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![Fibrinoly8c
Ac8va8on
in
APL
• Annexin
A2
– Cell
surface
receptor
for
tPA
and
plasminogen
– Found
on
endothelial
cells,
monocytes
and
some
tumor
cells
• Overexpressed
on
APL
cells
– Serves
as
a
co-‐factor
for
tPA
à
promo5ng
plasmin
genera5on
– [α2-‐AP]–
inhibitor
of
fibrinolysis
is
depleted
• At
presenta;on
in
APL
– Leukemic
cell
overexpresses
[TF
+
Annexin
A2]
à
low
grade
DIC
– Hyperfibrinoly;c
state
due
to
• Low
fibrinogen
• Low
plasminogen
• Low
α2-‐AP
• Increased
FDP
and
D-‐Dimer
levels
– Fibrinolysis
usually
predominates
à
increased
risk
of
bleeding
Bri8sh
Journal
of
Haematology,
156,
24-‐36](https://image.slidesharecdn.com/lecture7fall2014-141207132432-conversion-gate01/75/Lecture-7-fall-2014-28-2048.jpg)
Uploaded byShabab Ali
Lecture 7, fall 2014
Disseminated intravascular coagulopathy (DIC) is an acquired condition marked by a consumption of coagulation factors and platelets leading to bleeding and thrombosis. It can manifest acutely due to sudden procoagulant exposure or chronically with compensatory mechanisms in response to ongoing procoagulant stimulation, often seen in solid tumors and large aortic aneurysms. Diagnosis involves identifying prolonged clotting times, thrombocytopenia, and elevated fibrin degradation products, with treatment focused on supportive measures and addressing the underlying triggers.
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Similar to Lecture 7, fall 2014
Lecture 7, fall 2014
- 1. Disseminated Intravascular Coagulopathy • Acquired pathologic syndrome arising from heterogenous group of underlying medical condi8ons • Event that can accompany various disease processes • Leads to an imbalance in coagula8on characterized by 1. Consump8on of coagula8on factors and platelets 2. Proteoly8c degrada8on of fibrin • Variable clinical expression – Laboratory manifesta8ons alone, or in combina8on with – Hemorrhagic and thrombo8c complica8ons • Unregulated and excessive genera3on of thrombin and plasmin – Two caveats: 1. Excess thrombin with reduced plasmin expression à microvascular fibrin deposi;on and thrombosis à ischemic necrosis and organ dysfunc;on 2. Excess thrombin with vigorous secondary fibrinolysis Red Blood Cell à increased consump;on of the hemosta;c proteins à bleeding 1 6 Thrombosis Fibrin Platelet WWW. Coumadin.com
- 2. DIC • Acute DIC – Develops acutely when sudden exposure of blood to procoagulants (TF) à genera8on of intravascular coagula8on – Compensatory hemosta8c mechanisms overwhelmed à severe consump8ve coagulopathy à hemorrhage – Organ failure frequently occurs • Chronic DIC – Compensated state – Blood is con8nuously or intermiNently exposed to small amounts of TF – Liver and BM compensate with coagula8on factors and platelets – LiNle obvious clinical or laboratory indica;on of DIC – More frequently observed in solid tumors and large aor8c aneurysms
- 3. Sequence of Events in DIC • Ac5va5on of coagula8on is always the ini3a3ng event 3 Systemic ac3va3on of coagula3on Deple8on of coagula8on factors and platelets Intravascular deposi8on of fibrin Bleeding Thrombosis: small and midsize vessels DEATH Organ failure
- 4. DIC Thrombosis with Fibrinolysis 1. Brief period of hypercoagulability 2. Coagula8on cascade ini8a8on à causing widespread fibrin forma8on 3. Microthrombi are deposited throughout the microcircula8on 4. Fibrin deposits in 8ssue à hypoxia, ischemia, necrosis, organ failure Bleeding with Fibrinolysis 1. Period of hypocoagulability (the hemorrhagic phase) 2. Ac8va8on of the complement system 3. Genera8on of FDP’s à enhance bleeding by interfering with a. Platelet aggrega8on b. Fibrin polymeriza8on c. Thrombin ac8vity 4. Leads to hemorrhage
