated Leads to profuse bleeding Shock IO:10 Shock Definition of shock Either by decreased cardiac output or decreased circulating blood volume – tissues are not being perfused Either something’s wrong with the pump or something’s wrong with the pipes Bad news Initially, cellular injury is... Reversible Until it passes the point of no return Shock Shock Pump → Shock Pump → Shock cardiogenic obstructive Pump → Shock Pump → Pipes → Shock Pump → Pipes TBD... →  Shock Pump → (Blood) → Pipes →  Shock Pump → (Blood) → Pipes →  Shock Pump → (Blood) → Pipes → *neurogenic shock, think spinal cord injury  Shock Pump → (Blood) → Pipes → Septic Shock and Hypotension Endothelial activation through normal pathways in response to microbial infection MC → Gram positive, then negative, then virus and fungi Cytokines release endothelial tight junctions and vessels leak Activated endothelium upregulates nitrous oxide and other vasoactive mediators Smooth muscle relaxes Septic Shock Hypercoagulation Sepsis alters expression of clotting factors, and it favors coagulation Cytokines (TNF and IL-1) increase tissue factor production TNF → Initiates clotting cascade Inhibits tissue factor pathway inhibitor, thrombomodulin, and protein C → hypercoagulable Also, dampens fibrinolysis! Vascular leakage diminishes “washout” of activated coagulation factors One of the ways that clotting is regulated in normal physiology Septic Shock and Metabolic Derangement Cytokines (TNF and IL-1) upregulate stress hormones glucagon, growth hormone, cortisol → this drives gluconeogenesis At the same time inflammatory cytokines suppress insulin release and promote insulin resistance in the liver Leads to hyperglycemia (added complication → Hyperglycemia decreases neutrophil function) So, ability to fight infection is diminished After this phase, if enough time passes, there can be a respondent adrenal insufficiency and deficit of glucocorticoids Septic Shock and Metabolic Derangement As the cells continue bearing brunt of shock (inadequate perfusion) they become increasingly hypoxic, lactic acid is produced, leading to lactic acidosis Blood pH drops Septic Shock and organ dysfunction Systemic hypotension, interstitial edema and small vessel thrombosis all decrease oxygen and nutrients to tissues Mitochondria start to take damage due to oxidative stress Myocardial contractility starts to diminish Reducing cardiac output Increased vascular permeability leads to ARDS Finally, kidneys, liver, lungs, heart are all catastrophically effected, leading to death * Note well: severe shock by other means still leads to poor perfusion which can cause most of this to occur Stages of Shock Stages of Shock Compensated shock → Seeing metabolic derangements → Irreversible organ failure → Clinical Manifestations of Shock Depends on precipitating result. The primary threat to life is the underlying initiating event, though cardiac, cerebral, and pulmonary changes aggravate the situation Prognosis varies with origin and duration Cardiac & Hypovolemic presentations: Hypotension Weak pulse (How would you grade a weak pulse? ) Tachypnea (How fast would make you worry?) Cool, clammy, cyanotic skin Septic shock Here, skin may be warm and flushed secondary to peripheral vasodilation *** Sequlae after initial period Progressive oligouria Metabolic acidosis Electrolyte imbalances Blood Vessels Normal Blood Vessels Arteries have thicker walls with more smooth muscle cells (SMC) Veins are compressible, have valves Normal Blood Vessels Structural Aspects of Vessels Organized into 3 concentric layers (more apparent in larger arteries Intima Media Adventitia Layers separate by Internal elastic lamina –separates intima from media External elastic lamina- separates media from adventitia The Main forms of Vascular Disease Congenital anomalies 1. Clog the pipe Hypertension 2. Weaken the pipe This is basically this Arteriosclerosis 3. Born with bad pipes Atherosclerosis (type of above) Aneurysms and Dissections Vasculitis Tumors The Main forms of Vascular Disease Congenital anomalies 1. Clog the pipe Hypertension 2. Weaken the pipe Arteriosclerosis 3. Born with bad pipes Atherosclerosis (type of above) Aneurysms and Dissections Vasculitis Tumors The Main forms of Vascular Disease Congenital anomalies 1. Clog the pipe Hypertension 2. Weaken the pipe Arteriosclerosis 3. Born with bad pipes Atherosclerosis (type of above) Aneurysms and Dissections Vasculitis Tumors The Main forms of Vascular Disease Congenital anomalies 1. Clog the pipe Hypertension 2. Weaken the pipe Arteriosclerosis 3. Born with bad pipes Atherosclerosis (type of above) Aneurysms and Dissections Vasculitis Tumors The Main forms of