Exam IV: Hemodynamic Disorders and Thromboembolic Diseases I Flashcards
Body Water
60% of lean body weight is water
Two thirds of the body’s water is intracellular
Remainder is in extracellular compartments
About 5% of total body water is in blood plasma
Edema
Movement of water and low molecular weight solutes (salts) between the intravascular and interstitial spaces
Controlled primarily by opposing effect of:
Vascular hydrostatic pressure
Plasma colloid osmotic pressure
Increased interstitial fluid: increased capillary pressure and diminished colloid osmotic pressure
Fluid accumulation: movement of water into tissues (or body cavities) exceeds drainage
Abnormal increase in interstitial fluid within tissues= edema
Fluid Collection in Cavities
Fluid collections in the different body cavities
Hydrothorax
Hydropericardium
Hydroperitoneum (ascites)
Ansarca
Severe and generalized edema with widespread subcutaneous tissue swelling
When the patient is in multi organ system failure, all the systems are starting to shut down and the patient is completely swollen; can sometimes recover from this; very puffy all over like in hands, cheeks, feet. abdomen
Transudate
Edema caused by:
Increased hydrostatic pressure
Reduced plasma protein
Typically a protein-poor fluid
Heart failure, renal failure, hepatic failure, and certain forms of malnutrition
Mechanisms of Edema
Heart Failure:
increased capillary hydrostatic pressure leading to edema
decreased renal blood flow leading to the activation of the renin-angiotensin system + renal failure = retention in Na+ and H2O, which increases blood volume causing edema
Malnutrition, decreased hepatic synthesis, nephrotic syndrome: decreased plasma albumin and plasma osmotic pressure leading to edema
Inflammatory Edema
Protein-rich exudate
Result of increased vascular permeability- increased endothelial gaps
Lymphedema
Impaired lymphatic drainage
Typically localized
Causes: chronic inflammation with fibrosis, invasive malignant tumors, physical disruption, radiation damage
When you have edema, the lymphatics will try to move that fluid from interstitial tissue and move to vascular space
If lymphatics cannot take the fluid and move it = lymphatic edema
Tumors will clog the lymphatic drainage so fluid cannot get where it needs to go
Physical disruption: removing lymph nodes
Radiation: either tumor or something else, the area around it will have fibrosis and chronic inflammation
Lymphokinetics
Highest to lowest pressure
Blood capillaries, interstitial fluid, lymph capillaries, lymph veins, lymph ducts, and large circulation veins (system circulation)
Lymphatic Obstruction
Certain infectious agents, parasitic filariasis
Lymphatic obstruction:
Extensive inguinal lymphatic and lymph node fibrosis
Edema of the external genitalia and lower limbs
Massive = elephantiasis, which is permanent
Microfilarae – parasite in 3rd world country where animal/humans defecate on ground and humans walk on it and parasites get in and get into lymph nodes causing chronic inflammation and fibrosis from the parasitic eggs
Edema of the lower limbs and genitalia = elephantiasis
Surgical Lymphatic Obstruction
Complicate surgical removal and/or irradiation
Breast cancer and associated axillary lymph nodes
Radical mastectomies- used to remove the breast and axillary cavity lymph nodes… problem is when you remove/radiate those nodes, that arm will become enlarged with edema
Better with conservative therapy where they inject radioactive dye and the cancerous lymph nodes will light up and remove just those instead of removing all of them
Lymphatic Obstruction: Morphology of Edema
Morphology
Edema is easily recognized grossly; ECM looks white
Microscopic examination: clearing and separation of the extracellular matrix and subtle cell swelling
Most commonly seen:
Subcutaneous tissues, lungs, and brain
Lymphatic Obstruction: Subcutaneous Edema
Diffuse or more conspicuous in regions with high hydrostatic pressures
Distribution is influenced by gravity: legs when standing, the sacrum when recumbent
See with congestive heart failure – look at legs and notice fluid is much more distributed = collection of fluid in lower extremities
Standing and walking – see in legs and ankles
Laying flat: legs don’t look swollen… but has congestive heart failure… sacrum will have those edematous changes not the legs
Lymphatic Obstruction: Pitting Edema
Finger pressure over substantially edematous subcutaneous tissue
Displaces the interstitial fluid and leaves a depression
When on feet all day, pregnancy, etc.
