The Relationship between Circulating Microparticles and Complications of Pregnancy.

Abstract Uteroplacental thrombosis has been implicated in the pathogenesis of fetal loss, intrauterine growth restriction (IUGR) and preeclampsia. The role of inherited and acquired thrombophilias in such pregnancy complications is controversial. Recently, increased levels of circulating procoagulant microparticles (MPs) were related to fetal loss and preeclampsia (Laude et al. Thromb Haemost2001;85:18, Gonzalez-Quintero et al. Am J Obstet Gynecol2004;191:1418)). In this study, we measured the level of MPs derived from endothelial cells, platelets, and monocytes by flow cytometry using monoclonal antibodies against CD31, CD41 and CD14, respectively in 262 healthy unrelated primipara with a spontaneous singleton pregnancy. Expression of tissue factor by a monoclonal antibody and phosphatidyl serine by annexin 5 on MPs were also measured. All women were followed from the 24th week of gestation until delivery and IUGR, small for gestational age (SGA) at birth, pregnancy induced hypertension (PIH) or preeclampsia (PE) or none of the above were recorded. Blood sampling was carried out at 24th week of gestation. The levels of CD31 and CD41- positive MPs in women with and without the above pregnancy complications are presented in the table. Not shown are values of CD14, annexin 5 or tissue factor on MPs since their median levels were negligible in all study groups. There was no statistically significant difference in CD31 and CD41- positive MPs between women who developed or not the indicated pregnancy complications. Also, there was no significant difference in levels of these MPs between women with and without the common inherited thrombophilias, factor V Leiden and or prothrombin mutation (28 patients) and lupus anticoagulant (10 patients). These data indicate that measurement of the level of MP at the 24th week of gestation has no predictive value for development of PIH, PE, IUGR or SGA. CD31 CD41 Number Median % p Median % p PIH or PE No 226 1.50 0.22 1.80 PIH Yes 13 1.57 3.07 0.53 PE Yes 22 0.62 1.87 IUGR No 207 1.53 0.13 1.95 0.08 IUGR Yes 32 1.30 1.71 SGA No 232 1.48 0.64 1.85 0.81 SGA Yes 26 1.27 2.24

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Factor V Leiden Is Associated with Repeated and Recurrent Unexplained Fetal Losses

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656060 ◽

1997 ◽

Vol 77 (05) ◽

pp. 0822-0824 ◽

Cited By ~ 145

Author(s):

Elvira Grandone ◽

Maurizio Margaglione ◽

Donatella Colaizzo ◽

Marina d'Addedda ◽

Giuseppe Cappucci ◽

...

Keyword(s):

Protein C ◽

Strong Association ◽

Activated Protein C ◽

Fetal Loss ◽

Factor V Leiden ◽

Factor V ◽

Significant Difference ◽

History Of ◽

Fv Leiden ◽

Caucasian Women

SummaryActivated protein C resistance (APCR) is responsible for most cases of familial thrombosis. The factor V missense mutation Arg506>Gln (FV Leiden) has been recognized as the commonest cause of this condition. Recently, it has been suggested that APCR is associated with second trimester fetal loss. We investigated the distribution of FV Leiden in a sample (n = 43) of Caucasian women with a history of two or more unexplained fetal losses. A group (n = 118) of parous women with uneventful pregnancies from the same ethnical background served as control. We found the mutation in 7 cases (16.28%) and 5 controls (4.24%; p = 0.011). A statistically significant difference between women with only early fetal loss vs those with late events (p = 0.04) was observed. Our data demonstrate a strong association between FV Leiden and fetal loss. Furthermore, they indicate that late events are more common in these patients.

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Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis

Thrombosis and Haemostasis ◽

10.1160/th12-05-0280 ◽

2012 ◽

Vol 108 (10) ◽

pp. 633-639 ◽

Cited By ~ 16

Author(s):

Elena Campello ◽

Luca Spiezia ◽

Claudia M. Radu ◽

Maria Bon ◽

Sabrina Gavasso ◽

...

