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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

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

Primary (Familial) Thrombophilias
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

Secondary Thrombophilias(Acquired Risk Factors for Clinical Thrombosis)
slide5

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

slide7

Antithrombin Therapy and Heparin-Induced Thrombocytopenia (HIT)

Heparin as a Cause of Thrombosis!!

is hit a rare and over publicized disorder
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 !!!

hit is a thrombotic storm
HIT is a Thrombotic Storm!

Thrombosis Begets Thrombosis!

cumulative frequency of thrombosis in isolated hit w o effective anticoagulation
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.

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

Clinical Sequelae in HIT (despite discontinuation of Heparin)
lmwh vs ufh hit incidence
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.

lmwh vs ufh in hit
LMWH vs UFH in HIT

Patients with HIT (%)

Postoperative day

Warkentin TE et al. NEJM. 1995;332:1330-1335.

slide15
Arixtra has not been associated with HIT. A study evaluating Arixtra use as primary antithrombotic therapy in acute HIT is ongoing
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
apc resistance and fvl1
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
prothrombin gene mutation ptg 20210 g a
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
prothrombin gene mutation ptg 20210 g a1
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
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
natural anticoagulant deficiency1
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
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

Hyperhomocysteinemia
elevated factor viii
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
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 apla1
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
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

APLA Clinical Manifestations
who should be tested for thrombophilia
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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