High Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Levels May Protect against Recurrent Fetal Loss.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1815-1815
Author(s):  
Hendrika M Knol ◽  
Nic J.G.M. Veeger ◽  
Saskia Middeldorp ◽  
Karly Hamulyàk ◽  
Martin H Prins ◽  
...  
Keyword(s):  
Degradation Products ◽  
Absolute Risk ◽  
Fetal Loss ◽  
Factor V Leiden ◽  
Protein S ◽  
Normal Pregnancy ◽  
P Value ◽  
Factor V ◽  
Recurrent Fetal Loss ◽  
Fibrinolysis Inhibitor

Abstract Trombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase which suppresses fibrinolysis by removing carboxy-terminal lysine residues from partially degraded fibrin. A recent study in pregnant mice suggested that fibrin degradation products induced by the subsequent generation of thrombin and fibrin, cause apoptosis of throphoblasts and consequently fetal loss. This effect was reversed by anticoagulant and antifibrinolytic drugs, and by depletion of fibrinogen. We hypothesized that increased levels of TAFI during normal pregnancy in humans may similarly protect against fetal loss. This effect might be more pronounced in women with increased thrombin generation due to thrombophilic defects. To test this hypothesis, we analysed data from four pooled family cohort studies, which originally were designed to estimate the absolute risk of venous thromboembolism, associated with either hereditary deficiencies of antithrombin, protein C or protein S, factor V Leiden, the prothrombin 20210A mutation, elevated plasma levels of factor VIII:C, or hyperhomocysteinemia. The present study addressed fetal loss in female probands and relatives. In addition to above mentioned thrombophilic defects, TAFI activity was measured. Fetal loss rates were compared in women with high TAFI levels (³ 126 U/dl) and women with normal TAFI levels. Of 1557 women, 175 were excluded because they were younger than 15 years of age, had deceased or did not consent. Another 444 women were not evaluable because they had never been pregnant or had had only terminated pregnancies, and 95 women because of missing TAFI measurements. The remaining 843 women (including probands) were analysed, of whom 95 women had high TAFI levels and 748 women had normal TAFI levels. Age at time of first pregnancy was comparable in both groups, as was the distribution of thrombophilic defects. Results are summarized in the table. 18 women (18.9 %) with high TAFI levels experienced any, i.e. early or late fetal loss, compared to 205 women (27.5 %) with normal TAFI levels (p= 0.074). Overall 17 women (17.9 %) with high TAFI levels experienced one or recurrent early fetal loss compared to 180 women (24.2 %) with normal TAFI levels (p= 0.173). 1 woman (1.1 %) with high TAFI level had experienced recurrent early fetal loss, compared to 53 women (7.1 %) with normal TAFI levels (p=0.023). The number of fetal losses per woman ranged from 2 to 8 in women with normal TAFI levels (median was 2 fetal losses), while it was 2 in the woman with high TAFI level. In conclusion, women with high TAFI levels had less recurrent fetal loss in comparison with women with normal TAFI levels. Our results support the assumption that high TAFI levels protects against recurrent fetal loss. Normal TAFI levels High TAFI levels p-value Age at 1st pregnancy, median (range), yr 24.8 (11-42) 24.1 (17-40 ) TAFI levels, U/dL, mean (SD) 99.7 (13.6) 137.1 (10.6) Women, n (n=748) (n=95) Total fetal loss, n (%) 206 (27.5) 18 (18.9) 0.074 early 180 (24.2) 17 (17.9) 0.173 late 29 (3.9) 2 (2.1) 0.383 Total recurrent fetal loss, n (%) 56 (7.5) 2 (2.1) 0.050 early 53 (7.1) 1 (1.1) 0.023 late 2 (0.3) 0 (0) 0.613

The Outcome of Pregnancy in Patients with Thrombophilia after Anticoagulation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4164-4164
Author(s):  
Qingqi Jiang ◽  
Judith Andersen
Keyword(s):  
Unfractionated Heparin ◽  
Fetal Loss ◽  
Factor V Leiden ◽  
Protein S ◽  
Severe Bleeding ◽  
Factor V ◽  
Protein C Deficiency ◽  
Factor V Leiden Mutation ◽  
G20210a Mutation ◽  
History Of