Keyword(s):

Factor V Leiden ◽

Annexin V ◽

Factor V ◽

Thrombotic Risk ◽

Study Results ◽

Significant Difference ◽

Circulating Microparticles ◽

Venous Thromboembolic ◽

The Mean ◽

And Gender

SummaryAlthough factor V Leiden (FVL) is a major determinant of thrombotic risk, the reason why less than 10% of carriers eventually develop venous thromboembolic (VTE) events is unknown. Recent observations suggest that circulating levels of microparticles (MP) may contribute to the thrombogenic profile of FVL carriers. We measured the plasma level of annexin V-MP (AMP) platelet-MP (PMP), endothelial-MP (EMP), leukocyte-MP (LMP) and tissue factor-bearing MP (TF+MP), and the MP procoagulant activity (PPL) in 142 carriers of FVL (of these 30 homozygous and 49 with prior VTE), and in 142 age and gender-matched healthy individuals. The mean (± SD) level of AMP was 2,802 ± 853 MP/ μl in carriers and 1,682 ± 897 in controls (p<0.0001). A statistically significant difference between homozygous and heterozygous carriers of FVL was seen in the level of PMP, EMP and LMP, but not in that of the remaining parameters. When the analysis was confined to carriers with and without a VTE history, the mean level of AMP was 3,110 ± 791 MP/ μl in the former, and 2,615 ± 839 MP/μl in the latter (p<0.005). The mean level of all subtypes of circulating MP showed a similar pattern. The PPL clotting time was 39 ± 9 seconds (sec) in carriers, and 52 ± 15 sec in controls (p=0.003); and was 35 ± 8 sec in carriers with prior thrombosis, and 41 ± 10 sec in thrombosis-free carriers (p<0.005). Our study results suggest that circulating MP may contribute to the development of thrombosis in carriers of FVL mutation.

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Circulating microparticles in carriers of prothrombin G20210A mutation

Thrombosis and Haemostasis ◽

10.1160/th13-12-1006 ◽

2014 ◽

Vol 112 (09) ◽

pp. 432-437 ◽

Cited By ~ 7

Author(s):

Elena Campello ◽

Luca Spiezia ◽

Claudia Radu ◽

Sabrina Gavasso ◽

Patrizia Zerbinati ◽

...

Keyword(s):

Factor V Leiden ◽

Annexin V ◽

Prothrombin G20210a ◽

Factor V ◽

G20210a Mutation ◽

Significant Difference ◽

Circulating Microparticles ◽

Thrombotic Complications ◽

Prothrombin Gene Mutation ◽

And Gender

SummaryFactor V Leiden (FVL) and prothrombin gene mutation G20210A (PTM) are the two most common genetic polymorphisms known to predispose carriers to venous thromboembolism (VTE). A recent study in FVL carriers showed that circulating levels of microparticles (MP) may contribute to their thrombogenic profile. To further elucidate the prothrombotic state linked to genetic thrombophilia, we extended this study to carriers of PTM. The plasma level of annexin V-MP, endothelial- MP (EMP), platelet-MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) was measured in 124 carriers of PTM (105 heterozygous and 19 homozygous) and in 120 age- and gender-matched healthy individuals. Heterozygous and homozygous carriers of PTM showed significantly increased levels of annexin V-MP (2930 [1440–4646] MP/μl and 3064 [2412–4906] MP/μl, respectively) and significantly shorter PPL clotting time (54 [46–67] sec and 55 [46–64] sec) compared to controls (1728 [782–2122] MP/μl and 71 [61–75] sec, respectively; p<0.01). Similarly, heterozygous and homozygous subjects presented with significantly higher levels of EMP, PMP and TF+ than controls (p<0.05). PTM carriers with a VTE history had significantly higher MP numbers and activity than controls. No significant difference was seen between carriers with and without a VTE history. We conclude that the higher levels of circulating MP found in PTM carriers may play a role in the development of VTE possibly by increasing thrombin generation. Further studies are needed to better define the role of MP as triggering factors for the thrombotic complications characterizing mild genetic thrombophilic defects.

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Thrombophilic Polymorphisms Are Common in Women with Fetal Loss without Apparent Cause

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614620 ◽

1999 ◽

Vol 82 (07) ◽

pp. 6-9 ◽

Cited By ~ 127

Author(s):

G. Sarig ◽

Z. Weiner ◽

J. Younis ◽

Z. Blumenfeld ◽

N. Lanir ◽

...

Keyword(s):

