1 / 36

Thrombophilia

Learn about thrombophilia, inherited or acquired hypercoagulability leading to VTE, its risk factors, common types, and anticoagulation strategies. Understand the impact on pregnancy and high-risk situations.

ffrederick
Download Presentation

Thrombophilia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Maria Podolak-Dawidziak Donata Urbaniak-Kujda Thrombophilia Katedra i Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku UM, Wrocław

  2. Venousthromboembolism (VTE) In the US morethan 900 000 estimatedcasesanually Theaverageyearlyincidence 117 cases/100 000 population; withhigherratesinwomen of childbearingage, males > 45 yrs, elderly (ratesup to five-foldhigher

  3. Thrombophilia → inheritedoracquiredhypercoagulabilityleading to venousthromboembolism (VTE) 8% of populationin Europe hasinheritedthrombophilia ~ 30–50% patientswiththrombophiliahadvenousthromboticeventbeforeage 50 years

  4. Thrombophilia Acquired Inherited Thrombotic risk factors • Immobilization • Surgery/trauma • Malignancy • Oral contraceptives • HRT • Pregnancy • Lupus anticoagulant • Myeloproliferative neoplasmas • PNH • TTP, HIT • Nephrotic syndrome • Anticardiolipin anibodies • Drugs (thalidomide, L-ASPA) • Age, obesity • Congestive heart failure • FVL mutation • Prothrombin G20210A muation • Hyperhomocysteinemia • Protein C deficiency • Protein S deficiency • AT deficiency • Increased F VIII activity Mixed/unknown • F VIII • F IX • F XI • F I • TAFI • PAI-3 • homocysteine • Protein C resistance without FVL mutation • ¯TFPI

  5. Most commonthrombophilias Inherited: • Factor V Leiden • prothrombin G202 10 A mutation • 4G/4Gmutation of theplasminogenactivator inhibitor gene (PAI-1) • thermolabinevariant of methylenotetrahydrofolatereductase, the most commoncause of homocysteinamia • antithrombin (AT) deficiency • protein C deficiency • protein S deficiencyagulable state Acquired Antiphospholipidantibody

  6. Factor V LeidenmutationActivated Protein C Resistance Most commonhereditarythrombophiliaintheCaucasianpopulation ~5% More than 90 % of patientswith APCR havethe G1691A mutationinfactor V genewhichdecreasestherate of proteolyticcleavage by activated protein C In about 20% patientswithvenous thrombosis Relativerisk of thrombosis: heterozygous (4-5×) homozygous (24-80×)

  7. Prothrombin G20210A mutation • Increasedlevels of plasmaprothrombin (15% lor more) • Itleads to increasedgeneration of thrombin • In about 6% patientswithvenous thrombosis • Risk of thrombosis 2–3 x

  8. Antytrombin (AT) deficiency • Gene – on chromosome 1 • Production: liver, endothelialcells • Plasmaprotease inhibitor thatirreversiblybinds and neutralizesthrombin and Xa,IXa, and XIaresultinginreversalcoagulationcascade • Reactionisaccelerated by heparin • AT deficiencyincreasesrisk of thrombosis

  9. AT deficiency • Type I – decreasedlevels (< 50%) and decreasedactivity • Type II – decreasedproteaseactivity, but N level • IncidenceinCaucasianpopulation – 0,02% • Homozygous – possiblefeatusdeathinuterus • Heterozygous thrombosis in 80% of patients • Nearly 70% heterozygot presentwith first thromboticeventbeforeage 35 years XIIa ¯ XIa ¯ IXa ¯ Xa ¯ IIa ¯ fibrynogen AT fibryn

  10. Protein C and protein S • ArevitaminK-dependentenogenousanticoagulants • Homozygous protein C deficiencycancauseneonatal purpura fulminans • Patientswitheither protein C or protein S deficiency → warfin skin necrosisattheinitiation of anticoagulationdue to transienthypercoagulable state

