Chapter 34Chapter 34Vascular Thrombosis Due to Vascular Thrombosis Due to

Hypercoagulable StatesHypercoagulable States

Erika LuErika Lu

August 22, 2005August 22, 2005

Vascular Surgery ConferenceVascular Surgery Conference

EpidemiologyEpidemiology

Thrombosis is the major cause of death in the Thrombosis is the major cause of death in the worldworld MI and stroke (arterial thrombosis) are the #1 and #2 MI and stroke (arterial thrombosis) are the #1 and #2

killer worldwidekiller worldwide

Molecular defects increase a patient’s risk for Molecular defects increase a patient’s risk for thrombosis in 18%-30% of all cases of venous thrombosis in 18%-30% of all cases of venous thromboembolismthromboembolism

Arterial thrombosis more likely Arterial thrombosis more likely environmental/acquired cause rather than environmental/acquired cause rather than inherited disorderinherited disorder

Biochemistry of ThrombosisBiochemistry of Thrombosis

PKPK KallikreinKallikrein PlasminogenPlasminogen

XIIXII XIIaXIIa C4bBPC4bBP PAI-1PAI-1XIaXIa Protein SProtein S PlasminPlasminIXaIXa APCAPC Insol FibrinInsol Fibrin

FDPFDPVIIIaVIIIa

VIIa-TFVIIa-TF XaXa FVLFVL Sol FibrinSol FibrinVaVa ATAT

II G20210AII G20210A ThrombinThrombinHCIIHCII FibrinogenFibrinogen

Biochemistry of ThrombosisBiochemistry of Thrombosis

PKPK KallikreinKallikrein PlasminogenPlasminogen

XIIXII XIIaXIIa C4bBPC4bBP PAI-1PAI-1XIaXIa Protein SProtein S PlasminPlasminIXaIXa APCAPC Insol FibrinInsol Fibrin

FDPFDPVIIIaVIIIa

VIIa-TFVIIa-TF XaXa FVLFVL Sol FibrinSol FibrinVaVa ATAT

II G20210AII G20210A ThrombinThrombinHCIIHCII FibrinogenFibrinogen

Arterial ThrombosisArterial Thrombosis

White clot – platelet richWhite clot – platelet richRare to see arterial thrombus in a healthy Rare to see arterial thrombus in a healthy

vesselvesselUsually atherosclerotic change with…Usually atherosclerotic change with…

DiabetesDiabetesHyperlipidemiaHyperlipidemiaTobacco useTobacco use

Acquired procoagulant states (i.e. HIT and Acquired procoagulant states (i.e. HIT and antiphosholipid antibodiesantiphosholipid antibodies

Arterial ThrombosisArterial Thrombosis

Manifests in large vessel occlusionsManifests in large vessel occlusions MI and strokeMI and stroke Peripheral vascular occlusive diseasePeripheral vascular occlusive disease

There are genetic polymorphisms that may There are genetic polymorphisms that may increase your risk, but not really predictive of increase your risk, but not really predictive of risk of thrombus when you look at large risk of thrombus when you look at large population studiespopulation studies Elevated factor VIIElevated factor VII Elevated fibrinogenElevated fibrinogen HyperhomocysteinemiaHyperhomocysteinemia Elevated lipoprotein aElevated lipoprotein a

Venous ThromboembolismVenous Thromboembolism

Red clot – RBC’s trapped in fibrin strandsRed clot – RBC’s trapped in fibrin strandsVirchow’s TriadVirchow’s Triad: vessel wall change, : vessel wall change,

hypercoagulability and stasis have a major hypercoagulability and stasis have a major role!role!

Classic Protein Deficiencies:Classic Protein Deficiencies:Antithrombin III deficiencyAntithrombin III deficiencyProtein C deficiencyProtein C deficiencyProtein S deficiencyProtein S deficiency

Venous ThromboembolismVenous Thromboembolism

Less common causes for thrombosisLess common causes for thrombosis Abnormal fibrinogenAbnormal fibrinogen Abnormal plasminogenAbnormal plasminogen Elevated factors XI, IX, and VIIIElevated factors XI, IX, and VIII

Hematologic conditions that cause Hematologic conditions that cause hypercoagulabilityhypercoagulability TTPTTP HUSHUS DICDIC Polycythemia vera and essential thrombocythemiaPolycythemia vera and essential thrombocythemia

