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Hypercoagulability and Stroke Teresa L. Carman, M.D. Director, Vascular Medicine University Hospitals Case Medical Center October 7, 2010 No conflicts to disclose relative to lecture content

Objectives • To review general thrombotic risk factors • To identify which thrombophilic conditions are associated with arterial events • To discuss the goals of thrombophilic evaluation in patients with acute ischemic stroke

Embolic vs. Thrombotic Embolic Ø


Arteriopathies Thrombotic Artery-arteryØVasculitis embolism Ø Advanced atherosclerosis ØMoya-Moya » Aortic arch atheroma Ø Acute arterial thrombosis » Carotid/SCA plaque Traumatic Ø Thrombophilias » Ruptured arterial ØExternal injury plaque Ø Malignancy ØDissection » Fibromuscular dysplasia Ø Aneurysm thrombosis ØIatrogenic injury Cardiac Drugs » Arrhythmia/thrombus » Aneurysm ØSympathomimetics » Tumor/mass/vegetation » Paradoxical

Cryptogenic Stroke • 30-40% have an undetermined etiology Ø


Etiology is transient and reversible and the evaluation is outside the diagnostic window Inadequate investigation Knowledge deficit of underlying etiologies

J Thromb Haemost 2008;6:549-554.

Thrombophilia Natural anticoagulant deficiency Ø Ø Ø

Protein C Protein S Antithrombin (AT)

Factor excess Ø Ø Ø Ø Ø Ø

F VIII Fibrinogen F IX F XI F VII PAI-1

Genetic defects Ø Ø Ø Ø Ø Ø Ø

Factor V Leiden (FVL) Prothrombin gene mutation (PT G20210A) Hyperhomocysteinemia (tl-MTHFR) Lipoprotein(a) Dysplasminogemia Dysfibrinoginemia Heparin cofactor II

Antiphospholipid antibodies Ø Ø Ø

Lupus anticoagulant Anticardiolipin antibodies ? 2 - glycoprotein – I Ab

Thrombophilia Testing • Many natural anticoagulants will decrease in the acute setting • Factor VIII and lipoprotein (a) are acute phase reactants and testing may be inaccurate • Anticoagulation interferes with antithrombin and lupus anticoagulant testing • Most testing should be repeated for confirmation

Natural Anticoagulants Protein C, Protein S, Antithrombin • Associated with VTE – Early thrombosis and ? recurrent VTE • < 1% of the general population

• 2-3% of selected populations with venous thrombosis • Autosomal dominant inheritance • Unclear association with arterial events • Testing is likely not warranted

Factor V Leiden •

Single amino acid substitution (G1691A, Arg506Gln) renders FVa resistant to cleavage by activated protein C

Common mutation


3-7% of the population


3-8X increased risk for VTE in heterozygotes (50-100X increased risk in homozygotes)

No clear association with arterial events Ø


Minor associations in meta-analyses and population studies especially in young patients without traditional arterial risk factors Association with MI in young female smokers Increased prevalence noted in patients with PAD and graft failure Kim et al. Am Heart J 2003;146:948-957.

Prothrombin Gene Mutation • 2-3% of the general population • 2-3X increased risk of VTE • Not well associated with arterial events • Associated with cerebral sinus thrombosis (OCP)

Kim et al. Am Heart J 2003;146:948-957.

Inherited Thrombophilia and Stroke • Meta-analysis Ø 56

studies and 54,547 persons included in analysis


– OR 1.27 (CI 0.86-1.87) Ø PTG20210A – OR 1.30 (CI 0.91-1.87) Ø MTHFR (TT) – OR 1.46 (CI 1.19-1.79) Ø Risks slightly higher in patients <55 yrs and women Kim et al. Am Heart J 2003;146:948-957.

Genetic Testing and Stroke • 887 patients with non-disabling arterial cerebral ischemia Ø Ø Ø


Mean age 62.4 yrs (23.3-90.1) Evaluated 22 variants of 14 genetic traits 4.6 yr follow up for new arterial events No association of the variants with recurrent events Did not support the use of variants to identify patients at future risk nor to guide therapeutic choice of antithrombotic therapy

Pruissen et al. J Thromb Haemost 2008;6:1639-1644.

