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PubMed1999

Association of elevated levels of prothrombin fragment 1+2 and Arg506 to Gln mutation in patients with a history of ischemic stroke.

BACKGROUND: Recent findings have indicated the association between APC-resistance and cerebrovascular disease. These reports prompted us to investigate whether resistance to APC could be found in patients suffering from stroke. METHODS: Therefore, we studied APC-resistance in 50 young adults (< or =45 yrs) with a history of ischemic stroke. Eleven out of fifty cerebrovascular subjects showed APC-resistance, while 2 had PC deficiency and 3 PS deficiency. No deficiencies in the anticoagulant protein AT III and in fibrinolytic proteins were found. The family history demonstrated a distribution of APC-resistance compatible with dominant autosomal inheritance. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hypercoagulable states, was also measured in patients and family members of resistant subjects (n = 38). RESULTS: DNA analysis showed factor V R506Q mutation (Leiden mutation) in 11 patients and their relatives with poor response to activated protein C detected by APTT tests. Of 11 investigated subjects with APC-resistance, 9 were heterozygotes and 2, with the lowest APC-ratio values, were homozygotes for factor V mutation. Among 38 relatives, 22 showed a poor response to APC and according to the APC-ratio values, 18 were heterozygotes and 4 homozygotes for FV Leiden mutation. The mutation, in heterozygous form, was also found in 2% of our normal population (n = 100). The plasma concentration of F1+2 was significantly higher both in 11 individuals carrying the FV:Q506 mutation and in 39 patients without APC-resistance compared to that found in the control group. However, the patients with FV:Q506 mutation showed the highest values in F1+2. In the studied family members F1+2 plasma levels were within normal values. CONCLUSIONS: Our findings indicate a possible involvement of APC-resistance in the pathogenesis of cerebral thrombosis in young adults and agree with the hypothesis that individuals with APC-resistance have an imbalance between pro-and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.

Adult↗
PubMed1996

Resistance to activated protein C: a common inherited cause of venous thrombosis.

Resistance to activated protein C (RAPC) is a newly recognized hypercoagulable state that was first described in 1993. It has become apparent that RAPC is even more common than deficiencies in protein C, protein S, or antithrombin III (AT-III) and affects an estimated 5% of the general population. The majority of patients with RAPC have an abnormality in factor V (Arg506Gln), which renders factor Va resistant to degradation by activated protein C. Studies in 75 patients referred to the Hematology Laboratory at Walter Reed Army Institute of Research (WRAIR) over a 14-month period for evaluation of venous thromboembolism were reviewed to determine the percentage of those with RAPC. Of the 75 patients in the study, one was deficient in protein S, one was deficient in protein C, and none was deficient in AT-III. In contrast, 27 (36%) patients tested positive for RAPC. Blood was available for DNA analysis in 15 patients with RAPC. Of these 15 patients, nine (60%) tested positive for the Arg506Gln mutation in factor V. Six other patients with RAPC did not have the factor V mutation. Additional risk factors for thrombosis were immobility, obesity, use of oral contraceptives, and pregnancy. The majority of patients had deep venous thrombosis of the lower extremities; 71% had a recurrence if not placed on chronic anticoagulation therapy. Thus RAPC is a significant risk factor for venous thrombosis. Evaluation for inherited hypercoagulable states should include testing for this newly described condition.

Adolescent↗
PubMed2005

Systemic coagulation changes caused by pulmonary artery catheters: laboratory findings and clinical correlation.

