Download Secondary (Acquired) Thrombophilias

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 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A
•
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)