Abstract Background: Both inherited and acquired thrombophilia predispose pregnant women to venous thromboembolism and recurrent fetal loss. The safety profile and tolerability of low molecular heparin (LWMH) has allowed us to evaluate effects of anticoagulation in the outcome of pregnancy in patients with thrombophilia. Methods: 20 patients with thrombophilia received either tinzaparin or enoxaparin combined with aspirin before and during pregnancy and the outcome of pregnancy was monitored for a period of 2 years. The median age of the patients was 28 years (25–49); 75% were Caucasians, 20% were aferican-american, 5% were others. The inherited and acquired thrombophilias include Factor V leiden mutation, prothrombin mutation in G20210A, mutation in methylenetetrahydrofolate (MTHFR), protein S deficiency, protein C deficiency, hyperhomocyteinemia, antiphospholipid syndrome, sticky platelet syndrome, etc. The majority of patients had more than 2 thrombophilia factors and had history of miscarriage. 15 of 20 patients (75%) received tinzaparin and 4 of 20 (20%) patients received enxoparin subcutaneously before they were conceived. Only one patient received unfractionated heparin. The LWMH was continued during pregnancy until 34 to 36 weeks gestation when it was changed to unfractionated heparin in order to prevent large amount of bleeding from upcoming delivery. All of the patients also received aspirin prior, during, and after the pregnancy. There were 21 live births including one triplet and one twins. Only two patients were complicated with miscarriage. There was no episode of severe bleeding or thromboembolism during pregnancy or postpartum. Conclusion: LWMH and aspirin has been effective in the prevention of fetal loss in women with thrombophilia disorders.

Activated Protein C Sensitivity, Protein C, Protein S and Coagulation in Normal Pregnancy

1998 ◽  
Vol 79 (06) ◽  
pp. 1166-1170 ◽  
Author(s):  
J. Brennand ◽  
J. A. Conkie ◽  
F. McCall ◽  
I. A. Greer ◽  
Isobel Walker ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Coagulation Factors ◽  
Normal Pregnancy ◽  
Factor V ◽  
C Protein ◽  
Sensitivity Ratio ◽  
Protein C Activity

SummaryA prospective study of activated protein C sensitivity, protein C, protein S, and other coagulation factors in 239 women during normal pregnancy was carried out. Protein C activity appeared unaffected by gestation, although an elevation of protein C activity was observed in the early puerperium. A fall in total and free protein S with increasing gestation was observed. Activated protein C sensitivity ratio (APC:SR) showed a progressive fall through pregnancy. This fall correlated with changes in factor VIIIc, factor Vc and protein S. 38% of subjects, with no evidence of Factor V Leiden or anticardiolipin antibodies, showed a low APC:SR (APC:SR <2.6) in the third trimester of pregnancy. Aside from a significant reduction in birth weight, no difference in pregnancy outcome was observed between these subjects and those with a normal APC:SR. Activated protein C sensitivity ratio, modified by pre-dilution of patient samples with factor V depleted plasma, showed no consistent trend with gestation.

Factor V Leiden in patients with recurrent fetal loss

2000 ◽  
Vol 70 ◽  
pp. D142-D142
Author(s):  
M. Drabkova ◽  
M. Vojtiskova ◽  
A. Vasku ◽  
T. Burnog ◽  
P. Janku ◽  
...  
Keyword(s):  
Fetal Loss ◽  
Factor V Leiden ◽  
Factor V ◽  
Recurrent Fetal Loss

scholarly journals The Prevalence of Thrombophilia in Women With Recurrent Fetal Loss and Outcome of Anticoagulation Therapy for the Prevention of Miscarriages

2016 ◽  
Vol 24 (1) ◽  
pp. 122-128 ◽  
Author(s):  
Rawan Nahas ◽  
Walid Saliba ◽  
Adi Elias ◽  
Mazen Elias
Keyword(s):  
Anticoagulation Therapy ◽  
Fetal Loss ◽  
Factor V Leiden ◽  
Live Birth Rate ◽  
Protein S ◽  
Study Group ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
S Deficiency ◽  
Thrombophilia Screening

