Transcript Thrombophilia and Pregnancy—An Old Issue Revisited

Thrombophilia and Pregnancy
An Old Issue Revisited
Tripp Nelson, MD
Maternal Fetal Medicine Fellow
Medical University of South Carolina
Objectives
• Review coagulation basics and pregnancy
influence on clotting
• Inherited Thrombophilia
– Pregnancy management
– Therapy options
• Aquired Thrombophilia
– Pregnancy management
– Therapy options
• Anesthesia considerations with
thromboprophylaxis
Importance
• VTE responsible for 20% of pregnancy-related
deaths in US
• VTE prevalence 1:1600
– 77% DVT
– 23% PE
• VTE usually a disease of aging
– Pregnancy alone increases risk 6x
Virchow’s Triad
Venous Stasis
(Prog vasodilation, pelvic vein compression)
Hypercoagulability
Vascular Damage
(Increase pro-coagulant, decreased natural anticoagulant)
(Vessel Distention, Delivery Trauma)
Pregnancy Induced Hypercoagulability
Pro-coagulants
• Increased Fibrinogen
• Increased factor levels:
– V, VIII, IX, X  inc thrombin
• Decreased thrombolysis
– Increased PAI-1,2
– Decreased tPA activity
Anti-coagulants
• Protein S activity reduced
• Activated protein C
resistance increased
DVT in pregnancy
• 98% involved the lower extremities
– 80% left LE
• More common antepartum than postpartum
– 74% AP
– 26% PP
– 50% of antepartum DVT detected by 15 weeks
– Only 12% detected after 30 weeks
PE in pregnancy
• More likely diagnosed postpartum
– 60.5%
• Strongly associated with CD (RR 30.3)
Thrombophilia
• Inherited
–
–
–
–
–
Protein C/S Deficiency
Prothrombin mutation
ATIII Deficiency
Factor V Leiden
Hyperhomocysteinemia
• Aquired
– APAS
Incidence of Inherited Thrombophilia
Thrombophilia
General
population
Patients with VTE
AT III, Protein C, Protein S
1%
7%
Factor V Leiden
Caucasian 4-7%
Other 0-1%
21%
Prothrombin 20210A
Caucasian 2-3%
Other 0-1%
6%
Elevated FVIII:c levels
11%
25%
Hyperhomocysteinemia
5%
10%
Inherited Thrombophilia:
VTE Risk in Pregnancy
ACOG Practice Bulletin # 138
Protein C/S Deficiency
Diagnosis
• Protein C
– 55-70% activity = borderline
– repeat, family
– < 55% = deficiency
– False + = liver dz, OCP use, vit K deficiency, DIC
• Protein S
– < 55% free protein S
– False + = liver dz, oral anticoagulants, OCP use, vit K
deficiency, pregnancy, nephrotic syndrome
– < 30% in pregnancy
Hoffman, Hematology 4th Ed 2005
Protein C/S Deficiency
Protein C Deficiency
• Highly variable phenotype
Protein S Deficiency
• Highly variable phenotype
– 160 possible mutations
– 130 possible mutations
• Type 1 – reduction in
antigen and activity
• Type 2 – normal antigen
level, decreased activity
• Type 1: low levels of total
and free protein S
• Type 2: Nml total but
decrease free protein S
• May be associate with RPL,
stillbirth, preeclampsia/eclampsia
Antithrombin Deficiency
• Highly thrombogenic, but RARE
• Normal ATIII concentration = 75-120%
– No change with pregnancy
• 250 associated mutations can cause
• Prevalence 1:2,500
• In non-pregnant confers a 25x risk VTE
– Pregnancy certainly increases
– Although may be lower risk in those without personal
or family history of VTE
Protein C/S, ATIII
First VTE incidence
Overall (%/year)
1.5 (0.7-2.8)
Surgery/trauma (%/episode)
8.1 (4.5-13.2)
Pregnancy (%/pregnancy)
4.1 (1.7-8.3)
AT 7.2%
8-13%*
During pregnancy
1.2 (0.3-4.2)
Puerperium
3.0 (1.3-6.7)
OCP use (%/year)
4.3 (1.4-9.7)
Coppens, et al 2006; *ACCP Chest, 2012
Factor V Leiden Mutation
• Gene defect of clotting factor V
– Point mutation
– Replacement of arginine by glutamine
• In cleavage site for activated protein C (APC)
• Results in factor V more resistant to
inactivation by APC
– APC resistance
• Present in 20% of patient with VTE
• Present in 5% of caucasian population
Factor V Leiden
First VTE incidence
Overall (%/year)
0.5 (0.1-1.3)
Surgery/trauma (%/episode)
1.8 (0.7-4.0)
Pregnancy (%/pregnancy)
2.1 (0.7-4.9)
4-16%*
During pregnancy
0.4 (0.1-2.4)
Puerperium
1.7 (0.7-4.3)
OCP use (%/year)
0.5 (0.1-1.4)
Coppens, et al 2006, *ACCP Chest, 2012
Relative Risk VTE in pregnancy
• Factor V heterozygote
– 5.3 (3.7-7.6)
• Factor V homozygous
– 25.4 (8.8-66)
• PT
– 6.1 (3.4-11.2)
• PT and factor V
– 84 (19-369)
Prothrombin Gene Mutation
• G-A substitution at neucleotide 20210 of PT
gene
• Result = increased circulating levels of
prothrombin
– Increased hepatic biosynthesis of PT
