Edema: Causes, Risks, and Mechanisms

Hemodynamic Disorders, Thromboembolic Disease, and Shock

• Cell and tissue health relies on circulation, which delivers oxygen and nutrients and removes metabolic waste.
• Plasma proteins are retained within the vasculature as blood passes through capillaries, resulting in minimal net movement of water and electrolytes into tissues.
• Pathologic conditions can disrupt this balance by altering endothelial function, increasing vascular hydrostatic pressure, or decreasing plasma protein content, leading to edema.
• Edema is swelling caused by fluid accumulation in tissues resulting from net water movement into extravascular spaces.
• Edema ranges from minimal to profound effects.
• Lung edema can fill alveoli, causing life-threatening hypoxia.
• Trauma frequently compromises blood vessel structural integrity.
• Hemostasis is blood clotting preventing excessive bleeding after blood vessel damage.
• Compromised hemostasis leads to hemorrhage.
• Hemorrhage may cause hypotension, shock and death if blood loss is massive and rapid.
• Thrombosis (inappropriate clotting) or embolism (clot migration) obstruct blood vessels.
• Obstruction of blood vessels can cause ischemic cell death (infarction).
• Thromboembolism is a major cause of morbidity and death in high income countries.
• Thromboembolism underlies myocardial infarction, pulmonary embolism (PE), and cerebrovascular accident (stroke).
• Focus is on hemodynamics disorders (edema, effusions, congestion, and shock), abnormal bleeding and clotting disorders (thrombosis) and forms of embolism.

Edema and Effusions

• Diseases affecting cardiovascular, renal, or hepatic function are marked by fluid accumulation in tissues or body cavities.
• Vascular hydrostatic pressure pushes water/salts out of capillaries into the interstitial space.
• Plasma colloid osmotic pressure pulls water/salts back into vessels.
• Normally, hydrostatic and osmotic pressures are balanced, resulting in small net fluid movement.
• Fluid drains into lymphatic vessels, returning to the bloodstream through the thoracic duct and keeping tissues dry.
• Elevated hydrostatic pressure or colloid osmotic pressure disrupts balance and leads to fluid movement out of vessels.
• Excess fluid movement overwhelms lymphatic drainage.
• Edema forms within tissues.
• Effusion involves serosal surfaces, fluid accumulates within the adjacent body cavity.
• Edema fluids and effusions will either be inflammatory or non-inflammatory.

Increased Hydrostatic Pressure

• Primarily results from impaired venous return.
• If impairment is localized then edema is confined to the affected part.
• Systemic increases in venous pressure are associated with more widespread edema.

Reduced Plasma Osmotic Pressure

• Albumin accounts for nearly half of total plasma protein.
• Conditions leading to inadequate synthesis or increased albumin loss from the circulation are causes of reduced plasma oncotic pressure.
• Reduced albumin synthesis occurs primarily in severe liver diseases (e.g., end-stage cirrhosis) and protein malnutrition.
• Albumin loss occurs in nephrotic syndrome with albumin leaking into the urine through glomerular capillaries.
• Reduced plasma osmotic pressure leads to edema, reduced intravascular volume, renal hypoperfusion, 2nd hyperaldosteronism in stepwise fashion.
• Salt and water retention from the kidneys, fails to correct plasma volume deficit, exacerbating edema due to low plasma protein level.

Sodium and Water Retention

• Increased salt retention with obligate retention of associated water causes elevated hydrostatic pressure from intravascular fluid volume expansion.
• Salt retention also causes diminished vascular colloid osmotic pressure due to dilution.
• Salt retention from renal dysfunction or cardiovascular disorders decreasing renal perfusion.
• Congestive heart failure and hypoproteinemia result in renin-angiotensin-aldosterone axis activation.
• Sodium and water retention and increased vascular tone and antidiuretic hormone improve cardiac output and restore normal renal perfusion.
• Worsening heart failure and diminished cardiac output cause retained fluid to increase hydrostatic pressure, leading to edema and effusions.

Lymphatic Obstruction

• Trauma, fibrosis, invasive tumors, and infectious agents disrupt lymphatic vessels and impair interstitial fluid clearance, resulting in lymphedema in the affected body part.
• Parasitic filariasis induces obstructive fibrosis.

