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.
P-selectin fibrinogen fibronectin factors V and VIII plt factor 4 PDGF TGF-b
List the contents of the dense granules.
ADP ATP Ca Hist Serotonin Epinephrine
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.
arterial: - site of turbulence or endoth injury - toward ht against blood flow - usually occlusive, grey/white, friable venous: - 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