• Present in 3% of European population
• Reported to account for 17% of VTE in
pregnancy
– Family and personal hx important
– No hx of VTE, risk during pregnancy=1%
Prothrombin Mutation
First VTE incidence
Overall (%/year)
0.4 (0.1-1.1)
Surgery/trauma (%/episode)
1.6 (0.5-3.8)
Pregnancy (%/pregnancy)
2.3 (0.8-5.3)
4-10%*
During pregnancy
0.5 (0.1-2.6)
Puerperium
1.9 (0.7-4.7)
OCP use (%/year)
0.2 (0.0-0.9)
Coppens, et al 2006, *ACCP Chest, 2012
Hyperhomocysteinemia/MTHFR
• MTHFR mutation is most common reason for
hyperhomocysteinemia
– MTHFR converts homocysteine to methionine
• VTE risk associated with homocysteine levels
better than presence of MTHFR mutation
• Recent data:
– ELEVATED HOMOCYSTEINE LEVELS WEAK FACTOR
FOR VTE
– NO EVIDENCE TO INCLUDE IN W/U OR TO TREAT
Who should I screen?
• Controversial
• Screening should only be preformed when
results of testing would affect management!
• Personal History of VTE associated with a nonrecurrent risk factor (surgery, immobility)
• First degree relative with history of high risk
thrombophilia
What about recurrent pregnancy loss?
• Not recommended to screen for
thrombophilia!
– No proven benefit to treating in future
pregnancies
• Should be screened for APAS!
How to screen…
Thrombophilia
Testing
Method
Testing reliable Testing reliable
during
during acute
pregnancy?
thrombosis?
Testing reliable
during
anticoagulation?
FVL Mutation
APC ressistance
assay (2nd Gen)
If abnormal,
DNA analysis
Yes
Yes
No
Yes
Yes
Yes
Prothrombin
G20210A
DNA analysis
Yes
Yes
Yes
Protein C Def
Protein C
activity (<60%)
Yes
No
No
Protein S Def
Functional
Assay (<55%)
No*
No
No
ATIII Def
ATIII activity
(<60%)
Yes
No
No
Pregnancy Management
Pregnancy Management
Treatment Definitions
Treatment
Dose
Mini-dose UFH
sc, 5000 q 12 hour
Moderate-dose UFH
sc q 12 hour, Xa adjust
Adjusted dose UFH
sc q 12 hour, PTT adjust
Prophylactic LMWH
sc, enoxaparin 40mg/d
Intermediate dose LMWH
sc, enoxaparin 40mg /12 hr
Adjusted dose LMWH
sc, enoxaparin 1mg/kg/12h
Post partum
Warfarin (INR 2-3)
Blickstein, 2006
Treatment Definitions
• Prophylactic Dose UFH/trimester
– First Trimester: 5,000u SQ q12h
– Second Trimester: 7,500u SQ q12h
– Third Trimester: 10,000u SQ q12h
Risk of thromboprophylaxis
• Vitamin K antagonist
– 2-3% annual incidence of major bleeding
• 1% rate of lifethreatening
• 0.25% rate of fatal
• Osteoporosis (fracture; Monreal, 1994)
– UFH 15% (6-30%)
– LMWH 3% (0-11%)
• UFH
– 2% bleeding
– HIT – 3% with UFH
• Occurs 5-15 days after initiation
Need for therapeutic anticoagulation
• Acute DVT/PE
• Recent DVT/PE on therapeutic anticoagulation
prior to pregnancy
• Thrombophilia + 2 or more epidodes of VTE
– Regardless of whether on lifelong anticoagulation
Therapeutic Regimens
• Lovenox (LMWH)
– 1mg/kg SQ BID
– 1.5mg/kg SQ daily
– Check Anti-Xa level 6 hrs after most recent dose
– Therapeutic window 0.5-1
• UFH
– Heparin drip titrated to aPTT of 60-80
Aquired Thrombophilia
• Antiphospolipid Antibody Syndrome (APAS)
– Multi-functional plasma proteins that have regulatory
roles in coagulation, fibrinolysis
– Associated with variety of problems:
•
•
•
•
•
•
•
Arterial thrombosis
Venous thrombosis
Auto-immune thrombocytopenia
Fetal Loss
Pre-eclamsia
IUGR, placental insufficiency
Preterm birth
APAS
↑ TX2, PAF, ↓ Protein C
↑ Platelet activation, platelet aggregation, vasoconstriction
Decidual vasculopathy
Placental thrombosis/infarction
APAS Medical Complications
• Thrombosis
– 2% of VTE
– 65-70% venous
– Arterial – CVA (MCA); retinal, subclavian, brachial
arteries
•
•
•
•
25% occur in pregnancy or with OCP
APAS = 5-12% risk of VTE in pregnancy
25% recurrence risk in one year
Other risks:
– Autoimmune thrombocytopenia
– Hemolytic anemia
APAS Obstetrical Complications
• RPL
• Pre-eclampsia
• IUGR
– 15-30%
– Associated with increased titers
• PTB
APAS Diagnostic Criteria
Laboratory
• +LAC, 2 separate occasions
>12 weeks apart
• +aCL IgG/M, 2 separate
occasions, >12 weeks apart
– >40 GPL or MPL
– >99% for reference lab
• +beta2GP IgG/M,
2 separate occasions, > 12
weeks apart
– >99% for reference lab
Clinical
• Vascular Thrombosis
– Arterial
– Venous
– Small vessel
• Pregnancy Morbidity
– Stillbirth >10 weeks (nml fetal
morphology)
– PTB<34 weeks
• Due to Pre-eclampsia or
IUGR
– 3+ RPL < 10 weeks
When to test for APAS?
