Le eparine in ginecologia e ostetricia: quando utilizzarle ?

Elvira Grandone,Unità di Aterosclerosi e Trombosi

I.R.C.C.S. “Casa Sollievo della Sofferenza”S. Giovanni Rotondo (Foggia)

Le Eparine per:

1.Prevenzione del TEV in Ginecologia

1.Prevenzione del TEV in Ostetricia

2.Prevenzione delle Complicanze Ostetriche

Le Eparine per:

1.Prevenzione del TEV in Ginecologia

1.Prevenzione del TEV in Ostetricia

2.Prevenzione delle Complicanze Ostetriche

General Surgery VTE Prophylaxis

FalckFalck--Ytter Y. Chest. 2012 Feb;141(2 Suppl):e278SYtter Y. Chest. 2012 Feb;141(2 Suppl):e278S--325S. PMID: 22315265325S. PMID: 22315265

Low Bleeding Risk High Bleeding RiskVery Low VTE risk No Prophylaxis (2C) No prophylaxis (2C)Low VTE risk IPC (2C) IPC (2C)

Moderate VTE riskLMWH (2B)LDUH (2B)IPC (2C)

IPC (2C)

High VTE riskLMWH (1B)LDUH (1B)

Add IPC (2C)IPC and Pharm when possible (2C)

VTE Surgical Risk Stratification

Gould MK. Chest. 2012 Feb;141(2 Suppl):e227SGould MK. Chest. 2012 Feb;141(2 Suppl):e227S‐‐77S. PMID: 2231526377S. PMID: 22315263

Caprini Risk Assessment Model

Gould MK. Chest. 2012 Feb;141(2 Suppl):e227SGould MK. Chest. 2012 Feb;141(2 Suppl):e227S‐‐77S. PMID: 2231526377S. PMID: 22315263

Gould M

K. Chest. 2012 Feb;141(2 Suppl):e227SGould M

K. Chest. 2012 Feb;141(2 Suppl):e227S ‐‐ 77S. PMID: 22315263

77S. PMID: 22315263

Rogers VTE Risk  Assessment

Gould M

K. Chest. 2012 Feb;141(2 Suppl):e227SGould M

K. Chest. 2012 Feb;141(2 Suppl):e227S ‐‐ 77S. PMID: 22315263

77S. PMID: 22315263

Risk Factors  for Bleeding

Flashback: ACCP 8*Risk Level Examples Regimen

Low Minor surgery, mobile patientMedical patient, fully mobile

Early aggressive  ambulation

Medium Medical patient, bed rest or sickMost gen, gyn, uro surgery 

LMWH, UFH, or  Fondaparinux

High Major ortho surgery Major trauma, SCI

LMWH, fondaparinux,  or VKA (INR 2‐3)

Bleed Risk Various Mechanical: IPC or GCS

Geerts, Chest 2008

No such intuitive slide can be written for ACCP 9 

*“The descriptive terms are purposely left undefined to allow individual clinician interpretation”

General Surgery VTE Prophylaxis Very Low Risk

20122012• 3.6.1. For general and abdominal‐pelvic surgery 

patients at very low risk for VTE ( , 0.5%; Rogers score,  , 7; Caprini score, 0), we recommend that 

– no specific pharmacologic (Grade 1B) or mechanical (Grade  2C) prophylaxis be used other than early ambulation.

FalckFalck--Ytter Y. Chest. 2012 Feb;141(2 Suppl):e278SYtter Y. Chest. 2012 Feb;141(2 Suppl):e278S--325S. PMID: 22315265325S. PMID: 22315265

General Surgery VTE Prophylaxis Low Risk

20122012• 3.6.2. For general and abdominal‐pelvic surgery 

patients at low risk for VTE ( 

1.5%; Rogers score, 7‐ 10; Caprini score, 1‐2), we suggest 

– mechanical prophylaxis, preferably with intermittent  pneumatic compression (IPC), over no prophylaxis (Grade 

2C) .

