The hypercoagulability panel in
stroke:
Which tests should be done?
Michael Rippee, MD
Assistant Professor
Department of Neurology
University of Kansas Medical Center
Case #1: JS
• 38 y/o woman
• Sudden onset dizzness, right sided HA, slurred
speech, diplopia, left arm weakness, right
sided facial droop
• H/o headaches
• MRI reveals right thalamic infarct
• Hypercoagulable panel?
A. Yes
B. No
Case #1: JS
• AT3 126 (H) (nl = 80-120)
• Cardiolipin
– IgG 3.6
– IgM 14.9 (H) (nl = <12.5)
• Activated Protein C Activity nl
• Protein C & S nl
• DRVVT nl
– Hex lupus anticoagulant not done
•
•
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Factor 2 gene mutation neg
ANA neg
Beta2 glycoprotein neg
Homocysteine nl
Stroke Causes in Young
Which is most common?
• A. Hypercoagulable State
• B. Cardioembolism
• C. Atherosclerotic factors
• D. Other determined causes (e.g. dissection)
Risk factors: Young Adult
• Most frequent risk factors:
– Dyslipidemia 60%
– Smoking 44%
– Hypertension 39%
• Most common etiologies:
– Cardioembolism 20%
– Cervicocephalic arterial dissection 15%
• Proportions of small vessel disease (14%) and large artery
atherosclerosis (8%) increased beginning at age 30 to 35
• Frequency of undetermined etiology (33%) decreased with age
Case #2: TW
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34 y/o man
Nausea, vision loss (quadrantanopia), HA
MRI revealed right occipito-temporal infarct
No fam hx
Otherwise healthy
LDL 163
Hypercoagulable panel?
A. Yes
B. No
Case #2: TW
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AT3 nl
Factor 8 nl
Cardiolipin Abs nl
Activated Protein C nl
Protein C & S nl
DRVVT nl
– Hex lupus anticoagulant not done
•
•
•
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Factor 2 gene mutation neg
Homocysteine nl
ANA neg
MTHFR neg
• Angiogram confirmed vertebral artery dissection
Hypercoagulabilty & Stroke
• The role of hypercoagulable states in strokes is
controversial
– Blood disorders implicated 5-10%
• In patients without other traditional risk factors
and etiologies for stroke, hypercoagulable state
should be considered
– Abnormal findings on routine screening coagulation
tests (aPTT) should also raise a red flag
• Hypercoagulable state may be more important in
the younger patient with stroke
Hypercoagulabilty & Stroke
• Hypercoagulability should be suspected in
patients with ischemic stroke who have the
following characteristics:
– Younger than 50 years with no obvious cause of
stroke
– History of multiple unexplained strokes
– Previous history of venous thrombosis
– Family history of thrombosis
– Abnormalities on routine screening coagulation
tests
Thrombosis
• Virchow’s triad for venous thrombosis
Hypercoagulable State
• Defined as a group of inherited or acquired conditions associated with a
predisposition to:
– Venous thrombosis including:
• Upper and lower extremity deep venous thrombosis with or without pulmonary
embolism
• Cerebral venous thrombosis
• Intra-abdominal venous thrombosis
– Arterial thrombosis including:
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Myocardial infarction
Stroke
Acute limb ischemia
Splanchnic ischemia
• Venous thromboembolic disease is the most common
• Most inherited conditions appear to increase only the risk of venous
thrombosis
• Some of the acquired conditions have been associated with both venous
and arterial thrombosis
• Age of onset for initial thrombotic event is typically before age 45
Hypercoagulable State
• Recent data support the role of more than one
prothrombotic mutation or additional acquired conditions
to be necessary for clinically apparent clotting
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Immobilization
Surgery
Cancer
Pregnancy
Use of hormone therapy or oral contraceptive medication
• Clues to the diagnosis:
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History of recurrent fetal loss
Thrombocytopenia
Livedo reticularis or Sneddon syndrome
Skin necrosis during initiation of oral anticoagulant therapy
• Protein C and/or S deficiency
Hypercoagulable States
Inherited
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Factor V Leiden
Prothrombin gene mutation
Anti-thrombin deficiency
Protein C & S deficiencies
Elevated homocysteine
Dysfibrinogenemia
Elevated Factor VIII levels
Abnormal fibrinolytic system
Sickle Cell disease
Acquired
• Antiphospholipid antibody
syndrome
• Supplemental estrogen use
• HIT
• Cancer
• Medications
• Central venous catheter
• Obesity
• Pregnancy
Hypercoagulable workup
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PT and PTT
Protein C
Protein S
Antithrombin III activity
Prothrombin gene
mutations
• Factor V Leiden gene
mutation
• Activated Protein C
resistance
• Anticardiolipin antibodies
(IgG and IgM)
• Beta2-glycoprotein I
antibodies (IgG and IgM)
• Lupus anticoagulant tests
– dilute Russell viper venom
time
– dilute activated PTT
– hexagonal phospholipid
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Homocysteine
Factor VIII activity
D-dimer
Lipoprotein (a)
MTHFR
Hypercoagulable workup
How much does it cost?