Morphology

• Edema is grossly apparent and microscopically seen as the extracellular matrix separates and cells swell.
• Most commonly, edema is seen in skin, lungs, and brain tissues.
• Subcutaneous edema can be diffuse or more conspicuous in high hydrostatic pressure regions.
• Dependent edema distribution is influenced by gravity.
• Pitting edema is a depression left after finger pressure displaces interstitial fluid.
• Periorbital edema is an early sign from renal dysfunction with loose connective tissue surrounding the eyelids.
• Pulmonary edema presents with heavy lungs (two to three times normal.)
• Sectioning yields frothy blood-tinged fluid (air, edema, and extravasated red cells mixture).
• Brain edema is either localized or generalized with swollen brain exhibiting narrowed sulci and distended gyri.
• Hydrothorax is pleural cavity effusions; hydropericardium is the pericardial cavity; hydroperitoneum (ascites) is the peritoneal cavity.
• Transudative effusions are typically protein-poor, translucent, and straw-colored.
• Chylous effusion (lymphatic blockage.) is a milky peritoneal effusion with lipids absorbed from the gut.
• Exudative effusions are protein-rich and cloudy (white cells present.)

Clinical Features

• Edema ranges from annoying to rapidly fatal.
• Subcutaneous edema signals underlying cardiac or renal disease; significant edema impairs wound healing and infection clearance.
• Pulmonary edema commonly results from left ventricular failure, but also renal failure, acute respiratory distress syndrome, and pulmonary inflammation or infections.
• Edema in the pulmonary interstitium and alveolar spaces impedes gas exchange (hypoxemia) and creates an environment for bacterial infection.
• Gas exchange is further compromised from pleural effusions compressing pulmonary parenchyma complicating pulmonary edema
• Ascites is primarily from portal hypertension and is prone to bacterial seeding, leading to serious, sometimes fatal infections.
• Brain edema is life threatening with the brain substance extruding through the foramen magnum and the brain stem vascular supply compressing.
• Severe edema injures medullary centers and causes death.

Hyperemia and Congestion

• Both hyperemia and congestion stem from increased blood volumes within tissues, but differ in mechanisms and consequences.
• Arteriolar dilation leads to increased blood flow in hyperemia (active process), e.g., at sites of inflammation or muscles during exercise.
• Affected tissues turn red (erythema) because of increased oxygenated blood delivery.
• Resulting from reduced venous outflow from a tissue, congestion is a passive process.
• Systemic congestion can occur during cardiac failure, or localized during isolated venous obstruction.
• Congested tissues have an abnormal blue-red color cyanosis (deoxygenated hemoglobin accumulation.)
• Long-standing chronic passive congestion with chronic hypoxia may result in ischemic tissue injury/scarring.
• Capillary rupture can also produce small hemorrhagic foci in chronically congested tissues; subsequent red cell catabolism leaves hemosiderin-laden macrophages.
• Congestion commonly leads to edema from increased hydrostatic pressures.

Morphology

• Congested tissues take on a dusky reddish-blue color (cyanosis) due to red cell stasis and deoxygenated hemoglobin.
• Acute pulmonary congestion exhibits engorged alveolar capillaries, alveolar septal edema, and focal intra-alveolar hemorrhage.
• Chronic pulmonary congestion is often caused by congestive heart failure; the septa are thickened and fibrotic, and alveoli are filled with hemosiderin-laden macrophages.
• Acute hepatic congestion exhibits distended central vein and sinusoids.
• Centrilobular hepatocytes undergo ischemic necrosis, and periportal hepatocytes develop fatty change in chronically congested livers.
• Chronic passive hepatic congestion presents with grossly red-brown and slightly depressed centrilobular regions punctuated against surrounding uncongested zones.
• There is centrilobular congestion and hemorrhage, hemosiderin-laden macrophages, and hepatocytes displaying variable degrees of dropout and necrosis.

Hemostasis, Hemorrhagic Disorders, and Thrombosis

• Hemostasis is the blood clots forming at vascular injury sites.
• Deranged hemostasis is grouped into hemorrhagic disorders and thrombotic disorders.
• Excessive bleeding, due to blunted or insufficient hemostatic mechanisms characterizes hemorrhagic disorders.
• Blood clots (thrombi) form within intact blood vessels or heart chambers in thrombotic disorders.
• The division between bleeding and thrombotic disorders sometimes breaks down; generalized clotting activation sometimes produces bleeding due to coagulation factors being consumed.
• Normal hemostasis begins with contribution of platelets, coagulation factors, and endothelium.