BACKGROUND: A higher rate of pulmonary embolism has been associated with pulmonary artery (PA) catheters; however, no mechanism has been described. Conventional tests of coagulation reveal no changes related to PA catheterization. The purpose of this study was to determine whether PA catheterization resulted in a hypercoagulable state detectable by thrombelastography (TEG). METHODS ANIMAL: Healthy, anesthetized, swine (n = 19) underwent PA catheterization. Samples were drawn from 7F femoral arterial catheters before and two hours after PA catheterization, at 5 mL/min, and analyzed (native whole blood, n = 15, kaolin activated blood, n = 4) by TEG (Hemoscope, Niles, IL) at precisely two minutes. Human: An IRB-approved prospective, observational trial was conducted in critically ill patients (n = 19). Samples were drawn from 22-gauge radial artery catheters, before and three hours after PA catheterization. Kaolin-activated TEG samples were analyzed at precisely five minutes. Data are mean +/- SE; Groups were compared with analysis of variance and significance was assessed at the 95% confidence interval. RESULTS: In both animals and patients, PA catheterization truncated R times (time to initial fibrin formation). In swine, the R times were 17.6 +/- 1.3 minutes (native) and 3.8 +/- 0.4 (kaolin) before PA catheterization, and decreased to 6.3 +/- 1.0 minutes (p = 0.002) and 1.9 +/- 0.5 minutes (p = 0.010) afterward. There were no changes in pH or temperature during the experiment. In patients, 4 of 19 were excluded for protocol violations. The R time was 6.3 +/- 1.0 minutes (kaolin) before and 3.0 +/- 0.3 minutes after catheterization (p = 0.003). No changes were observed in conventional coagulation parameters, temperature or pH. CONCLUSION: In healthy swine, and critically ill patients, PA catheters may enhance thrombin formation and fibrin polymerization, indicating a systemic hypercoagulable state. This may explain why PA catheters are associated with an increased risk of pulmonary emboli.

Adult↗
PubMed2001

Effect of acute exercise on the raised plasma fibrinogen, soluble P-selectin and von Willebrand factor levels in chronic atrial fibrillation.

BACKGROUND: There is increasing evidence that chronic atrial fibrillation (AF) is associated with a prothrombotic or hypercoagulable state. HYPOTHESIS: This study was undertaken to determine whether short-term exercise in patients with chronic AF would shift the overall hemostatic balance toward a more prothrombotic state with a reduction in fibrinolytic potential. METHODS: We recruited 20 patients (13 men; mean age 65 years +/- 11 standard deviation [SD]) with chronic AF who were not treated with antithrombotic therapy and exercised them to exhaustion using a multistage treadmill exercise (standard Bruce) protocol. Blood samples were taken pre exercise, immediately after cessation of exercise, and at 20 min post exercise. The prothrombotic state was quantified by fibrinogen (an index of hemorheology and a coagulation factor), soluble P-selectin (sP-sel, marking platelet activation), von Willebrand factor (vWF, an index of endothelial dysfunction), and plasminogen activator inhibitor-1 (PAI-1, a regulator of fibrinolytic activity) levels. There were two groups of age- and gender-matched controls in sinus rhythm: (1) healthy controls, and (2) "hospital controls" who were patients with vascular disease. RESULTS: Baseline levels of vWf (p = 0.034) and fibrinogen (p < 0.0001), but not sP-sel (p = 0.075) were significantly elevated in patients with AF compared with both control groups in sinus rhythm. The PAI-1 levels were highest in the hospital control patients, but not in chronic AF (p = 0.041). Following treadmill exercise, achieving a mean metabolic equivalent of 4.9 METS (+/- 1.75 SD) and total exercise duration of 4.9 min (+/- 2 SD), there was a significant rise in plasma fibrinogen (repeated measures analysis of variance [ANOVA] p = 0.047) and a reduction in PAI-1 levels (p = 0.025) in patients with AF. There were no significant changes seen in vWf (p = 0.308) or sP-sel (p = 0.071) levels. No significant changes in these indices were seen in hospital controls (all p = not significant), despite a much longer duration of exercise with greater workload. CONCLUSION: Patients with chronic AF have increased vWf and fibrinogen levels compared with sinus rhythm. Exercise to exhaustion influences the hypercoagulable state in chronic AF, with a rise in plasma fibrinogen and possible increase in fibrinolytic activity. Nevertheless, acute exercise does not appear to have a significant influence on endothelial dysfunction or platelet activation in patients with AF.

Adult↗
PubMed2001

Systemic coagulation and fibrinolysis after laparoscopic and open gastric bypass.

