Hypercoaguable StatesWhat 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

• 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

Thrombosis and Cancer go Hand in Hand…

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

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

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 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 !!!

HIT is a Thrombotic

Storm!

Thrombosis Begets Thrombosis!

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

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

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

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)

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 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

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 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

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%

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%

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

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

• 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)

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)