Hypercoagulable Hypercoagulable StatesStates

Hypercoagulable Hypercoagulable StatesStates Acquired versus inheritedAcquired versus inherited ““Provoked” vs idiopathic VTEProvoked” vs idiopathic VTE Who should be tested for inherited Who should be tested for inherited

thrombophilia?thrombophilia? What tests should be done & when?What tests should be done & when? Anticoagulation recommendationsAnticoagulation recommendations Should family members be tested?Should family members be tested?

Virchow’s triadVirchow’s triad

Was VTE “provoked”?Was VTE “provoked”?

Medical and surgical historyMedical and surgical history MedicationsMedications Travel – air & groundTravel – air & ground Review of systems Review of systems Cancer screening historyCancer screening history

Was VTE “provoked”?Was VTE “provoked”?

Physical exam – including breast Physical exam – including breast exam, rectal exam, pelvic exam for exam, rectal exam, pelvic exam for females, prostate exam for malesfemales, prostate exam for males

Age-appropriate cancer screening – Age-appropriate cancer screening – MMG, Pap smear, colonoscopy, PSAMMG, Pap smear, colonoscopy, PSA

Do not recommend CT scans, etc.Do not recommend CT scans, etc. Chest x-ray is reasonableChest x-ray is reasonable

Was VTE “provoked”?Was VTE “provoked”?

CBC with diffCBC with diff CMPCMP UrinalysisUrinalysis Fecal occult blood testFecal occult blood test

Inherited Inherited thrombophiliathrombophilia Factor V Leiden (2.2)Factor V Leiden (2.2) Prothrombin gene mutation (2.8)Prothrombin gene mutation (2.8) Protein C deficiency (7.3)Protein C deficiency (7.3) Protein S deficiency (8.5)Protein S deficiency (8.5) Antithrombin III deficiency (8.1)Antithrombin III deficiency (8.1)

Acquired – antiphospholipid antibody Acquired – antiphospholipid antibody syndrome (APS)syndrome (APS)

Who to testWho to test

<45 years old with unprovoked <45 years old with unprovoked venous or arterial thromboembolic venous or arterial thromboembolic diseasedisease

>>2 idiopathic thrombotic episodes 2 idiopathic thrombotic episodes Thrombosis in unusual site Thrombosis in unusual site VTE & strong family history of VTEVTE & strong family history of VTE History of recurrent fetal lossHistory of recurrent fetal loss ? VTE in reproductive age female? VTE in reproductive age female

Unusual sitesUnusual sites

Cerebral veinsCerebral veins IVC, renal veinsIVC, renal veins Mesenteric veinsMesenteric veins Portal and hepatic veinsPortal and hepatic veins

Recurrent fetal lossRecurrent fetal loss

Unexplained death at Unexplained death at >>10 10 weeks gestation–weeks gestation–morphologically normalmorphologically normal

Three or more 1st-trimester Three or more 1st-trimester pregnancy losses without an pregnancy losses without an intercurrent term pregnancyintercurrent term pregnancy

Who to testWho to test

What about a strong family history What about a strong family history without personal history of VTE?without personal history of VTE?

Test affected family member firstTest affected family member first If history is very suggestive of If history is very suggestive of

inherited thrombophilia and there inherited thrombophilia and there is no affected family member alive is no affected family member alive to be tested – needs appropriate to be tested – needs appropriate counselingcounseling

Hypercoagulable Hypercoagulable Work-upWork-up ““Hypercoag panel”Hypercoag panel”

-Protein C, protein S, AT III (functional)-Protein C, protein S, AT III (functional)

-Lupus anticoagulant-Lupus anticoagulant

-APC resistance-APC resistance Factor V Leiden (if APC resistance Factor V Leiden (if APC resistance

low)low) Prothrombin gene mutationProthrombin gene mutation Anticardiolipin antibodiesAnticardiolipin antibodies

Timing of testsTiming of tests

Factor V Leiden and prothrombin Factor V Leiden and prothrombin mutation can be checked at any timemutation can be checked at any time

Wait at least 4-6 weeks after acute Wait at least 4-6 weeks after acute event to check lupus anticoagulant event to check lupus anticoagulant and cardiolipin antibodies (or later)and cardiolipin antibodies (or later)