Lymphatic Obstruction: Renal Dysfunction
Edema secondary to renal dysfunction
Affect all parts of the body
Manifests in tissues with loose connective tissue matrix (eyelids)
Periorbital edema: characteristic finding in severe renal disease
Renal dysfunction: if patient has edema around eyes and not see edema anywhere else (periorbital) = indicates renal disease/failure
Lymphatic Obstruction: Soft Tissue Edema
Important because it signals underlying cardiac or renal disease
Impairs wound healing or the clearance of infection
Most patients with edema are older and have chronic illness, or diabetic (sometimes with wound) = must get rid of edema/extra fluid
Cannot inject needle into edematous tissue because like sponge and can’t do that to a sponge
Lymphatic Obstruction: Pulmonary Edema
Lungs are often two to three times their normal weight
Sectioning yields frothy, blood-tinged fluid from mixture of air, edema, and extravasated red cells
Common clinical problem
Most frequently seen with left ventricular failure
In a patient that is intubated, and starting to see pink frothy stuff coming out of tube, need to check their heart = pulmonary edema
Red cells outside of the vasculature have been mixing with fluid
Lymphatic Obstruction: Brain Edema
Localized or generalized depending on the nature and extent of the pathologic process or injury
Generalized edema:
Brain is grossly swollen with narrowed sulci
Distended gyri show evidence of compression against the unyielding skull
Not much room so edema doesn’t have anywhere to go because thick skull, so the brain stem can herniate through foramen magnum or brain stem vascular supply can be compressed
Either condition can injure the medullary centers= severe injury or death
Hyperemia
Stem from locally increased blood volumes
Hyperemia: active process and arteriolar dilation
Sites of inflammation and skeletal muscle during exercise
Leads to increased blood flow
Affected tissues turn red (erythema)
Engorgement of vessels with oxygenated blood
Congestion
Passive process
Reduced outflow of blood from a tissue
Systemic like cardiac failure
Local: isolated venous obstruction
Dusky reddish-blue color (cyanosis): red cell stasis and accumulation of deoxygenated hemoglobin
Chronic Passive Congestion
Lack of blood flow causes chronic hypoxia and results in ischemic tissue injury and scarring
Capillary rupture: cause small hemorrhagic foci
Subsequent catabolism of extravasated red cells
Leave residual telltale clusters of hemosiderin-laden macrophages
Morphology of Congestion: Acute vs. Chronic
Cut surfaces: discolored due to the presence of high levels of poorly oxygenated blood
Acute pulmonary congestion:
Engorged alveolar capillaries
Alveolar septal edema
Focal intra-alveolar hemorrhage
Chronic pulmonary congestion:
Septa are thickened and fibrotic
Alveoli often contain numerous hemosiderin-laden macrophages
Heart failure cells
Acute vs. Chronic Hepatic Congestion
Acute hepatic congestion:
Central vein and sinusoids are distended
Centrilobular hepatocytes can be frankly ischemic
Chronic passive hepatic congestion:
Centrilobular regions are grossly red-brown
Areas are accentuated against uncongested parenchyma
Nutmeg liver
Centrilobular hemorrhage
Hemosiderin-laden macrophages
Degeneration of hepatocytes
Hemorrhage
Extravasation of blood into the extravascular space
Increased tendency to hemorrhage (usually with insignificant injury)
Occurs in a variety of clinical disorders
Collectively called hemorrhagic diatheses
Vascular fragility from medication (blood thinners) = can causes bruising from hemorrhaging
Patterns of Tissue Hemorrhage
Distinct patterns of tissue hemorrhage
Hemorrhage may be external
Contained within a tissue
Hematoma- in soft tissue
Petechiae
Minute 1- to 2-mm (very tiny pinpoint) hemorrhages into skin/cutaneous, mucous membranes, or serosal surfaces
Most commonly associated:
Locally increased intravascular pressure
Low platelet counts (thrombocytopenia)
Defective platelet function (as in uremia)
Platelet count drop = thrombocytopenia, start to see pinpoint hemorrhages in serosal parts of organs
