Ch. 4 Hemostasis and Thrombosis Flashcards Preview

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Flashcards in Ch. 4 Hemostasis and Thrombosis Deck (73):


severe and generalized edema with widespread subcutaneous tissue swelling



= edema caused by increased hydrostatic pressure
o Heart failure, renal failure, hepatic failure and malnutrition



= inflammatory edema, protein rich, the result of increased vascular permeability


3 causes of increased hydrostatic pressure

• Regional increases can result from a focal impairement in venous return (i.e. DVT), where as generalized increases in venous pressure result in systemic edema (i.e. CHF)
• Impaired venous return: CHF, constrictive pericarditis, Ascites (liver cirrhosis)
• Venous obstruction/compression: Thrombosis, External pressure, lower extremity inactivity
• Arteriolar dilation: Heat, neurohormonal dysregulation


hypoproteinemia and edema

2. Reduced Plasma Oncotic Pressure (Hypoproteinemia):
• Occurs when albumin is not synthesized in adequate amounts or is lost. The reduced intravascular volume leads to decreased renal perfusion. This triggers increased production of renin/ANG/ALDO but the resulting water/salt retention doesn’t correct the plasma volume defecit because it is due to low serum proteins.
• Nephrotic syndrome (protein-losing glomerulopathies) = loss of albumin due to leaky glomeruluar capillaries
• Liver Cirrhosis (ascites) = causes reduced albumin synthesis
• Protein malnutrition = reduced albumin synthesis
• Protein-losing gastroenteropathy


what causes sodium and water retention edema?

• Salt and water retention result in increased hydrostatic pressure (due to intravascular fluid volume expansion) with diminished vascular colloid osmotic pressure (dilution)
• Renal insufficiency: salt retention due to decreased renal perfusion
• Increased tubular reabsorption of Na+: renal hypoperfusion, increased renin-ANG-Aldo secretion (often seen as a result of CHF)


lymphatic obstruction: paraiste asssociated with this?

• Lymphedema = localized lymph accumulation
• Inflammation, neoplastic,
• Ex. Chronic inflammation with fibrosis, invasive tumors, radiation damage, infectious agents
• Parasitic filariasis: causes lymphatic obstruction and edema of external genitalia and lower limbs → elephantiasis.


path of edema of CHF

• Cardiac dysfunction → decreased CO → kidney and sodium retention → increased venous pressure → increased capillary hydrostatic pressure → mvmt of fluid into interstitium → edema → increased left ventricular filling → pulmonary edema


path of pumonary edema

• MI → decreased LV fn → increase in LV EDV → transmission back to LA and pulmonary aa → increased venous pressure → increased capillary hydraulic pressure → mvmt of fluid into interstitium → edema



an active process in which arteriolar dilation leads to increased blood flow and increased volume of blood in capillaries and small vessels
• Affected tissue turns red (erythema)
• Ex. Blushing, exercise, inflammation, red blood vessels seen in eyes


morphology of congestion

• Acute pulmonary congestion: engorged alveolar capillaries with alveolar septal edema
• Chronic pulmonary congestion: septa thickened and fibrotic. Alveoli contain numerous hemosiderin-laden macrophages called “heart failure cells” (generally due to CHF)
• Acute hepatic congestion: central vein and sinusoids are distended; centrilobular hepatocytes are ischemic while periportal hepatocytes (closer to hepatic arterioles) may only develop fatty changes
• Chronic passive hepatic congestion: centrilobular regions are grossly red-brown and depressed due to cell death, and are accentuated against uncongested tan liver (nutmeg liver).
o Microscopically see centrilobular hemorrhage, hemosiderin-laden macrophages and degeneration of hepatocytes.



= minute 1-2 mm hemorrhages into skin
• Often associated with increased intravascular pressure, low platelet counts (thrombocytopenia) or defective platelet function (uremia)



= 3mm hemorrhages that may be associated with causes of petichia
• can also be due to trauma, vasculitis (vacular inflammation), or increased vascular fragility (seen in amyloidosis)



= subcutaneous hematomas (ie. bruises)
• RBCs are degraded and phagocytized by macrophages
• Hgb (red-blue) → bilirubin (blue-green) → hemosiderin (gold-brown )


steps in normal hemostasis

1. arteriolar vasoconstriction: endothelin (endothelium-derived vasoconstrictor)
2. ECM is exposed which facilitates platelet adherence and activation
• Activation of platelets results in shape change from flat, to increased SA
• Aggregation results in formation of hemostatic plug –-> primary hemostasis
3. Tissue factor (i.e. factor III, thromboplastin) exposed → generates thrombin which cleaves fibrinogen into insoluble fibrin → fibrin meshwork → secondary hemostasis
4. Polymerized fibrin forms a solid permanent plug, at this stage counter regulatory mechanisms set to limit the hemostatic plug (i.e. t-PA)


antiplatelet effects?

