hypercoaguable states what every clinician needs to know amjad almahameed, md, mph division of...
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Hypercoaguable StatesWhat Every Clinician Needs to Know
Amjad AlMahameed, MD, MPH
Division of Cardiology
Beth Israel Deaconess Medical Center
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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
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Secondary Thrombophilias(Acquired Risk Factors for Clinical Thrombosis)
• 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
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Thrombosis and Cancer go Hand in Hand…
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Bick, R. L. N Engl J Med 2003;349:109-111
Mechanisms of Thrombosis in Cancer Patients
1
2
3
4
5
6
3
78
9
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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
Risk of VTE in Cancer Patients
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Antithrombin Therapy and Heparin-Induced Thrombocytopenia (HIT)
Heparin as a Cause of Thrombosis!!
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R foot “rash” following R TKA
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Is HIT a Rare and Over Publicized Disorder?
LET’S DO THE MATH
12 million patientsExposed to heparin Products annually
xUp to 5% incidence
of HIT
Up to600,000cases
every year
=
However, the number of HIT cases recognized and treated properly is only
18,000/year !!!
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HIT is a Thrombotic
Storm!
Thrombosis Begets Thrombosis!
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Warkentin and Kelton. Am J Med. 1996;101:502-507.
Days after isolated HIT recognized
Cumulative Frequency of Thrombosis in Isolated HIT w/o effective anticoagulation
52.8%
0 4 6 10 12 14 168 18 22 26 28 302420
Cu
mu
lativ
e fr
equ
ency
of
thro
mbo
sis
(%)
20
10
20
30
40
50
60
70
80
90
100
N=62
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Clinical Sequelae in HIT (despite discontinuation of Heparin)
Sequelae Incidence
New thrombosis 30%–75% Clinical situation dependent
Amputation 10% Associated with arterial thrombosis
Associated with venous limb gangrene
10%–20%DEATH
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LMWH vs. UFHHIT Incidence
Warkentin TE, et al. N Engl J Med 1995;332:1330-5.
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
UFH vs Enoxaparin for VTE prevention in patients undergoing elective joint replacement surgery
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LMWH vs UFH in HIT
Warkentin TE et al. NEJM. 1995;332:1330-1335.
Patients with HIT (%)
Postoperative day
0
1
2
3
4
5
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
UFH (N=332)
Enoxaparin (N=333)
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Arixtra has not been associated with HIT. A study evaluating Arixtra
use as primary antithrombotic therapy in acute HIT is ongoing
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Bilateral foot ischemia secondary to HIT post open heart surgery
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Bilateral foot ischemia secondary to HIT post open heart surgery
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Arm ischemia secondary to HIT post open heart surgery
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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
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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 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
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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
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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
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Natural Anticoagulant 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%
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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 4-27%
• Each pregnancy (including the postpartum period) is associated with VTE incidence of 4%
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Hyperhomocysteinemia
• 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
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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
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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
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• 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)
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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)
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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
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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)