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Hypercoaguable States What Every Clinician Needs to Know Amjad AlMahameed, MD, MPH Division of Cardiology Beth Israel Deaconess Medical Center Primary (Familial) Thrombophilias • Factor V Leiden (APC Resistance) • • • Antithrombin (formerly Antithrombin III) Protein C Protein S • Prothrombin G20210A mutation • Dysfibrinogenemia • Plasminogen • Homocysteine • Factor VIII (?) and XI Secondary Thrombophilias (Acquired Risk Factors for Clinical Thrombosis) • Previous thrombosis • Age • Immobilization (age dependent) • Major surgery, multiple trauma • Medically ill (CHF, AMI, Shock) • Antiphospholipid/LA syndrome • HIT • Travel • Orthopedic surgery • Nephrotic Syndrome • Venous Instrumentation • • Malignancy/Anticancer meds/Myeloprolifirative Dz Paroxysmal Nocturnal Hemoglobinuria • Inflammatory Bowel Disease • Hormones • Thromboangiitis Obliterans • pregnancy, postpartum • Bechet’s Syndrome Thrombosis and Cancer go Hand in Hand… Mechanisms of Thrombosis in Cancer Patients 1 5 9 4 6 2 3 7 8 3 Bick, R. L. N Engl J Med 2003;349:109-111 Risk of VTE in Cancer Patients Patient Population RR of VTE Hospitalized, noncancer, 60-70 y/o 1 Hospitalized, noncancer, 70-80 y/o 2 Breast CA 4 Lung CA 90 Breast CA on chemo Rx 140 Pancreatic CA 150 Gastrointestinal CA 150 Antithrombin Therapy and Heparin-Induced Thrombocytopenia (HIT) Heparin as a Cause of Thrombosis!! R foot “rash” following R TKA Is HIT a Rare and Over Publicized Disorder? LET’S DO THE MATH 12 million patients Exposed to heparin Products annually x Up to 5% incidence of HIT = Up to 600,000 cases every year However, the number of HIT cases recognized and treated properly is only 18,000/year !!! HIT is a Thrombotic Storm! Thrombosis Begets Thrombosis! Cumulative Frequency of Thrombosis in Isolated HIT w/o effective anticoagulation 100 Cumulative frequency of thrombosis (%) 90 80 70 52.8% 60 50 40 30 N=6 2 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. Clinical Sequelae in HIT (despite discontinuation of Heparin) Sequelae New thrombosis Incidence 30%–75% Amputation DEATH Clinical situation dependent 10% Associated with arterial thrombosis Associated with venous limb gangrene 10%–20% LMWH vs. UFH HIT Incidence UFH vs Enoxaparin for VTE prevention in patients undergoing elective joint replacement surgery UFH Clinical HIT 9/332 (2.7%) HIT-T 8/9 HIT seroconversion 7.8% Warkentin TE, et al. N Engl J Med 1995;332:1330-5. LMWH 0/333 (0%) 2.2% P Value 0.0018 0.02 LMWH vs UFH in HIT 5 UFH (N=332) Enoxaparin (N=333) 4 Patients with HIT (%) 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Postoperative day Warkentin TE et al. NEJM. 1995;332:1330-1335. Arixtra has not been associated with HIT. A study evaluating Arixtra use as primary antithrombotic therapy in acute HIT is ongoing Bilateral foot ischemia secondary to HIT post open heart surgery Bilateral foot ischemia secondary to HIT post open heart surgery Arm ischemia secondary to HIT post open heart surgery APC Resistance and FVL • • 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 • 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 2GP 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 Prothrombin Gene Mutation (PTG 20210 GA • • • • 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 GA • Southern European, N and S America, Middle East and India – NOT SEEN IN • 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 ASIANS AND AFRICANS • Leads to plasma prothrombin VTE Natural Anticoagulant Deficiency • of protein C, S or antithrombin are seen in 10-15% of VTE patients • Use of OCP increases the annual absolute risk to 427% • Lifetime risk of VTE is x31, 36 and 40 with Prot. C, S, antithrombin deficiency • Each pregnancy (including the postpartum period) is associated with VTE incidence of 4% Natural Anticoagulant Deficiency • • 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 427% • Each pregnancy (including the postpartum period) is associated with VTE incidence of 4% Hyperhomocysteinemia • • VTE risk increased with fasting plasma HCY level(x2-4) Acquired: folate, B6, or • B12 deficiency, CRI, DM, hyperparathyroidism, pernicious anemia, IBD, lymphoblastic anemia, breast/ovarian, and pancreatic CA, MTX /theo-phylline/ and phenytoin Rx Hyper Hcy was associated w 3.4-fold risk of idiopathic (but not situational) VTE in PHS • Persistent hyper Hcy associated with 2 to 3fold increase risk of recurrent VTE Inherited: MTHFR, CBS or cobalamin metabolism errors • 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 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 Antiphospholipid Antibodies (APLA) • • • 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 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) APLA Clinical Manifestations • 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 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)