Objective: To estimate the prevalence of thrombophilia in women with recurrent miscarriages and to assess the effect of antithrombotic therapy. Design: A retrospective cohort study between the years 2004 and 2010. Setting: A hypercoagulation community clinic in northern Israel. Patients: Four hundred ninety pregnant women referred for thrombophilia screening. Main Outcome Measures: Screening results for thrombophilia and antithrombotic treatment with enoxaparin, aspirin, or both and pregnancy outcomes. Results: The most common thrombophilia in our study group was factor V Leiden mutation with a prevalence of 20.9% followed by protein S deficiency with a prevalence of 19%. Live birth rate was higher in the group of women who received enoxaparin regardless of whether a specific thrombophilia could be found. This finding was more pronounced in women who had ≥4 miscarriages. Conclusion: The prevalence of thrombophilia was higher in our study group than in the general population. Furthermore, treatment with enoxaparin might improve the rate of live births in women with or without evidence of thrombophilia, especially in women with ≥4 miscarriages.

Acquired coagulation disorders

2020 ◽  
pp. 5546-5562
Author(s):  
T.E. Warkentin
Keyword(s):  
Prothrombin Time ◽  
Protein C ◽  
Complete Blood Count ◽  
Degradation Products ◽  
Factor V Leiden ◽  
Protein S ◽  
Blood Film ◽  
Factor V ◽  
Antifibrinolytic Agents ◽  
Acquired Coagulation Disorders

Acquired disorders of coagulation may be the consequence of many underlying conditions, and although they may share abnormality of a coagulation test, for example, a prolonged prothrombin time, their clinical effects are diverse and often opposing. General clinical approach: diagnosis—most acquired disorders of coagulation can be identified by screening haemostasis tests, including (1) prothrombin time; (2) activated partial thromboplastin time; (3) thrombin clotting time; (4) fibrinogen degradation products, including (5) the cross-linked fibrin assay (D-dimer); and (6) complete blood count with examination of a blood film. Few bleeding disorders give normal results in all these tests, but disorders predisposed to thrombosis as a result of deficiency of natural anticoagulants (e.g. antithrombin, protein C, and protein S) or certain mutations (e.g. factor V Leiden) must be specifically sought. Treatment—patients with coagulopathies who are bleeding or who require surgery are usually treated with blood products such as platelets and frozen plasma. Other treatments used in particular circumstances include (1) vitamin K—required for the post-translational modification of factors II, VII, IX, and X as well as the anticoagulant factors, protein C, and protein S; (2) cryoprecipitate—used principally for the treatment of hypofibrinogenaemia; (3) concentrates of specific factors—used in isolated deficiencies (e.g. of factors VIII, IX, XI, VIIa, or fibrinogen); (4) antifibrinolytic agents (e.g. ε‎-aminocaproic acid and tranexamic acid); (5) desmopressin (1-deamino-8-d-arginine vasopressin)—increases factor VIII and von Willebrand factor.

scholarly journals State-of-the-Art Review: Thrombophilia and Pregnancy: Review of the Literature and Some Original Data

2001 ◽  
Vol 7 (4) ◽  
pp. 259-268 ◽  
Author(s):  
Yale S. Arkel ◽  
De-Hui W. Ku
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Fetal Loss ◽  
Factor V Leiden ◽  
Protein S ◽  
Coagulation Factors ◽  
Original Data ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
S Deficiency

The association of thrombophilia with pregnancy complications has received increasing attention. It is now apparent that thrombophilia is respernsihle for a large number of the serious complications of pregnancy such as venous thrombosis, pulmonary embolism, fetal loss, pregnancy loss, intrauterine fetal demise, and preeclampsia. The inherited thrombophilia abnormalities, factor V Leiden mutation, prothrombin gene mutation 20210A, and antithrombin III, protein C, and protein S deficiency, and the acquired disorders, the anticardiolipin syndrome and lupus inhibitor, are responsible for a large share of the incidences of premature termination of pregnancy and many of the above complications. The normal physiology of pregnancy may be prothrombotic, with evidence for increased markers of activated coagulation and coagulation factors. There is a decrease in protein S and resistance to activated protein C occurs in a significant number of pregnancies in the absence of the factor V Leiden mutation. In the following article, we review some of the major studies that have correlated the thrombophilia and other acquired disorders that adversely impact pregnancies.