Vascular Disease Congenital anomalies 1. Clog the pipe Hypertension 2. Weaken the pipe Arteriosclerosis 3. Born with bad pipes Atherosclerosis (type of above) Aneurysms and Dissections Vasculitis Tumors Congenital Anomalies of Vasculature (IO:11) Berry aneurysms – small dilations in cerebral vessels (often in circle of Willis) Fatal if ruptured Arteriovenous fistulas – abnormal connections between arteries and veins that bypass capillaries May be benign, may cause abnormal shunting of blood into venous system Done intentionally for dialysis Fibromuscular dysplasia – irregular thickening of walls of medium to large sized arteries as a result of medial and intimal hyperplasia – results in luminal stenosis (clogged pipe) Seen in young women Arteriosclerosis Arteriosclerosis – a generic term that means “hardening of the arteries”:arterial wall thickening & loss of elasticity 3 patterns Arteriosclerosis – affects small arteries and arterioles; vessel wall thickening; Mönckeberg medial calcific sclerosis – calcium Fibromuscular Intimal Hyperplasia: SMC and ECM deposits in muscle walls; people older than 50; Hyaline lesion driven by inflammation usually no stenosis and not clinically significant Hyperplastic Arteriosclerosis Arteriosclerosis – a generic term that means “hardening of the arteries”:arterial wall thickening & loss of elasticity 3 patterns Arteriosclerosis – affects small arteries and arterioles; vessel wall thickening; Mönckeberg medial calcific sclerosis – calcium Fibromuscular Intimal Hyperplasia: SMC and ECM deposits in muscle walls; people older than 50; Hyaline lesion driven by inlammation usually no stenosis and not clinically significant Hyperplastic Atherosclerosis (IO:12) Characterized by atheromas which impinge on lumen and can rupture to cause sudden occlusion Composed of friable lipid cores (cholesterol with necrotic debris) covered with a fibrous cap Atherosclerosis (IO:12) Generalized All arteries Localized Cerebral Coronary Aortic Atherosclerosis (IO:12) Generalized All arteries Localized Cerebral – stroke Coronary – MI Aortic – Aneurysm rupture  Atherosclerosis → aneurysm (IO:12) Soft lipid core covered by firm fibrous cap Protrudes into lumen, obstructing flow (stenosis) Weakens underlying media (arterial wall) Plaque ruptures in vessel, thrombus forms Vessel wall expands – aneurysm and rupture  Atherosclerosis → aneurysm (IO:12) Soft lipid core covered by firm fibrous cap Protrudes into lumen, obstructing flow (stenosis) Weakens underlying media (arterial wall) Kidney Plaque ruptures in vessel, thrombus forms Vessel wall expands – aneurysm and rupture  Atherosclerosis → aneurysm (IO:12) Soft lipid core covered by firm fibrous cap Kidney Protrudes into lumen, obstructing flow (stenosis) Weakens underlying media (arterial wall) Kidney Plaque ruptures in vessel, thrombus forms Vessel wall expands – aneurysm and rupture  Atherosclerosis → aneurysm (IO:12) Soft lipid core covered by firm fibrous cap Kidney Protrudes into lumen, obstructing flow (stenosis) Weakens underlying media (arterial wall) Kidney Plaque ruptures in vessel, thrombus forms Vessel wall expands – aneurysm and rupture Holy crap! Types of Aneurysms (IO:13) True, saccular – wall focally bulges True, fusiform – circumferentially bulges False – wall is ruptured, collection of blood bounded by extravascular tissues Dissection – blood has entered wall of vessel and separated layers Tunica intima from media AAA (IO:13) Clinical consequences Obstruction of branch vessel Iliac, renal, mesenteric Compression of adjacent structure Abdominal mass Rupture into peritoneal cavity – usually fatal  AAA (IO:13) Atherosclerotic aneurysms occur most frequently in the abdominal aorta and common illiac Left: Aortic aneurysm that ruptured (arrow) Right: Opened view with probe in rupture tract; wall of aneurysm is thin, lumen filled with thrombus Aortic Dissection (IO:16) Dissection (IO:16) Aortic Sudden onset of excruciating pain Type A more common and more dangerous Most common cause of death is rupture into pericardial, pleural, peritoneal spaces Marfan Syndrome (IO:11) Marfan syndrome An autosomal dominant genetic disorder that affects the skeletal system, cardiovascular system, and eyes Individuals are tall and thin, with long arms and legs, and thin fingers Caused by a loss-of-function mutation in the fibrillin 1 (FBN1) gene Major component of microfibrils in ECM; scaffold for elastin Cardiovascular Effects of Marfan Syndrome (IO:11) Marfan syndrome weakens connective tissue around the base of the aorta Hypertension Hypertension Primary hypertension is idiopathic BP regulation Blood pressure is a function of cardiac output and peripheral vascular