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Hypercoagulable States
Hypercoagulable States
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Acquired versus inherited
“Provoked” vs idiopathic VTE
Who should be tested for inherited
thrombophilia?
What tests should be done & when?
Anticoagulation recommendations
Should family members be tested?
Virchow’s triad
Was VTE “provoked”?
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Medical and surgical history
Medications
Travel – air & ground
Review of systems
Cancer screening history
Was VTE “provoked”?
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Physical exam – including breast
exam, rectal exam, pelvic exam for
females, prostate exam for males
Age-appropriate cancer screening –
MMG, Pap smear, colonoscopy, PSA
Do not recommend CT scans, etc.
Chest x-ray is reasonable
Was VTE “provoked”?
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CBC with diff
CMP
Urinalysis
Fecal occult blood test
Inherited thrombophilia
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Factor V Leiden (2.2)
Prothrombin gene mutation (2.8)
Protein C deficiency (7.3)
Protein S deficiency (8.5)
Antithrombin III deficiency (8.1)
Acquired – antiphospholipid antibody
syndrome (APS)
Who to test
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<45 years old with unprovoked venous
or arterial thromboembolic disease
>2 idiopathic thrombotic episodes
Thrombosis in unusual site
VTE & strong family history of VTE
History of recurrent fetal loss
? VTE in reproductive age female
Unusual sites
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Cerebral veins
IVC, renal veins
Mesenteric veins
Portal and hepatic veins
Recurrent fetal loss
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Unexplained death at >10 weeks
gestation–morphologically normal
Three or more 1st-trimester pregnancy
losses without an intercurrent term
pregnancy
Who to test
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What about a strong family history
without personal history of VTE?
Test affected family member first
If history is very suggestive of
inherited thrombophilia and there is no
affected family member alive to be
tested – needs appropriate counseling
Hypercoagulable Work-up
“Hypercoag panel”
-Protein C, protein S, AT III (functional)
-Lupus anticoagulant
-APC resistance
 Factor V Leiden (if APC resistance low)
 Prothrombin gene mutation
 Anticardiolipin antibodies
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Timing of tests
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Factor V Leiden and prothrombin
mutation can be checked at any time
Wait at least 4-6 weeks after acute
event to check lupus anticoagulant
and cardiolipin antibodies (or later)
Most efficient to check all other tests
>2 weeks after course of
anticoagulation is completed
Timing of Tests
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In setting of acute VTE, proteins C & S
and AT III may be decreased
Cardiolipin antibodies may be present
as an acute phase reactant
Heparin interferes with AT III activity
and lupus anticoagulant assays
Coumadin lowers proteins C & S
Timing of Tests
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In acute phase, if protein C or S is
normal, that test does not need to be
repeated
Some evidence that coumadin may
increase AT III levels – if AT III is at
low end of normal range, then test
needs to be repeated off coumadin
Never need to repeat FVL or PTM test
Antiphospholipid
Antibody Syndrome (APS)
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Clinical criteria: One or more episodes
of venous, arterial, or small vessel
thrombosis and/or morbidity with
pregnancy
Laboratory criteria: Presence of antiphospholipid antibodies on 2 or more
occasions at least 12 weeks apart and
<5y prior to clinical manifestations
APS Clinical Criteria
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Imaging or histologic evidence of
thrombosis in any tissue or organ
Fetal death at >10 wks gestation
Premature birth before 34 weeks
because of eclampsia, preeclampsia or
placental insufficiency
>3 pregnancy losses <10 weeks
APS Laboratory Criteria
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Positive lupus anticoagulant
Moderate or high titer IgG and/or IgM
anticardiolipin antibodies
IgG or Ig M antibodies to beta2glycoprotein-1
On two or more occasions at least
12 weeks apart
Antiphospholipid
Antibody Syndrome
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VTE
Stroke, white matter lesions
MI, nonbacterial endocarditis
Renal failure
Thrombocytopenia, TTP/HUS
Livedo reticularis
Catastrophic APS
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Involvement of 3 or more organs,
systems, or tissues
Develop simultaneously or in <1 week
Histopathologic evidence of small
vessel occlusion
Presence of antiphospholipid
antibodies
Asherson et al., Lupus, 2003, 12:530
Catastrophic APS
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Treatment of underlying illness
Heparin acutely then warfarin
High dose steroids
Plasma exchange +/- IVIG if there is
evidence of TTP/HUS
For survivors, lifelong warfarin
Anticoagulation
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Low molecular weight heparin acutely
until INR therapeutic for 2 days
Warfarin for 3-6 months
INR 2.0-3.0
For idiopathic DVT or inherited
thrombophilia can discuss prolonged
therapy – delays risk of recurrence
What is this?
Why does it happen?
Warfarin skin necrosis
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Protein C deficiency
Vitamin K dependent protein with
relatively short half-life
Start warfarin after full heparinization
documented by PTT or anti-Xa assay
Start at a low dose (2 mg a day) then
gradually increase
Warfarin skin necrosis
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Stop warfarin
Give vitamin K
Heparinize
Consider protein C administration
(FFP, protein C concentrate)
Can retreat with warfarin in setting of
protein C administration
AT III deficiency
Sometimes show resistance to heparin
 May require larger doses
 Consider antithrombin concentrate
-Unusually severe thrombosis
-Recurrent thrombosis in setting of
adequate anticoagulation
-Inability to adequately anticoagulate
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Discussion of lifelong
anticoagulation
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Recurrent idiopathic VTE
Idiopathic life-threatening VTE
Antiphospholipid antibody syndrome
(with persistently elevated antibodies)
Antithrombin III deficiency
Homozygous or compound
heterozygous defects
Inherited thrombophilia
& surgical prophylaxis
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Consider as “high risk” group
Exception may be Factor V Leiden –
prophylaxis based on risk of surgery
AT III deficiency – could consider
antithrombin concentrate
(retrospective & case reports only)
Inherited thrombophilia
and pregnancy
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Anticoagulate during pregnancy and 6
weeks post-partum
AT III deficiency, homozygous FVL or
PTM, compound heterozygotes
Personal history of VTE or strong
family history of VTE use therapeutic
dose, otherwise prophylactic dose
Inherited thrombophilia
and pregnancy
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Heterozygous FVL or PTM, protein C or
S deficiency
Prophylaxis if personal history of VTE
Consider if 1st degree relative with VTE
at age <50
If no prior history of VTE then only
postpartum prophylaxis if C-section
Should family members
be tested?
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Need to be counseled on how result
will be used
Females of reproductive age
Protein C deficiency
If there is more than one inherited
thrombophilia in the family
Usually we do
When to refer to
Hematology
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Inherited thrombophilia with VTE
Recurrent idiopathic VTE without
inherited thrombophilia
Contemplating lifelong anticoagulation
Patient request
Questions?