FalckFalck--Ytter Y. Chest. 2012 Feb;141(2 Suppl):e278SYtter Y. Chest. 2012 Feb;141(2 Suppl):e278S--325S. PMID: 22315265325S. PMID: 22315265

General Surgery VTE Prophylaxis Moderate Risk

20122012• 3.6.3. For general and abdominal‐pelvic surgery patients at moderate risk 

for VTE ( 

3.0%; Rogers score, . 10; Caprini score, 3‐4) who are not at high  risk for major bleeding complications, we suggest 

– low‐molecular‐weight heparin(LMWH) (Grade 2B ), – low‐dose unfractionated heparin (LDUH) (Grade 2B) , or – mechanical prophylaxis, preferably with IPC (Grade 2C) , over no prophylaxis.

• 3.6.4. For general and abdominal‐pelvic surgery patients at moderate risk  for VTE (3.0%; Rogers score, . 10; Caprini score, 3‐4) who are at high risk for 

major bleeding complications or those in whom the consequences of  bleeding are thought to be particularly severe, we suggest 

– mechanical prophylaxis, preferably with IPC, over no prophylaxis

(Grade 2C).

FalckFalck--Ytter Y. Chest. 2012 Feb;141(2 Suppl):e278SYtter Y. Chest. 2012 Feb;141(2 Suppl):e278S--325S. PMID: 22315265325S. PMID: 22315265

General Surgery VTE Prophylaxis High Risk

20122012• 3.6.5. For general and abdominal‐pelvic surgery patients at high risk for VTE 

( 

6.0%; Caprini score, 

5) who are not at high risk for major bleeding  complications, we recommend pharmacologic prophylaxis with 

– LMWH (Grade 1B) or – LDUH (Grade 1B) over no prophylaxis. – We suggest that mechanical prophylaxis with elastic stockings (ES) or IPC should 

be added to pharmacologic prophylaxis (Grade 2C) .

• 3.6.7. For high‐VTE‐risk general and abdominal/pelvic surgery patients who  are at high risk for major bleeding complications or those in whom the 

consequences of bleeding are thought to be particularly severe, we suggest  use of 

– mechanical prophylaxis, preferably with IPC, over no prophylaxis

until the risk  of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade  2C) .

FalckFalck--Ytter Y. Chest. 2012 Feb;141(2 Suppl):e278SYtter Y. Chest. 2012 Feb;141(2 Suppl):e278S--325S. PMID: 22315265325S. PMID: 22315265

Outpatient Recommendations

• Post Discharge: No (2B)• Low risk cancer: No heparins (2B), VKA

(1B)• High risk cancer: Yes, LMWH / UFH (2B)

– Prior VTE, immobility, hormonal Rx, angiogenesis inhibitors, thalidomide or lenalidomide

• Chronic immobility or SNF: No (2C)• Asymptomatic thrombophilia: No (1C)• Travel: mobility and GCS, no meds (2C)

Le Eparine per:

1.Prevenzione del TEV in Ginecologia

1.Prevenzione del TEV in Ostetricia

2.Prevenzione delle Complicanze Ostetriche

INCIDENCE PER YEAR OF DVT (/ 1,000) J. Int. Med. 232, 155, 1992

• Males < 40 years           0.08• Males 40 ‐

60 years       1.10

• Males > 60 years           4.66  Overall 1.58

• Females < 40 years        0.12• Females 15 ‐

40 years    0.18

• Females 40 ‐

60  years   1.00• Females > 60 years        4.20

INCIDENCE OF VTE DURING PREGNANCY AND  PUERPERIUM

(PER 1,000 DELIVERIES)

• 72.201 deliveries (Glasgow, Scotland)51 cases of DVT and 11 cases of PE (of 50 investigated, 12% AT defect, 8% FV 

Leiden, 8% FII 20210A)VTE in pregnancy  0.57 VTE in puerperium 0.29 VTE in pregnancy and puerperium 0.86T&H 78,1183,1997  ‐