resistance Cardiac output is a function of HR and stroke volume Stroke volume is dependent upon 1. Filling pressure – which comes from blood volume 2. Myocardial contractility – alpha and beta adrenergic inputs BP regulation Blood pressure is a function of cardiac output and peripheral vascular resistance Cardiac output is a function of HR and stroke volume Stroke volume is dependent upon 1. Filling pressure – which comes from blood volume 2. Myocardial contractility – alpha and beta adrenergic inputs BP regulation Blood pressure is a function of cardiac output and peripheral vascular resistance Cardiac output is a function of HR and stroke volume Stroke volume is dependent upon 1. Filling pressure – which comes from blood volume 2. Myocardial contractility – alpha and beta adrenergic inputs BP regulation Blood pressure is a function of cardiac output and peripheral vascular resistance Cardiac output is a function of HR and stroke volume Stroke volume is dependent upon 1. Filling pressure – which comes from blood volume 2. Myocardial contractility – alpha and beta adrenergic inputs BP regulation Peripheral resistance is mostly controlled by arterioles Neural and humoral factors Vasoconstrictors Vasodilators Autoregulation comes from self- protective response where vasoconstriction occurs from high blood flow to prevent hyperperfusion pH and hypoxia fine tune arterial tone to adjust perfusion of tissues BP regulation Peripheral resistance is mostly controlled by arterioles Neural and humoral factors Vasoconstrictors Vasodilators Autoregulation comes from self protective response where vasoconstriction occurs from high blood flow to prevent hyperperfusion pH and hypoxia fine tune arterial tone to adjust perfusion of tissues BP regulation Peripheral resistance is mostly controlled by arterioles Neural and humoral factors Vasoconstrictors Vasodilators Autoregulation comes from self protective response where vasoconstriction occurs from high blood flow to prevent hyperperfusion pH and hypoxia fine tune arterial tone to adjust perfusion of tissues BP regulation Peripheral resistance is mostly controlled by arterioles Neural and humoral factors Vasoconstrictors Vasodilators Autoregulation comes from self protective response where vasoconstriction occurs from high blood flow to prevent hyperperfusion pH and hypoxia fine tune arterial tone to adjust perfusion of tissues Hypertension (IO:15) Essential hypertension (primary) Elevated blood pressure, consistently above 140/90 mm Hg Major sequelae are > 25% of general population Cardiac hypertrophy 90% to 95% of cases of hypertension are essential hypertension which is idopathic Heart failure Contributing factors are complex genetic inheritance and environmental factors – salt, obesity CVA Without treatment, 50% die from IHD or HF, and another 1/3 Dissection CVA Secondary hypertension Most other cases of hypertension are secondary to renal disease, renovascular disease, or, less often, adrenal glands Malignant hypertension 5% if HTN patients rapid progression if untreated to severe HTN >200/120 Vasculitis and Vascular Tumor I0:17 Vasculitis 4 main types discussed here Giant-cell Polyarteritis (Temporal) nodosa arteritis Thrombangiitis Kawasaki obliterans disease (Buerger disease) Giant Cell (temporal) arteritis Most common vasculitis Over 50-60 years of age Pain and tenderness One-sided HA Involves temporal artery Can involve ophthalmic artery and lead to blindness  Giant Cell (temporal) arteritis Granulomatous inflammation with giant cells, lymphocytes, intimal fibrosis Possibly T-cell mediated autoimmune response to vessel wall antigen a) giant cells near fragmented internal elastic membrane Formed by fusion of epithelial cells and macrophages b) focal destruction of internal elastic membrane Polyarteritis Nodosa Fibrinoid necrosis of arterial wall Kawasaki disease Kawasaki Disease Kawasaki Disease Diagnosis: fever for 5 days + four of the following without other explanation 1. Bilateral conjunctivitis 2. Oral mucous membrane changes 3. Peripheral extremity changes Erythema of palms/soles, desquamation 4. Polymorphous rash 5. Cerivical LAD at least 1 greater than 1.5 cm Kawasaki Disease Cause unknown Potential autoimmune component Appx 20% correlation with upper respiratory illness Now seen in SARS Covid 2 with “Kawasaki Like” illness Multisystem inflammatory syndrome Thrombangitis Obliterans (Buerger Disease) Affects medium-sized and small arteries, mainly of the extremities (especially tibial and radial arteries) Acute and chronic inflammation of the vessel wall, with luminal thrombosis Almost exclusively in heavy smokers, usually before 35 Cessation can be curative