Normal Hemostasis

• Hemostasis is orchestrated process of platelets, clotting factors, and endothelium that happens at a vascular injury site and halts bleeding.
• Arteriolar vasoconstriction is immediate which reduces blood flow to the injured area.
• Reflex neurogenic mechanisms mediate arteriolar vasoconstriction and enhance local secretion of factors (e.g., endothelin).
• Endothelin is potent endothelium-derived vasoconstrictor although vasoconstriction effect is transient.
• Disrupted endothelium exposes subendothelial von Willebrand factor (vWF) and collagen, which promote platelet adherence and activation in primary hemostasis.
• Platelets undergo shape change and release of secretory granules.
• Shape changes are from small rounded discs to flat plates with spiky protrusions that markedly increases surface area.
• Secreted products recruit additional platelets that aggregate and form a primary hemostatic plug.
• Secondary hemostasis vascular injury exposes tissue factor at the injury site.
• In the vessel wall subendothelial cells such as smooth muscle cells and fibroblasts normally express bound procoagulant glycoprotein which is tissue factor.
• Tissue factor binds and activates factor VII.
• Activation of factor VII sets in motion a reaction cascade culminating in thrombin generation which cleaves fibrinogen into insoluble fibrin.
• Creates fibrin meshwork which activates platelets leading to additional aggregation at the site of injury. Fibrin meshwork also converts circulating fibrinogen into insoluble fibrin.
• Referred to as secondary hemostasis, this sequence consolidates the platelet plug.
• Polymerized fibrin and platelet aggregates undergo contraction to form solid, preventing further hemorrhage.
• At this stage counterregulatory mechanisms set into motion.
• Endothelial cells are central regulators of hemostasis; antithrombic and prothrombotic activities determine thrombus formation, propagation or dissolution
• Normal endothelial cells inhibit platelet aggregation/coagulation and promote fibrinolysis.
• After injury/activation, endothelium acquires procoagulant activities i.e. activating platelets and clotting factor.
• Microbial pathogens, hemodynamic forces, and pro-inflammatory mediators activate the endothelium.
• Platelets play a role in hemostasis forming a primary plug that initially seals vascular defects and provides a surface for binding which concentrates the activated coagulation factors.
• A critical role is by forming the primary plug that initially seals vascular defects.
• Another critical role is by providing a surface that binds and concentrates the activated coagulation factors.
• Platelets are disc-shaped anucleate fragments that shed from marrow megakaryocytes into bloodstream.
• Several glycoprotein receptors, a contractile cytoskeleton, and two types of cytoplasmic granules regulate its function.
• On their membranes (Chapter 3) adhesion molecule P-selectin reside in alpha granules.

Coagulation Cascade

• Enzymes require activation and a catalyst or accelerating agent.
• Reactions occur on a complex assembled on a phospholipid surface.
• Calcium acts as a cofactor.
• Negatively charged substances (e.g., glass) activate it in lab tests.
• Tissue factor activates it in vivo.
• A cascade of amplifying enzymatic reactions results in this deposition of insoluble fibrin clot.
• The dependency of clot formation factors differs in the test tube and in blood vessels.
• Vitamin K-dependent factors (II, VII, IX, and X) are synthesized.
• Coumadin impairs the synthesis of Vitamin K-dependent factors and is used as an anticoagulant.
• Clinical labs use the the extrinsic and intrinsic pathways to divide this coagulation (see Fig. 4.6A).
• Function of proteins are in assessed using the pathway for the prothrombin time (PT) assay (factors VII, X, V, II [prothrombin], and fibrinogen).
• Clotting of plasma starts when phospholipids, tissue factor, calcium are added to plasma, and measures the time for a fibrin clot to form.
• Aided negatively charged particles and reagents activate the partial thromboplastin time (PTT) assay proteins, a function of the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen).
• The ability to initiate the clotting of plasma allows for a measurement of when a fibrin clot forms.
• The PT and PTT assays are of great utility in evaluating coagulation factor function in patients, they do not recapitulate the events that lead to coagulation in vivo.
• Clinically deficiencies of factor XI are only with mild bleeding, and factor XII do not bleed and in fact may be susceptible to thrombosis
• Factor VIIa/tissue factor complex is the most important in vivo activator of factor IX.
• Factor IXa/factor VIIIa complex is the most important in vivo activator of factor X.
• Thrombin also activates XI as well as factors V and VIII, a feedback mechanism that amplifies the coagulation cascade.
• Its various enzymatic activities control thrombin's diverse aspects of hemostasis and link clotting to inflammation and repair.
• This action is accomplished by, thrombin directly converting soluble fibrinogen into fibrin monomers.
• Activation of multiple enzymatic activities control diverse aspects of hemostasis and link clotting to inflammation and repair.
• Activation of coagulation factor XI is dependent of two critical cofactors
• Activating multiple pathways of coagulation, is only one of the many important activities thrombin fulfills.
• Thrombin will activate platelets through its ability to switch on and directly affect PAR-1.

Factors that Limit Coagulation

• Coagulation must be restricted to vascular injury site to prevent consequences.
• Limiting factor: blood flowing washes out and the liver quickly clears factors.
• Phospholipids from platelet contact with subendothelial matrix is a requirement.
• Counterregulatory mechanisms in intact adjacent endothelium limits vascular injury.
• Fibrinolytic cascade limits clot size and to later dissolve.
• Plasminogen activator (t-PA) synthesis (mainly endothelium), is active when bound to fibrin.
• Activated plasmin tightly regulated by plasma protein a2-plasmin inhibitor.
• Fibrinolytic system illustrates plasminogen activators and inhibitors.

