1. Chapter 34 Vascular Thrombosis Due to Hypercoagulable States
Erika Lu
August 22, 2005
Vascular Surgery Conference

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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)

15. 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)

16. 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

17. 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 mutation Tx
-Lifelong anticoagulation if you have recurrent VTE’s or concurrent factor V Leiden

18. 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

19. 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

20. 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”

21. 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

22. 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