Thrombus typically contains microabscesses (arrow) Buerger Disease Superficial nodular phlebitis Cold sensitivity in the hands Pain in instep of foot Severe pain, even at rest Chronic ulceration of toes, feet, or fingers, which may be followed by gangrene Raynaud Phenomenon Exaggerated vasoconstriction of digital arteries and arterioles Pallor or cyanosis of fingers and toes Prevalence of 3% to 5%, often in young women Primary – usually benign Secondary – caused by other autoimmune disease; maybe first manifestation of those conditions  Vascular Tumors Can originate from blood vessels or lymphatics Can be composed of endothelial cells Hemangioma – Lymphangioma – Angiosarcoma – benign benign malignant Can be composed of vascular support cells Hemangiopericytoma - Glomus tumor – benign malignant  Vascular Tumors Can originate from blood vessels or lymphatics Can be composed of endothelial cells Hemangioma – Lymphangioma – Angiosarcoma – benign benign malignant Can be composed of vascular support cells Hemangiopericytoma - Glomus tumor – benign malignant Hemangioma Increased numbers of normal or abnormal vessels Especially head and neck, but also liver Common in infancy (7% of all benign tumors), rarely ever become malignant Capillary hemangioma – closely packed thin-walled capillaries Cavernous hemangioma – composed of large vascular spaces Kaposi Sarcoma Most frequently associated with AIDs Forms of KS, similar viral pathogenesis Classic (European) Endemic (African) Transplant-associated (immunosuppression) Angiosarcoma Familial Hypercholesterolemia IO:14 Familial Hypercholesterolemia Lipoproteins Particles with protein and phospholipid coats that transport cholesterol and other lipids in blood Low density lipoproteins (LDLs), 45% cholesterol High density lipoproteins (HDLs), 20% cholesterol Familial Hypercholesterolemia Disease Etiology and Incidence FH occurs among all races FH accounts for somewhat less than 5% of patients with hypercholesterolemia Familial hypercholesterolemia (FH) is a disorder of cholesterol and lipid metabolism caused by mutations in the low-density lipoprotein receptor (LDLR) gene Familial Hypercholesterolemia Pathogenesis LDL receptor is expressed in the liver and adrenal cortex Hepatic LDL receptors clear half of intermediate-density lipoproteins and up to 80% of LDL from circulation by endocytosis Mutations occur through combination of large insertions, deletions and recombination involving Alu repeats Mutations in the LDLR gene disrupt production of LDL receptor and cause accumulation of plasma LDL Familial Hypercholesterolemia Phenotype and Natural History In heterozygotes, hypercholesterolemia usually manifests at birth and is the only finding in the first decade of life In heterozygotes of all ages, the plasma cholesterol concentration is twice as high in unaffected individuals In heterozygotes, arcus corneae and tendon xanthomas begin to appear by the end of the second decade Familial Hypercholesterolemia Familial Hypercholesterolemia Phenotype and Natural History (cont.) The development of coronary artery disease among heterozygotes depends on gender and age (e.g., at age 50, 50% of males have CAD and only 20% of females) Homozygous FH presents in the first decade of life with arcus corneae and tendon xanthomas. Plasma cholesterol concentration is twice that of heterozygotes and without aggressive treatment homozygotes will usually die by age 30. Familial Hypercholesterolemia Management Aggressive normalization of LDL cholesterol concentration is required to reduce the risk of CAD Rigorous adherence to a low-fat, high-carbohydrate diet usually produces only a 10-20% reduction in LDL cholesterol, which is usually insufficient Therefore, heterozygous patients receive bile acid sequestrants They block bile acid in your stomach from being absorbed in your blood Also they will be given statin drugs that inhibit hepatic cholesterol synthesis Also LDL apheresis Where LDL is filtered from the blood using a machine Familial Hypercholesterolemia Inheritance Risk Because FH is an autosomal dominant disorder, each child of an affected heterozygous parent has a 50% chance of inheriting the mutant LDLR allele Thank you! Nussbaum, R. L., McInnes, R. R., Williard, H. F., Thompson, J. S., & Thompson, M. W. (2007). Genetics in medicine. Estados Unidos: Saunders. Robbins, S. L., Aster, J. C., Perkins, J. A., Abbas, A. K., & Kumar, V. (2018). Robbins basic pathology. Philadelphia: Elsevier. Smarter decisions. better care. (2020, December 09). Retrieved February 03, 2021, from https://www.uptodate.com/home 2021, J. (n.d.). Drugs & diseases. Retrieved February 03, 2021, from https://reference.medscape.com/