ࡱ> +( / 0DArialngsRomanttX< 0DTimes New RomanttX< 0 DWingdingsRomanttX< 0@ .  @n?" dd@  @@`` h`tL     3! ! 0AA 33@83ʚ;ʚ;g4JdJd 0ppp@ <4dddd@k 0t4< 80___PPT10 ?  %&<Chapter 34 Vascular Thrombosis Due to Hypercoagulable States==,&4Erika Lu August 22, 2005 Vascular Surgery Conference Epidemiology Thrombosis is the major cause of death in the world MI and stroke (arterial thrombosis) are the #1 and #2 killer worldwide Molecular defects increase a patient s risk for thrombosis in 18%-30% of all cases of venous thromboembolism Arterial thrombosis more likely environmental/acquired cause rather than inherited disorder@4G4G3]Biochemistry of ThrombosisPK Kallikrein Plasminogen XII XIIa C4bBP PAI-1 XIa Protein S Plasmin IXa APC Insol Fibrin FDP VIIIa VIIa-TF Xa FVL Sol Fibrin Va AT II G20210A Thrombin HCII FibrinogenxP> E  3   0Biochemistry of ThrombosisPK Kallikrein Plasminogen XII XIIa C4bBP PAI-1 XIa Protein S Plasmin IXa APC Insol Fibrin FDP VIIIa VIIa-TF Xa FVL Sol Fibrin Va AT II G20210A Thrombin HCII FibrinogenxP> E  3   0Arterial ThrombosisWhite clot  platelet rich Rare to see arterial thrombus in a healthy vessel Usually atherosclerotic change with& Diabetes Hyperlipidemia Tobacco use Acquired procoagulant states (i.e. HIT and antiphosholipid antibodies@rZ$ZFZr$3F>{   Arterial ThrombosisAManifests in large vessel occlusions MI and stroke Peripheral vascular occlusive disease There are genetic polymorphisms that may increase your risk, but not really predictive of risk of thrombus when you look at large population studies Elevated factor VII Elevated fibrinogen Hyperhomocysteinemia Elevated lipoprotein ad%Z4ZZTZ%43T3 Venous ThromboembolismRed clot  RBC s trapped in fibrin strands Virchow s Triad: vessel wall change, hypercoagulability and stasis have a major role! Classic Protein Deficiencies: Antithrombin III deficiency Protein C deficiency Protein S deficiency>F+3eF3P  = : Venous ThromboembolismLess common causes for thrombosis Abnormal fibrinogen Abnormal plasminogen Elevated factors XI, IX, and VIII Hematologic conditions that cause hypercoagulability TTP HUS DIC Polycythemia vera and essential thrombocythemia\"K5<"K35<3t? #   Venous ThromboembolismAcquired Risk Factors: Immobility Obesity Chronic neurologic disease Cardiac disease Pregnancy, use of OCP s Surgery, particularly thoracoabdominal, ortho, GYN Trauma Malignancy Nephrotic syndrome V3 3b2 +    Venous ThromboembolismRInteresting Factoids on Cancer and VTE Occult cancer in 0.5  5% of VTE pts 3x more likely to get cancer in next 3 yrs if idiopathic VTE 19% of cancer pts have a VTE Chemo increases risk of VTE because it increases tissue factor and expression of E-selectin, thereby increasing thrombus potential D''33) Antithrombin Deficiency (1-2%)3  #Protein C and S Deficiencies (2-5%)$$(3 BHeparin-Induced Thrombocytopenia & Thrombosis Syndrome (up to 30%)CC3 -Lupus Anticoagulant/Antiphospholipid Syndrome..3 #Factor V Leiden (resistance to APC)$$3 Hyperhomocysteinemia (10%)3&Prothrombin G20210 Polymorphism (4-6%)''3 >Defective Fibrinolysis, Dysfibrinogenemia, and Lipoprotein (a)??3, Abnormal Platelet Aggregation3+Elevated Procoagulant Factors: VIII, IX, XI,,3 What tests do we order?Antithrombin activity and antigen assay Protein C activity and antigen assay Free protein S antigen assau APC resistance assay Factor V Leiden by PCR Homocysteine level Prothromnin G20210A by PCR Antiphospholipid or anticardiolipin Ab Clottable fibrinogen and fibrinogen antigen Dilute Russell viper venom time Tissue thromboplastin inhibition time 2 glycoprotein I antibodies PT/PTT D-dimer0P]" X   J Suggested Treatment Algorithm 3-6 months Aggessive ppx anticoag for 2nd VTE Yes VTE Acute Identifiable Therapy Risk/Etiology No Test for Hypercoag ? 6 months State Neg Anticoagulation + Low risk recur Hi-risk recurrence Life-long anticoagulation.Z1 b \ n  0` 3fff` 3R|:33` ff` ffmo` #fT=` WXcmwnI` v^Xf̙` 3f` ff~bWf3>?" dd@,?lKd@    @ `  n?" dd@   @@``PR    @ ` `0p>>   @v (  bT  ^  " ^  c BWC DEFy2@ IB *CN, me;>VvK W !vVJ5ka2IBIBBD@`" ^  c B>CBDEF@ >BB>B>B @`" >  c \BC)DEdFny2@ha))qWs%Fl&N Y1bQiha48@`"   c tBCDEpFzy2@ Xv02PzNPFW p(E;%N:<@`" 2  T?d?" 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Congenital: autosomal dominant; heterozygotes live Acquired: liver dz, malignancy, sepsis, malnutrition, ESRD, DIC8    . @` < <y?_0  jMech @` < <~?0_ NVenous @` < <?0_ PSite @``B  < 0o ?ZB < s *1 ?__ZB < s *1 ?  ZB < s *1 ?  `B < 0o ?`B < 0o ?ZB < s *1 ?00`B < 0o ?RB %< s *D`P`H < 0޽h ? 3fff___PPT10i.Ϧpr+D=' {= @B +4  0 KCD(  Dx D c $} ``}   o  `z D #""_wo `z V D <? `z -anticoagulate with heparin, then lifelong -only tx those that are sx atic, since many subclinical, but aggressive periop ppx if genotype knownt #  @` D <0? z hTx @` D <q? `  dLow Protein C or S Ag levels @` D <;?   hDx @` D <( ?i`  FProtein C: inactivates Factos Va & VIIa less thrombin -also stimulates t-PA liberation, ! fibrinolysis Protein S: cofactor to APC, regulated by C4b -free protein S is an active anticoagulant Congenital: autosomal dominant; heterozygotes live Acquired: liver failure, DIC, nephrotic syndrome$ 3P" &3O" &3)"&3("4 e  $   @`  D <( ?i  jMech @`  D <( ? `i cVenous, occasional arterial @`  D <( ? i PSite @``B  D 0o ? ` ZB  D s *1 ?i`iZB D s *1 ? ` ZB D s *1 ? ` `B D 0o ?z`z`B D 0o ? zZB D s *1 ? z`B D 0o ?` `zRB D s *D`P`RB D s *D H D 0޽h ? 3fff___PPT10i.Ϧpr+D='  = @B +M  0 d\ H(  Hx H c $ ``}      `  H #""_o `   H <P( ? `  -stop all heparin, including flushes -coumadin only if initially used w/ other anticoagulant due to initial prothrombotic state -cannot use LMW heparin (92% cross-reactivity) -Hirudin or argatroban or abciximabb&> 7   @` H <T( ?   hTx @` H <( ?`  -suspect if plts ! by 50% or if Plts<100K -suspect if thrombosis in unusual area -ELISA usually used, but SRA more accurate$|k", X @` H < ( ?  hDx @`s H <( ?i` Heparin-dependent IgG has and Fc receptor that causes platelets to aggregate together -starts 3-14 days after initiation of heparin, d @`  H <!