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Describe the pathogenesis of edema in ht failure.
- 1) Decr cardiac output
- 2) Decr. effective bld vol --- incr. ADH --- incr. renal H2O retention
- 3) Incr. renin
- 4) Incr. aldosterone
- 5) Renal Na retention
- 6) Incr plasma volume
- 7) Transudation
Describe pathogenesis of renal failure causing edema.
- 1) Incr. renal Na and water retention
- 2) Incr. plasma volume
- 3) Transudation
Name the pro-thrombotic properties of endothelium.
- 1) Anti-platelet: intact endothelium, NO, PGI2 (vasodil, inh plt ag), ADPase
- 2) Anti-coag: hep sulfate (binds AT - inactivates T, IXa, Xa, XIa, XIIa), thrombomodulin (binds T then activates prot C which attachs to prot S and cleaves Va and VIIIa), TFPI (complexes with TF-Va and Xa)
- 3) Fibrinolytic effects - tPA
Name the pro-thrombotic effects of endothelium.
- 1) Plt effects: plts adhere to subend collagen via vWF (in WP bodies of endo)
- 2) Procoag effects: TF prod (induced by IL6, TNF), bind IXa and Xa
- 3) Anti-fibrinolytic: plasminogen activator inhibitors
Describe the steps in normal hemostasis.
- 1) Vascular injury leads to transient vasoconstriction.
- 2) Plts adhere to exposed ECM via vWF --- plt activation -- shape change -- granule release -- ADP and TxA2--- plt ag --- plt plug
- 3) Activation of coag cascade d/t TF exposure --- x-linked fibrin
- 4) Fibrinolysis via tPA, thrombomodulin
List contents of alpha granules.
- factors V and VIII
- plt factor 4
List the contents of the dense granules.
What three things happen when plts contact ECM.
- 1) Adhesion and shape change - vWF bridge with GP1b on plt
- 2) Secretion - after adhesion granule contents secreted
- 3) Aggregation - d/t ADP and TxA2, reversible until T generated, fibrinogen bridges plts via GPIIbIIIa
- PGI2 - vasodil and inh aggregation, TxA2 vasocontr and cause plt aggregation - ASA block syn of TxA2
Summarize the effects of thrombin.
- Plt aggregation and granule release
- Induces endoth to produce:
- - adhesion molecules
- - tPA
- - NO, PGI2
- - PDGF
- Activate inflam cells
List the steps of the intrinsic pathway.
- XII -- XIIa via HMWK, and Prekallikrein -- Kallikrein
- XIIa - activates XI -- XIa
- XIa activates IX to IXa
- IXa, VIIIa, Ca and PL comprise the tenase complex and activates X to Xa
List the steps of the extrinsic pathway.
- TF-VII -- activates IX to IXa
- IXa along with VIIIa, Ca and PL --- tenase complex activates X to Xa
List the steps of the common pathway.
- Xa, Va, Ca, PL make up the prothrombinase complex
- Activates II -- IIa (prothrombin to thrombin)
- Thrombin then cleaves fibrinogen to fibrin
- Fibrin is crosslinked by VIII
Name the three endogenous anticoagulants:
- 1) AT - inh T, IXa, Xa, XIa and XIIa - activated by hep
- 2) Protein C and S - vit K dep, inh Va and VIIIa (in prothrombinase and tenase), activated by T-thrombomodulin
- 3) TFPI - binds factor Xa and TF-VIIa and inactivates
Describe the process of fibrinolysis.
- Plasminogen --- cleaved to plasmin by:
- 1) tPA or uPA - tPA most NB, most active when bound to fibrin
- 2) Factor XII dep - XIIa conververts prekal to kal, kal then converts plasminogen to plasmin
- INHIBITED by: free plasmin binds to a2-antiplasmin, endoth can produce PAIs (increased by T and other cytokines - to favor coag)
What three factors predispose to thrombosis (Virchow's triad).
- 1) endothelial injury
- 2) altered bld flow - laminar bld flow keeps plts in center, away from endoth
- 3) hypercoag - AT loss in PLN or PLE; liver dz; cushings (d/t incr in procoag by liver)
State differences between arterial and venous thrombi.
- - site of turbulence or endoth injury
- - toward ht against blood flow
- - usually occlusive, grey/white, friable
- - site of stasis
- - toward ht with bld flow
- - always occlusive - red or stasis thrombi
List types of embolisms.
- 1) Pulmonary
- 2) Systemic
- 3) Fat
- 4) Air
- 5) Amniotic fluid
Where do red (venous) infarcts occur vs while (arterial) infarcts?
- Red: lung, SI, with dual bld supply
- White: solid organs with end-arterial circulation - ht, spleen, kidney
Describe the pathogenesis of endotoxic shock.
- 1) Free LPS binds to LPS binding protein
- 2) Complex binds to cell surface CD14
- 3) LPS then binds to TLR4 - directly activate endoth cells, WBCs or initiate cytokine production
- - binding of TLR4 on endo cells decr. TFPI and thrombomodulin --- hypercoag
- - binding of TLR4 on monos - activation, release of IL1 and TNF
- 4) LPS can also directly activate complement
- 5) Monos react to LPS by prod IL1, IL6, TNF and IL8
- 6) IL1 and TNF - stim exp of adhesion mol by endoth cells - enhance inflammation and clear infection
What happens with low doses of LPS?
- 1) WBC activation - produce TNF, IL1, IL6, IL8
- 2) Complement activation
- 3) TNF and IL1 activatae endothelial cells to produce adhesion mol - local inflammation and clear infection
What happens with moderate doses of LPS?
- 1) more cytokines produced
- 2) see systemic effects of IL1 and TNF (fever, APP)
- 3) decr endoth prod of TFPI and thrombomod -- tip coag toward thrombosiss
What happens with high doses of LPS?
- Septic shock d/t high concentrations of cytokines and 2ry effectors
- systemic vasodilation, decreased myocardial contractility, widespread endoth injury and activation leading to leukocyte adhesion and pulmonary alveolar damage (ARDS) -- activation of coag --- DIC
- NOTE: mice without CD14 or TLR4 do not react to LPS
What is the progression of cytokine production during septic shock?
TNF, then IL1, then IL6/IL8
What are the stages of shock?
- 1) Nonprogressive stage
- - compensatory mech activated and vital organs protected
- - baroreceptor reflexes, catechol release, activation of renin-angiotensin, ADH, sympathetic stim
- - see tachycardia, peripheral vasocontriction, renal fluid conservation
- 2) Progressive stage
- - tissue hypoperfusion, hypoxia and lactic acidosis - pH blunts arteriole response and get pooling of bld
- - worsening of cardiac output, endoth damage d/t hypoxia --- DIC
- - organ failure, urine output fails
- 3) Irreversible stage
- - widespread cell injury, organ shut-down
- - in adrenal get cortical cell lipid depletion - conversion of inactive cells to active cells to produce steroids