Impact of highly purified urinary FSH and recombinant FSH on haemostasis: an open-label, randomized, controlled trial.

BACKGROUND: It has recently been suggested that recombinant FSH administration may result in an increased risk of venous thrombosis. An open-label, randomized, controlled trial was carried out to compare the impact of urinary and recombinant FSH on haemostasis. METHODS: Fifty infertile women were randomized, using a random number generator on a personal computer, to receive either highly purified urinary FSH (u-hFSH) or recombinant human FSH (r-hFSH); a starting dose of 150 IU. Human chorionic gonadotrophin 10000 IU was administered once there was at least one follicle > or =18 mm. The luteal phase was supported with progesterone 50 mg/day for at least 15 days. Fifty normally menstruating women were recruited as controls. Repeated measurements of estradiol, progesterone, prothrombin time (PT) expressed as INR, activated partial thromboplastin time (APTT) ratio, fibrinogen (FBG), factor VIII (FVIII), normalized activated protein C ratio (nAPC ratio), antithrombin III activity (AT), protein C activity (PC), protein S activity (PS), tissue-type plasminogen activator antigen (t-PA), type 1 plasminogen activator inhibitor (PAI), prothrombin fragments 1+2 (F1+2), were performed during both hyperstimulated and natural cycles, and at onset of the following menstruation or at 8 weeks of pregnancy. RESULTS: At the end of gonadotrophin administration PT INR increased in the u-hFSH group, while AT and t-PA significantly decreased. In the patients treated with r-hFSH, only F1+2 significantly decreased. No significant changes were observed in the control group. In the luteal phase FBG increased significantly in all groups. In the u-hFSH group no other significant changes were noted compared to pre-ovulatory values, while compared to baseline values AT, PS and t-PA significantly decreased. In the r-hFSH group during the luteal phase PT INR significantly decreased, but did not differ from baseline levels. Other parameters such as FBG, FVIII, t-PA, rose significantly, but only FVIII and FBG values were significantly higher than baseline levels. In the women who became pregnant a significant increase in t-PA and a significant decrease in PS at the midluteal phase were observed. After one month all the haemostatic parameters returned to baseline value if pregnancy failed to occur, while in the pregnant women a significant increase in FVIII and a significant decrease in PS were observed. CONCLUSIONS: Ovarian stimulation with recombinant FSH does not influence coagulation and fibrinolysis significantly, as already reported for urinary gonadotrophins. The moderate changes induced by both treatments are no longer detectable after 4 weeks.

Variations in hemostatic parameters after near-maximum exercise and specific tests in athletes.

BACKGROUND: The clotting state of the blood changes according to the type of physical exercise to which a group of healthy subjects are subjected. We studied the behaviour of the coagulation system before and after near-maximum, specific and standardized exercise tests in three groups of males practising sports defined as demanding in terms of cardiovascular output. METHODS: The study was a comparative investigation between athletes and the group of controls composed of presumably healthy males. SETTING: athletes training for competitions such as marathon, rowing and weightlifting. PARTICIPANTS AND INTERVENTIONS: we tested 7 rowers using the rowing machine, 12 marathon runners using the treadmill, 7 weightlifters using their own exercise equipment, and 7 healthy subjects (controls) using the cycle ergometer. MEASURES: during the tests we monitored heart rates, maximal oxygen intake, anaerobic threshold, respiratory quotient, maximum ventilation, and lactic acid. The following coagulation tests were performed before and after near-maximum exercise: prothrombin time (PT), partial activated thromboplastin time (PTT), fibrinogen (FBG), antithrombin III (ATIII), protein C (PC), protein S (PS), prothrombin fragment 1 + 2 (F1 + 2), tissue activator of plasminogen (t-PA) and its inhibitor (PAI). RESULTS: The most significant results showed a low basal PC in the rowers which decreased further after near-maximum exercise; significantly higher basal activities of ATIII, PC and PS in the marathon runners compared to the rowers; a high proportion of weightlifters showed a reduction in t-PA after exercise and an increase of PAI; the controls were the only group in which fibrinolytic activity and all the circulating anticoagulants increased after near-maximum exercise. Thus subjects who practise aerobic sports differ principally in terms of variations in inhibitors (low PC in rowers and marathon runners, increased presence of inhibitors in controls). The weightlifters did not show any significant variations, and so the kind of exercise involved (training to increase resistance and maximum strength) and the recovery times between the exercises do not seem to trigger changes in coagulation/fibrinolysis. CONCLUSIONS: We can therefore confirm that only relatively prolonged effort can trigger a mechanism beneficial to the cardiovascular system. In conclusion, physical activity benefits the coagulation system particularly as regards fibrinolysis, but certain subjects may be at risk of thrombosis and these must be identified and followed. We suggest that fibrinolytic activity be studied in athletes who practise weightlifting and have a history of cardiovascular disease, and that inhibitors (protein C in particular) be studied in rowers with a family history of thromboembolism.

Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis.