- 5. Pathophysiology of DIC • Involves 4 physiologic processes 1. Ac8va8on of Blood Coagula8on 2. Suppression of Physiologic An8coagulant Pathways 3. Impaired Fibrinolysis 4. Prolifera8on of pro-‐inflammatory cytokines
- 6. Pathogenesis of DIC 1. Ac5va5on of coagula5on cascade – TF expression at the injury site, monocytes – Thrombin genera8on via ac8va8on of the coagula8on factors • Ac8vates V, VIII, XI à con8nued ac8va8on of coagula8on cascade • Converts fibrinogen à fibrin monomers • Ac8vates FXIII à cross-‐linking of fibrin monomers 6 hNp://www.biochem.ucl.ac.uk/pavithra/fix/images/coagula8on%20cascade_pavithra_rallapalli.jpg
- 7. Pathogenesis of DIC 1. Thrombin genera8on is normally localized to the site of injury à ac8va8on of platelets and deposi8on of cross-‐linked fibrin à hemosta8c plug 2. Thrombin genera8on is 8ghtly regulated by the naturally occurring an8coagulants 3. These mechanisms are overwhelmed due to increased produc8on of thrombin 4. Thrombin circulates and leads to DIC 5. Widespread deposi8on of fibrin results in a. Tissue ischemia b. Consump8on of platelets, fibrinogen, FII, FV and FVIII à bleeding 7 www.nature.com/bmt/journal/v41/n8/fig_tab/1705990f2.html
- 8. Pathogenesis of DIC 2. Suppression of Physiologic An5coagulant Pathways – Down-‐regula5on of the naturally occurring inhibitors • TFPI decreased à modulates the extrinsic tenase complex (TF:VIIa:X) • AT decreased à interacts with glycosaminoglycans on endothelial surface à inhibi8on of IIa, IXa, Xa – Exhausted due to con8nuous thrombin genera8on – Reduc;on in glycosaminoglycans occurs due to pro-‐inflammatory cytokines • PC/PS decreased à decreased aPC à can’t inhibit FVa and FVIIIa • C4BBP increased à decrease in free PS • TM à thrombin specific receptor on endothelial surface – Converts thrombin from procoagulant to an;coagulant – TM à prevents thrombin from ac8va8ng platelets hNp://physrev.physiology.org/content/93/3/1247
- 9. Pathophysiology of DIC 3. Cytokine genera5on – Cytokines promote increase in TF expression a. Increased Thrombin genera8on b. Suppression of fibrinolysis • Cytokines – IL-‐1 and TNF-‐ α à up-‐regulate TF and down-‐regulate TM – IL-‐6, and IL-‐10 increase ac8va8on of coagula8on – Monocytes secrete IL-‐1 and TNF à modula8on of procoagulant ac8vity – Endotoxin increases monocyte produc8on of TF • Normal individuals: PC has an5-‐inflammatory effect à inhibits endotoxin-‐ induced produc8on of these cytokines • DIC: Decrease in PC à decreased regula8on of these cytokines • Interac8on between inflamma8on and coagula8on 9 Inflammation Coagula5on Tips balance in favor of procoagulant state
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- 12. Pathophysiology of DIC 4. Impaired fibrinolysis – rela8vely suppressed at maximal ac8va8on of coagula8on due to elevated levels of PAI-‐1 • Plasmin – Produced from Plasminogen by Tissue Plasminogen ac8vator (tPA) – Degrades fibrin/fibrinogen, FV, VIII, IX, XI, XII – Ac8vity is inhibited by an3plasmin • An8plasmin – Inac8vates plasmin rapidly • Acts slowly on plasmin sequestered in the fibrin clot • Plasminogen ac8vator inhibitor-‐1 (PAI-‐1) – Inhibits the func5on of tPA www.cancernetwork.com/oncology-‐journal/thromboembolism-‐and-‐ble.