Factor V Leiden, Prothrombin Gene Mutation (G20210A) Protein C, Protein S, and Antithrombin: Arterial Thrombosis

General conclusions: these are not major risk factors for stroke, MI, or other arterial thrombosis â&#x20AC;˘ Small studies have suggested a role in select populations â&#x20AC;˘ No effect seen in larger studies including the PHS

Including individuals at a young age (<50), females, with no predisposing risk factors (no HTN, DM, smoking, HPL) and no flow limiting arterial lesions at angiography

Feinbloom D. Arterioscler Thromb Vasc Biol 2005; 25: 2043

Andreotti F. Circulation 2005; 111: 1855

Antiphospholipid Antibodies • Lupus anticoagulant (LA), Anticardiolipin antibodies (ACA) and ß2 - glycoprotein – I antibodies Ø Bind

negatively charged phospholipids or phospholipid-protein complexes Ø ß2 - glycoprotein - I, prothrombin, protein C

• Risk of thrombosis is variable (30%) Ø Risk

of recurrent thrombosis 20-70%* Ø May be primary or secondary (associated with CTD, autoimmune d/o, malignancy, infection) Ø May be transient or persistent *Petri M. Rheum Dis Clin 2001;27:633.

Antiphospholipid Antibody Syndrome • Antiphospholipid antibody syndrome (APS) Ø Ø Ø

Antiphospholipid antibodies (confirmed at 12 weeks) Associated arterial or venous thrombosis Recurrent fetal loss, pregnancy morbidity or thrombocytopenia (?)

• Prevalence in the general population is unknown Healthy blood donor studies – LA 8% and ACA 16% Ø Unknown significance of “asymptomatic” occurrences Ø

• Other APLA syndromes Ø Catastrophic APS Ø Intracardiac thrombi Ø Cardiomyopathy Ø Non-infectious vegetations (Liebman-Sacks endocarditis) Ø Sneddon syndrome

APLA and Recurrent Stroke • 1000 patient with diagnosed APLA Ø Ø Ø Ø Ø Ø Ø

European cohort - followed prospectively for 5 years 82% female; mean age 42 years (range 0-82) 53% primary APS and 41% SLE or lupus-like syndrome 42% were anticoagulated and 35% were on antiplatelets 16.6% developed recurrent thrombosis over 5-years 2.4% strokes and 2.3% TIA 90 patients were on OAC and 49 on anti-platelets at the time of the thrombotic event

Cervera et al. Ann Rheum Dis 2009;68:1428-1432.

APLA Testing • Lupus anticoagulant testing Ø Prolongation of a phospholipid dependent clotting test (sensitive aPTT, DRVVT, Kaolin clotting time) Ø No evidence for an inhibitor on mixing studies (Acquired factor inhibitors, heparin, or direct thrombin inhibitors (TT/FVIII) Ø Confirmation demonstrating phospholipid dependence (PNP)

ACA testing by ELISA Ø IgG probably most significant (IgM testing currently recommended) Ø Best interpreted as low, medium, high titers » < 20 GPL - probably not significant » 20-40 GPL - indeterminate significance (event considerations) » > 40 GPL – significant (Lab variable) B2-GP1 testing by ELISA Ø Currently not included in diagnostic criteria Ø Laboratory assays are not standardized Ø Titers > 40 are likely significant

APLA Testing Pearls • ACA and ß2-GP-1 ab ELISA testing are not affected in the acute setting or by anticoagulants • Lupus anticoagulant testing may be affected by anticoagulants – avoid testing while on UFH, LMWH, fondaparinux, or warfarin • Confirmation testing must be repeated at 12 weeks after diagnosis

APLA Pearls Treatment • Demonstration of prolonged clotting times may influence the choice of anticoagulant and the monitoring of the anticoagulant Ø Ø Ø