( ?i jMech @`  H <v( ? `i cVenous, occasional arterial @`  H <( ? i PSite @``B  H 0o ? ` ZB  H s *1 ?i`iZB H s *1 ?`ZB H s *1 ? ` `B H 0o ? ` `B H 0o ?  ZB H s *1 ?  `B H 0o ?` ` RB H s *D`P`RB H s *D H H 0޽h ? 3fff___PPT10i.Ϧpr+D='  = @B +  0 0 L}(  Lx L c $(  ``}  (    `  L #""_# ` ( J L <( ?` Z-heparin, then coumadin to keep INR >3 -heparin or LMW heparin in pregnancy (ck Factor Xa)[[,@ @` L <$( ? hTx @` L <( ? ` -prolonged APTT -! antiphospholipid or anticardiolipin Ab titer -prolonged Russell viper venom time ! by adding excess phospholipids$t">L @` L <H( ?  hDx @` L <( ?i`  VIgG against 2 glycoprotein I and prothrombin. -lots of theories on mechanisms (inhibits APC activation, increase PAI-1 levels, directly activates plts, endothelial cell activation, ! tissue factor -5-16x ! risk thrombosis, graft thrombosis in 27-50% -33% pts will have at least one thrombotic event$,  "^  f  @`  L <6( ?i  jMech @`  L <9( ? `i cVenous, occasional arterial @`  L <V( ? i PSite @``B  L 0o ? ` ZB  L s *1 ?i`iZB L s *1 ? ` ZB L s *1 ?``B L 0o ?``B L 0o ? ZB L s *1 ? `B L 0o ?` `RB L s *D`P`RB L s *D H L 0޽h ? 3fff___PPT10i.Ϧpr+D='  = @B +  0 @PY(  Px P c $0b(  ``}  (     ` P #""_# ` ( k P <$A ? ` i-heparin, then coumadin -long-term coumadin controversial b/c of low risk of recurrent VTE (RR only 2.4)jj> , @` P <C ?  hTx @` P <U ?v `  g-clot based assay$" @` P <^ ?v   hDx @`g P <l ?i`v  -Resistance to inactivation of Factor Va by APC asa a result of substitution of a glutamine for arginine in the protein for Factor V -Heterozygotes have 7-fold increased risk -Homozygotes have 80-fold increased risk -RR 2.4 for recurrent VTE, more if taking OCP, pregnant, concurrent prothrombin 20210A.."t%-  a  @`  P <v ?iv  jMech @`  P <x ? `i z2Venous, occasional arterial, LE revascularizations33 @`  P <t ? i PSite @``B  P 0o ? ` ZB  P s *1 ?i`iZB P s *1 ?v `v ZB P s *1 ? ` `B P 0o ?``B P 0o ? ZB P s *1 ? `B P 0o ?` `RB P s *D`P`RB P s *D H P 0޽h ? 3fff___PPT10i.Ϧpr+D=' {= @B +  0   PT (  Tx T c $  ``}      `  T #""_# `   % T <T ?`  G-folate supplements -long-term benefit has not been shown in literatureHHA @` T < ?  hTx @` T < ?` -fasting homocysteine levels$"  @` T <0 ? hDx @` T < ?i` V-homocysteine elevation injures endothelial cells -in combo with factor V Leiden, ! risk thrombosis -RR 2.5mm", > @`  T <` ?i jMech @`  T < ? `i YVenous = Arterial @`  T <2 ? i PSite @``B  T 0o ? ` ZB  T s *1 ?i`iZB T s *1 ?`ZB T s *1 ?``B T 0o ? ` `B T 0o ?  ZB T s *1 ?  `B T 0o ?` ` RB T s *D`P`RB T s *D H T 0޽h ? 3fff___PPT10i.Ϧpr+D=' ( = @B +v  0 `X(  Xx X c $;  ``}      ` X #""_# `   X < ? ` "-Lifelong anticoagulation if you have recurrent VTE s or concurrent factor V LeidenTT,0 @` X <P ?  hTx @` X < ? `  z$-genetic analysis for 20210 mutation$%$" @` X < ?   hDx @` X <ג?i`   -genetic polymorphism, G20210A, in the prothrombin gene causes it to be expressed at higher levels -2-7 fold increase in VTE -only increase arterial thrombus risk if you smoke -!risk in pregnant women and women with early MI s -syngergistic with factor V Leiden">'   @`  X <4ݒ?i  jMech @`  X <? `i YVenous > Arterial @`  X <? i PSite @``B  X 0o ? ` ZB  X s *1 ?i`iZB X s *1 ? ` ZB X s *1 ? ` `B X 0o ?