The Risk of Venous and Arterial Thrombosis in Hyperhomocysteinemic Subjects Is Caused by Elevated Factor VIII:C Levels.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 273-273 ◽  
Author(s):  
Willem M. Lijfering ◽  
Nic J.G.M. Veeger ◽  
Jan-Leendert P. Brouwer ◽  
Marlene H.W. van de Poel ◽  
Jan van der Meer
Keyword(s):  
Relative Risk ◽  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Vitamin B6 ◽  
Absolute Risk ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Increased Risk ◽  
Thrombophilia Screening

Abstract Hyperhomocysteinemia is demonstrated as a risk factor for venous and arterial thrombosis. Experimental evidence suggests that its thrombogenic propensity results from endothelial dysfunction and injury followed by platelet and fibrin formation. However, lowering homocysteine concentrations with vitamin B6, B12 or folic acid has not resulted in a reduced risk of recurrent venous and arterial thrombosis in large prospective clinical trials. This suggests that hyperhomocysteinemia is a surrogate for another thrombophilic related specimen. As high factor VIII:C levels are associated with an increased risk of both venous and arterial thrombosis, and with endothelial injury, we hypothesize that hyperhomocysteinemia and factor VIII:C levels are closely related to each other. Therefore, we performed a study to assess the absolute risk of thrombosis in hyperhomocysteinemia and the effects of elevated factor VIII:C levels on this risk in a large cohort of families with hereditary (index) deficiencies of protein S, protein C or antithrombin. Hyperhomocysteinemia was defined as a fasting plasma homocysteine level above 18.5 μmol/l and factor VIII:C levels were elevated when higher than 150%. A total of 405 relatives were included. Median factor VIII:C levels in hyperhomocysteinemic relatives (n=26, 6%) were 169%, compared to 136% in normohomocysteinemic relatives (P=0.004) (Figure) and were more often elevated (65 vs. 38%, P=0.006). Other thrombophilic defects, including the index deficiencies, factor V Leiden and the prothrombin mutation were equally divided. Hyperhomocysteinemia was associated with an increased risk of venous and arterial thrombosis (relative risk’s 2.6 [1.3–4.8] and 3.7 [1.5–8.4)], respectively). Relatives with elevated factor VIII:C levels were also at risk; relative risk 2.3 (1.4–4.0) for venous thrombosis and 2.3 (1.0–5.1) for arterial thrombosis. After excluding all relatives with elevated factor VIII:C levels, relative risk for venous thrombosis and hyperhomocysteinemia dropped to 1.3 (0.2–9.8) and nil relatives had arterial thrombosis. These results suggest that hyperhomocysteinemia indeed is an epiphenomenon for elevated factor VIII:C levels and therefore homocysteine measurements can be omitted in risk assessment for venous and arterial thrombosis when factor VIII:C measurements are incorporated in thrombophilia screening. Figure Figure

Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

1995 ◽  
Vol 74 (05) ◽  
pp. 1255-1258 ◽  
Author(s):  
Arnaldo A Arbini ◽  
Pier Mannuccio Mannucci ◽  
Kenneth A Bauer
Keyword(s):  
Hemophilia A ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor V ◽  
Bleeding Diathesis ◽  
Mutation Site ◽  
Spontaneous Bleeding ◽  
Factor V Leiden Mutation

SummaryPatients with hemophilia A and B and factor levels less than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20–30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in amelio rating the hemorrhagic tendency in these so-called “mild severe” hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme Mnll. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.

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

1997 ◽  
Vol 77 (05) ◽  
pp. 0822-0824 ◽  
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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