• A. $450
• B. $900
• C. $2200
• D. $5000
From: Hypercoagulability Syndromes
Arch Intern Med. 2001;161(20):2433-2439. doi:10-1001/pubs.Arch Intern Med.-ISSN-0003-9926-161-20-ira00051
Figure Legend:
Costs of Hypercoagulable Workup at the University of Miami
Date of download: 9/25/2012
Copyright © 2012 American Medical
Association. All rights reserved.
$1873.50
Hypercoagulable workup:
Cost
• A lot of facilities conduct these as send-out
tests
– Quest $1300-$2500 (avg $2000)
• Pts bill $2200-$3000
• Safe estimates are $2-4K
• Generally the panel is repeated at least once!
So which test to order?
Case #3: TS
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35 y/o woman
Severe, unrelenting HA
Venous sinus thrombosis
On OCPs
No Fam Hx
What tests to order?
• A. Routine stroke, but no hypercoagulable
• B. Full hypercoagulable panel
• C. Anti-cardiolipin, lupus anticoagulant panels
only
• D. Protein C & S, AT3, Factor V Leiden,
Prothrombin mutation only
• E. None
Case #3: TS
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Cardiolipin nl
Protein C&S nl
DRVVT nl
Hex lupus anticoagulant 11 (H) (nl <8)
Factor 2 mutation neg
ANA neg
RF neg
Beta2 glycoprotein nl
9 mos later
• Hex lupus 6.1
• DRVVT 47.6
Case #4: JR
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45 y/o man
Left hemiparesis & facial droop
MRI showed right pontine infarct
LDL 129, quit smoking 3 weeks prior to stroke
No Fam Hx
What tests to order?
• A. Routine stroke, but no hypercoagulable
• B. Full hypercoagulable panel
• C. Anti-cardiolipin, lupus anticoagulant panels
only
• D. Protein C & S, AT3, Factor V Leiden,
Prothrombin mutation only
• E. None
Case #4: JR
October
• Cardiolipin
– IgG 6.8
– IgM 13.0 (H) (nl = <12.5)
•
Protein C & S nL
November
• AT3 nl
• DRVVT nl
• Homocysteine 18.6 (H) (nl <15)
• Beta2 glycoprotein IgG 16 (H) (nl <15)
April
• Cardiolipin tests normalized
• Factor 8 nL
• Activated Protein C nl
• MTHFR neg
• Hex Lupus Anticoagulant nl
• Factor 2 mutation neg
• Factor V Leiden ordered but not done
– IgM nl
– IgA nl
•
Alphagalactosidase (Fabry’s) ordered
but not done due to cost
Antiphospholipid Ab Syndrome
Which tests to order?
• Keep in mind whether the results will influence therapy
and/or patient outcome
• Not advocated to screen all stroke patients for a
“hypercoagulable workup”
• Typically, will have a prior history of one or more
unexplained thromboembolic events
• Yield for diagnosing a hypercoagulable state is typically
greatest for:
– Young stroke patients
– Family history of thrombosis
– No other explanations for their stroke (cryptogenic stroke)
• Assaying for specific prothrombotic states has limitations
based on the assay and the timing of the test
Levine SR. Hypercoagulable States & Stroke: A Selective Review. CNS Spectr. 2005;10(7):567-578.
Which tests to order?
• Blood work to diagnose a hypercoagulable state does not
preclude the routine work up of any stroke patient:
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Neuroimaging (brain CT and MRI)
Carotid ultrasound
Echocardiogram
Basic blood tests including a CBC, prothrombin time (PT), partial
thromboplastin time (aPTT), and a fasting lipid profile
• Important points to be noted before ordering a work-up for
hypercoagulable state:
– Use of anticoagulation can affect results of aCL, LA, protein C,
protein S, and antithrombin III
– Results should be repeated in 4–8 weeks to exclude false
positives that may be related to an acute phase reaction
Vaishnav, AG. (2008). “Hypercoagulable States and Stroke.” In D. Alway, J.W. Cole (Eds.).