- 13. Laboratory Findings in DIC • Diagnosis – No test “says” DIC – You need a (screening test) + (one test indica;ve of thrombin genera;on) • 3 groups of tests 1. Screening assays to test for severity • PT, aPTT, PLT à demonstrate consump3ve process 2. Thrombin genera8on A. D-‐dimer – D-‐dimer à proteoly8c by product of plasmin degrada8on of cross-‐linked fibrin monomers 1. Fibrinogen to fibrin conversion 2. Cross-‐linking by FXIII 3. Degrada8on by plasmin – FDP does not dis8nguish between plasmin degrada8on of fibrin and fibrinogen B. Fibrin monomer 3. Plasmin genera8on 13 D-‐Dimer reflects that these 3 processes have occurred
- 14. Laboratory Tests Used in DIC • D-‐dimer* • An3thrombin III* • F. 1+2* • Fibrinopep8de A* • Fibrin Degrada3on Products • Platelet count • Thrombin-‐an3thrombin complex • Thrombin 8me • Fibrinogen • Prothrombin 3me* • Ac3vated PTT • Rep8lase 8me • Coagula8on factor levels *Most reliable test NEJM 346: No. 1, 59
- 15. Laboratory Diagnosis in DIC • Thrombocytopenia – Platelet count <100,000 or rapidly declining • Prolonged clorng 8mes (PT, aPTT) • Presence of D-‐Dimer/FDP • Low levels of coagula8on inhibitors – AT III, protein C, S • Low levels of coagula8on factors – Factors II, V, VII, IX, X, XI, XIII • FVIII levels are osen elevated • Fibrinogen levels not useful diagnos8cally Acute Phase Proteins!!!
- 16. Clinical Manifesta8ons of DIC ORGAN ISCHEMIC HEMOR. Skin Pur. Fulminans Gangrene Acral cyanosis Petechiae Echymosis Oozing CNS Delirium/Coma Infarcts Intracranial bleeding Renal Oliguria/Azotemia Cortical Necrosis Hematuria Cardiovascular Myocardial Dysfxn Pulmonary Dyspnea/Hypoxia Infarct Hemorrhagic lung GI Endocrine Ulcers, Infarcts Adrenal infarcts Massive hemorrhage. Ischemic Findings are earliest! Bleeding is the most obvious clinical finding
- 17.
- 18. Laboratory Findings in DIC Acute DIC Ø Elevated PT, aPTT, FDP, DD Ø Decreased Fib, Plt Ct, AT C hronic DIC Ø PT, aPTT are normal to increased – May be normal due to compensatory mechanism Ø Elevated FDP, DD 18 Ø Consumable factors – Fib, II, V, VIII Ø VIII and Fib – acute phase reactants – may be elevated in early DIC Ø AT levels decrease as AT binds to thrombin to inac8vate it Ø FDPs are diges8on products for either fibrinogen or fibrin Ø DD – demonstrates a diges8on product of crosslinked fibrin –only specific for ongoing clot forma8on –a sensi5ve test with a very high nega8ve predictability Ø No test is SPECIFIC for DIC
- 19.
- 20. Treatment of DIC • Differen8al Diagnosis – Severe liver failure – Vitamin K deficiency – Liver disease – Thrombo8c thrombocytopenic purpura – Congenital abnormali8es of fibrinogen – HELLP syndrome • No specific treatments – suppor8ve therapy – Plasma and platelet subs8tu8on therapy – An8coagulants – Physiologic coagula8on inhibitors • Fresh frozen plasma(FFP):-‐-‐ provides clorng factors, fibrinogen, inhibitors, and platelets in balanced amounts • Platelets—add fuel to the fire • Heparin -‐-‐ Turns off coagula8on, but you already have a bleeding pa8ent—may be contraindicated—also requires AT in order to be effec8ve • Inhibitor therapy – AT—major inhibitor of the coagula8on cascade – PC concentrate—inhibits Va and VIIIa—decreases morbidity due to sepsis – TFPI—inhibits thrombin genera8on via extrinsic pathway • Stop the triggering process – The only proven treatment! Rule out 20
- 21. Acute vs Chronic DIC Acute DIC • Diagnosis of severe, acute • Prolonga8on of PT, aPTT, TT – Due to consump5on and inhibi5on of clorng factors • Thrombocytopenia – Due to BM unable to compensate • FDP’s + D-‐Dimer – Increased due to secondary fibrinolysis • Schistocytes may be seen in the peripheral blood smear – Neither sensi8ve nor specific for DIC Chronic DIC • Chronic or “compensated” form • Highly variable paNerns of abnormali8es in DIC “screening” tests for DIC • Increased FDPs + D-‐Dimer • Prolonged PT • Generally more sensi;ve measures than abnormali8es of the aPTT and PLTCT • Overcompensated (increased) synthesis of 1. Consumed clorng factors à normaliza8on of aPTT 2. Platelets à thrombocytosis 3. Elevated levels of FDPs à result from 2o fibrinolysis
- 22.