Pregnancy Termination ◽

Fetal Loss ◽

Factor V Leiden ◽

Late Pregnancy ◽

Mthfr C677t ◽

Control Group ◽

Factor V ◽

Third Trimester ◽

Factor Ii ◽

Significant Difference

SummaryAn association between fetal loss and thrombophilia has recently been described but has not been yet fully elucidated. We have evaluated prospectively the prevalence of the three common thrombophilic polymorphisms (TP) factor V G1691A (Leiden), thermolabile-methyl-enetetrahydrofolate reductase (TL-MTHFR) C677T and factor II G20210A mutations, in 76 women with fetal loss (≥3 in first, ≥2 in second, ≥1 in third trimester) without apparent cause and 106 controls without fetal loss. Thirty seven out of 76 (49%) of the women in the fetal loss group had at least one TP compared to only 23/106 (22%) in the control group (p = 0.0001). Factor V-Leiden was more common in the fetal loss group 24/76 (32%) compared to the control group 11/106 (10%) (OR = 4.0, 95% CI: 1.8-8.8, p <0.001). Five of the 76 patients (7%) were homozygous for factor V-Leiden compared to none of the controls (p = 0.012). A trend, albeit no statistically significant difference was found between women with fetal loss and control groups regarding factor II G20210A (8% vs. 4% respectively, OR = 2.2, 95% CI: 0.6-8.0, p = 0.23) and MTHFR C677T (18% vs. 10% respectively, OR = 1.95, 95% CI: 0.83-4.6, p = 0.12). Combined TP were documented in 6/76 (8%) patients compared to 1/106 (1%) in controls (OR = 9.0, 95% CI: 1.1-76, p = 0.02). Second or third trimester fetal loss were more common cause of pregnancy termination in 37 patients with TP compared to 39 patients without TP (57/158 (36%) vs. 23/135 (17%) respectively, (p = 0.0004). Thrombophilic polymorphisms are common in women with fetal loss without apparent cause and are associated with late pregnancy wastage. Combinations of TP increase the risk for fetal loss.

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The procoagulant effects of factor V Leiden may be balanced against decreased levels of factor V and do not reflect in vivo thrombin formation in newborns

Thrombosis and Haemostasis ◽

10.1160/th05-05-0375 ◽

2006 ◽

Vol 95 (03) ◽

pp. 434-440 ◽

Cited By ~ 4

Author(s):

Satu Hyytiäinen ◽

Ulla Wartiovaara-Kautto ◽

Veli-Matti Ulander ◽

Risto Kaaja ◽

Markku Heikinheimo ◽

...

Keyword(s):

Tissue Factor ◽

Platelet Rich Plasma ◽

Venous Blood ◽

Factor V Leiden ◽

Factor V ◽

Cord Plasma ◽

Adult Plasma ◽

Thrombin Formation

SummaryThrombin regulation in newborns remains incompletely understood.We studied tissue factor-initiated thrombin formation in cord plasma in vitro, and the effects of Factor VLeiden (FVL) heterozygosity on thrombin regulation both in vitro and in vivo in newborns. Pregnant women with known thrombophilia (n=27) were enrolled in the study. Cord blood and venous blood at the age of 14 days were collected from 11 FVL heterozygous newborns (FVL-positive) and from 16 FVL-negative newborns. Prothrombin fragment F1+2 and coagulation factors were measured. Tissue factor-initiated thrombin formation was studied in cord platelet-poor plasma (PPP) of FVL-negative and -positive newborns, and in both PPP and platelet-rich plasma (PRP) of healthy controls. The endogenous thrombin potential (ETP) in cord PPP or PRP was ∼60% of that in adult plasma, while thrombin formation started ∼55% and ∼40% earlier in cord PPP and PRP, respectively. Further, in FVL-positive newborns thrombin formation started significantly earlier than in FVL-negative newborns. Exogenous activated protein C (APC) decreased ETP significantly more in cord than in adult PRP. In FVL-negative cord plasma 5nM APC decreased ETP by 17.4±3.5% (mean±SEM) compared with only 3.5±3.8% in FVL-positive cord plasma (p=0.01). FVL-positive newborns showed similar levels of F1+2 but significantly decreased levels of factor V compared with FVL negative newborns both in cord plasma (FV 0.82±0.07 U/ml vs. 0.98±0.05 U/ml, p=0.03) and at the age of two weeks (FV 1.15±0.04 U/ml vs. 1.32±0.05 U/ml, p=0.03). In conclusion, newborn plasma showed more rapid thrombin formation and enhanced sensitivity to APC compared with adult plasma. FVL conveyed APC resistance and a procoagulant effect in newborn plasma. Lack of elevated F1+2 levels in FVL-positive infants, however, suggested the existence of balancing mechanisms; one could be the observed lower level of factor V in FVL heterozygous newborns.