  11. Protein C and protein S deficiency • Protein C inhibitsthrombin • Protein C and protein S areaffected by liverdisease, anticoagulationwithwarfin, nephroticsyndrome, DIC, vitamin K deficiency, oralcontraceptives, pregnancy, and hormonalreplacementtherapy

  12. Elevated F VIII levels • Relativerisk of thrombosis=4.8 • Arefound with increasedage, obesity, pregnancy, surgery, inflammation, liverdisease, hyperthyreoidism, and diabetes • No genealterationhasbeenfound, althoughfamilialclustering of increased FVIII levelsisnoted

  13. Hereditarythromboticdysfibrinogenemia Qualitativedefectsinthefibrinmolecule VTE in 20 % of pts and bleedingtendencyin 25 % of pts, but 55 % areasymptomatic N orlowlevels of FBG Prolongedthrombin time (TT)

  14. Thrombophilia and pregnancy Recurrentmiscarrigeearly/late (risk) • FVL mutation 1,91/2,06 × • ProthrombinG20210A mutation 2,7/2,66 × • PS deficiencylate 20,9 × • Acquired APCR early 4,04 × Analysis of 11183 patients Sarig G. et al.: Assessment and management of high-risk pregnancies in women with thrombofilia.Blood Reviews 2009.23

  15. Anticoagulationinptswithhereditarythrombophilia • Longerduration: activecancer, AT deficiency, Protein C or S deficiency, morethan one thromboticevent, antiphospholipidantibodysyndrome • Lifelong: TwoormoreunprovocedVTEs, unprovoked VTE with AT deficiency, multiplegeneticabnormalities, one life-threatening VTE

  16. Prophilacticanticoagulation in ptswith history of thromboembolicevent • Unfractionatedheparinor LMWH duringhigh-risksituationincluding: surgery, trauma, immobilization • Women – increasedrisk of recurrentthromboticevents: oralcontraceptives, pregnancy, HRT

  17. Consideration of a hypercoagulableworkup Thrombosis atage < 50 years Recurrent VTE Thrombosis atunusualsites (cerebral sinus, mesentericvein, portal vein, hepaticvein) Recurrentsecondor third trimesterfetalloss, placentalabruption, orseverepreeclampsia

  18. Anticoagulationintheprimarytreatment and prophilaxis of VTE Thepurpuse of anticoagulationis to: preventadditionalclotsfrom developing, immediately stop furtherpropagation of theexistingclot Permitendogenousfibrinolysis to begin to dissolvetheclotphysiologically

  19. Anticoagulationintheprimarytreatment and prophilaxis of VTE LMWH orfondaparinuxorrivaroxaban LMWH and fondaparinuxarepreferable to UFH ifwarfin (VKA) isused, itshould be startedafterinitiation of UFH, LMWH orfondaparinus anticoagulation – for atleast 3 months

  20. Patient No 1 • 28 years old, whiteman • Suddensymptoms: dyspnea, cough, chestpain, hemoptysis. BMI 19 kg/m2 • No thrombotichistory; one weekprior to eventhedrived a car for 8 hourswithoutany break • Laboratorytests: bloodmorphology – N, PT- N, APTT- N, dimer D 4054 ng/ml (N < 500 ng/ml) • CT: acutebilateralpulmonaryembolism • Doppler USG: DVT inbothlegs!! (lShaheen K et al.: Factor V Leiden: How great istherisk of venousthromboembolism Cleveland Clin J Med. 2012; 79: 265-272

  21. Patient No 1 • FV Leidenmutationheterozygoustype • Treatment: UFH, laterwarfin ► INR 2-3 for 2 consecutivedays • Athome: oralanticoagulation for 6 months (INR 2-3). Twoweeksafterend of treatment: AT, FVIII, PC i PS - normal

  22. Patient No 2 • 17 years old girl with no thrombotichistory; since 6 months on oralcontraceptives • Suddenpaininleftgroin • DVT i PE • No familyhistory of thrombosis • Diagnosis: FVL mutationheterozygoustype, FII G20210A mutation and MTHFR C677T, 4G/5G PAI gen- type 1 mutationhomozygoustype Krieza L et al: PathophysiolHaemostThromb 2010; 37: 24-29