Purpura
Slightly larger (≥3 mm) hemorrhages compared to petechiae Associated with many of the same disorders that cause petechiae Secondary to trauma, vascular inflammation (vasculitis), or increased vascular fragility (amyloidosis)
Ecchymoses
Larger (>1 to 2 cm) subcutaneous hematomas (bruises)
Red cells in these lesions are degraded and phagocytized by macrophages
Hemoglobin (red-blue color) is enzymatically converted into bilirubin (blue-green color)
Hemosiderin (gold-brown color), accounting for the characteristic color changes in a bruise
Hemorrhage in Body Cavities
Large accumulation of blood in a body cavity Hemothorax Hemopericardium Hemoperitoneum Hemarthrosis (in joints)
Normal Hemostasis
Consequence of tightly regulated processes
Maintain blood in a fluid state in normal vessels
Permit the rapid formation of a hemostatic clot at the site of a vascular injury
Normally occurring process in body because regulates blood in vessels
Thrombosis
Pathologic counterpart of hemostasis that involves blood clot (thrombus) formation
Favored by: Exposure basement membrane and collagen = activates, and platelets release granules causes more activation
Both hemostasis and thrombosis involve three components:
- Vascular wall (particularly the endothelium)
- Platelets
- Coagulation cascade
Steps of Clot Formation
- Vasoconstriction: short time then vasodilation occurs
- Exposed collagen and basement membrane = platelets activated and become adherent/sticky
- Platelets adhere to basement membrane and change conformational shape and squishes down and granular release (ADP and TxA2) to call other platelets to area (recruitment)
- End up with primary hemostatic plug temporarily
- Other things adhere like RBCs and WBCs forming the secondary hemostatic plug, then hardens
- Endothelial cells release factors that lyse the clot and break it up via blocking coagulation cascade
Endothelial Cells
Key players in the regulation of homeostasis
Exhibit antiplatelet, anticoagulant, and fibrinolytic properties
After injury or activation acquire numerous procoagulant activities; injury from endotoxins, bacteria, high BP, etc.
Activated by infectious agents, hemodynamic forces, plasma mediators, and cytokines
Intact, nonactivated endothelial cells inhibit platelet adhesion and blood clotting
Endothelial injury or activation results in a procoagulant phenotype that enhances thrombus formation
Anti-Platelet Effects
Intact endothelium prevents platelets from engaging the highly thrombogenic subendothelial ECM
Nonactivated platelets: do not adhere to endothelial cells
Even if platelets are activated, prostacyclin (PGI2) and nitric oxide produced by the endothelial cells impede platelet adhesion
Endothelial cells also elaborate adenosine diphosphatase to degrade adenosine diphosphate (ADP)
Further inhibits platelet aggregation
Anticoagulant Effects
Mediated by endothelial membrane-associated heparin-like molecules
Thrombomodulin: binds to thrombin and converts it from a procoagulant into an anticoagulant via its ability to activate protein C, which inhibits clotting by inactivating factors Va and VIIIa (5a and 8a)
Tissue factor pathway inhibitor is a cell surface protein that directly inhibits tissue factor-factor VIIa and factor Xa activities aka anticoagulant
**These are all endogenous to our system
Anticoagulant Effects: Heparin-like Molecules
Heparin-like molecules: act indirectly and consist of cofactors that enhance the inactivation of thrombin and several other coagulation factors
Through the use of plasma protein antithrombin III
Fibrinolytic Effects
Endothelial cells synthesize tissue-type plasminogen activator (t-PA)
Protease that cleaves plasminogen to form plasmin
Plasmin cleaves fibrin to degrade thrombi
Endothelial cells caused the clot to develop, but now must break up the clot once job is completed
Platelet Effects
Endothelial injury allows platelets to contact the underlying extracellular matrix
Subsequent adhesion occurs through interactions with von Willebrand factor (vWF), a product of normal endothelial cells and an essential cofactor for platelet binding to matrix elements