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The association of factor V Leiden mutation (G1691A) with pregnancy complications (miscarriage) in the Iran, East Azerbaijan

Clinical and Experimental Health Sciences ◽

10.33808/clinexphealthsci.742378 ◽

2021 ◽

Author(s):

Selma HOUJAGHANİ ◽

Abolfazl GHORBANİ

Keyword(s):

Pregnancy Complications ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

East Azerbaijan

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Abstract 43: Prothrombinase Assembled with Factor V Leiden is Resistant to Inhibition by Tissue Factor Pathway Inhibitor α Lowering the Procoagulant Threshold for Initiation of Coagulation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.43 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Jeremy P Wood ◽

Lisa M Baumann Kreuziger ◽

Susan A Maroney ◽

Rodney M Camire ◽

Alan E Mast

Keyword(s):

Tissue Factor ◽

Thrombin Generation ◽

Tissue Factor Pathway Inhibitor ◽

Platelet Rich Plasma ◽

Anticoagulant Activity ◽

Factor V Leiden ◽

Factor Xa ◽

Factor V ◽

Activation Threshold ◽

Tissue Factor Pathway

Factor V (FV) assembles with factor Xa (FXa) into prothrombinase, the enzymatic complex that converts prothrombin to thrombin. Tissue factor pathway inhibitor α (TFPIα) inhibits prothrombinase by high affinity interactions with FXa-activated FV and the FXa active site, thereby blocking the initiation of coagulation. FV Leiden (FVL) is strongly linked to venous thrombosis through its resistance to degradation by activated protein C (aPC), which enhances the propagation of coagulation. FVL combined with a 50% reduction in TFPI causes severe thrombosis and perinatal lethality in mice, suggesting that FVL also promotes the initiation of coagulation. To examine this possibility, thrombin generation assays initiated with limiting FXa were performed with control or FVL plasma and platelet-rich plasma (PRP). The activation threshold for thrombin generation was 10 to 20 pM FXa in 10 control plasmas, but was 5 pM in 4 of 10 homozygous FVL plasmas. FVL PRP had a similar decrease in the activation threshold. The differences in activation threshold were totally normalized by an anti-TFPI antibody, while exogenous TFPIα and a FV-binding peptide that mimics TFPIα had reduced anticoagulant activity in FVL plasma, revealing that the procoagulant effects of FVL in these assays rely on TFPIα. Next, FVL plasmas were studied in fibrin clot formation assays, as they are sensitive to small amounts of thrombin. In reactions activated with 0.5 pM FXa, 1 of 8 control plasmas, compared to 7 of 8 homozygous FVL plasmas, clotted within 60 minutes, with differences again normalized by the anti-TFPI antibody. In prothrombinase activity assays using purified proteins, TFPIα was a 1.7-fold weaker inhibitor of prothrombinase assembled with FVL compared to FV. Thus, in addition to its aPC-mediated effect on the propagation of coagulation, FVL is resistant to TFPIα inhibition, exerting a procoagulant effect on coagulation initiation. This is evident in responses to small stimuli, where TFPIα blocks clotting in plasmas with FV but not FVL. The TFPIα-mediated modulation of the procoagulant threshold may explain the severe perinatal thrombosis in FVL mice with decreased TFPI and be clinically relevant in the clotting associated with oral contraceptives, which cause acquired TFPI deficiency.

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Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia

Thrombosis and Haemostasis ◽

10.1160/th10-05-0334 ◽

2011 ◽

Vol 105 (02) ◽

pp. 295-301 ◽

Cited By ~ 98

Author(s):

Jantien Visser ◽

Veli-Matti Ulander ◽

Frans Helmerhorst ◽

Katja Lampinen ◽

Laure Morin-Papunen ◽

...

Keyword(s):

Adverse Effects ◽

Live Birth ◽

Pregnancy Complications ◽

Birth Rate ◽

Neonatal Outcome ◽

Recurrent Miscarriage ◽

Fetal Loss ◽

Live Birth Rate ◽

First Trimester ◽

Significant Difference

SummaryRecurrent miscarriage affects 1–2% of women. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about 50% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment. A randomised double-blind (for aspirin) multicentre trial was performed among 207 women with three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester (13–24 weeks) miscarriages or one third trimester fetal loss combined with one first trimester miscarriage. Women were analysed for thrombophilia. After complete work-up, women were randomly allocated before seven weeks’ gestation to either enoxaparin 40 mg and placebo (n=68), enoxaparin 40 mg and aspirin 100 mg (n=63) or aspirin 100 mg (n=76). The primary outcome was live-birth rate. Secondary outcomes were pregnancy complications, neonatal outcome and adverse effects. The 0.92–1.48] was found for enoxaparin and placebo and 65% [RR 1.08, 95% CI 0.83–1.39] for enoxaparin and aspirin when compared to aspirin alone (61%, reference group). In the whole study group the live birth rate was 65% (95% CI 58.66–71.74) for women with three or more miscarriages (n=204). No difference in pregnancy complications, neonatal outcome or adverse effects was observed. No significant difference in live birth rate was found with enoxaparin treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage.

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