Consideration may be given to using a LMWH instead of UFH Baseline elevated aPTT may require monitoring of UFH with Heparin assay (anti-Xa assay) = 0.3-0.7 Warfarin therapy adjusted to maintain an INR which correlates to factor X and factor II of 20-25% normal (most patients INR = 2-3)

• Persistently positive results typically require indefinite AC therapy

Hyperhomocysteinemia • Associated with atherothrombosis and VTE • Fasting plasma homocysteine (>15 µmol/L) Ø

No clinical role for tl-MTHFR testing


RBC folate


Vitamin B12

• Acquired deficiency Ø

Vitamin deficiency - folate/B12/B6


CKD, hypothyroidism, pernicious anemia, DM, malignancy


Medications (MTX, phenytoin, theophylline)

• May be attributed to genetic defects Ø



Thermolabile-methylene tetrahydrofolate reductase (tl-MTHFR)


Methionine synthase

Hyperhomocysteinemia Treatment - ??????? • Folic acid (400 mcg – 1 mg) Ø Approx 25% reduction • Vitamin B12 (250-500 mcg oral/200-1000 mcg IM) Ø 7% reduction • Vitamin B6 (10-50 mg) • Betaine/choline (methyl donors)

No reduction in arterial event rate, venous events or demonstrable VTE prophylaxis benefits

Lipoprotein (a) Diagnosis • Lp(a) levels > 30 mg/dL increase risk • May be elevated as an acute phase reactant • Found in 20% of patients with VTE • Associated with accelerated atherothrombosis and venous thromboembolism • Measured in the absence of usual risk factors • No therapeutic trials have been performed • Difficult to treat – statins provide minimal reduction in levels • Niacin reduces Lp(a) but tolerability may be an issue

Lipoprotein (a) • Apo(a) has homology to plasminogen – competes for fibrin binding (no fibrinolytic activity) Ø Stimulates

PAI-1 synthesis Ø Promotes ICAM-1 expression on endothelium Ø Inhibits tPA activation of plasminogen Ø Inhibits binding of tPA and plasminogen to fibrin Ø Competes with plasminogen for endothelial and fibrin binding sites

• Functionally impaired fibrinolysis

One Recommendation

Rahemtullah et al. Arch Pathol Lab Med 2007;131:890.

Caveat of Thrombophilias • Knowledge is in flux Ø

Keep up to date

• Testing is complex Ø

Know the limitations of testing with respect to timing, anticoagulant use, and reliability

• Little role for testing in the acute setting Ø Ø Ø

FVL, PTG, APLA before anticoagulation is started Protein C, Protein S, and antithrombin – not likely helpful Homocysteine and lipoprotein (a) best associated with arterial disease but treatment is uncertain

• Tailor your testing to avoid unhelpful information

Medical Morbidity • Do not overlook Ø Medication related events (HITT/TTP) Ø Inflammatory states Ø OCP and HRT use Ø Toxicology Ø Age and gender appropriate solid and hematologic screening

Malignancy Ø Ø Ø Ø

Solid tumors Polycythemia Essential thrombocythemia Hyperviscosity states (MM)

Other Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø

Heparin induced thrombocytopenia HIT(T) DIC Hyperhomocysteinemia HRT/OCP/pregnancy Inflammatory Bowel Disease Sepsis/infection Paroxysmal nocturnal hemoglobinuria Advancing age Nephrotic syndrome Smoking/DM/hyperlipidemia Vasculitis/Inflammation Obesity Drugs (cocaine/sympathomimetics)

Myeloproliferative Disorders • Polycythemia rubra vera Ø Increased

RBC mass (elevated HCT) Ø Iron deficiency (microcytosis)

• Essential thrombocythemia Ø Increased

platelet counts (>600K)

• Multiple myeloma or Waldenstom’s macroglobulinemia Ø Anemia,

renal insufficiency, bone pain, proteinemia

Myeloproliferative Disorders

De Stefano et al. Haematologica 2008;3:372-380.