BJOG 107,565,2000         

INCIDENCE OF VTE DURING PREGNANCY  AND PUERPERIUM

• DVT rate 21.9% during the 1st trimester• 33.7% during the 2nd trimester• 47.6% during the 3rd trimester(meta‐analysis of 12 studies)

• antepartum: 65.5% (0.23 per day),     puerperium: 34.5% (0.82 per day)

(meta‐analysis of 9 studies)Obstet Gynecol Surv 54,265,1999

Population‐based studies• In a population‐based nested case–control study of 

100,000 

consecutive 

pregnancies 

in 

Finland 

34  cases with VTE an 641 controls were studied. 

• FVL 

(OR 

11.6, 

CI 

3.6–33.6), 

age 

> 35 

vs. 

< 25 

(OR  6.3, CI 1.7–23.1), and BMI > 30 vs. 

< 25 (OR 5.6, CI 

2.3–13.9) were associated with thrombosis. • Overall 

absolute 

risk 

of 

a 

FVL 

carrier 

was 

1 

in 

314. 

FVL interacted with age, BMI, and blood group.

Hiltunen et al, Thromb Res 2007; 119: 423

Virkus RA et al, Thromb Haemost 2011; 106: 304–309

Virkus RA et al, Thromb Haemost 2011; 106: 304–309

Table 1. Characteristics of probands (n=177).

Median age at the enrolment, yrs (range) 25 (17-76)

Median age at the first event, yrs (range) 25 (16-41)

Pregnancy-related VTE, n (%) 24 (13.4)

during pregnancy, n (%) in puerperium, n (%)

7 (29)17 (71)

Pregnancy losses, n (%) 88 (50)

early PL, n (%) late PL, n (%)

83 (94)5 (6)

Pregnancy-related hypertensive disorders, n (%) 4 (2.1)

SGA newborns, n (%) 3 (1.7)

Ischemic stroke during pregnancy/ puerperium, n (%) 2 (1.1)

Placenta abruptio, n (%) 3 (1.7)

Multiple* pregnancy-related complications, n (%) 53 (30)

*Multiple: either the simultaneous occurrence of two obstetric complications or a history of different obstetric complications occurred in two or more pregnancies. Abbreviations: VTE, venous thromboembolism; PL, pregnancy loss; SGA, small for gestational age Villani M, et al, JTH 2012

Table 2. Characteristics of relatives (n=560).

Median age at the first event, yrs (range) 30 (0-72)

VTE events, n (%) 28 (5)

pregnancy-related VTE, n (%) 4 (14.3)

Pregnancy losses, n (%) 48 (8.6)

early PL, n (%)

late PL, n (%)44 (92)4 (8)

Pregnancy-related hypertensive disorders, n (%) 3 (0.5)

SGA newborns, n (%) 7 (1.3)

Multiple* pregnancy-related complications, n (%) 18 (3.2)

*Multiple: either the simultaneous occurrence of two obstetric complications or a history of different obstetric complications occurred in two or more pregnancies. Abbreviations: VTE, venous thromboembolism; PL, pregnancy loss.

Villani M et al , JTH 2012

Tale 4. Logistic regression

FVL PTm Male sex

Risk for VTE (excluded relatives of

women with pregnancy- related VTE)

OR: 4.06(95% CI, 1.78 to 9.27)

p=0.001

OR: 4.18(95%CI, 1.84 to 9.52)

p=0.001

OR: 3.12(95%CI, 1.39 to 6.99)

p=0.001

Risk for Obstetric

Complications

OR: 1.98(95% CI,1.03 to 3.83)

p=0.040

OR: 4.18(95%CI, 0.46 to 2.32)

p=n.s. not applicable

Risk for VTE ( included relatives of women with pregnancy-related VTE )