o PGI2 and NO: produced by endothelial cells, impede platelet adhesion and cause vasodilation
o Adenosine diphosphatase: degrades ADP - inhibits platelet aggregation


anticoagulatnt effects?

o Heparin-like molecule: cofactor that enhances inactivation of thrombin by antithrombin III
o Thrombomodulin: binds to thrombin and converts it from a procoagulant into an anticoagulant via activation via protein C
o Tissue factor pathway inhibitor (TFPI): cell surface protein that inhibits factor VIIa and Xa


fibrinolytic effects?

o Tissue plasminogen activator (t-Pa): protease that cleaves plasminogen to form plasmin, which cleaves fibrin and degrades thrombi


platelet aggregation effects?

o Von Willebrand factor (vWF): exposed upon tissue damage


procoagulant effects?

o TNF and IL-1
o Tissue factor: major activator of extrinsic clotting cascade


antifibrinolytic effects?

o Inhibitor of plasminogen activator (PAIs) secreted by endothelial cells, limit fibrinolysis and favor thrombosis


platelet adhesion due to what? defects?

- When endothelium is exposed, results in vWF
- vWF binds to GpIb (glycoprotein Ib) on platelets, anchoring it to ECM and activating platelets

Defects in Adhesion:
- von Willebrand disease
- Bernarnd- Soulier syndrome (defect in GpIb)

--> results in secretion of granules


alpha granules

• Alpha granules: have P-selectin on membranes
o Fibrinogen: allows for platelet aggregation
o Fibronectin
o Factors V and VIII
o Heparin-binding chemokine
o TGF-beta


delta (dense) granules

o ADP: platelet activator and aggregator
o Ca2+: activates coagulation factors of intrinsic pathway
o Histamine
o Serotonin: vasoconstrictor
o Epinephrine


platelet aggregation mediated by?

• Thoromboxane (TxA2): platelet-derived stimulus that is a vasoconstrictor and amplifies platelet aggregation leading to formation of primary hemostatic plug
• Thrombin: formed via concurrent activation of coagulation cascade which stabilizes the platelet plug
• Platelet contraction occurs and the secondary plug is formed


glanzmann thrombasthenia

inherited deficiency of GpIIb-IIIa results in bleeding disorder


Platelet-Endothelial Cell Interactions:

• PGI2: platelet derived prostaglandin that inhibits platelet aggregation and is a vasodilator
• TxA2: platelet derived prostaglandin that activates platelet aggregation and vasoconstriction
• Aspirin: blocks TXA2 synthesis predominantly
• eNOS: NO derived by endothelial cells is similar to PGI2


coagulation cascade?

• both pathways congerge on Factor X and ultimately results in thrombin production
• thrombin cleaves fibrinogen to fibrin, fibrin forms an insoluble gel
• Factor XIIIa: results in cross-linked fibrin

Extrinsic Pathway:
• Requires the addition of exogenous trigger
• Most physiologically relevant: activated by tissue factor

Intrinsic Pathway:
• Requires exposed Hageman factor (Factor XII)



antagonist of vitamin K (cofactor of coagulation cascade) – used as an anticoagulant



• Prothrombin Time (PT): asses the fn of proteins in extrinsic pathway
o Includes addition of tissue factor and phospholipids to citrated plasma (sodium citrate chelates CA2+ and prevents spontaneous clotting)
o Coagulation initiated via adding exogenous Ca2+

• Partial Thromboplastin Time (PTT): asses fn of proteins in intrinsic pathway
o Clotting is initiated through addition of negative charged particles (i.e. ground glass), which results in activation of Hageman factor


Endogenous anti-coagulants that control clotting:

1. Antithrombins: inhibit activity of thrombin, and are activated by binding to heparin-like molecules on endothelial cells
2. Protein C and S: vitamin K dependent proteins that cleave factors Va and VIIIa
3. TFPI: endothelial protein that inactives tissue factor- factor VIIa complexes


virchow's triad

Virchow’s Triad: three primary abnormalities resulting in thrombus formation
1. Endothelial injury
2. Stasis or turbulent blood flow
3. Hypercoagubility of blood


endothelial injury

• Often seen in heart and arteries where normally high flow rates might occur over ulcerated plaques and atherosclerotic arteries or at sites of vascular injury
• Dysfunction endothelial cells can produce more procoagulant factors (i.e. platelet adhesion molecs, tissue factor, PAIs) and synthesize less anticoagulant effectors (i.e. thrombomodulin, PGI2, t-PA)
• Can be induced by HTN, turbulent blood flow, bacterial endotoxins, radiation injury, homocystinemia, hypercholesterolemia and toxins absorbed in cigarette smoke


turbulence and stasis

turbulence = contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction and by forming countercurrents and local pockets of stasis

•Stasis: contributes to development of venous thrombi

•Stasis and turbulence promote:
o Endothelial activation, enhancing coagulation and leukocyte adhesion
o Disrupts laminar flow and brings platelets into contact with endothelium
o Prevents washout and dilution of clotting factors


laminar flow

normal blood flow is laminar, such that platelets and other blood cellular elements flow centrally in vessel lumen and are thus separated from endothelium by slower moving layer of plasma.


ulcerated atherosclerotic plaques

expose subendothelial ECM and cause turbulence



• Aneurysms: aortic and arterial dilations
o Result in local stasis and are retile sites for thrombosis


acute MIs

• Acute MI’s: result in areas of noncontractile myocardium, sometimes causing aneurysms, stasis and cardiac mural thrombi


rheumatic mitral valve stenosis

• Rheumatic mitral valve stenosis: causes left atrial dilation and Atrial fibrillation → dilated atrium causes stasis and thrombi


polycythemia vera

•Hyperviscosity: (i.e. polycythemia vera) increases resistance to flow → stasis

its a disease of bone marrow causing too much production of RBCs


sickle cell anemia

• Sickle cell anemia: causes vascular occlusions → stasis → thrombosis



3. Hypercoagulability (Thrombophilia):
•Any alteration in coagulation pathways predisposing to thrombosis

Common Primary (genetic) Hypercoagulable States: inherited causes of hypercoagulability must be considered in patients under 50 who present with thrombosis - even when acquired risk factors are present

Secondary = acquired


leiden mutation

1. **Leiden mutation (Factor V mutation)
• mutation results in glutamine to arginine substitution that renders factor V resistant to cleavage by protein C


prothrombin mutation

2. **Prothrombin mutation
a. mutation in prothrombin gene associated with elevated prothrombin levels and increased risk of venous thrombosis

results in hypercoaguable state - i.e. thrombophilia


high risks for secondary thrombosis?

1. Prolonged bed rest
2. MI
3. Atrial fibrillation
4. Tissue injury (surgery, burn, fracture)
5. Cancer
6. Prosthetic cardiac valves
7. Disseminated intravascular coagulation
8. heparin induced thryombocytopenia
9. antiphospholipid Ab syndrome


8. Heparin-induced thrombocytopenia:

heparin is widely used as an injectable anticoagulant

a. HIT syndrome occurs following administration of unfractionated heparin, which may induce appearance of Abs that recognize complexes of heparin and platelet factor 4 on surface of platelets
b. Binding of Abs to platelets results in platelet activation, aggregation and consumption
c. Produces a prothrombotic stateeven in face of heparin administration andn low platelet counts


9. Antiphospholipid Ab syndrome:

a. See recurrent thrombosis, repeated miscarriages, cardiac valve vegetations and thrombocytopenia (low number of platelets)
b. Fetal loss caused by antibody-mediated inhibition of t-PA necessary for trophoblastic invasion of uterus
c. Thought that its mediated through binding of Abs to epitopes on plasma proteins like prothrombin that are unveiled by phospholipids.
d. In vivo, these auto-Abs induce hypercoagulable state by causing endothelial injury, by activating platelets and C’ directly
e. Secondary syndrome: people with AI disease concurrently
f. Primary syndrome: patients exhibit only the manifestations of hypercoagulable state and lack evidence of other AI disease.


arterial vs. venous thrombi

• Arterial thrombi = grow retrograde from point of attachment
• Venous thrombi extend in the direction of blood flow (both propogate to the heart)
• Propogating portion of thrombi is poorly attached and prone to fragmentation and embolization


lines of zahn

• Lines of Zahn: thrombi have laminations that represent pale platelet and fibrin deposits alternating with darker red cell-rich layers
o These laminations signify that thrombus formed in flowing blood, and distinguishes antemortem thrombosis


mural thrombi

• Mural Thrombi: thrombi occurring in heart chambers and aortic lumen
o Causes: Arrhythmias, dilated cardiomyopathy, MI, myocarditis, catheter trauma, ulcerated atherosclerotic plaques and vasculitis


arterial thrombi



• Arterial Thrombi: frequently occlusive
o Most common sites: coronary, cerebral and femoral aa.
o Consist of meshwork of platelets, fibrin, RBCs and leukocytes
o Usually superimposed on ruptured atherosclerotic plaque