HYPOTHESIS: Laparoscopic gastric bypass (GBP) induces a postoperative hypercoagulable state that is similar or reduced compared with open GBP. SETTING: University hospital. PATIENTS: Between May 1999 and June 2000, 70 patients were randomly assigned to laparoscopic (n = 36) or open (n = 34) GBP. Deep venous thrombosis (DVT) prophylaxis consisted of antiembolism stockings and sequential pneumatic compression devices. MAIN OUTCOME MEASURES: Plasminogen, thrombin-antithrombin complex (TAT), prothrombin fragment 1.2 (F1.2), fibrinogen, D-dimer, antithrombin III (AT), and protein C levels were measured at baseline and at 1, 24, 48, and 72 hours postoperatively. A venous duplex examination of both lower extremities was performed preoperatively and between the third and fifth day postoperatively. RESULTS: The 2 groups were similar in age, weight, and body mass index. Plasminogen levels decreased, and TAT, F1.2, and fibrinogen levels increased after laparoscopic and open GBP. There was no significant difference in these levels between groups. D-dimer levels increased in both groups, but the levels were significantly higher after open GBP than after laparoscopic GBP (P<.01). Antithrombin III and protein C levels decreased in both groups. The reduction of AT (at 1 hour) and protein C (at 72 hours) was significantly less after laparoscopic GBP than after open GBP (P<.05). Postoperative venous duplex examination revealed DVT in 1 (2.9%) of 34 patients after open GBP but in none of 36 patients after laparoscopic GBP. One patient developed pulmonary embolism after open GBP. CONCLUSIONS: Laparoscopic GBP induces a hypercoagulable state similar to that of open GBP. Our findings suggest that DVT prophylaxis should be used during laparoscopic GBP as in open GBP.

Adult↗
PubMed2003

Is there a hypercoagulable phase during initiation of antithrombotic therapy with oral anticoagulants in patients with atrial fibrillation?

INTRODUCTION: During commencement of oral anticoagulant therapy (OAT) a theoretical possibility of a transient hypercoagulable state emerges from the difference in plasma half-life between the vitamin K-dependent pro-coagulation factors II and X, and the vitamin K-dependent anticoagulant proteins C and S. In the present study, markers reflecting the activity in the haemostatic system (prothrombin fragment 1+2 [F1+2], D-dimer and soluble fibrin) was assessed during initiation of OAT compared to subcutaneously administered low-molecular weight heparin (LMWH) which does not cause any imbalance between the concentrations of the pro- and anticoagulation proteins. METHODS: Thirty-three patients with atrial fibrillation were randomly treated either with OAT (warfarin 10, 7.5, and 5 mg for three consecutive days) or LMWH administered in a fixed dose of 200 anti-Xa IU/kg body weight in one subcutaneous injection daily. The biochemical markers were measured at baseline, and after 12, 36 and 60 h of treatment. RESULTS AND CONCLUSIONS: After introducing antithrombotic therapy, none of the biochemical markers increased within the study period in the two treatment groups. The level of F1+2 had declined significantly at 60 h in both groups. The level of soluble fibrin showed a significant decrease within the first 60 h in the OAT group, and no significant changes were seen in the LMWH group. No significant change in the level of D-dimer was seen during the first 60 h of treatment in either group. Taken together, no transient hypercoagulable state could be identified within the first 60 h of commencing OAT in patients with atrial fibrillation.

Administration, Oral↗
PubMed2002

Platelet activation markers in patients with nephrotic syndrome. A comparative study of different platelet function tests.

BACKGROUND/AIM: Enhanced platelet reactivity may play a significant role in the genesis of the hypercoagulable state of nephrotic syndrome. However, the role of platelet function testing in nephrosis is controversial, partly because the methods used to assess platelet function (platelet aggregation and immunoassays of plasma beta-thromboglobulin and platelet factor 4) have such marked methodological problems. In the present study, we evaluated several tests assessing platelet function in 18 adult patients with idiopathic nephrotic syndrome and normal renal function. METHODS: Platelet function was assessed by measurement of plasma beta-thromboglobulin (enzyme-linked immunosorbent assay, ELISA), plasma P-selectin (ELISA), circulating platelets exposing the activation-dependent antigens P-selectin (CD62P) and lysosomal GP53 (CD63) (flow cytometry), and by aggregation response to agonists such as ADP and collagen. Results were compared to those obtained in a group of 16 age- and gender-matched healthy subjects. RESULTS: Levels of plasma beta-thromboglobulin (p = 0.001), plasma P-selectin (p < 0.001), and CD62P/CD63-positive platelets (p < 0.001 for both) were increased in nephrotic patients as compared to healthy controls. Platelet hyperaggregability in vitro was found in 13/18 patients. The reproducibility of platelet activation markers, as assessed by blood sample collection a week later from all patients, was found to be higher for plasma P-selectin (Spearman correlation coefficient, R = 0.99) and circulating activated platelets (CD62P: R = 0.97; CD63: R = 0.96) than for plasma beta-thromboglobulin (R = 0.78). CONCLUSIONS: Pronounced platelet activation takes place in nephrotic syndrome and may contribute to the hypercoagulability of nephrosis. Whole blood flow cytometry assay of platelet activation and plasma P-selectin assay may represent useful tests to assess the hypercoagulable state in nephrotic patients.