Single mutationFVL or PTm

OR: 5.19(95%CI,1.70 to 15.91)

p=0.004

Severe Thrombophilias

OR: 23.20(95%CI,6.0 to 89.85)

p<0.001

Male sexOR: 3.49

(95%CI,1.51 to 8.05) 0 003

Villani M,et al,  JTH 2012

PRIMARY PROPHYLAXIS

• No randomized study is so far available; however  heparin prophylaxis in preventing first VTE among  women 

carrying 

inherited 

thrombophilia 

is 

considered fully effective.• Considering 

the 

low 

absolute 

risk 

of 

VTE 

during 

pregnancy 

among 

women 

carrying 

factor 

V  Leiden 

or 

prothrombin 

G20210A 

the 

indication 

for 

primary 

antithrombotic 

prophylaxis 

during  pregnancy is debated

Cavazza S et al, Thromb Res 2011

Cavazza S et al, Thromb Res 2011

Cavazza S et al, Thromb Res 2011

Cavazza S et al, Thromb Res 2011

(Blood 2005;106:401‐407)

Rate of bleeding: 2%

Antenatal bleeding:0.4%

• www.fcsa.it

raccomandazioni 2005

• www.siset.org

linee guida 2007statement SISET ‐

SIGO

SINOSSI DELLE RACCOMANDAZIONI(quesiti di intervento - 1)

Grado Raccomandazione

B EBPM viene preferita all’eparina non frazionata

SINOSSI DELLE RACCOMANDAZIONI(quesiti di intervento - 1)

Grado Raccomandazione

B EBPM viene preferita all’eparina non frazionata

RCOG 2009

Le Eparine per:

1.Prevenzione del TEV in Ginecologia

1.Prevenzione del TEV in Ostetricia

2.Prevenzione delle Complicanze Ostetriche

Starting in the 1990s reports of an increase in placenta mediated  pregnancy complications (recurrent miscarriage, late fetal loss,

preeclampsia, placental abruption, and birth of a small for  gestational age (SGA) child) in women with thrombophilia began 

to appear in the medical literature [Dekker GA et al AJOG, 1995, Grandone  E. et al T&H, 1997, Grandone E. et al T&H 1999…. ].

Thrombophilia and  Placenta Mediated Pregnancy  Complications

Association: Thrombophilia and adverse pregnancy outcomes: Danish  National Birth Cohort

Likke et al J Thromb Haemost 2012

• FVL, PTm and MTHFR C677T assessed for risk of severe preeclampsia, FGR, very  preterm delivery, abruption and a composite of these.

• Nested case‐cohort study of 2032 cases and 1851 random controls

• FVL increased the risk of composite outcome (OR: 1.4, 95%CI: 1.1‐1.8), severe  preeclampsa (OR 1.6, 95%CI: 1.1‐2.4) and abruption (OR 1.7, 95%CI 1.2‐2.4).

• PTm was not significantly associated with any outcomes

• MTHFR C677T associated with severe preeclampsia (OR 1.3, 95%CI 1.1‐1.6).

Impact of common thrombophilias and JAK2 V617F on pregnancy  outcomes in unselected Italian women

Grandone E et al,  on behalf of PRENACEL study Group, J Thromb Haemost 2011 

Of 

the 

original 

sample 

formed 

by 

5345 

pregnant 

women 

admitted 

to

the 

14 

hospitals 

of 

the 

5 

provinces 

of 

the 

Campania 

region 

(Italy), 

3097 

samples 

were  investigated for FVL, PTm and JAK2 somatic mutation ; obstetric history was also   collected. 

Nested case‐

control study and prospective evaluation of the outcomes

No positive association with any adverse outcomes

Carriership 

of 

one 

of 

thrombophilias 

considered 

showed 

a 

positive 

trend 

with 

a  delivery of a SGA neonate (OR: 1.5, 95% C.I.: 0.9‐2.5).

Grandone E et

al, JTH 2011

While

strong associations

and consistent

associations

are important factors

to

consider

in determining

causation

other

factors

must

be

considered

prior

to

concluding

a  causal

association

between

a risk factor

and disease. 

