Septic Shock and Vascular Biology Quiz

Pathogen 4.1 Vessels - Study Notes

• Objectives include illustrating fluid distribution between intravascular and extravascular spaces in normal circulation.
• Objectives also cover distinguishing oncotic and hydrostatic causes of edema, analyzing the role of renal pathology in fluid balance and hemorrhage, and illustrating normal hemostasis.
• Objectives further include analyzing hypercoagulability, illustrating infarction and shock, differentiating major types of vascular disease, and analyzing hypertension causes and types, and discussing vasculitis and vascular tumors.

Fluid Balance

• Fluid balance involves two opposing forces: hydrostatic pressure and oncotic pressure.
• Hydrostatic pressure typically "wins," but only slightly.
• Lymphatics remove excess fluid.

Causes of Edema

• Edema results from issues with venous return, oncotic pressure, lymphatic obstruction, or sodium retention.
• Causes include issues with venous return, congestive heart failure, constrictive pericarditis, ascites, venous obstruction, thrombosis, and external pressure.
• Oncotic pressure causes include protein-losing glomerulopathies, liver cirrhosis, malnutrition, protein-losing gastroenteropathy, lymphatic obstruction, inflammatory diseases, and neoplasms.
• Sodium retention causes include too much salt and/or kidney function issues, increased Na+ uptake, renal hypoperfusion, and increased renin-angiotensin-aldosterone secretion.

Terms

• Edema is fluid accumulation in tissues.
• Hyperemia is excessive arterial blood flow.
• Congestion is excess venous blood in tissues.
• Hemostasis is blood clotting.
• Thrombosis is a blood clot.
• Embolism is a dislodged clot.
• Infarction is tissue death due to ischemia (lack of blood supply).
• Effusion is extravascular fluid collected in body tissues.

Renin, Angiotensin, Aldosterone

• Renin, released by hypoperfused kidneys, activates angiotensinogen to angiotensin I.
• Angiotensin I is converted to angiotensin II in the lungs.
• Angiotensin II increases blood pressure by constricting blood vessels and releasing aldosterone.
• Aldosterone promotes sodium retention, which in turn increases water retention, and further elevates blood pressure, which, in turn, relieves the renin trigger.

BP regulation

• Blood pressure regulation involves the kidneys, adrenals, and heart.
• Kidneys regulate salt, renin-angiotensin-aldosterone (RAAS).
• Myocardium releases natriuretic peptides to inhibit sodium reabsorption when volume expansion is sensed.
• The system works to control blood volume, blood pressure, and maintains a balance.

One Thing Leads to Another (Heart/Kidney Failure)

• Heart failure can lead to decreased kidney blood flow resulting in renal failure.
• This can lead to increased fluid in the heart.
• Albumin issues can further impact oncotic force.

Hemorrhage Terms

• Hemorrhage is blood leakage.
• Hematoma is a blood mass.
• Petechiae/Purpura are small hemorrhages into the skin, mucous membranes.
• Ecchymoses are bruises under the skin.
• RBC degradation creates hemosiderin.

Clinical Tie-ins for Hemorrhage

• Massive hemorrhage causes exsanguination and potentially death.
• Hematoma can compress tissues.
• Intracerebral hemorrhage leads to stroke and potentially death.
• Chronic hemorrhage causes iron deficiency anemia.

Hemostasis Review

• Hemostasis is the process of stopping bleeding.
• Steps include arteriolar vasoconstriction, platelet plug formation, and fibrin clot formation.
• Then, clot stabilization and resorption follow.

Clinical Point (Clotting Testing)

• D-dimer is a measurable fibrin breakdown product.
• Elevated D-dimer indicates ongoing clotting activity.

Clotting Pathway

• PT/INR assesses the extrinsic pathway.
• PTT assesses the intrinsic pathway.
• Feedback loops amplify the clotting cascade.

Clotting Inhibition - Heparin-Like Molecules

• Heparin-like molecules activate antithrombin, disrupting thrombin activity during coagulation.
• Endothelial cells release anticoagulants in their passive state.
• After injury, endothelial cells become procoagulant for a time to balance coagulation.

Clotting Inhibition - Thrombomodulin and endothelial protein C receptor

• Thrombomodulin and endothelial protein C receptor disrupt the clotting pathway by binding factors.
• This prevents thrombin activation from causing clots.

Clotting Inhibition - t-PA and Other endothelial products

• t-PA and other products like prostacyclin, nitric oxide, and adenosine diphosphatase inhibit clotting.

Medicinal Clotting Inhibition

• Warfarin inhibits vitamin K-dependent clotting factors.
• Heparin activates antithrombin.
• Xa inhibitors and low molecular weight heparins act directly on clotting factors.