•Venous Thrombosis (Phlebothrombosis): almost always occlusive
o Thrombus forms a long cast of the lumen
o Contains more enmeshed RBC’s b/c thrombi form in sluggish venous circulation
o Aka “Red or Stasis” thrombi
o most often occurs in lower extremity vv.


postmortem clots

o Gelatinous with dark red dependent portion where cells have settled by gravity and yellow “chicken fat” upper portion
o Usually not attached to underlying wall


vegetations? liban-sacks endocarditis?

o Thrombi on heart valves
o Can be caused by bacteria, fungi, rheumatic heart disease, infective endocarditis
o Non-bacterial endocarditis
o Libman-Sacks endocarditis: occurs in setting of Lupus erythematosus



• Venous thrombi → congestion and edema in vascular beds distal to obstruction. They are worrisome for capacity to embolize to lungs and cause death

•Venous Thrombosis (Phlebothrombosis):
o Most often seen in superficial or deep vv of legs
o Superficial may cause local congestion, swelling, pain and tenderness but rarely embolize
o DVT are more serous b/c they often embolize to the lungs and give rise to pulmonary infarction (50% asymptomatic)
• DVTs: often seen with bed rest, CHF, trauma, surgery, burns, altered t-PA production


arterial thrombosis

• Arterial and Cardiac Thrombosis:
o Atherosclerosis: major cause, b/c it is associated with loss of endothelial integrity and abnormal vascular flow
o Can be due to MI and damage to endocardium
o Rheumatic heart disease
o Atrial mural thrombi
o *** brain, kidneys, and spleen are also targets due to rich blood supply



Disseminated Intravascular Coagulation (DIC)
• Sudden and insidious onset of widespread fibrin thrombi in microcirculation
• Pathological activation of coagulation mechanisms in response to a variety of disease. DIC leads to formation of small blood clots inside the blood vessels throughout the body. Small clots consume coagulation proteins and platelets and normal coagulation is disrupted and abnormal bleeding occurs from the skin.
• usually not grossly visible
• can cause diffuse circulatory insufficiency in brain, lungs heart and kidneys
• fibrinolytic mechanisms activated at same time
• can evolve into a bleeding catastrophe
• DIC is a potential complication of any condition associated with widespread activation of thrombin


embolus, embolism, thrombeoembolus

Embolus: detached intravascular solid, liquid or gaseous mass carried by blood to distant site. Often results in infarction

Embolism: sudden blocking of an artery by clot of foreign body that has MOVED to its site of lodgement

Thrombus: an in-situ process, typically by organization

Thromboembolus: detached thrombus

Cholesterol emboli: atherosclerotic debris


pulmonary embolism

• Originate from DVT’s and carried through progressively larger channels → right side of heart → pulmonary arterial vasculature
• “saddle embolus” – straddles pulmonary aa. Bifurcation
• often will occur multiple times
• paradoxical embolism: very rarely can pass through interatrial or interventricular defect and gain access to systemic circulation
• 60-80% are clinically silent b/c they are small and w/ time will be incorporated into vascular wall
• cor pulmonale: right heart failure → sudden death occurs when emboli obstructs 60% or more of pulmonary circulation
• multiple emboli over time → pulmonary HTN → RV failure


systemic thromboembolism

Systemic Thromboembolism:
• emboli in the arterial circulation
• moist arise from intracardiac mural thrombi : left ventricular wall infarcts and left atrial dilation and fibrillation
• paradoxical emboli: unknown origin
• often end up in LE’s, brain, intestines, kidneys, spleen and UE’s


Fat and Marrow Embolism:

• seen in circulation and impacted in pulmonary vasculature after fractures of long bones (which have fatty marrow)
• rarely occurs after soft tissue trauma and burns
• Fat is released by marrow or adipose injury and enters circulation after the rupture of the marrow vascular sinusoids or venules
• Fat Embolism Syndrome: characterized by pulmonary insufficiency, neurologic symptoms, anemia, thrombocytopenia (due to platelet adhesion to fat globules)
o Usually 1-3 days after injury there is sudden onset of tachypnea, dyspnea, tachycardia, irritability and restlessness


air embolism

• Gas bubbles w/in circulation coalesce to obstruct vascular flow
• Decompression sickness: occurs when rapid ascent → nitrogen diffuses out of tissues and into blood rapidly
o “the bends” (tissues and joints pain)
o “ the chokes” in the lungs, gas bubbles cause edema, hemorrhage, and emphysema
o Caisson disease: persistence of gas emboli in skeletal system leads to ischemic necrosis in femoral heads, tibia and humeri


red infarcts

o Occur with venous occlusions: i.e. ovary
o Occur in loose tissues where blood can collect in infarcted zone
o Occur in tissues with dual circulations (i.e. lung and small intestine) that allow blood to flow from unobstructed parallel supply to necrotic zone
o Occur in tissues previously congested by sluggish venous outflow
o Occur when flow is re-established to a site of previous arterial occlusion and necrosis (i.e. following angioplasty)

* often see hemorrhagic infarcts in lung


white infarcts

o Occur with arterial occlusion in solid organs with end-arterial circulation (i.e. heart, spleen, kidney) where tissue density limits seepage of blood from adjoining capillary beds into necrotic area


ischemic coagulative necrosis

o Dominant histological characteristic seen in infarctions


septic infarctions

occur when infected cardiac valve vegetations embolize. The infarct is converted into an abscess with a large inflammatory response


most/least prone to infarction?

a. Lungs and liver have dual supply and are less prone to infarction
b. Spleen and renal circulations are end-arterial and more prone to infarction



- Shock is characterized by systemic hypotension due to reduced CO or reduced effective circulating blood volume. Results in impaired tissue perfusion and cellular hypoxia. Prolonged shock becomes irreversible.


cardiogenic shock

. Cardiogenic Shock: results from low CO due to myocardial pump failure
• Can be due to myocardial damage (infarct), ventricular arrhythmias, extrinsic compression (cardiac tamponade) or outflow obstruction (pulmonary embolism)
• Patient presents with hypotension, weak, rapid pulse, tachypnea, cool clammy and cyanotic skin


hypovolemic shock

results from low CO due to loss of blood or plasma volume
• Can be due to hemorrhage or fluid loss from severe burns
• Patient presents with hypotension, weak, rapid pulse, tachypnea, cool clammy and cyanotic skin


septic shock

results from vasodilation and peripheral pooling of blood as part of systemic immune reaction against bacterial or fungal infection
• Triggered most often by gram positive bacterial infections, and also gram-negative and fungal
• Leads to tissue hypoperfusion, even though CO may be preserved or increased in the beginning
• Due to overactive neutrophils, macrophages and innate immune system cells during an infection
• Patient presents with skin that may initially be warm and flushed because of peripheral vasodilation


how does endothelial cell injury lead to septic shock?

• Endothelial cells activated by microbial constituents resulting in
o Thrombosis: deposition of fibrin-rich thrombi in small vessels throughout vody
o Increased vascular permeability: exudation of fluid into intersitium → edema → further impediment to blood flow to tissues
o Vasodilation
o Can cause DIC: can lead to deficiencies in coagulation and platelets → bleeding and hemorrhage
o Sepsis alters expression of factors so as to favor coagulation (increased PAI-1), which is further aggravated by decreased blood flow, producing stasis and diminishing washout


metabolic abnormalities with septic shock patients?

Metabolic Abnormalities:
• Septic patients are insulin resistant and hyperglycemic
• Increased catecholamines, TNF, IL-1 all drive gluconeogenesis → hyperglycemia
• Hyperglycemia → impaired neutrophil function → suppresses bactericidal activity → increased adhesion molecs expressed on endothelial cells


stages of shock

1. Nonprogressive phase: reflex compensatory mechanisms are activated and perfusion of vital organs is maintained
• Neurohormonal mechanisms maintain CO and blood pressure (baroreceptors, catecholamine release, renin-ang system)
• Net effect: tachycardia, peripheral vasoconstriction, renal conservation of fluid. See coolness of skin (though initially the vasodilation results in flushing of skin)
2. Progressive stage: tissue hypoperfusion, onset of worsening circulatory and metabolic imbalances and acidosis
• Widespread tissue hypoxia
• Lactic acidosis lowers tissue pH and blunts vasomotor response
• Dilation of arterioles and pooling of blood → worsened CO → risk of DIC
3. Irreversible Stage: cellular and tissue injury is severe
• Lysosomal enzyme leakage due to cell injury