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Hypercoaguable States What Every Clinician Needs to Know

Hypercoaguable States What Every Clinician Needs to Know. Amjad AlMahameed, MD, MPH Division of Cardiology Beth Israel Deaconess Medical Center. Factor V Leiden (APC Resistance)  Antithrombin (formerly Antithrombin III)  Protein C  Protein S. Prothrombin G20210A mutation

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Hypercoaguable States What Every Clinician Needs to Know

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  1. Hypercoaguable StatesWhat Every Clinician Needs to Know Amjad AlMahameed, MD, MPH Division of Cardiology Beth Israel Deaconess Medical Center

  2. Factor V Leiden (APC Resistance)  Antithrombin (formerly Antithrombin III)  Protein C  Protein S Prothrombin G20210A mutation Dysfibrinogenemia  Plasminogen  Homocysteine  Factor VIII (?) and  XI Primary (Familial) Thrombophilias

  3. Previous thrombosis Age Immobilization (age dependent) Major surgery, multiple trauma Orthopedic surgery Venous Instrumentation Malignancy/Anticancer meds/Myeloprolifirative Dz Hormones pregnancy, postpartum Medically ill (CHF, AMI, Shock) Antiphospholipid/LA syndrome HIT Travel Nephrotic Syndrome Paroxysmal Nocturnal Hemoglobinuria Inflammatory Bowel Disease Thromboangiitis Obliterans Bechet’s Syndrome Secondary Thrombophilias(Acquired Risk Factors for Clinical Thrombosis)

  4. Thrombosis and Cancer go Hand in Hand…

  5. 1 5 9 4 6 3 2 7 8 3 Mechanisms of Thrombosis in Cancer Patients Bick, R. L. N Engl J Med 2003;349:109-111

  6. Risk of VTE in Cancer Patients

  7. Antithrombin Therapy and Heparin-Induced Thrombocytopenia (HIT) Heparin as a Cause of Thrombosis!!

  8. R foot “rash” following R TKA

  9. Is HIT a Rare and Over Publicized Disorder? LET’S DO THE MATH Up to 5% incidence of HIT Up to 600,000 cases every year 12 million patients Exposed to heparin Products annually x = However, the number of HIT cases recognized and treated properly is only 18,000/year !!!

  10. HIT is a Thrombotic Storm! Thrombosis Begets Thrombosis!

  11. Cumulative Frequency of Thrombosis in Isolated HIT w/o effective anticoagulation 100 90 80 70 52.8% 60 Cumulative frequency of thrombosis (%) 50 40 30 N=62 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Days after isolated HIT recognized Warkentin and Kelton. Am J Med. 1996;101:502-507.

  12. Sequelae Incidence • New thrombosis 30%–75% • Clinical situation dependent • Amputation 10% • Associated with arterial thrombosis • Associated with venous limb gangrene • 10%–20% DEATH Clinical Sequelae in HIT (despite discontinuation of Heparin)

  13. LMWH vs. UFHHIT Incidence UFH vs Enoxaparin for VTE prevention in patients undergoing elective joint replacement surgery UFH LMWH P Value Clinical HIT 9/332 (2.7%) 0/333 (0%) 0.0018 HIT-T 8/9 HIT seroconversion 7.8% 2.2% 0.02 Warkentin TE, et al. N Engl J Med 1995;332:1330-5.

  14. LMWH vs UFH in HIT Patients with HIT (%) Postoperative day Warkentin TE et al. NEJM. 1995;332:1330-1335.

  15. Arixtra has not been associated with HIT. A study evaluating Arixtra use as primary antithrombotic therapy in acute HIT is ongoing

  16. Bilateral foot ischemia secondary to HIT post open heart surgery

  17. Bilateral foot ischemia secondary to HIT post open heart surgery

  18. Arm ischemia secondary to HIT post open heart surgery

  19. Northern and Western European, American, Australian, Middle Eastern, and Indian descent Causes of APC resistance:FVL (90%), pregnancy, OCP use, other factor V point mutations, specific APLA Ab (Anti 2-GP I) Risk of VTE with FVL: - Heterozygous: x2-10 lifetime risk, w pregnancy ( x9), w OCP use ( x 36), w HRT ( x13-16) - Homozygous: x 10-80 fold  VTE lifetime risk Role in risk of recurrent VTE: Controversial for heterozygous but  recurrence w homozygous APC Resistance and FVL

  20. Populaqtion affected: Northern and Western European, American, Australian, Middle Eastern, and Indian descent It causes of 90% of APC resistance cases Other causes of APC resistance: FVL (90%), pregnancy, OCP use, other factor V point mutations, specific APLA Ab (Anti 2-GP I) Risk of VTE with FVL: - Heterozygous: x2-10 lifetime risk, w pregnancy ( x9), w OCP use ( x 36), w HRT ( x13-16) - Homozygous: x 10-80 fold  VTE lifetime risk Role in risk of recurrent VTE: Controversial for heterozygous but  recurrence w homozygous APC Resistance and FVL