- 23. DIC versus Primary Fibrinolysis Secondary fibrinolysis: increased fibrinolysis due to thrombin genera5on – s8mulates EC’s to produce tPA à an increase in fibrinolysis in DIC Primary fibrinolysis: increased fibrinolysis independent of thrombin genera8on
- 24. APL • Life threatening coagulopathy – requires prompt diagnosis and recogni8on of coagula8on defect • Hemorrhage – major cause of “early” death 1. Caused directly/indirectly by the leukemic cells 2. Compounded by failure of platelet produc;on – BM invasion by leukemic cells • Predominant feature at presenta8on is hyperfibrinolysis • Paradigm of DIC – Meningococcal sepsis • Ac8va8on of IL-‐1 and TNF-‐α à up-‐regula8on of TF expression on monocytes and endothelial cells – Ac8va8on of coagula8on cascade à widespread microvascular thrombosis Consump8on of coagula8on factors + platelets + natural an8coagulants – Increased thrombin produc8on » S8mula8on of tPA from the endothelial cells à further complicates risk of bleeding • 2o fibrinolysis
- 26. APL • Cancer procoagulant protease – CP – protease that directly ac8vates FX à thrombin genera8on – Present in serum and 8ssues of many pa8ents with various types of malignancies – Highest levels seen in APL cells • Other proteases – Elastases – granulocy8c proteases • Cleave fibrinogen – Elastase-‐degraded fibrinogen produces a different paNern of FDP than plasmin cleavage • Degrade fibrinoly8c inhibitors • Increased in DIC • Inflammatory cytokines – IL-‐1 and TNF-‐α à ac8va8on of monocyte and endothelial cells à up-‐regulate TF / down-‐regulate TM – Causes switch from normal an8coagulant state to prothrombo8c state
- 27. Fibrinolysis in APL • Normal in cells – Fibrinolysis à breakdown of fibrin clots – Thrombin converts fibrinogen to fibrin monomers – FXIIIa crosslinks fibrin monomers – EC’s release tPA which converts plasminogen to plasmin – Plasmin breaks the fibrin into D-‐Dimer fragments
- 28. Fibrinoly8c Ac8va8on in APL • Annexin A2 – Cell surface receptor for tPA and plasminogen – Found on endothelial cells, monocytes and some tumor cells • Overexpressed on APL cells – Serves as a co-‐factor for tPA à promo5ng plasmin genera5on – [α2-‐AP]– inhibitor of fibrinolysis is depleted • At presenta;on in APL – Leukemic cell overexpresses [TF + Annexin A2] à low grade DIC – Hyperfibrinoly;c state due to • Low fibrinogen • Low plasminogen • Low α2-‐AP • Increased FDP and D-‐Dimer levels – Fibrinolysis usually predominates à increased risk of bleeding Bri8sh Journal of Haematology, 156, 24-‐36
- 29. Coagulopathy in APL versus DIC • Microvascular thrombosis in APL is uncommon – Suggests fibrin forma;on is kept in check due to increased fibrinoly;c ac;va;on • Decreased PLTCT – Explained by BM invasion rather than consump;on • Physiologic levels of naturally occurring an8coagulants (AT, PC, PS) are beNer “preserved” – Not being consumed trying to inhibit ac;va;on of coagula;on cascade à LESS ac;va;on than in DIC • Fibrinogen levels are lower (especially in 2o fibrinolysis) • D-‐Dimer levels are higher • FV levels are lower • Main driving force of bleeding in APL is NOT aberrant TF expression but due to increased fibrinoly;c ac;va;on à hyperfibrinolysis In APL
- 30. Etiology of DICin Sepsis Zeerleder, S. et al. Chest 2005;128:2864-2875
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