Adult↗
PubMed2004

Endothelial cell activation and hypercoagulability in ocular Behçet's disease.

PURPOSE: To investigate the presence of a hypercoagulable state and vascular endothelial dysfunction in patients with ocular Behçet's disease and relate the results to the activity of ocular and systemic involvement. DESIGN: Cross-sectional laboratory and clinical study. METHODS: Prospective study of blood samples of 24 patients diagnosed with ocular Behçet's disease, which were analyzed for factor VIII, factor XI, von Willebrand factor antigen and ristocetin (vWF ag and risto), antithrombin III (ATIII), protein C and S, fibrinogen and activated protein C (APC) resistance. The results were compared with 40 healthy controls and analyzed for association with ocular and systemic clinical features. RESULTS: The mean values of factor VIII, factor XI, vWF ag, vWF risto, ATIII, and fibrinogen were significantly raised compared to healthy population (for all: P <.001). Most striking were factor VIII activity levels above 130% in 79% (19 of 24) of our patients. 67% (16 of 24) had levels of factor VIII above 150%, which correlates with a fivefold increase in risk of thrombosis. Other prothrombogenic factors were negative in all but 2 patients (1 protein C deficiency, 1 factor V Leiden mutation). Endothelial cell activation, measured by vWF activity, revealed elevated levels in 42% (10/24). Complete/incomplete Behçet's disease patients with present or previous macular edema had significantly higher FVIII levels than complete/incomplete Behçet's disease patients who had never shown any signs of macular edema (P =.04). Further correlations between the laboratory results and clinical symptoms were not found. CONCLUSIONS: We found a generalized hypercoagulable state with endothelial cell activation in ocular Behçet's disease, irrespectively of current ocular disease activity.

Activated Protein C Resistance↗
PubMed2004

Risk factors for venous thromboembolism in children.

The incidence of venous thromboembolism (VTE) is increasing in children as a result of therapeutic advances and improved clinical outcome in primary illnesses that previously caused mortality. VTE is mostly diagnosed in hospitalized children, especially sick newborns with central venous catheters and older children with a combination of risk factors. Infants older than 3 months and teenagers are the largest groups developing VTE. The most important triggering risk factors are the presence of central venous lines, cancer and chemotherapy. Pathological conditions such as severe infection, sickle cell disease, trauma and antiphospholipid syndrome are associated with the presence of a hypercoagulable state in children. The thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be extremely low. Venous thromboembolism in pediatric patients is mainly caused by combinations of at least 2 prothrombotic risk factors for venous thromboembolic events in children are usually associated with underlying clinical conditions and a triggering risk factor. In addition, recurrence of VTE after withdrawal of anticoagulant treatment occurs in about 20% of patients after re-exposure to a triggering risk factor. A non negligible mortality and morbidity is related to VTE in childhood. This supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with VTE. Risk factor assessment for VTE in children has to be improved in order to optimize the prophylactic and therapeutic strategies. The specific evolutionary characteristics of the hemostasis in children has to be taken into consideration when a prophylactic or therapeutic strategy is applied.The incidence of venous thromboembolism (VTE) is increasing in children as a result of therapeutic advances and improved clinical outcome in primary illnesses that previously caused mortality. VTE is mostly diagnosed in hospitalized children, especially sick newborns with central venous catheters and older children with a combination of risk factors. Infants older than 3 months and teenagers are the largest groups developing VTE. The most important triggering risk factors are the presence of central venous lines, cancer and chemotherapy. Pathological conditions such as severe infection, sickle cell disease, trauma and antiphospholipid syndrome are associated with the presence of a hypercoagulable state in children. The thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be extremely low. Venous thromboembolism in pediatric patients is mainly caused by combinations of at least 2 prothrombotic risk factors for venous thromboembolic events in children are usually associated with underlying clinical conditions and a triggering risk factor. In addition, recurrence of VTE after withdrawal of anticoagulant treatment occurs in about 20% of patients after re-exposure to a triggering risk factor. A non negligible mortality and morbidity is related to VTE in childhood. This supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with VTE. Risk factor assessment for VTE in children has to be improved in order to optimize the prophylactic and therapeutic strategies. The specific evolutionary characteristics of the hemostasis in children has to be taken into consideration when a prophylactic or therapeutic strategy is applied.