Most efficient to check all other tests Most efficient to check all other tests >>2 weeks after course of 2 weeks after course of anticoagulation is completedanticoagulation is completed

Timing of TestsTiming of Tests

In setting of acute VTE, proteins C & In setting of acute VTE, proteins C & S and AT III may be decreasedS and AT III may be decreased

Cardiolipin antibodies may be Cardiolipin antibodies may be present as an acute phase reactantpresent as an acute phase reactant

Heparin interferes with AT III activity Heparin interferes with AT III activity and lupus anticoagulant assaysand lupus anticoagulant assays

Coumadin lowers proteins C & SCoumadin lowers proteins C & S

Timing of TestsTiming of Tests

In acute phase, if protein C or S is In acute phase, if protein C or S is normal, that test does not need to be normal, that test does not need to be repeated repeated

Some evidence that coumadin may Some evidence that coumadin may increase AT III levels – if AT III is at increase AT III levels – if AT III is at low end of normal range, then test low end of normal range, then test needs to be repeated off coumadinneeds to be repeated off coumadin

Never need to repeat FVL or PTM testNever need to repeat FVL or PTM test

Antiphospholipid Antiphospholipid Antibody Syndrome Antibody Syndrome (APS)(APS) Clinical criteria: One or more Clinical criteria: One or more

episodes of venous, arterial, or small episodes of venous, arterial, or small vessel thrombosis and/or morbidity vessel thrombosis and/or morbidity with pregnancywith pregnancy

Laboratory criteria: Presence of anti-Laboratory criteria: Presence of anti-phospholipid antibodies on 2 or more phospholipid antibodies on 2 or more occasions at least 12 weeks apart occasions at least 12 weeks apart and and <<5y prior to clinical 5y prior to clinical manifestationsmanifestations

APS Clinical CriteriaAPS Clinical Criteria

Imaging or histologic evidence of Imaging or histologic evidence of thrombosis in any tissue or organthrombosis in any tissue or organ

Fetal death at Fetal death at >>10 wks gestation10 wks gestation Premature birth before 34 weeks Premature birth before 34 weeks

because of eclampsia, because of eclampsia, preeclampsia or placental preeclampsia or placental insufficiencyinsufficiency

>>3 pregnancy losses <10 weeks3 pregnancy losses <10 weeks

APS Laboratory APS Laboratory CriteriaCriteria Positive lupus anticoagulantPositive lupus anticoagulant Moderate or high titer IgG and/or Moderate or high titer IgG and/or

IgM anticardiolipin antibodiesIgM anticardiolipin antibodies IgG or Ig M antibodies to beta2-IgG or Ig M antibodies to beta2-

glycoprotein-1glycoprotein-1 On two or more occasions at On two or more occasions at

least 12 weeks apartleast 12 weeks apart

Antiphospholipid Antiphospholipid Antibody SyndromeAntibody Syndrome VTEVTE Stroke, white matter lesionsStroke, white matter lesions MI, nonbacterial endocarditisMI, nonbacterial endocarditis Renal failureRenal failure Thrombocytopenia, TTP/HUSThrombocytopenia, TTP/HUS

Livedo reticularisLivedo reticularis

Catastrophic APSCatastrophic APS

Involvement of 3 or more organs, Involvement of 3 or more organs, systems, or tissuessystems, or tissues

Develop simultaneously or in <1 Develop simultaneously or in <1 weekweek

Histopathologic evidence of small Histopathologic evidence of small vessel occlusionvessel occlusion

Presence of antiphospholipid Presence of antiphospholipid antibodiesantibodies

Asherson et al., Lupus, 2003, 12:530Asherson et al., Lupus, 2003, 12:530

Catastrophic APSCatastrophic APS

Treatment of underlying illnessTreatment of underlying illness Heparin acutely then warfarinHeparin acutely then warfarin High dose steroidsHigh dose steroids Plasma exchange +/- IVIG if there Plasma exchange +/- IVIG if there

is evidence of TTP/HUSis evidence of TTP/HUS For survivors, lifelong warfarinFor survivors, lifelong warfarin

AnticoagulationAnticoagulation

Low molecular weight heparin Low molecular weight heparin acutely until INR therapeutic for 2 acutely until INR therapeutic for 2 daysdays

Warfarin for 3-6 monthsWarfarin for 3-6 months INR 2.0-3.0INR 2.0-3.0 For idiopathic DVT or inherited For idiopathic DVT or inherited

thrombophilia can discuss prolonged thrombophilia can discuss prolonged therapy – delays risk of recurrencetherapy – delays risk of recurrence

What is this? What is this? Why does it happen?Why does it happen?