Stroke Essentials for Primary Care. Human Press.
Which disorders associated with
stroke?
• Prothrombotic states implicated in ischemic
stroke:
– Deficiencies of factors inhibiting coagulation
• Antithrombin III, protein S, and protein C
– Increased levels of factors promoting coagulation
• Factors V and VII
– Decreased activity in the fibrinolytic pathway
• Plasminogen or plasminogen activator deficiencies
Association with stroke
• Inherited thrombophilias (eg, protein C, protein S, or antithrombin III
deficiency; factor V Leiden; prothrombin G20210A mutation), and MTHFR
– Rarely contribute to adult stroke
– May play a larger role in pediatric stroke
• Studies in younger patients (<55 years of age) have shown an association
between prothrombotic genetic variants and ischemic stroke
– Remains controversial in an older population with vascular risk factors
• Even in the young, results have been inconsistent
– Small study of cryptogenic stroke patients <50 years of age
• Increased risk associated with the PT G20210A mutation
• No significant association with FVL
– 2 other studies of young (<50 years) patients
• Found no association between ischemic stroke and the FVL, PT G20210A, or MTHFR
• The association between APL antibodies and stroke is strongest for young
adults (<50 years of age)
Furie KL, et al. Guidelines for the Prevention of Stroke in Patients with Stroke or Transient Ischemic Attack: A Guideline for Healthcare
Professionals. Stroke. 2011;42:227-276.
Hereditary Hypercoagulable Disorders
• Factor V Leiden mutation
– Most common hereditary
hypercoagulable disorder
associated with cerebral
venous thrombosis
– Scant evidence of its
association with arterial strokes
– Caused by a mutation that
makes Factor V resistant to
inactivation by activated
Protein C (APC resistance)
– APC resistance can also be
induced by pregnancy and
estrogen
– Homozygous forms are much
more prone to thrombosis than
a heterozygous mutation
Vaishnav, AG. (2008). “Hypercoagulable States and Stroke.” In D. Alway, J.W. Cole (Eds.).
Stroke Essentials for Primary Care. Human Press.
Hereditary Hypercoagulable Disorders
• Antithrombin III, Protein C, and Protein S
deficiency:
– These conditions are relatively rare
– More potent cause of cerebral venous thrombosis
than Factor V Leiden
– No evidence of their association with arterial strokes
• Prothrombin gene mutation (G20210A)
– Occurs in approximately 2–5% of individuals and in
itself is a weak procoagulant in its action
Hereditary Hypercoagulable Disorders
• Protein C
– Used to screen for a primary protein C deficiency or to diagnose protein C
deficiency secondary to dysproteinemia
– To confirm protein C deficiency, and to differentiate it from dysproteinemia,
the protein C antigen is measured
• Protein S
– Activity is measured by a functional assay
– Both the total Protein S and free Protein S functional assays are performed
because the free assay is a more reliable marker for hypercoagulability
– To confirm protein S deficiency, and to differentiate it from dysproteinemia,
the protein S antigen is measured
• Antithrombin III
– It is recommended to repeat the level in 4–6 weeks if a deficiency was initially
found in the setting of an acute thrombotic event, pregnancy, or warfarin use
Vaishnav, AG. (2008). “Hypercoagulable States and Stroke.” In D. Alway, J.W. Cole (Eds.).
Stroke Essentials for Primary Care. Human Press.
Antiphospholipid Antibody (aPL)
Syndrome
• Antiphospholipids have been associated with both arterial and
venous strokes
• The two major types of clinically relevant aPLs:
– Anticardiolipin antibodies (aCLs)
• Require the presence of serum cofactor beta-2 glycoprotein for binding
– Lupus anticoagulant (LA)
• May not require the presence of beta-2 glycoprotein
– About 70% of patients with aPS have both aCL and LA.
• Antiphospholipid antibody syndrome (APS) is defined as both:
– Thrombosis or recurrent, unexplained fetal loss AND
– aCLs (IgG or IgM) of medium to high titres or LA on at least two
occasions at least 8 weeks apart
• Patients with primary APS do not have systemic lupus
erythematosus (SLE) or any other underlying autoimmune disorders
• Patients with aPLs suffer from both venous and arterial strokes
Vaishnav, AG. (2008). “Hypercoagulable States and Stroke.” In D. Alway, J.W. Cole (Eds.).
Stroke Essentials for Primary Care. Human Press.