Adolescent↗
PubMed1994

Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.

BACKGROUND: The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization. METHODS AND RESULTS: We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n = 81) or acute myocardial infarction (n = 32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n = 57; myocardial infarction, n = 23). We quantitated the plasma levels of F1 + 2 and FPA in control patients with stable angina (n = 37) or healthy individuals (n = 32) who were matched for age and sex. The median plasma concentrations of F1 + 2 and FPA are significantly higher in patients presenting with unstable angina (F1 + 2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1 + 2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1 + 2, 0.74 nmol/L; FPA, 1.3 nmol/L; P < .0001) or healthy individuals (F1 + 2, 0.71 nmol/L; FPA, 0.80 nmol/L; P < .0001). At 6 months, the median plasma levels of F1 + 2 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P = NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P = NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P = .0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P = .0028). CONCLUSIONS: During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin.

Adult↗
PubMed1999

A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors.

Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 microg/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 +/- 0.32 U/ml to 1.83 +/- 0.69 U/ml; P < 0.001), in vWF activity (from 1.04 +/- 0.34 U/ml to 1.78 +/- 0.50 U/ml; P < 0.001) and in FVIII:C (from 1.12 +/- 0.37 U/ml to 1.73 +/- 0.57 U/ml; P < 0.001) after G-CSF. Of note, four donors with low baseline vWF had a two- to three-fold increase after receiving G-CSF. G-CSF had no impact on the platelet count, beta-TG, PF-4, GMP-140 or PAC-1. The final% of platelet aggregation decreased from 73 +/- 22% to 37 +/- 26% after G-CSF (P < 0.001). We found a significant decrease in aPTT after G-CSF (29.9 +/- 3.1 s to 28.3 +/- 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.

Adult↗
PubMed1997

Defective fibrinolysis occurs after infrainguinal reconstruction.

PURPOSE: Early thrombosis of infrainguinal bypass grafts may occur as a result of hypercoagulable states. Major surgical procedures are known to induce a procoagulant state that is manifested in part by reduced endogenous fibrinolytic activity or fibrinolytic shutdown. This study was performed to assess the timing and biologic mechanism of fibrinolytic shutdown after infrainguinal bypass procedures by direct assay of the serologic markers of in vivo fibrinolytic activity. METHODS: Twenty patients underwent infrainguinal bypass procedures under epidural anesthesia. Endogenous fibrinolytic activity was assessed by measurement of tissue plasminogen activator (tPA) and its naturally occurring inhibitor, plasminogen activator inhibitor (PAI-1). The tPA and PAI-1 antigen (total protein) levels were determined using enzyme-linked immunosorbent assays, and measurements of in vivo biologic activity were performed using an amidolytic method. Measurements of tPA and PAI-1 were made before surgery, after surgery, and on postoperative days 1, 2, 7, and 30. RESULTS: The mean preoperative PAI-1 activity was 20.6 +/- 1.4 arbitrary units (AU)/ml, which was higher than that of an age-matched population without severe atherosclerosis. PAI-1 activity rose significantly after surgery (29.6 +/- 2.2 AU/ml; p = 0.002) and remained elevated through the second day after surgery. Preoperative tPA activity level was 2.04 +/- 0.59 IU/ml and fell to 0.79 +/- 0.23 IU/ml (p = 0.046) immediately after the bypass procedure. All serologic indicators of fibrinolytic shutdown returned to baseline levels by 72 hours after surgery. No early graft thrombosis or other atherothrombotic complications occurred in these study patients. CONCLUSIONS: Defective endogenous fibrinolytic activity occurs in the early postoperative period after infrainguinal bypass grafting procedures. Diminished endogenous fibrinolytic activity in these patients appears to be mediated by a combination of reduced tPA activity and significantly increased PAI-1 activity. No practical method is available to directly treat postoperative fibrinolytic shutdown, but postoperative antithrombotic therapy may be useful during this period to prevent early graft occlusion related to a relative hypercoagulable state.

Aged↗
PubMed1993

Effects of chemoendocrine therapy on the coagulation-fibrinolytic systems in patients with advanced breast cancer. Japan Advanced Breast Cancer Study Group and Japan Clinical Oncology Group.