These

other

factors

to

consider

include •specificity

of association

•temporal

relationship

between

the risk

factor

and disease•biologic

plausibility

•biologic

gradient

(more risk

factor

causes

worse

disease),  • experimentation, where

manipulating

the risk

factor

exposure

affects

disease

risk

.

Thrombophilia

and  Placenta Mediated

Pregnancy Complications

LMWH has

been

used

to

prevent

pregnancy

complications

in  women with

heritable

thrombophilia

predicated

on…..

The association

of thrombophilia

with

adverse

outcomes

The effectiveness

in APS

Safety

of LMWH in pregnancy

Lack

of an

alternative treatment

Underlying

biological

plausibility• Anticoagulant

effect

eg

anti‐Xa

increase

in TFPI

• Modulation

of inflammatory

/immune response• Direct

effect

on throphoblast: apoptosis, angiogenesis

• LMWH rescues

pregnancies

in a murine model

of APS‐induced

fetal

loss by suppressing

complement

activity

( Girardi

et

al, 2004)

• Does

antithrombotic

therapy

prevent

PMPC?

NOH‐AP &  NOH‐PE studiesGris

J.C.

et

al. 2010, 2011

NOH‐AP: 160 women                                  NOH‐PE: 224 women

Abruption

in 1st pregnancy

Severe PE in 1° pregnancy16.3% with

trombophilia

14.2% with

thrombophilia

LMWH vs no LMWH                                          LMWH/LDA vs LDALDA at discretion

of the

treating

physician

(n=48)

Composite outcome:                                             Preeclampsia:PE, IUGR/SGA<the 5° LMWH 5.8%percentile, abruption, IUFD after

Control

16.7%

20 weeks

Enoxaparin

12.6%                                                   Severe PE:No enoxaparin

31.3%                                              LMWH 0.9%

Control

7.1%

LMWH/LDA and Thrombophilia

FRUIT‐139 women with

thrombophilia+previous

delivery at <34/52 for preeclampsia/SGA

LDA/LMWH vs LDA

Recurrent

HD at <34 weeks

lower

with

LMWH, risk

difference

8.7% ( CI

1.9‐15.5%;  p 0.012 ).

Reduced

steroids, but

no difference

to

clinical

outcome

( De Vries

et

al., Journ Thromb

Haemost

2012).

TIPPS: ( Rodger

et

al, 2013) Women with

thrombophilia

and previous

PMPC  randomised

to

LMWH or no treatment

?benefit

Should

be

more selective

?

Despite

biological

plausibility

from

Association

between

thrombosis, thrombophilia

and placental

damage

Benefit in only

some groups

in some studies

treated

with

antithrombotics

eg LDA and Preeclampsia

Pragmatic intervention with LMWH +/‐LDA for

RPL and other

PMPC shows inconsistent

benefit

PMPC have

heterogeneous

causes, so should

we

focus on more homogeneous groups

such

as

women with

thrombophilia

or start earlier

to

influence

placentation?

So where

does

this

take us?

Association

and biological

plausibility

for

coagulationmechanisms

underlying

PMPC

No consistent

or clear

benefit from

antithrombotic

intervention

But

PMPC are complex

in origin Multigenic

factors‐

Maternal

and Fetal

Phenotype

and Environment Obesity

and smoking

Classification

by

outcome

rather

than

cause

LMWH and adverse

pregnancy

outcome: Are we

missing

something?

Benefits

may

be

limited

to

particular

phenotypes

or genotypes

Specific

thrombophilias

and their

interaction

with

disease

Thrombotic

damage

such

as

placental

infarction

Are there

biomarkers

or phenotypes

to

guide treatment?

OTTILIA REGISTER

Prevention

of pregnancy

loss in carriers

of  thrombophilia:  The OTTILIA register

(Observational sTudy

on antiThrombotic

prevention in  thrombophILIA

and pregnancy loss).

e.grandone@operapadrepio.it