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Thrombophilia is considered now

as a multifactorial disease, with an interplay of acquired and genetic thrombotic risk factors Hemostasis has an impact in recurrent spontaneous abortion. Approximately half of venous thromboembolic episodes in patients with inherited thrombophilia occur in relation to events that are generally recognized as predisposing states, such as surgery, , and immobilization

Inherited thrombophilic states (1)
AT, PC, PS, (Gris et al, 1997), high Factor VIII plasma levels (Facchinetti, 2003), aPCr, Factor V mutation - (FV Leiden, FV Cambridge) Dahlback et al., 1993; Bertina et al., 1994), and prothrombin mutation G20210A, enhancement of thrombin generation (Vincent, 1998),

Inherited thrombophilic states (2)
Dysfibrynogeneimia Abnormalities in fibrinolytic system
- hypo- or dysplasminogenemia - elevated plasminogen activator inhibitor - decreased tissue plasminogen activator

Hyperhomocysteinemia Heparin cofactor II defciency Elevated histidine-rich glycoprotein of platelets Factor XII deficiency

Inherited thrombophilic states

On the other hand, homozygosity for the mutation C677T in the gene encoding methylenetetrahydrofolate reductase (MTHFR) results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine, and results in an increase of plasma homocysteine concentrations. This is a risk factor (in question ?) for venous and arterial thromboses

(Frosst et al., 1995; de Franchis et al., 1996; Arruda et al., 1997; Margaglione et al., 1998).

of inherited thrombophilic syndromes in the general population and in patients with venous thrombosis (VT)
Syndrome AT deficiency PC deficiency PS deficiency APC-resistance General population 0.02-0.17 0.14-0.5 ~ 0.5 3.6-21 Unselected patients with VT 1.1 3.2 2.2 21 Selected patients with VT* 0.5-4.9 1.4-8.6 1.4-7.5 10-64

*- age < 45 years and/or recurrent thrombosis
Rees et al., 1995; Lambropoulos … Makris, 1997

50% of all conceptions fail (most unrecognized) 13-15% of recognized pregnancies are lost, 90 % of these before 12-14 weeks 10-20% of pregnant women have 1 sporadic spontaneous abortion 2% have 2 consecutive Spontaneous Abortion (SAb) 0.4-1% have 3 consecutive SAb

Affects 0.5-3% of all women Risk of subsequent loss –
24% after 2 30% after 3 40% after 4
Many syndromes associated with recurrent fetal loss include anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects.

Clinical investigation should however be initiated after 2 consecutive losses specially
when fetal heart activity has been identified before the pregnancy loss,

when the woman is >35 yr or when the couple has difficulty in conceiving.

Definition of recurrent spontaneous abortions
Definition Equivalent : : 3 successives embryo losses before term of 12 weeks of amenorrhea (WA) 3 spontaneous abortions of 1st trimester or three early pregnancy losses or early recurrent miscarriages... 3 late spontaneous abortions 3 spontaneous abortions of 2nd trimester 3 in utero death 3 fetal losses (> 12 WA)

Different from :

1) Ware Branch, lupus 1994

Increase in Clotting Factors:
20 to 200% increase in levels of fibrinogen and factors II, VII, X, VIII and XI

Fibrinolytic Activity:

PAI-1 levels increase two to three-fold in pregnancy

free Protein S : levels fall to 40%-60% of normal in the first trimester Protein S levels (free and total) decrease by 40% but this requires confirmation 3 months post partum Protein C: constant in all 3 trimesters Antithrombin: unchanged by pregnancy but can fall in severe pre-eclampsia or DIC Homocysteine: falls by 30%-50%

Hemostasis impact in

Data accumulated over the past years suggest a possible association between thrombophilia and fetal losses, mainly in combined defects (Brenner and Blumenfeld 1997, Foka et al 2000, Sanson et al 1996, Regan 1998).

Abortive disease and prothrombotic status Fibrinolysis deficit (Gris et al, 1997 ) Enhancement of thrombin generation (Vincent, 1998) High Factor VIII plasma levels (Facchinetti, 2003) Factor XII deficiency (Pauer, Fertil Steril, 2003)

Congenital thrombophilia is not a risk factor for early RFL
4 Case-control prospective studies n RFL term
Gris (1997) Coumans (99) Kutteh (1999) Alonso (2002) ≥3 ≥2 ≥1 ≥1 <16 Wks <16 Wks <12 Wks <12 Wks

Nb of Pts
500/100 52/67 50/50 53/75

2 epidemiologic studies on Factor V Leiden
Lindqvist (1998) = 2480 pregnancies Rai (2001) = 904 fetal losses

High frequency of MTHFR 677TT meta-analysis by Nelen (2000) OR=1,4 (IC=1,0-2,0)

RFL in the first trimester

Antithrombin: no association with
Recurrent fetal loss (one study) Non recurrent fetal loss (two studies)

Protein C: no association in two studies MTHFR: (8 studies) no association with
Recurrent fetal loss in the first trimester Two or more fetal losses Three or more fetal losses
Rey E et al Lancet 2003; 361: 901-908

Many researchers, beside the usual causes, implicate disturbances in haemostasis (haemorrhagic or hyper coagulant) for recurrent fetal losses. It appears that during the 1st trimester of pregnancy fetal losses occur that are connected mainly with haemorrhagic diathesis (such as minor Willebrand disease or other minor coagulant factors deficiencies), while fetal losses between the 2nd and 3d trimester are connected with thrombophilic diathesis (such as hereditary or acquired thrombophilia e.g. antiphospholipid syndrome).

In the last three years we examined 91 women with recurrent fetal losses in order to determine the causes of this losses. We followed up their courses applying if possible anticoagulant treatment in the cases that were connected with hereditary or acquired thrombophilic diathesis and on the cases that haemorrhagic diathesis was responsible we treated with DDAVP to control this diathesis.

In order to make an estimate on the success of the treatment we applied on these cases, we made a record.

we studied 91 women with mean age 33,9 ±4,8 years that had about 2,9±1,3 fetal losses each.

We studied all the possible factors of haemostasis that can be implicated for disturbances with the automatic instruments of DADE-Behring and IL (Advance) and also full genetic control with the strip assay of Vienna Lab with extracted DNA by Qiagen kit.

we found : 11 women heterozygote for FV-Leiden, 9 women were carriers of the Gp-IIIa mutation and also 3 more women had the FV -HR2 with the Gp-IIIa mutation, 1 woman with FII 20210 G>A mutation, 2 women with the 455 G>A mutation of fibrinogen. 2 more women with protein S deficiency, 1 woman with FXII deficiency, 1 woman showed plasminogen deficiency,

3 women with antiphospholipid syndrome and 8 women had haemorrhagic diathesis (mainly mild von Willebrand disease). Overall in 41 women we found risk factors connected with recurrent fetal losses. From those women 29 were able to have one effective pregnancy with the help of antithrombotic treatment (μΜΒΗ, or antipllatelets mainly aspirin) or with DDAVP in order to increase the levels of factor Willebrand. In the other women an effective therapeutic approach was not possible and they seized their attempts.

140 1142 144 138 1143 141

The determination of the causes of recurrent fetal losses by a hematologist, who can make a full functional and genetic control of the haemostasis, can help in an effective pregnancy.

one unexplained fetal deaths after ten weeks of pregnancy one preeclampsia or placental insufficiencies occurring before 34 weeks

any of these must invite a big question mark

One previous preterm birth one or more confirmed
episodes of venous or arterial thrombosis.