Chapter 34 Vascular Thrombosis Due to Hypercoagulable States Erika 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

Biochemistry of Thrombosis PK 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 Fibrinogen

Biochemistry of Thrombosis PK 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 Fibrinogen

Arterial Thrombosis White 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

Arterial Thrombosis Manifests 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 a

Venous Thromboembolism Red 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

Venous Thromboembolism Less 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

Venous Thromboembolism Acquired Risk Factors: Immobility Obesity Chronic neurologic disease Cardiac disease Pregnancy, use of OCP’s Surgery, particularly thoracoabdominal, ortho, GYN Trauma Malignancy Nephrotic syndrome

Venous Thromboembolism Interesting 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

Antithrombin Deficiency (1-2%) Site Venous Mech AT is a serine protease inhibitor (SERPIN) of thrombin, kallikrein, factors Xa, IXa, VIIa, XIIa, XIa. Congenital: autosomal dominant; heterozygotes live Acquired: liver dz, malignancy, sepsis, malnutrition, ESRD, DIC Dx Cannot be adequately anticoagulated on heparin (heparin potentiates anticoagulant effect of AT) -check AT Ag and AT activity Tx -heparin + FFP (2 u q8 hr 1 u q12 hr) -hirudin, argatroban, bivalirudin (direct thrombin inhibitor) -lifelong anticoagulation

Protein C and S Deficiencies (2-5%) Site Venous, occasional arterial Mech Protein 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 Dx Low Protein C or S Ag levels Tx -anticoagulate with heparin, then lifelong -only tx those that are sx’atic, since many subclinical, but aggressive periop ppx if genotype known

Heparin-Induced Thrombocytopenia & Thrombosis Syndrome (up to 30%) Site Venous, occasional arterial Mech Heparin-dependent IgG has and Fc receptor that causes platelets to aggregate together -starts 3-14 days after initiation of heparin Dx -suspect if plts ↓ by 50% or if Plts<100K -suspect if thrombosis in unusual area -ELISA usually used, but SRA more accurate Tx -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 abciximab

Lupus Anticoagulant/Antiphospholipid Syndrome Site Venous, occasional arterial Mech IgG against β2 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 Dx -prolonged APTT -↑ antiphospholipid or anticardiolipin Ab titer -prolonged Russell viper venom time ↓ by adding excess phospholipids Tx -heparin, then coumadin to keep INR >3 -heparin or LMW heparin in pregnancy (ck Factor Xa)

Factor V Leiden (resistance to APC) Site Venous, occasional arterial, LE revascularizations Mech 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 Dx -clot based assay Tx -heparin, then coumadin -long-term coumadin controversial b/c of low risk of recurrent VTE (RR only 2.4)

Hyperhomocysteinemia (10%) Site Venous = Arterial Mech -homocysteine elevation injures endothelial cells -in combo with factor V Leiden, ↑ risk thrombosis -RR 2.5 Dx -fasting homocysteine levels Tx -folate supplements -long-term benefit has not been shown in literature

Prothrombin G20210 Polymorphism (4-6%) Site Venous > Arterial Mech -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 Dx -genetic analysis for 20210 mutation Tx -Lifelong anticoagulation if you have recurrent VTE’s or concurrent factor V Leiden

Defective Fibrinolysis, Dysfibrinogenemia, and Lipoprotein (a) Site Venous = Arterial Mech -abnormal fibrinogens: defective thrombin binding or resistant to plasmin-mediated brkdwn;digital ischemia -Lp (a) + LDL is atherogenic and prothrombotic; assoc with childhood VTE Dx -fibrinogen clotting activity-to-Ag ratio -prolonged thrombin clotting or reptilase time -serum lipoprotein (a) Tx -”standard of anticoagulation therapy” -too few documented cases to understand the true long-term risk

Abnormal Platelet Aggregation Site Arterial > Venous, thrombus in peripheral vasc recon Mech -hyperactive or hyperresponsive platelets -diabetes worsens condition -seen s/p CEA, in advanced uterine or lung CA Dx -Check if platelets respond to a platelet agonist (i.e. ADP, epinephrine, collagen) at concentreations below normal Tx -”standard of anticoagulation therapy” -too few documented cases to understand the true long-term risk -ASA or clopidigrel may help

Elevated Procoagulant Factors: VIII, IX, XI Site Venous > Arterial Mech -Factor VIII: if above 90th percentile, 5-fold ↑ risk -Factor XI: if above 90th percentile, 2-fold ↑ risk Dx -Direct measure of factors with activity assay Tx -”standard of anticoagulation therapy”

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 Β2 glycoprotein I antibodies PT/PTT D-dimer

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