•
•
•
•
Recurrent pregnancy loss, >3
Unexplained fetal death >10 weeks
Severe pre-eclampsia, eclampsia <34 weeks
Unexplained thrombotic event
– Venous, arterial, CVA/TIA
• SLE
• Severe IUGR
• Auto-immune: thrombocytopenia, hemolytic
anemia
APAS Pregnancy Management
• Treatment goals to improve =
– Maternal Outcome
– Neonatal outcome
• Cases fall into one of two categories:
– APAS with prior hx of thrombotic event
– APAS with no history of thrombotic event
APAS Pregnancy Management
• Prior VTE Event
– Prophyalctic
anticoagulation
– UFH
– ASA 81mg daily
– Continue anticoagulation
until 6 weeks
postpartum
• No hx prior VTE
– Less well studied
– Expert consensus:
• VTE Surveillance + PP
prophylactic
anticoagulation
• OR prophylactic
anticoagulation
throughout pregnancy
and pp
In cases of RPL: heparin prophylaxis + ASA daily may reduce
pregnancy loss as much as 50%!!
Additional Therapies
• Steroids
– Heparin/LDA superior to LDA alone or prednisone
therapy
• Empson M, Obstet Gynecol 2002.
• IVIG
– Most trials evaluating use contained women also
treated with combination of heparin/LDA/pred
– Small RCT using IVIG + heparin/LDA found no
improved outcomes than with heparin/LDA alone
• Branch et al, Am J Obstet Gynecol 2000
Antenatal Surveillance with APAS
• High potential risk of IUGR, stillbirth
• Insufficient data to support/refute specific
practice
• Recommend developing local protocols:
– Serial ultrasonographic assessment of growth
– Antenatal surveillance in the third trimester
reasonable even if no detection of growth abn
Anesthesia Considerations
Risk of Spinal / epidural hematoma
• With epidural: 1/220,000
• With spinal: 1/320,000
– RR with traumatic tap 11.2
– RR with aspirin use 2.54
• RR heparin after procedure
– >1 hr post procedure: 2.18
– <1 hr post procedure: 25.2
Horlocker, Reg Anes Pain Med 2003
Anesthesia - UFH
• Duration of heparin >4 days – check plt prior
to epidural placement
– Goodier, et al. Anesth Analg 2015
• Multicenter retrospective cohort estimation of
neuraxial hematoma in parturients plt<100k
• 173 pts with spinal or epidural
• Risk estimate of epidural hematoma 0-0.6% if plt >80K
Anesthesia - UFH
• Dose of 5000u BID should not preclude
anesthesia
• >10,000u BID await normalization of aPTT
• Hold IV/SQ for at least 2 hrs prior to epidural
insertion or removal
• Prophylactic dose heparin may be restarted 12
hrs post cesarean
• Therapeutic dose heparin should not be
restarted until 24 hrs post cesarean
Horlocker TT, ASRA and Pain Medicine, 3rd Ed, 2010
Anesthesia - LMWH
• Plan to convert patients on LMWH to
prophylactic or therapeutic UFH at 36 weeks
or earlier as indicated
• For prophylactic dose LMWH:
– Epidural ok 12 hrs after the last dose
• For therapeutic dose LMWH:
– Epidural ok 24 hrs after the last dose
• No benefit to monitor anti Xa levels
Horlocker TT, ASRA and Pain Medicine, 3rd Ed, 2010
Anesthesia - LMWH
• For resumption of anticoagulation after
therapeutic dosing
– Removal of epidural should be 10-12 hrs from the
last dose
– Subsequent dosing minimum of 2 hrs after
epidural catheter removal
– If bloody tap, LMWH should be held for 24 hrs
Horlocker TT, ASRA and Pain Medicine, 3rd Ed, 2010
Questions?