Antiphospholipid Antibody (aPL)
Syndrome
Cerebral Venous Sinus Thrombosis
• Routine blood studies:
– CBC, chemistry panel, PT and aPTT
should be performed
• Screening for potential
prothrombotic conditions that
may predispose a person to CVT
– Use of contraceptives, underlying
inflammatory disease, infectious
process
• Testing for prothrombotic
conditions
– Testing for protein C, protein S,
and antithrombin deficiency is
generally indicated 2 to 4 weeks
after completion of
anticoagulation
– There is a very limited value of
testing in the acute setting or in
patients taking warfarin
Saposnik G, et al. Diagnosis & Management of Cerebral Venous Thrombosis. Stroke.
2011;42:1158-1192.
Strategies for testing
Which tests to order?
Use of screening tests
Screening Test
Confirmatory Test
Activated Protein C Resistance
Factor V Leiden PCR
Antithrombin, Protein C & S activity
(functional) levels
Antigenic assays
DRVVT
Lupus anticoagulant
Selecting tests
• Use of pre-test probablity, appropriate
selection of patients, and sensitivity/specifity
yield higher post-test probabilities
Bushnell CB, Goldstein LB. Screening for Hypercoagulable Syndromes Following
Stroke. Current Atherosclerosis Reports. 2003, 5:291-298.
Common mistakes
• Ordering too many tests
– Specifically ones with a low pre-test probability
– Duplicate tests (APC and FVL)
• Testing in the acute phase
• Testing while on warfarin or heparin
Summary
• Common causes of venous thrombosis are unlikely to cause
stroke
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Activated Protein C resistance/Factor V Leiden
Protein C, Protein S, Antithrombin
Prothrombin mutation
This “typical” hypercoagulable panel is low yeild in arterial
stroke
– These tests are more high yield in CVT
• In young patients without known etiology/risk factors
anticardiolipin and lupus anticoagulant are high yield
– Should also order beta-2 glycoproteins
• MTHFR and homocysteine are not helpful
• Testing in the acute phase can be misleading
• Testing should be done off of heparin or warfarin
Questions
JM 58 y/o man
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H/o RA and SLE
HLD and tobacco
Driving back from vacation
Developed left sided weakness, facial droop
MRI revealed right hemisphere ischemic
stroke
• No Fam Hx
What tests to order?
• A. Routine stroke, but no hypercoagulable
• B. Full hypercoagulable panel
• C. Anti-cardiolipin, lupus anticoagulant panels
only
• D. Protein C & S, AT3, Factor V Leiden,
Prothrombin mutation only
• E. None
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Prolonged aPTT
DRVVT 1.6 (H) (nl = <1.2)
Hex Lupus Anticoagulant 31 (H) (nl = <8)
Cardiolipin
– IgG 9.616.2
– IgM 20.615.2
• Homocysteine 10.7
• Anti-phospholipid Ab Syndrome
TP 44 y/o woman
• Admitted with prolonged, severe headache
• Found to have extensive venous sinus
thrombosis
• On OCP, also on HCG diet (shown to increase
potential for thrombus)
• No Fam Hx
What tests to order?
• A. Routine stroke, but no hypercoagulable
• B. Full hypercoagulable panel
• C. Anti-cardiolipin, lupus anticoagulant panels
only
• D. Protein C & S, AT3, Factor V Leiden,
Prothrombin mutation only
• E. None
• Factor 8: 140 (nl 100-150)
• Cardiolipin Ab
– IgG 4.0
– IgM 8.2
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Activated PC resistance nL
Hex Lupus Anticoagulant nL
DRVVT nL
Protein C nL
Protein S nL
Factor 2 mutation neg
AT3 130 (H) (nl = 80-120)
Beta-2 glycoprotein neg
GM 62 y/o man
• Sudden onset homonymous hemianopia,
dizziness/imbalance
• MRI confirmed left PCA infarct
• H/o hypertension & HLD
What tests to order?
• A. Routine stroke, but no hypercoagulable
• B. Full hypercoagulable panel
• C. Anti-cardiolipin, lupus anticoagulant panels
only
• D. Protein C & S, AT3, Factor V Leiden,
Prothrombin mutation only
• E. None
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•
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AT3 nl
Prothrombin gene mutation neg
Homocysteine nl
Cardiolipin Abs nl
Activated protein C nl
LP 29 y/o woman
• Stroke in 2005, found to have PFOclosed
• Had sudden vision loss on right side and
difficulty forming words
• MRI negative
• Fam Hx of dysrhythmia but not stroke or
blood clots