Venous ThromboembolismVenous Thromboembolism

Acquired Risk Factors:Acquired Risk Factors: ImmobilityImmobility ObesityObesity Chronic neurologic diseaseChronic neurologic disease Cardiac diseaseCardiac disease Pregnancy, use of OCP’s Pregnancy, use of OCP’s Surgery, particularly thoracoabdominal, ortho, GYN Surgery, particularly thoracoabdominal, ortho, GYN TraumaTrauma MalignancyMalignancy Nephrotic syndromeNephrotic syndrome

Venous ThromboembolismVenous Thromboembolism

Interesting Factoids on Cancer and VTEInteresting Factoids on Cancer and VTEOccult cancer in 0.5 – 5% of VTE ptsOccult cancer in 0.5 – 5% of VTE pts3x more likely to get cancer in next 3 yrs if 3x more likely to get cancer in next 3 yrs if

idiopathic VTEidiopathic VTE19% of cancer pts have a VTE19% of cancer pts have a VTEChemo increases risk of VTE because it Chemo increases risk of VTE because it

increases tissue factor and expression of E-increases tissue factor and expression of E-selectin, thereby increasing thrombus selectin, thereby increasing thrombus potentialpotential

Antithrombin Deficiency (1-2%)Antithrombin Deficiency (1-2%)SiteSite VenousVenous

MechMech AT is a serine protease inhibitor (SERPIN) of AT is a serine protease inhibitor (SERPIN) of thrombin, kallikrein, factors Xa, IXa, VIIa, XIIa, XIa.thrombin, kallikrein, factors Xa, IXa, VIIa, XIIa, XIa.

Congenital: autosomal dominant; heterozygotes liveCongenital: autosomal dominant; heterozygotes live

Acquired: liver dz, malignancy, sepsis, malnutrition, Acquired: liver dz, malignancy, sepsis, malnutrition, ESRD, DICESRD, DIC

DxDx Cannot be adequately anticoagulated on heparin Cannot be adequately anticoagulated on heparin (heparin potentiates anticoagulant effect of AT)(heparin potentiates anticoagulant effect of AT)

-check AT Ag and AT activity-check AT Ag and AT activity

TxTx -heparin + FFP (2 u q8 hr 1 u q12 hr)-heparin + FFP (2 u q8 hr 1 u q12 hr)

-hirudin, argatroban, bivalirudin (direct thrombin -hirudin, argatroban, bivalirudin (direct thrombin inhibitor)inhibitor)

-lifelong anticoagulation-lifelong anticoagulation

Protein C and S Deficiencies (2-5%)Protein C and S Deficiencies (2-5%)SiteSite Venous, occasional arterialVenous, occasional arterial

MechMech Protein CProtein C: inactivates Factos Va & VIIa less thrombin: inactivates Factos Va & VIIa less thrombin

-also stimulates t-PA liberation, -also stimulates t-PA liberation, ↑ fibrinolysis↑ fibrinolysis

Protein SProtein S: cofactor to APC, regulated by C4b: cofactor to APC, regulated by C4b

-free protein S is an active anticoagulant-free protein S is an active anticoagulant

CongenitalCongenital: autosomal dominant; heterozygotes live: autosomal dominant; heterozygotes live

AcquiredAcquired: liver failure, DIC, nephrotic syndrome: liver failure, DIC, nephrotic syndrome

DxDx Low Protein C or S Ag levelsLow Protein C or S Ag levels

TxTx -anticoagulate with heparin, then lifelong-anticoagulate with heparin, then lifelong

-only tx those that are sx’atic, since many subclinical, -only tx those that are sx’atic, since many subclinical, but aggressive periop ppx if genotype knownbut aggressive periop ppx if genotype known

Heparin-Induced Thrombocytopenia & Thrombosis Heparin-Induced Thrombocytopenia & Thrombosis Syndrome (up to 30%)Syndrome (up to 30%)

SiteSite Venous, occasional arterialVenous, occasional arterial

MechMech Heparin-dependent IgG has and Fc receptor that Heparin-dependent IgG has and Fc receptor that causes platelets to aggregate togethercauses platelets to aggregate together

-starts 3-14 days after initiation of heparin-starts 3-14 days after initiation of heparin

DxDx -suspect if plts -suspect if plts ↓ by 50% or if Plts<100K↓ by 50% or if Plts<100K

-suspect if thrombosis in unusual area-suspect if thrombosis in unusual area

-ELISA usually used, but SRA more accurate-ELISA usually used, but SRA more accurate