OBJECTIVE: To establish the physiologic changes in the coagulation and fibrinolytic systems during normal pregnancy and puerperium. STUDY DESIGN: One hundred and seventeen normal pregnant women were investigated in a longitudinal study involving five measurements: blood samples were collected at 10, 20, 30, 36 weeks and on the second day puerperium and were assayed for prothrombin time (PT expressed in INR), activated partial thromboplastin time (PTT), fibrinogen (FBG), antithrombin III activity (AT III), protein C activity (PC), protein S activity (PS), prothrombin fragments 1+2 (F1+2), type 1 plasminogen activator inhibitor activity (PAI) and tissue-plasminogen activator antigen (t-PA). Student t-test, One Way Analysis of Variance (ANOVA) and Bonferroni test were used for statistical analysis. P<0.05 (two tails) was assumed to indicate a significant difference. RESULTS: Fibrinogen concentrations were always increased with respect to controls (P<0.001), while protein S was always decreased, with values averaging 60% of those of controls from the 10th week of pregnancy onwards (P<0.001). Variance analysis showed a statistically significant increase with gestational age for procoagulant factors (INR: P<0.001; FBG: P<0.001), a reduction for anticoagulants (PC: P<0.0001; PS: P<0.0001), and a rise for F1+2 (P<0.0001). With regard to fibrinolysis, there was an increase both for t-PA (P<0.0001) and PAI-1 (P<0.0001) during pregnancy. The t-PA values were always comprised in the normal range. PAI-1 were increased with respect to control values starting from 31st week. The most significant variations in the procoagulants (expressed by PT and FBG) were recorded up to the 20th week (P<0.001); from the 30th week onwards, they remained stable until after the delivery. The same was true for protein S levels (P<0.001), except that the difference between the 10th and the 20th weeks was not statistically significant. The level of F1+2 gradually increased throughout pregnancy (P<0.001), and then fell in the puerperium (P<0.001). CONCLUSIONS: The parameters showing the greatest variation during pregnancy were PT, FBG, PS, F1+2 and PAI-1. The existence of a hypercoagulable state in pregnancy was suggested by the increased levels of F1+2.

Treatment of patients with Niemann-Pick type is using repeated amniotic epithelial cells implantation: correction of aggregation and coagulation abnormalities.

Variations of platelet aggregation and plasma levels of clotting factors V, IX, XI, and XII were studied in 5 patients with Niemann-Pick disease type Is in the course of a 3-year study of treatment with periodic subcutaneous infusions of amniotic epithelial cells. Before commencement of treatment, the concentrations of these factors were found to be abnormal in four of five patients. It was possible to complete the study protocol in only two patients. Platelet aggregation and plasma levels of V, IX, XI, and XII clotting factors had been determined before each epithelial amniotic cells implantation and after 24, 48, and 72 hours. In both patients the aggregation test and the plasma levels of coagulation factors V, IX, XI, and XII were below the normal values of reference. Results showed that the epithelial amniotic cells treatment normalized platelet aggregation after each implantation in the two studied patients, both in terms of intensity of response (increase in light transmission after addition of adenosine diphosphate up to 350%) and in terms of obtaining an irreversible aggregation with 3 and 8 microM of adenosine diphosphate. The data related to clotting factors showed an increase of these concentrations up to 60% and some of these concentrations normalized completely.

A description of two cases of factor V deficiency.

We report two cases of factor V deficiency. A 12-year-old girl with thalassemia major was admitted for bone marrow transplant (mismatched). She was found to have a heterozygous deficiency of factor V (21%), but this was considered compatible with the transplant, which was performed without the support of suppernatant cryoprecipitate. A 14-year-old girl (factor V 2%) with a negative history (menarche at age 12, menstrual cycle regular and normal in quantity and length). One year previously she had complained of menorrhagia (length of period, 9 days); tests revealed server anaemia (Hb 4.9 g/dl). We show how even severe cases of factor V deficiency may often be silent, and not require transfusion in surgical procedures, thus avoiding the risks associated with such therapy.

The importance of hematocrit in the interpretation of coagulation tests in the full-term newborn infant.

BACKGROUND: Hematocrit (HCT) is significantly higher in newborns than in adults, but this fact is not usually considered when performing coagulation tests in newborns. We studied 71 healthy full-term newborns and compared them to 100 healthy adults to test the hypothesis that correcting the anticoagulant-to-blood ratio for neonatal HCT would reduce the differences among the two populations. METHODS: PT, PTT, fibrinogen, platelets and factors II, VII, IX, X, V, VIII were measured in 71 healthy full-term newborns and 100 healthy adults. An anticoagulant-blood ratio corrected for HCT was used. In 16 newborns, a non corrected value was also used and results were compared with the corrected ratio. RESULTS: A significant difference was observed between newborns and adults in all tests with the exceptions of fibrinogen and factor V. In the 16 newborns from whom blood was collected without correcting in the anticoagulant, a significant difference was also found in all parameters but fibrinogen. A weak correlation linked the different variables. CONCLUSIONS: After correction for HCT, neonatal PT and factors V, VII, VIII and IX were much closer to adult values; neonatal PTT and factors II and X were still definitely lower.

Migraine: possible role of platelet insensitivity to prostaglandin E1 (PGE1).

Platelet aggregation inhibition, induced by prostaglandin E1 (PGE1), was evaluated in 38 patients affected by migraine. Our data indicate a complete insensitivity to PGE1 in these subjects. The insensitivity to PGE1 leads to decreased cyclic-AMP (cAMP) levels, determining an imbalance in the inhibitory mechanism. From this observation we can suppose that the decreased affinity of PGE1-receptors, causing decreased cAMP levels, may be involved in pathogenesis of migraine.