``B X 0o ? ZB X s *1 ? `B X 0o ?` `RB X s *D`P`RB X s *D H X 0޽h ? 3fff___PPT10i.Ϧpr+D=' ( = @B +  0 p \I(  \x \ c $  ``}      `  \ #""_# `   \ <ϒ? ` - standard of anticoagulation therapy -too few documented cases to understand the true long-term riskgg @` \ <,?  hTx @`[ \ <Ò?h`  o-fibrinogen clotting activity-to-Ag ratio -prolonged thrombin clotting or reptilase time -serum lipoprotein (a)$po"J  @` \ <ɒ?h  hDx @` \ <?i`h g-abnormal fibrinogens: defective thrombin binding or resistant to plasmin-mediated brkdwn;digital ischemia -Lp (a) + LDL is atherogenic and prothrombotic; assoc with childhood VTE"bB     @`  \ <?ih jMech @`  \ <? `i YVenous = Arterial @`  \ <? i PSite @``B  \ 0o ? ` ZB  \ s *1 ?i`iZB \ s *1 ?h`hZB \ s *1 ? ` `B \ 0o ?``B \ 0o ? ZB \ s *1 ? `B \ 0o ?` `RB \ s *D`P`RB \ s *D H \ 0޽h ? 3fff___PPT10i.Ϧpr+D=' ( = @B +  0 `y(  `x ` c $ ``}      ` ` #""_# `  ` <d? ` p- standard of anticoagulation therapy -too few documented cases to understand the true long-term risk -ASA or clopidigrel may helpo   @` ` <?  hTx @`` ` < ?`  t-Check if platelets respond to a platelet agonist (i.e. ADP, epinephrine, collagen) at concentreations below normal $ut"W @` ` <?  hDx @`e ` <(?i` s-hyperactive or hyperresponsive platelets -diabetes worsens condition -seen s/p CEA, in advanced uterine or lung CAtt",-% @`  ` <?i jMech @`  ` <? `i 4Arterial > Venous, thrombus in peripheral vasc recon55* @`  ` <`? i PSite @``B  ` 0o ? ` ZB  ` s *1 ?i`iZB ` s *1 ?`ZB ` s *1 ? ` `B ` 0o ?``B ` 0o ? ZB ` s *1 ? `B ` 0o ?` `RB ` s *D`P`RB ` s *D H ` 0޽h ? 3fff___PPT10i.Ϧpr+D=' ( = @B +  0   dO (  dx d c $ ``}      `  d #""_# `   d < ?o`  L- standard of anticoagulation therapy '' @` d < ?o  hTx @` d < ?P`o .-Direct measure of factors with activity assay$/." @` d < ?Po hDx @` d <T ?i`P P-Factor VIII: if above 90th percentile, 5-fold ! risk -Factor XI: if above 90th percentile, 2-fold ! riskLj"*2"*" @`  d <84{?iP jMech @`  d <>{? `i YVenous > Arterial @`  d <F{? i PSite @``B  d 0o ? ` ZB  d s *1 ?i`iZB d s *1 ?P`PZB d s *1 ?o`o`B d 0o ? ` `B d 0o ?  ZB d s *1 ?  `B d 0o ?` ` RB d s *D`P`RB d s *D H d 0޽h ? 3fff___PPT10i.Ϧpr+D=' ( = @B +}  0 p$(  pr p S    `}   r p S    `    H p 0޽h ? 3fff___PPT10i.+D=' ( = @B +[  0 rjt(  tr t S    `}   r t S        RB t s *D`RB t s *DRB t s *D RB t s *D RB  t s *D RB  t s *D` pRB  t s *D  RB  t s *D0 RB t s *D P  RB t s *D  RB t s *Dp@pH t 0޽h ? 3fff___PPT10i. +D=' ( = @B +rh+S>LnOQ\hj-mo7rtYw Gz4? N!1Oh+'0U hp  $ 0 <HP@Chapter 34 Vascular Thrombosis Due to Hypercoagulable States Erika LuOrbitJason T. 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Lee, MDJason T. Lee, MD  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root EntrydO)Current UserSummaryInformation(0UPowerPoint Document(E"DocumentSummaryInformation8