8/1/11 Morgan L. McLemore, M.D.! Hematology and Leukemia Section! Winship Cancer Institute! • 28 yo AAM, Acute SOB, Pleuritic CP. – Bilateral PE, with right heart strain. – No DVT, no family history, no obvious risk factors • 38 yo Female, ?unprovoked DVT on coumadin for 2 years. Protein C & S deficient. – no family history, no obvious risk factors per chart • 22 yo female claudication left LE for 8 months. Left femoral artery thrombosis. – Was on OCP, no family history 1 8/1/11 Strongly Supportive Data Antithrombin deficiency Protein C deficiency Protein S deficiency Activated protein C resistance Factor V Leiden Prothrombin G20210A Homocystinuria Supportive Data Increased plasma factors I (fibrinogen), II (prothrombin), VIII, IX, XI Factor XIII polymorphisms Hyperhomocysteinemia Dysfibrinogenemia Reduced tissue factor pathway inhibitor Weakly Supportive Data Reduced protein Z and Z-dependent protease inhibitor Tissue plasminogen activator deficiency Increased plasminogen activator inhibitor (PAI)-1 Increased thrombin-activatable fibrinolysis inhibitor Hypoplasminogenemia and dysplasminogenemia Hypofibrinolysis • Deficiencies of ATIII, Proteins C&S • Factor V Leiden (APCr) • Prothrombin Gene Mutation • LAC, ACL, APL • Elevated Factor VIII levels • Homocysteine • Other Protein Z, Lipoprotein a etc. • Deficiencies of ATIII, Proteins C&S • Factor V Leiden (APCr) • Prothrombin Gene Mutation • LAC, ACL, APL • Elevated Factor VIII levels ? ? 2 8/1/11 JA Heit Hematology Educatioon Book 2007 Favaloro et al Semin Thromb Hemost 2009 • Antiphopholipid Antibodies • Pregnancy/postpartum • Therapy-related: • Malignancy – Hormone replacement • Myeloproliferative therapy disorders: – Oral contraceptives – Tamoxifen/raloxifene – Chemotherapy/thalidomide – Heparin-induced thrombocytopenia – Polycythemia vera – Essential thrombocythemia • Paroxysmal nocturnal hemoglobinuria • Nephrotic syndrome • Inflammatory bowel disease • • • • Travel Trauma Surgery Presence of a central venous catheter • Immobilization 3 8/1/11 • The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence. • First event with reversible or time limited risk factor – 3 months at INR 2-3 • Unprovoked VTE, first or second event – 3-6 months at target INR, then consider – indefinite anticoagulation at INR 2-3 • First (unprovoked) event in high risk thrombophilas – thrombophilias - indefinite anticoagulation – Cancer until remission (consider chronic LMWH) – Antiphospholipid antibody syndrome – Antithrombin deficiency or multiple genetic defects 4 8/1/11 • First event with reversible or time limited risk factor – 3 months at INR 2-3 • Unprovoked VTE, first or second event – 3-6 months at target INR, then consider – indefinite anticoagulation at INR 2-3 • First (unprovoked) event in high risk thrombophilas – thrombophilias - indefinite anticoagulation – Cancer until remission (consider chronic LMWH) – Antiphospholipid antibody syndrome – Antithrombin deficiency or multiple genetic defects • Arterial- Not routinely recommended – Very young- unusual sites consider • Portal/Mesenteric vein thrombosis, – PNH – JAKII -> up to 50% positive without complete evidence of MPD • Cerebral Vein Thrombosis • • Normal • Oral Contraceptives • Factor V Leiden Heterozygote • Both • Homozygote FVL %/year 0.008 0.03 0.06 0.30 0.50 or > 5 8/1/11 • Venous Thromboembolism < 50 with a family history – Unprovoked – Provoked ? Strong Family History/Young – Unprovoked- consider workup without family history – Evidence of thrombophilia may raise threshold to withdrawal AC in future • Unusual Site- Cerebral venous and Portal/Mesenteric vein thrombosis – JAKII and PNH • Second and third trimester pregnancy loss • Consider – Unprovoked in patients >50 APL/ACL/LAC – Women on OCP – Arterial LAC/APL only for unusual cases • Acquired or inherited thrombophilia with 1st provoked venous VTE – Ensure