Clinical Point (Bridge to Warfarin)

• Initial heparin use helps resolve clotting issues before warfarin reduces synthesis of Protein C and S.

Clinical Points (Factor V Leiden/Other Pathology)

• Genetic mutations (Factor V Leiden, Protein C/S deficiency, Antithrombin III deficiency, Von Willebrand disease) can affect hemostasis.
• Use anticoagulants (heparin, NOAC, DOAC) to manage blood clots.
• Use antiplatelets (ASA, P2Y12 inhibitors) to manage platelets.
• Use thrombolytic therapy (tPA) to dissolve clots

Virchow's Triad

• Endothelial injury, abnormal blood flow, and hypercoagulability are the major factors that trigger clotting.

Hypercoagulability

• Various conditions can increase clotting risk, including Factor V Leiden mutation, Anti-thrombin III deficiency, Protein C/S deficiency, immobility, cancer, surgery, tissue injury, prosthetic valves, antiphospholipid antibody syndrome, smoking, atrial fibrillation, pregnancy, and oral contraceptives (especially in smokers).

Thrombi and Emboli

• Thrombi (blood clots) can form in arteries or veins, growing towards the heart.
• Emboli are dislodged thrombi that travel through the bloodstream to other parts of the body.

Embolism

• Pulmonary emboli are common, arising from deep vein thrombosis in legs, potentially causing various fatal complications.
• Systemic emboli can arise from the heart, targeting lower extremities, brain, and other areas causing tissue infarction.
• Other embolism types include fat emboli (from bone fractures) and amniotic fluid emboli (from complications during pregnancy).

Fate of the Thrombus

• Thrombi can grow (propagate), travel (embolize), or dissolve.
• Other steps can result in dissolution, organization, and recanalization.

Infarct

• An infarct is a region of ischemic necrosis (tissue death) due to blood vessel blockage.
• Infarct risk factors include vascular supply anatomy, occlusion rate, and tissue vulnerability to hypoxia.
• White infarcts result from arterial occlusion (aneomic).
• Red infarcts result from venous occlusion (hemorrhagic).

Factor V Leiden

• Factor V Leiden is an inherited condition that increases risk of blood clotting.
• It has varying degrees of dominance.

Two Clinically Important Conditions

• Heparin-induced thrombocytopenia (HIT) occurs when patients develop antibodies against heparin-platelet complexes, leading to severe thrombocytopenia (low platelet count) and potentially a prothrombotic state.
• Disseminated intravascular coagulation (DIC) features widespread clotting in the microcirculation of the body, often as a complication of widespread infections, injuries, or malignancies. This results in thrombosis in various parts of the body, but also results in a deficiency of clotting factors, leading to profuse bleeding.

Shock

• Shock is inadequate blood flow to tissues.
• Types include cardiogenic, hypovolemic, and septic, each with particular underlying causes.
• The initial stages in shock are often reversible with treatment.
• Subsequent cellular injury in severe shock usually leads to an irreversible state.

Septic Shock and Hypotension

• Endothelial activation, cytokine release, and vessel leakiness cause reduced blood flow to tissues.
• These issues also result in hypercoagulation.
• Metabolic derangements develop that include elevated blood sugars and lactic acidosis.
• This can compromise organ function and lead to death.

Stages of Shock

• Shock has different stages—a nonprogressive stage with compensatory mechanisms, a progressive one with hypoperfusion and metabolic imbalances, and an irreversible phase with damage leading to organ failure, sometimes fatal.

Clinical Manifestations of Shock

• Specific manifestations depend on the underlying cause of the shock.
• Manifestations may include hypotension, rapid weak pulse, tachypnea, cold and/or clammy skin, etc.

Normal Blood Vessels

• Arteries have thicker walls with more smooth muscle cells compared to veins.
• Veins have valves to prevent backflow, and are generally compressible.

Structural Aspects of Vessels

• Blood vessels are organized in layers: intima, media, and adventitia.
• Layers are separated by elastic laminae.

The Main Forms of Vascular Disease

• Vascular diseases can involve clogging (e.g., atherosclerosis), weakening (e.g., aneurysms), or having anatomical issues (congenital, genetic).

Congenital Anomalies of Vasculature

• Congenital issues affecting vascular structures include berry aneurysms, arteriovenous fistulas, and fibromuscular dysplasia.

Arteriosclerosis

• This generic term ("hardening of the arteries") refers to arterial wall thickening and loss of elasticity.
• This can occur in various ways - including hyaline, or hyperplastic; calcium buildup in media (Monckeberg medial sclerosis.
• An additional process is Fibromuscular intimal hyperplasia.