  23. Consideration of a hypercoagulableworkup Thrombosis atage < 50 years Recurrent VTE Thrombosis atunusualsites (cerebral sinus, mesentericvein, portal vein, hepaticvein) Recurrentsecondor third trimesterfetalloss, placentalabruption, orseverepreeclampsia

  24. Thrombophilia and pregnancy Recurrentmiscarrigeearly/late (risk) • FVL mutation 1,91/2,06 × • Prothrombin G20210A mutation 2,7/2,66 × • PS deficiencylate 20,9 × • Acquired APCR early 4,04 × Analysis of 11183 patients Sarig G. et al.: Assessment and management of high-risk pregnancies in women with thrombofilia.Blood Reviews 2009.23

  25. Risk of VTE inpregnantwomenwiththrombophilia High: • Previous VTE on contraceptives • VTE in present pregnancy • Recurrent VTE • Previous VTE due to high risk thrombophilia - AT deficiency -combined thrombophilia -homozygous type FVL and prothrombin gen 20210A • APS with past thrombosis Moderate: • previous VTE in moderate risk thrombophilia • VTE with positive family history • Asyptomatic risk thrombophilia Low: • Single VTE event with transient risk factors • Asymptomatic moderate risk thrombophilia

  26. LMWH in high prophilaticortherapeuticdose, warfininpuerperium minimum for 6 weeks Enoxparyna 40 mg/12h or 1mg/kg Deltaparin 5000j/12h or 90 j/kg/12h LMWH inprophylacticdoseup to 6 weeks of puerperium Enoxparyna 40 mg/24h or 40 mg/12h >90 kg Deltaparin 5000j/24h lorb 5000/12h >90 kg LMWH inprophylacticdoseinpuerperium (6 weeksafterdelivery) Enoxparyna 40 mg/24h or 40mg/12h >90kg Deltaparin 5000j/24h or 5000j/12h >90 kg Anticoagulationinpregnantwomanwiththrombophiliaaccordingly to risk of VTE • High • Moderate • Low

  27. Patient No 3 • 29 yrs old female • History: DVT - 3 yrs ago, • First pregnancy: 2 yrs ago: in 23 weekfoetusintrauterinedeath; autopsy: multipleemboli and infarctionin placenta • Presentpregnancy:thromboticcomplications: DVT (LMWH from 6 weekpregnancy to 7 dayafterdelivery- enoksaparyna 60 mg/d) • Deliveryin 39 weeks, foetuswithmultiplemalformations • 18 daysafterdelivery: suddenweakness, hipotonia • EF - 20%

  28. Patient No 3 • Department of Cardiology • 1 dayafter: pulmonaryedema, cardiogenicshock, acuterenalfailure • Treatment: mechanicalventilation, intra-aorticballoon pomp (IABP), pressoramines • Bloodmorphology: Hgb-9,1 g/dl, PLT-34G/l • Immunologicaltests: anticardiolipinantibodiesIgG class-76 U/ml; LA+++ • ANA Hep-2 1:2560 • p/dsDNA-261 IU/ml

  29. Diagnosis and therapy • Diagnosis: LED, antiphospholipidsyndrome • Differential: inheritedthrombophilia, TTP • Therapy:Metylprednison 1,0 g for 5 days; IVIG- totaldose 150 g • LMWH intherapeuticdose • EF-35%; PLT-143 G/l

  30. 15 daysafter: leftside hemiplegia, unconcious • MRI- acutemultifocalcerebral ischemia • USG Doppler- multiplethrombiinleftjugulrathery • Therapy: anticoagulation (ASA, warfin) immunosupression: CPD (5 pulses), metylprednisolon, plasmapheresis (5 times) • A yearafter: clicalimprovement (no thromboticorneurologicevents), decreasein APS abs

More Related