prophylaxis in high risk settings. • Unprovoked VTE consider indefinite anticoagulation. – Need to constantly reassess need and desire for continued AC – Bleeding risk, Severity of event, family history, underlying thrombophilia, lifestyle • 28 yo AAM, Acute SOB, Pleuritic CP. – Bilateral PE, with right heart strain. – No DVT, no family history, no obvious risk factors • Extensive thrombophilia workup negative • FVL, PTGm, LAC, APL negative. Protein C, S and ATIII normal • Recommended Indefinite anticoagulation 6 8/1/11 • Acquired or inherited thrombophilia with 1st provoked venous VTE – Ensure prophylaxis in high risk settings. • Unprovoked VTE consider indefinite anticoagulation. – Need to constantly reassess need and desire for continued AC – Bleeding risk, Severity of event, family history, underlying thrombophilia, lifestyle • 28 yo AAM, Acute SOB, Pleuritic CP. Hypoxic – Bilateral PE, with right heart strain. – No DVT, no family history, no obvious risk factors • 42 yo AAM, Pleuritic CP. Not hypoxic – Unilatareal PE – No DVT, no family history,no obvious risk factors – No DVT, no family history, no obvious risk factors • Extensive thrombophilia workup negative • Extensive thrombophilia workup negative • Recommended Indefinite anticoagulation • Indefinite anticoagulation recommended • 7 years later……. • 22 yo female claudication left LE for 8 months. Left femoral artery thrombosis. – Was on OCP*, no family history • FVL, PTGm, LAC, Protein C, s and ATIII normal • Multiple positive APL/LAC. ANA +, DAT+ 7 8/1/11 • 28 yo WM TIAs • High titer APLs • 55 yo WF TIAs • Low titer + LAC • Smoker, HTN, Chol • 44 year old • Marked increased LFTs • Moderate Anemia, thrombocytopenia • Portal Vein thrombosis • 80% GPI negative granulocytes • 13 of the 46 family members determined to be protein-C deficient • Blood. 1989;73(3):712 • Protein S 30-50% affected family members • Ann Intern Med. 1987;106(5):677 • • Normal • Oral Contraceptives • Factor V Leiden Heterozygote • Both • Homozygote FVL %/year 0.008 0.03 0.06 0.30 0.50 or > 8 8/1/11 ATIII Pregnancy Liver Disease DIC Nephrotic Syndrome Major Surgery Acute Thrombosis Protein C Heparin Estrogens Warfarin Warfarin Estrogens ATIII Pregnancy Liver Disease DIC Nephrotic Syndrome Major Surgery Acute Thrombosis Protein C Protein S Pregnancy Liver Disease DIC Heparin Estrogens Warfarin Liver Disease DIC Protein S Pregnancy Liver Disease DIC Inflammation Acute Thrombosis Acute Thrombosis Liver Disease DIC Inflammation Acute Thrombosis Acute Thrombosis Warfarin Estrogens 9 8/1/11 38 yo Female, ?unprovoked DVT on coumadin for 2 years. Protein C & S deficient*. – no family history, no obvious risk factors per chart • Taken off Coumadin for three weeks, Protein C and S levels normal • Further Discussion/History • Deficiencies of ATIII, Proteins C&S • Factor V Leiden (APCr) • Prothrombin Gene Mutation • LAC, ACL, APL • Elevated Factor VIII levels • JAKII, PNH for mesenteric/portal thrombosis ? • Venous Thromboembolism < 50 with a family history – Unprovoked – Provoked ? Strong Family History/Young – Unprovoked- consider workup without family history – Evidence of thrombophilia may raise threshold to withdrawal AC in future • Unusual Site- Cerebral venous and Portal/Mesenteric vein thrombosis – JAKII and PNH • Second and third trimester pregnancy loss • Consider – Unprovoked in patients >50 APL/ACL/LAC – Women on OCP – Arterial LAC/APL only for unusual cases 10 8/1/11 • Venous Thromboembolism < 50 with a family history – Unprovoked – Provoked ? – Unprovoked- consider workup without family history – Evidence of thrombophilia may raise threshold to withdrawal AC in future • Unusual Site- Cerebral venous and Portal/Mesenteric vein thrombosis – JAKII and PNH • Second and third trimester pregnancy loss • Consider – Unprovoked in patients >50 – Women on OCP – Arterial LAC/APL only for unusual cases 11