Atherosclerosis

• Characterized by atheromas, composed of friable lipid cores (cholesterol with necrosis) covered by a fibrous cap.
• Can impact many major vascular areas (generalized or located).
• This disease can impact arteries and arterioles.

Atherosclerosis → Aneurysm

• Atherosclerosis can lead to aneurysms due to progressive weakening of the arterial wall.

Types of Aneurysms

• True aneurysms (saccular or fusiform) involve wall bulging.
• False aneurysms (pseudoaneurysms) involve a tear in the vessel wall resulting in blood accumulation outside the vessel.
• Dissection involves blood penetrating into aortic layers.

AAA (Abdominal Aortic Aneurysm) – Clinical Consequences

• Obstructed blood supply is a major factor.
• The loss of supply can lead to tissue damage.
• Compression and rupture are common and fatal complications.

Aortic Dissection

• Blood tears the layers of the aortic media, resulting in a blood-filled channel.
• Rupture into body cavities can cause fatal hemorrhaging and tamponade, especially impacting the pericardium.

Marfan Syndrome

• A genetic disorder characterized by connective tissue abnormalities, primarily affecting the skeletal, cardiovascular, and ocular systems.
• Fibrillin 1 gene mutations are the cause.

Cardiovascular Effects of Marfan Syndrome

• Connective tissue weakness around the aortic root leads to potential problems like aortic aneurysmal dilation and subsequent rupture.

Hypertension

• Primary hypertension has unclear etiology.
• Secondary hypertension commonly has underlying issues with renal or adrenal disease.
• Hypertension, if untreated, can lead to multiple cardiac, vascular, and cerebrovascular sequelae.

Vasculitis and Vascular Tumor

• These diseases encompass a range of inflammation affecting blood vessels (Vasculitis) and benign/malignant tumors derived from the vascular system (vascular tumors).

Vasculitis

• Giant cell (temporal) arteritis, Polyarteritis Nodosa, Kawasaki disease, and Thrombangitis Obliterans (Buerger disease) are all types of vasculitis.

Giant Cell Arteritis

• This type of vasculitis impacts the temporal artery commonly affecting people over 50 years old.

Polyarteritis Nodosa

• This involves necrotizing inflammation of medium-sized arteries, commonly found in young adults and often associated with hepatitis B.

Kawasaki Disease

• Characterized by fever and inflammation, often related to upper respiratory issues, impacting primarily infants and young children. Also the most common cause of acquired heart disease in children under 4 years old.

Thrombangitis Obliterans (Buerger Disease)

• Almost entirely linked to heavy smoking and affects younger individuals, causing inflammation and thromboses in vessels of the extremities.

Raynaud Phenomenon

• Characterized by exaggerated digital artery vasoconstriction, often benign, leading to pallor or even cyanosis in the extremities, primary affects women.

Vascular Tumors

• Types of vascular tumors include benign (hemangioma, lymphangioma, glomus tumors) and malignant (Angiosarcoma, Hemangiopericytoma).

Hemangioma

• Benign vascular tumors characterized by varying amounts of normal or abnormal vessels.
• Commonly encountered in young children (up to 7% of all benign tumors).

Kaposi Sarcoma

• Associated with immunosuppression conditions such as HIV/AIDS.

Angiosarcoma

• A malignant tumor derived from endothelial cells typically affecting the skin, tissues, and organs.

Familial Hypercholesterolemia

• Inherited disorder from low-density lipoprotein receptor (LDLR) disruptions.
• Results in significantly elevated LDL cholesterol.
• Leads to various problems including xanthomas and early onset cardiovascular issues.

Familial Hypercholesterolemia: Disease Etiology and Incidence

• FH is a disorder of cholesterol and lipid metabolism.
• FH affects all races but presents differently.

Familial Hypercholesterolemia: Pathogenesis

• LDL receptor function is disrupted (due to mutations), resulting in LDL accumulation.

Familial Hypercholesterolemia: Phenotype and Natural History

• Heterozygotes exhibit elevated cholesterol from birth.
• Arcus corneae and tendon xanthomas may appear in heterozygotes' second decade.
• Homozygotes may have high cholesterol from birth, and early onset cardiovascular disease (usually by age 30), with a risk of death.

Familial Hypercholesterolemia: Management

• Treatment includes diet (low-fat, high-carbs), bile acid sequestrants, statins to inhibit cholesterol synthesis, and LDL apheresis (filtering LDL from blood).

Familial Hypercholesterolemia: Inheritance Risk

• Autosomal dominant disorder, so each child of an affected heterozygous parent has a 50% risk of inheriting the mutation.