Multigenic/Multifactorial Hypothesis More than one risk factor is necessary to develop venous thrombosis Likely true in unusual arterial events

1 Congenital risk factor


1 Acquired = risk factor (or 2nd congenital risk factor)


Multigenic/Multifactorial Hypothesis

Slooter et al. J Thromb and Haemost 2005;3:1213-1217.

Martinelli et al. Haematologica 2006;91:844-847.

OCP and Stroke 697 cases vs. 1962 controls Ø OCP use - OR 2.99 Ø age

> 35 yo

» OR 5.94

Ø Current

smoking >10 cig/day

» w/ OCP OR 7.20

Ø HTN » w/OCP OR 10.7 vs. w/o OCP OR 2.71

Lancet 1996;348:498

OCP and Stroke • Meta-analysis Ø 16


» Overall summary risk estimate – 2.75 (2.24-3.38)


studies evaluated CVST risk

» RR 15.9 (6.98-36.2)

Gillum et al. JAMA 2000;284;72-78.

Cerebral Vein Thrombosis 40 CVT/80 DVT/120 control Ø PT G20210A » 20% CVT » 18% DVT » 3% controls

(OR 10.2)

Ø OCP use (OR » 96% CVT » 61% DVT » 32% controls Ø Combined


FV Leiden (OR 3.2) » 14% CVT » 7% (estimated)


(OR 149.3)

N Engl J Med 1998;338:1793

40 CVT/2248 controls

controls Ø OCP

(OR 18)

» 85% CVT » 45% controls

Ø Combined

(OR 34)

BMJ 1998;316:589

Who to test for thrombophilia?

Arterial Thrombosis Risk • Early onset thrombosis (< 45 yrs) • Onset before 55 yrs and the absence of usual arterial risk factors • Early occlusion following a procedure • Paradoxical embolism (VTE) • Event associated with an unexplained personal or FH of VTE

What tests to consider for Arterial Events? • • • • • • • • • •

Echocardiography for PFO, arrhythmia, arch atheroma Lipid profile, Lipoprotein (a) Lupus anticoagulant , anticardiolipin antibodies, ß2glycoprotein-1 antibodies Fasting plasma Homocysteine Drug screen (cocaine) CBC/peripheral blood smear (TTP/HUS, myeloproliferative disorder) Vasculitis work up (WSR, CRP, ANA) Age appropriate malignancy evaluation Check for pregnancy, oral contraceptives or HRT use Heparin-induced thrombocytopenia antibodies Genetic tests: FVL and PTG may be indicated in young people without additional risk factors

Thrombophilia Testing • Only FVL, PTG20210A, anticardiolipin antibodies and ß2-glycoprotein-1 may be tested accurately in the acute setting • Lupus anticoagulant and antithrombin testing may be OK before heparin is initiated • Warfarin interferes with protein C and S testing • Acute phase reactants may be increased in the acute setting (FVIII, fibrinogen, protein S, PAI-1, Lipoprotein (a)) • Be aware of specific needs for testing ie. fasting, withholding medications, confirmation etc.

Thrombophilia Guidelines â&#x20AC;˘ Current guidelines do not suggest the use of longterm anticoagulation for stroke Ă&#x2DC; Antiplatelet

agents are preferred in most clinical settings Ă&#x2DC; No data regarding anticoagulation in the setting of thrombophilia and stroke

Albers et al. Chest 2008;133:630S-669S.

Final Recommendations • Know your goals of testing before you test Ø

How will the results impact care of the patient?

• Reserve testing for situations that will impact the management of the patient Ø Ø Ø

Affect the type, intensity, or duration of anticoagulation Alter therapy/intervention Provide education/counseling to the patient or their family members

Thank you!!


Teresa L. Carman, M.D. Director, Vascular Medicine University Hospitals Case Medical Center October 7, 2010 No conflicts to disclose relativ...


Teresa L. Carman, M.D. Director, Vascular Medicine University Hospitals Case Medical Center October 7, 2010 No conflicts to disclose relativ...