Warfarin skin necrosisWarfarin skin necrosis

Protein C deficiencyProtein C deficiency Vitamin K dependent protein with Vitamin K dependent protein with

relatively short half-liferelatively short half-life Start warfarin after full Start warfarin after full

heparinization documented by PTT heparinization documented by PTT or anti-Xa assay or anti-Xa assay

Start at a low dose (2 mg a day) Start at a low dose (2 mg a day) then gradually increasethen gradually increase

Warfarin skin necrosisWarfarin skin necrosis

Stop warfarinStop warfarin Give vitamin KGive vitamin K HeparinizeHeparinize Consider protein C administration Consider protein C administration

(FFP, (FFP, protein C concentrateprotein C concentrate)) Can retreat with warfarin in Can retreat with warfarin in

setting of protein C administrationsetting of protein C administration

AT III deficiencyAT III deficiency

Sometimes show resistance to Sometimes show resistance to heparinheparin

May require larger dosesMay require larger doses Consider antithrombin concentrateConsider antithrombin concentrate

-Unusually severe thrombosis-Unusually severe thrombosis

-Recurrent thrombosis in setting of -Recurrent thrombosis in setting of adequate anticoagulationadequate anticoagulation

-Inability to adequately anticoagulate-Inability to adequately anticoagulate

Discussion of lifelong Discussion of lifelong anticoagulationanticoagulation Recurrent idiopathic VTERecurrent idiopathic VTE Idiopathic life-threatening VTEIdiopathic life-threatening VTE Antiphospholipid antibody Antiphospholipid antibody

syndrome (with persistently syndrome (with persistently elevated antibodies)elevated antibodies)

Antithrombin III deficiencyAntithrombin III deficiency Homozygous or compound Homozygous or compound

heterozygous defectsheterozygous defects

Inherited Inherited thrombophilia & thrombophilia & surgical prophylaxissurgical prophylaxis Consider as “high risk” groupConsider as “high risk” group Exception may be Factor V Leiden Exception may be Factor V Leiden

– prophylaxis based on risk of – prophylaxis based on risk of surgerysurgery

AT III deficiency – could consider AT III deficiency – could consider antithrombin concentrate antithrombin concentrate (retrospective & case reports (retrospective & case reports only) only)

Inherited Inherited thrombophilia and thrombophilia and pregnancypregnancy Anticoagulate during pregnancy Anticoagulate during pregnancy

and 6 weeks post-partumand 6 weeks post-partum AT III deficiency, homozygous FVL AT III deficiency, homozygous FVL

or PTM, compound heterozygotes or PTM, compound heterozygotes Personal history of VTE or strong Personal history of VTE or strong

family history of VTE use family history of VTE use therapeutic dose, otherwise therapeutic dose, otherwise prophylactic dose prophylactic dose

Inherited Inherited thrombophilia and thrombophilia and pregnancypregnancy Heterozygous FVL or PTM, protein C Heterozygous FVL or PTM, protein C

or S deficiencyor S deficiency Prophylaxis if personal history of VTEProphylaxis if personal history of VTE Consider if 1Consider if 1stst degree relative with degree relative with

VTE at age <50VTE at age <50 If no prior history of VTE then only If no prior history of VTE then only

postpartum prophylaxis if C-sectionpostpartum prophylaxis if C-section

Should family Should family members be tested?members be tested? Need to be counseled on how Need to be counseled on how

result will be usedresult will be used Females of reproductive ageFemales of reproductive age Protein C deficiencyProtein C deficiency If there is more than one inherited If there is more than one inherited

thrombophilia in the familythrombophilia in the family Usually we doUsually we do

When to refer to When to refer to HematologyHematology Inherited thrombophilia with VTEInherited thrombophilia with VTE Recurrent idiopathic VTE without Recurrent idiopathic VTE without

inherited thrombophiliainherited thrombophilia Contemplating lifelong Contemplating lifelong

anticoagulationanticoagulation Patient requestPatient request

Questions?Questions?