In order to predict a hypercoagulable state in patients with advanced breast cancer receiving medical treatment, the effects of chemoendocrine therapy on the coagulation-fibrinolytic systems were investigated prospectively. The patients were randomly divided into two groups. The ACT group had 38 patients, who received 20 mg/m2 adriamycin (ADM) i.v. on days 1 and 8, 100 mg cyclophosphamide (CPA) p.o. on days 1-14, and 20 mg tamoxifen (TAM) p.o. daily. The ACM group had 44 patients, who received 20 mg/m2 ADM i.v. on days 1 and 8, 100 mg CPA p.o. on days 1-14 and 1200 mg medroxyprogesterone acetate (MPA) p.o. daily. The treatment was repeated every 28 days until there was evidence of progressive disease or until the full ADM dose (550 mg/m2) had been given. The following 9 hematologic parameters were measured every 4 weeks: alpha 2-plasmin inhibitor plasmin complex (PIC), anti-thrombin-III (AT-III), D-dimer (Dd), fibrinogen (Fg), plasminogen (Pg), protein C (PC), thrombin-antithrombin-III complex (TAT-III), tissue plasminogen activator (t-PA), and factor X (FX). Compared to the ACT group, patients in the ACM group showed significantly higher values of AT-III and PC, which exceeded the normal ranges. The levels of Pg, t-PA and FX were significantly higher in the ACM group than in the ACT group, but were still within the normal ranges. The levels of TAT-III, Dd and PIC decreased in the ACT group and were unchanged in the ACM group after the start of treatment. Fg remained unchanged in both groups after the start of treatment. One patient in the ACM group had thrombophlebitis of the lower extremities with high levels of TAT-III, Dd and PIC and a decrease of Fg, but her condition returned to normal after reduction of the MPA dose. Although these data are not directly indicative of a hypercoagulable state in patients receiving chemoendocrine therapy, changes in AT-III, TAT-III, Dd and PIC should be monitored carefully when this type of treatment is given.

Adult↗
PubMed2004

The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility.

BACKGROUND: D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia. PATIENTS AND METHODS: We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient's section of vascular medicine for suspected deep venous thrombosis.Statistical analysis was based on chi2 test, differences were considered to be significant if p < 0.05. RESULTS: D-dimer was increased in 25/39 and 20/25 showed inherited/acquired thrombophilia while patients with normal d-dimer showed inherited/acquired thrombophilia in 7/14 (p: < 0.05, s). DISCUSSION: D-dimer is a well known marker of hypercoagulable state, in particular its high predictive negative value in case of suspected thrombosis has been recognised by several reports. Yet, increased d-dimer has been identified also for subclinical thrombophilia besides for vascular thrombosis. Our data, in fact, for the first time suggest an interesting role of d-dimer to identify women affected by unexplained primary or secondary infertility and thrombophilia. So, probably there is a role for d-dimer in these subjects for its predictive positive value. Of course, further data on large based population are needed to confirm our results, because these findings may speed up a diagnostic screening in these patients also for a good cost/effectiveness of this test.

Journal Article↗
PubMed1988

Automated fluorogenic methods for the evaluation of the extrinsic coagulation reactions in human plasma.

Highly sensitive automated methods for the evaluation of the extrinsic coagulation reactions in human plasma were developed by the combination of fluorogenic peptide substrate (MCA) for thrombin and a centrifugal autoanalyzer (Cobas Bio). Prothrombin time (PT) was measured by the reaction time to reach 0.1 relative fluorescence which was caused by the action of thrombin generated after the activation of 3 microliters plasma with human placental tissue factor (Thromborel S). Factors X and VII contents in plasma were measured by the same method after mixing diluted plasma with each factor deficient plasma, tissue factor, calcium and MCA in which 10-800% of each factor was quantitatively measured. Prothrombin content in plasma was quantitated by measuring thrombin activity after the activation with human activated Factor X in the presence of phospholipid and calcium in which 10-160% of prothrombin was measured. By the application of these fluorogenic methods to the patients with cardiovascular diseases, it was demonstrated that these methods are highly sensitive not only to hypocoagulable state, but also to hypercoagulable state, particularly to the increase of Factors X and VII concentrations in plasma.

Blood Coagulation Factors↗