TxTx -stop all heparin, including flushes-stop all heparin, including flushes

-coumadin only if initially used w/ other anticoagulant -coumadin only if initially used w/ other anticoagulant due to initial prothrombotic statedue to initial prothrombotic state

-cannot use LMW heparin (92% cross-reactivity)-cannot use LMW heparin (92% cross-reactivity)

-Hirudin or argatroban or abciximab-Hirudin or argatroban or abciximab

Lupus Anticoagulant/Antiphospholipid SyndromeLupus Anticoagulant/Antiphospholipid Syndrome

SiteSite Venous, occasional arterialVenous, occasional arterial

MechMech IgG against IgG against ββ2 glycoprotein I and prothrombin.2 glycoprotein I and prothrombin.

-lots of theories on mechanisms (inhibits APC -lots of theories on mechanisms (inhibits APC activation, increase PAI-1 levels, directly activates activation, increase PAI-1 levels, directly activates plts, endothelial cell activation, ↑ tissue factorplts, endothelial cell activation, ↑ tissue factor

-5-16x ↑ risk thrombosis, graft thrombosis in 27-50%-5-16x ↑ risk thrombosis, graft thrombosis in 27-50%

-33% pts will have at least one thrombotic event-33% pts will have at least one thrombotic event

DxDx -prolonged APTT-prolonged APTT

--↑ antiphospholipid or anticardiolipin Ab titer↑ antiphospholipid or anticardiolipin Ab titer

-prolonged Russell viper venom time ↓ by adding -prolonged Russell viper venom time ↓ by adding excess phospholipidsexcess phospholipids

TxTx -heparin, then coumadin to keep INR >3-heparin, then coumadin to keep INR >3

-heparin or LMW heparin in pregnancy (ck Factor Xa)-heparin or LMW heparin in pregnancy (ck Factor Xa)

Factor V Leiden (resistance to APC)Factor V Leiden (resistance to APC)

SiteSite Venous, occasional arterial, LE revascularizationsVenous, occasional arterial, LE revascularizations

MechMech Resistance to inactivation of Factor Va by APC asa a Resistance to inactivation of Factor Va by APC asa a result of substitution of a glutamine for arginine in the result of substitution of a glutamine for arginine in the protein for Factor Vprotein for Factor V

-Heterozygotes have 7-fold increased risk-Heterozygotes have 7-fold increased risk

-Homozygotes have 80-fold increased risk-Homozygotes have 80-fold increased risk

-RR 2.4 for recurrent VTE, more if taking OCP, -RR 2.4 for recurrent VTE, more if taking OCP, pregnant, concurrent prothrombin 20210Apregnant, concurrent prothrombin 20210A

DxDx -clot based assay-clot based assay

TxTx -heparin, then coumadin -heparin, then coumadin

-long-term coumadin controversial b/c of low risk of -long-term coumadin controversial b/c of low risk of recurrent VTE (RR only 2.4)recurrent VTE (RR only 2.4)

Hyperhomocysteinemia (10%)Hyperhomocysteinemia (10%)

SiteSite Venous = ArterialVenous = Arterial

MechMech -homocysteine elevation injures endothelial cells -homocysteine elevation injures endothelial cells

-in combo with factor V Leiden, ↑ risk thrombosis-in combo with factor V Leiden, ↑ risk thrombosis

-RR 2.5-RR 2.5

DxDx -fasting homocysteine levels-fasting homocysteine levels

TxTx -folate supplements-folate supplements

-long-term benefit has not been shown in literature-long-term benefit has not been shown in literature

Prothrombin G20210 Polymorphism (4-6%)Prothrombin G20210 Polymorphism (4-6%)

SiteSite Venous > ArterialVenous > Arterial

MechMech -genetic polymorphism, G20210A, in the prothrombin -genetic polymorphism, G20210A, in the prothrombin gene causes it to be expressed at higher levelsgene causes it to be expressed at higher levels

-2-7 fold increase in VTE-2-7 fold increase in VTE

-only increase arterial thrombus risk if you smoke-only increase arterial thrombus risk if you smoke

-↑risk in pregnant women and women with early MI’s-↑risk in pregnant women and women with early MI’s