Endothelium

• Balance determines clot formation, propagation, or dissolution.
• Multiple factors inhibit platelet procoagulant activities coagulation and augment fibrinolysis.
• Serves as a barrier by shielding platelets Subendothelial vWF and collagen.
• Releases a number of platelet activation and aggregation inhibitors such as prostacyclin (PGI2) and Nitric Oxide NO and adenosine diphosphatase.
• The major regulator of NO and PGI2 is flow.
• Normal endothelium shields them from tissue and expresses multiple that actively oppose coagulation.
• Multiple factors actively interfere with coagulation, those notably are, thrombomodulin, endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor.
• Thrombomodulin and endothelial protein C receptor binds thrombin+protein C (respectively) in a complex on the endothelial cell surface and thrombin loses ability.
• Normal endothelial cells Synthesize T-PA as components for the fibrinolytic pathway.
• Anticoagulant and procoagulant activities exist.

Hemorrhagic Disorders

• Stem from vessel walls defects platelets or coagulation factors and function to ensure homeostasis.
• Presentation depends on volume, rate, and location of bleed.
• Massive bleeds are associated with the ruptures such as the aorta or the heart; often are fatal.
• Diseases of massive hemorrhage range from aortic dissection and aortic abdominal.
• Subtle defects evident under conditions of hemostatic stress.
• Mild bleeding is inheritable defects in vWF as well as use of aspirin or suffering from uremia.
• Defects in can be either inherited or caused in patients with other underlying conditions.
• Small vessel disruptors presents with small bleeds in skin or Mucosal membranes.
• Defects from small vessels can present in the form of petechiae (minute 1-2mm hemorrhages (Fig. 4.11A), or purpura (slightly larger or 3mm).
• Edema presents in capillary pressure in parts where defects from small vessels disrupt the mucosal linings of a patient.
• Epistaxis is one form of that is linked defects in vessel bleeding.
• Defects often present with bleeds into soft tissues; presenting in muscle or joints
• Generalized also happens in patients due to vessel or fragility
• Significance depends the volume location and or if there are potential effects.

Thrombosis

The primary abnormalities leading to thrombosis are linked to three key components: endothelial injury, stasis or turbulent blood flow, and hypercoagulability of blood.

Endothelial Injury

• Endothelial injury leading to platelet activation almost inevitably underlies thrombus formation in the heart and the arterial circulation, where blood flow impedes clot formation.
• Cardiac and arterial clots are typically rich is a prerequisite in thrombus formation when under high shear stress.
• Severe triggers thrombosis by exposing as well.
• By shifting the paradigm, this change is referred to as activation.
• Arterial can be down listed into various categories.
• Alter endothelia cells affect the anti-activation.

Alteration in Normal Blood Flow

• Flow contributes to where a lot of turbulence happens, cardiac can also be responsible.
• That help is caused when are not working and can disrupt laminar as well.
• Factor causes include endothelial , and platelets.

Hypercoagulability

• To an abnormal high tendency of the blood and typically and important role in vein thrombosis.
• Is particularly prevalent and in table4.2 are listed the in primary and secondary.
• Common is related to and single nucleotide mutation in a factor.

Disseminated Intravascular Coagulation (DIC)

• Thrombosis within the microcirculation with conditions by systemic.

Embolism

• Detaches intravascular various forms of it are of it can of tissue is linked.

Pulmonary Embolism (PE)

• Occurs from to from PE are the same can.
• Can into the of to PE.

Fat Embolism

• Refers to the of with in the skeletal.
• Often occurs in a variety of conditions including with and symptoms often show in symptoms.

Air Embolism

• Can coalesce to ischemic vascular, the when are in.

Amniotic Fluid Embolism

• A amniotic is in in the 2 to the show.

Infarction

• Supply is the of and by important percentage of the cardiovascular.
• Thrombosis and to all occur due to infection.

Morphology

• Tissue according the all the are be for of an.

Key Embolism

• From and by.

Shore

• State circulation for.
• That with and that and for

Hypercoagulation

• It is important to note and as has been stated that.

Summary

• The chapter provides information on a variety of conditions in the body linked to improper blood/fluid dynamics. Emphasis was given thrombosis and how they affect different areas in the body, how they are formed as well as various related conditions.

Explore the causes, risks, and mechanisms of edema, including liver failure, heart failure, and cancer treatment. Learn about microscopic changes, fluid types (transudate vs. exudate), and complications related to increased pressure.