Cytokines present because bacterial endotoxins could be present during injury
Procoagulant Effects
Response to cytokines (TNF or IL-1) or bacterial endotoxin
Endothelial cells synthesize tissue factor, a major activator of the extrinsic clotting cascade
Activated endothelial cells augment the catalytic function of activated coagulation factors IXa and Xa
Antifibrinolytic Effects
Endothelial cells secrete inhibitors of plasminogen activator (PAIs)
Limit fibrinolysis and tend to favor thrombosis
von Willebrand Disease
Collagen of basement membrane= exposure to vWF
No “houses” aka vWF, the platelet roof will not be able to bind so bleeding is prolonged… either missing vWF or deficiency = von Willebrand disease
No vWF – no clotting = prolonged bleeding
Bernard Soulier Syndrome
If missing roofs aka glycoprotein 1B (Gp1B), won’t get platelet to adhere to vWF so still issue for clotting = Bernard Soulier syndrome
Glanzmann Thrombasthenia
Have platelets, but no C shaped things aka Gp2b-3a = no connection of platelets = Glanzmann thrombasthenia
Platelets
Disc-shaped, anucleate cell fragments
Shed from megakaryocytes in the bone marrow into the blood stream
Play a critical role in normal hemostasis
Forming the hemostatic plug that initially seals vascular defects
Providing a surface that recruits and concentrates activated coagulation factors
Platelet Functions
Function depends on several glycoprotein receptors Contractile cytoskeleton Two types of cytoplasmic granules 1. α-Granules 2, Dense (or δ) granules
Following vascular injury platelets encounter ECM constituents- collagen and the adhesive glycoprotein vWF
On contact with these proteins, platelets undergo:
Adhesion and shape change, secretion (release reaction), and aggregation
Platelet Adhesion to ECM
Mediated largely via interactions with vWF
Acts as a bridge between platelet surface receptors (glycoprotein Ib) and exposed collagen
vWF-GpIb associations: necessary to overcome the high shear forces of flowing blood
Genetic deficiencies of vWF or its receptor result in bleeding disorders
Von Willebrand Disease- no vWF
Bernard-Soulier syndrome – no glycoprotein 1B (receptor)
Platelet Secretion
Occurs soon after adhesion
Various agonists can bind platelet surface receptors
Initiate an intracellular protein phosphorylation cascade
Leads to degranulation (dependent on conformational change of platelets)
Release of the contents of dense-bodies:
Important
Calcium is required in the coagulation cascade
ADP is a potent activator of platelet aggregation that causes additional ADP release and amplifies aggregation process
Platelet Activation
Appearance of negatively charged phospholipids (particularly phosphatidylserine) on their surfaces
Bind calcium and serve as critical nucleation sites for the assembly of complexes containing the various coagulation factors
Platelet Aggregation
Platelet aggregation follows adhesion and granule release
Vasoconstrictor thromboxane A2: TxA2
Important platelet-derived stimulus
Amplifies platelet aggregation
Formation of the primary hemostatic plug
Initial wave of aggregation is reversible
Platelet Aggregation: Activation of Coagulation Cascade
Concurrent activation of the coagulation cascade:
Generates thrombin
Stabilizes the platelet plug via two mechanisms:
1. Thrombin binds to a protease-activated receptor on the platelet membrane in concert with ADP and TxA2 causes further platelet aggregationand platelet contraction (dependent on the platelet cytoskeleton)
Creates an irreversibly fused mass of platelets
Constitutes the definitive secondary hemostatic plug
2. Thrombin converts fibrinogen to fibrin in the vicinity of the platelet plug to cement the platelets in place
Platelet Aggregation: Fibrinogen
Noncleaved fibrinogen is an important component of platelet aggregation
Platelet activation by ADP:
Triggers a conformational change in the platelet GpIIb-IIIa receptors
Induces binding to fibrinogen
Large protein that forms bridging interactions between platelets that promote platelet aggregation