-syngergistic with factor V Leiden-syngergistic with factor V Leiden

DxDx -genetic analysis for 20210 mutation-genetic analysis for 20210 mutation

TxTx -Lifelong anticoagulation if you have recurrent VTE’s -Lifelong anticoagulation if you have recurrent VTE’s or concurrent factor V Leidenor concurrent factor V Leiden

Defective Fibrinolysis, Dysfibrinogenemia, and Defective Fibrinolysis, Dysfibrinogenemia, and Lipoprotein (a)Lipoprotein (a)

SiteSite Venous = ArterialVenous = Arterial

MechMech -abnormal fibrinogens: defective thrombin binding or -abnormal fibrinogens: defective thrombin binding or resistant to plasmin-mediated brkdwn;digital ischemiaresistant to plasmin-mediated brkdwn;digital ischemia

-Lp (a) + LDL is atherogenic and prothrombotic; -Lp (a) + LDL is atherogenic and prothrombotic; assoc with childhood VTEassoc with childhood VTE

DxDx -fibrinogen clotting activity-to-Ag ratio-fibrinogen clotting activity-to-Ag ratio

-prolonged thrombin clotting or reptilase time-prolonged thrombin clotting or reptilase time

-serum lipoprotein (a)-serum lipoprotein (a)

TxTx -”standard of anticoagulation therapy”-”standard of anticoagulation therapy”

-too few documented cases to understand the true -too few documented cases to understand the true long-term risklong-term risk

Abnormal Platelet AggregationAbnormal Platelet Aggregation

SiteSite Arterial > Venous, thrombus in peripheral vasc reconArterial > Venous, thrombus in peripheral vasc recon

MechMech -hyperactive or hyperresponsive platelets-hyperactive or hyperresponsive platelets

-diabetes worsens condition-diabetes worsens condition

-seen s/p CEA, in advanced uterine or lung CA-seen s/p CEA, in advanced uterine or lung CA

DxDx -Check if platelets respond to a platelet agonist (i.e. -Check if platelets respond to a platelet agonist (i.e. ADP, epinephrine, collagen) at concentreations below ADP, epinephrine, collagen) at concentreations below normal normal

TxTx -”standard of anticoagulation therapy”-”standard of anticoagulation therapy”

-too few documented cases to understand the true -too few documented cases to understand the true long-term risklong-term risk

-ASA or clopidigrel may help-ASA or clopidigrel may help

Elevated Procoagulant Factors: VIII, IX, XIElevated Procoagulant Factors: VIII, IX, XI

SiteSite Venous > ArterialVenous > Arterial

MechMech -Factor VIII: if above 90-Factor VIII: if above 90thth percentile, 5-fold ↑ risk percentile, 5-fold ↑ risk

-Factor XI: if above 90-Factor XI: if above 90thth percentile, 2-fold ↑ risk percentile, 2-fold ↑ risk

DxDx -Direct measure of factors with activity assay-Direct measure of factors with activity assay

TxTx -”standard of anticoagulation therapy”-”standard of anticoagulation therapy”

What tests do we order?What tests do we order? Antithrombin activity and antigen assayAntithrombin activity and antigen assay Protein C activity and antigen assayProtein C activity and antigen assay Free protein S antigen assauFree protein S antigen assau APC resistance assayAPC resistance assay Factor V Leiden by PCRFactor V Leiden by PCR Homocysteine levelHomocysteine level Prothromnin G20210A by PCRProthromnin G20210A by PCR Antiphospholipid or anticardiolipin AbAntiphospholipid or anticardiolipin Ab Clottable fibrinogen and fibrinogen antigenClottable fibrinogen and fibrinogen antigen Dilute Russell viper venom timeDilute Russell viper venom time Tissue thromboplastin inhibition timeTissue thromboplastin inhibition time ΒΒ2 glycoprotein I antibodies2 glycoprotein I antibodies PT/PTTPT/PTT D-dimerD-dimer

Suggested Treatment AlgorithmSuggested Treatment Algorithm

3-6 months3-6 months Aggessive ppxAggessive ppxanticoaganticoag for 2for 2ndnd VTE VTE

YesYesVTEVTE AcuteAcute IdentifiableIdentifiable

TherapyTherapy Risk/EtiologyRisk/EtiologyNoNo

Test for HypercoagTest for Hypercoag ? 6 months? 6 monthsStateState Neg Neg

AnticoagulationAnticoagulation++

Low risk recurLow risk recurHi-risk recurrenceHi-risk recurrence Life-long Life-long

anticoagulationanticoagulation