  21. Prothrombin Gene Mutation (PTG 20210 GA • Southern European, N and S America, Middle East and India – NOT SEEN IN ASIANS AND AFRICANS • Leads to  plasma prothrombin   VTE • Heterozygous: VTE risk  by x 2-6, w pregnancy ( x15), w OCP ( x16) • Risk of cerebral vein thrombosis in women w OCP use  by x150 and w/o OPC  x10

  22. Southern European, N and S America, Middle East and India – NOT SEEN IN ASIANS AND AFRICANS Leads to  plasma prothrombin   VTE Heterozygous: VTE risk  by x 2-6, w pregnancy ( x15), w OCP ( x16) Risk of cerebral vein thrombosis in women w OCP use  by x150 and w/o OPC  x10 Prothrombin Gene Mutation (PTG 20210 GA

  23. of protein C, S or antithrombin are seen in 10-15% of VTE patients Lifetime risk of VTE is  x31, 36 and 40 with Prot. C, S, antithrombin deficiency Use of OCP increases the annual absolute risk to 4-27% Each pregnancy (including the postpartum period) is associated with VTE incidence of 4% Natural Anticoagulant Deficiency

  24. Deficiency of protein C, S or antithrombin are seen in 10-15% of VTE patients Lifetime risk of VTE is  x31, 36 and 40 with Prot. C, S, antithrombin deficiency Use of OCP increases the annual absolute risk to 4-27% Each pregnancy (including the postpartum period) is associated with VTE incidence of 4% Natural Anticoagulant Deficiency

  25. Inherited:MTHFR, CBS or cobalamin metabolism errors Acquired: folate, B6, or B12 deficiency, CRI, DM, hyper-parathyroidism, pernicious anemia, IBD, lymphoblastic anemia, breast/ovarian, and pancreatic CA, MTX /theo-phylline/ and phenytoin Rx VTE risk increased with  fasting plasma HCY level(x2-4) Hyper Hcy was associated w 3.4-fold  risk of idiopathic (but not situational) VTE in PHS Persistent hyper Hcy associated with 2 to 3-fold increase risk of recurrent VTE Hyperhomocysteinemia

  26. Elevated Factor VIII • Associated with x3 to 6-fold  risk of VTE • VTE risk is not accentuated by concomitant OCP use • Difficult to differentiate true elevation form transient acute phase response • May contribute to the increased VTE risk seen in acutely ill pts or those with CA or IBD

  27. Antiphospholipid Antibodies (APLA) • 2-4% of the general population. About 50% of them have SLE • Lupus Anticoagulant (LA) and Anticardiolopin (ACL) Abs are most common. ACLA approximately 5 times more common than the LA • Other APLA that are not routinely measured include: - anti-beta 2 glycoprotein 1 - anti-prothrombin - the "false-positive" test for syphilis • Antibody titer can fluctuate over time • Primary or secondary APLA syndrome (SLE, infections, malignancy, chronic illness) • Two independent risk factors for thrombotic events: a previous history of thrombosis and the presence of an IgG ACA titer exceeding 40 U/mL. • RR of VTE in pts with LA x11 and w ACL x3

  28. 2-4% of the general population. About 50% of them have SLE Lupus Anticoagulant (LA) and Anticardiolopin (ACLA) Abs are most common. ACLA is 5 times more common than LA Other APLA that are not routinely measured include: - anti-beta 2 glycoprotein 1 - anti-prothrombin - the "false-positive" test for syphilis Antibody titer can fluctuate over time Primary or secondary APLA syndrome (SLE, infections, malignancy, chronic illness) Two independent risk factors for thrombotic events: a previous history of thrombosis and the presence of an IgG ACA titer exceeding 40 U/mL. RR of VTE in pts with LA x11 and w ACL x3 Antiphospholipid Antibodies (APLA)

  29. Diagnostic Criteria • VTE, or MI, or Stroke < age 55 years • OB complications: - Fetal loss > 10 weeks (Nl morphology) -> 3 fetal loss < 10 weeks, or -> 1 premature birth < 34 weeks • Diagnosis: • LA > 2 phospholipid-dependent clotting assays • APL Abs > 30-40 GPL or MPL units • Persistently positive for at least 6 weeks (3 mos)

  30. Venous thrombosis: Most common: deep or superficial veins of the legs Less common: IVC, iliofemoral, axillary, renal, portal, hepatic, or retinal veins Arterial thrombosis: Most common: Cerebral infarct, cardiogenic emboli. Less common: Coronary, retinal, and visceral artery Cutaneous: Livedo reticularis (up to 80%), splinter hemorrhages, leg ulcer, skin insarcts, blue toe syndrome Neuro: Multi-infarct dementia, chorea, transverse myelopathy, Pseudotumor cerebri, cerebral venous thrombosis APLA are found in as many as 50% of patients who get migraines Cardiac: CAD, valve vegetations or thickening 30%, intracardiac thrombus Hematologic: Thrmobocytopenia (40% of patients), hemolytic anemia Obstetric: Fetal loss (15-75%), IUGR APLA Clinical Manifestations

  31. Who Should Be Tested for Thrombophilia? • Venous or arterial thrombosis at an early age • Family history of thrombophilia • Recurrent VTE • Unusual site: cerebral, mesenteric, renal • Thrombosis during pregnancy • Idiopathic thrombosis (venous or arterial)

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