[Pharmacological Thromboprophylaxis during Pregnancy and the Puerperium: Recommendations from Current Guidelines and their Critical Comparison]. / Medikamentöse Thromboembolie-Prophylaxe in Schwangerschaft und Wochenbett: neue Leitlinienempfehlungen & kritischer Leitlinienvergleich.

Venous thromboembolism (VTE) is one of the leading causes of maternal deaths worldwide. Due to the increasing number of pregnant women with risk factors, the incidence of VTE has risen over the past decades. Mortality and morbidity of VTE are potentially preventable, since more than two-thirds of these women have identifiable risk factors and may benefit from appropriate thromboprophylaxis. The cornerstones for prevention of VTE are the individual and careful assessment of preexisting and new-onset/transient risk factors during pregnancy as well as before and after delivery and a risk-stratified pharmacological thromboprophylaxis. Current recommendations for thromboprophylaxis must rely on consensus statements and expert opinions. The recently published German AWMF-Guideline 003/001 and the Green-top Guideline No. 37a from the Royal College of Obstetricians and Gynaecologists (RCOG) are discussed. The RCOG Guideline recommends antenatal thromboprophylaxis in women with previous VTE, high-risk thrombophilia or in the presence of ≥ 4 risk factors from the beginning of pregnancy, in women with 3 current risk factors from 28 weeks of gestation. After delivery women with intermediate risk should receive prophylactic LMWH for at least 10 days and women with high risk for 6 weeks postnatally. All women who have had an elective caesarean section and who have>1 additional risk factor should be given prophylactic NMH as well as all women who have had a caesarean section in labour or an emergency caesarean section. At the onset of labour, in case of any vaginal bleeding, prior to scheduled labour induction or at least 12 h before an elective caesarean section, antenatal LMWH prophylaxis should be discontinued. LMWH prophylaxis can be continued 4-6 h after vaginal delivery and 6-12 h after caesarean delivery when women do not have an increased risk of haemorrhage. Current guidelines recommend weight-based LMWH.

[Preoperative identification of patients with impaired (primary) haemostasis. A practical concept]. / Präoperative Identifikation von Patienten mit (primären) Hämostasestörungen. Ein praktisches Konzept.

The findings of a large prospective study designed to identify primary and/or secondary haemostatic disorders before surgical interventions are presented. A total of 5649 unselected adult patients were enrolled to identify impaired haemostasis before surgical interventions. Each patient was asked to answer a standardized questionnaire concerning bleeding history. Activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet counts (PC) including PFA-100 (platelet function analyzer): collagen-epinephrine (C/E), and collagen-ADP (C/ADP) were routinely done in all patients. Additional tests, bleeding time (BT), von Willebrand factor (VWF:Ag, VWF:Rcof) and a further haemostaseological diagnostic was performed only in patients with a positive bleeding history and/or evidence of impaired haemostasis; e.g., drug ingestion. The bleeding history was negative in 5021 patients (88.8%) but positive in the remaining 628 (11.2%). Impaired haemostasis could be verified only in 256 (40.8%) of these patients. The vast majority was identified with PFA-100: C/E (n = 250; 97.7%). The sensitivity of the PFA-100: collagen-epinephrine was the highest (90.8%) in comparison to the other screening tests (BT, aPTT, PT, VWF : Ag). The positive predictive value (to detection of impaired haemostasis) of the PFA-100: collagen-epinephrine with the standardized questionnaire was high (82%), but the negative predictive value was higher (93%). The use of a standardized questionnaire and, if indicated, the PFA-100: C/E and/or other specific tests not only ensure the detection of impaired haemostasis in almost every case but also a significant reduction of the costs. Based on these data, national regards are formulated or under construction.

Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer.

PURPOSE: Influences of adjuvant epirubicin/cyclophosphamide (EC) chemotherapy on blood coagulation were investigated in patients with operable breast cancer and the incidence of thromboembolic events was recorded. PATIENTS AND METHODS: In 50 consecutive node-positive breast cancer patients, serial coagulation studies (fibrinogen method of Clauss, antithrombin III, protein C amidolytic methods, D dimer enzyme-linked immunoadsorbent assay [ELISA] techniques, and plasminogen activator inhibitor [PAI] activity u-PA inhibition test) and impedance plethysmography (IPG) for screening of deep vein thrombosis (DVT) were performed preoperatively and postoperatively, before each of six cycles of adjuvant chemotherapy (60 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide) and 3 months thereafter. Seventy-two healthy women served as controls. RESULTS: During chemotherapy, the phlebographically proven DVT incidence was 10% (n = 2 after second cycle; n = 3 after third cycle). Preoperative levels of D-dimer, fibrinogen, and the PAI activity were significantly higher than in healthy women and only mean levels of the D-dimer were significantly higher in patients with DVT compared with patients without DVT. Postoperatively, only D-dimer and fibrinogen levels significantly increased, while in the course of chemotherapy, these levels were significantly decreased. Mean D-dimer levels and PAI increased steadily in patients with DVT. Preoperatively and during chemotherapy, levels of antithrombin III and protein C were within the normal range. Only one patient with DVT had decreased protein C levels throughout chemotherapy. CONCLUSION: Monitoring with sophisticated coagulation tests during adjuvant EC chemotherapy for breast cancer does not identify patients at higher risk for DVT development. Preoperatively, in patients with later DVT, an imbalance of hemostasis is already present; thus, thrombosis might predominantly be initiated by malignancy-induced hypercoagulability and secondarily by the influence of EC chemotherapy. Prospective randomized trials must determine whether prophylactic anticoagulation during EC chemotherapy reduces the incidence of DVT.

Features of Polycystic Ovary Syndrome in adolescence.

RATIONALE: To elucidate the prepubertal risk factors associated with the development of Polycystic Ovary Syndrome (PCOS) and determine the special clinical manifestations of the syndrome in this transitional time of a woman's life. OBJECTIVE: To propose therapeutic targets and regimens, not only to prevent the long-term complications of the syndrome, but also to improve the self-esteem of a young girl who matures into womanhood. METHODS AND RESULTS: A systematic review of literature was performed through electronic database searches (Pubmed, Medline and Embase). Studies published in English-language, peer-reviewed journals from 1996 to 2013 were included. The selected studies focused on the risk factors, the unique features and treatment options of the PCOS in puberty. The pathogenesis of the PCOS was hypothesized to be based on interactions between genetic and certain environmental factors. The diagnosis was usually difficult in young girls. The syndrome was related to a greater risk of future infertility, type II diabetes mellitus, the metabolic syndrome and cardiovascular disease. Early treatment was crucial to prevent the long-term complications of the syndrome, especially infertility and cardiovascular disease. DISCUSSION: The recognition of the early signs of PCOS during or even before adolescence is of great importance. It is essential to establish the correct diagnosis for PCOS and rule out other causes of androgen excess in young women with hyperandrogenism. The type of treatment applied should be considered on an individual basis. ABBREVIATIONS: PCOS = Polycystic Ovary Syndrome.

Blood coagulation and thrombosis in patients with ovarian malignancy.

Ovarian cancer cells appear to be capable of both thrombin formation and induction of fibrin degradation which may be essential prerequisites for the development of deep vein thrombosis (DVT) as well as the spread of malignancy. To study further this coagulation-cancer interaction in 60 patients with untreated ovarian cancer of FIGO stage I-IV the incidence of DVT was recorded pre-operatively, post-operatively on day 1, 3, 5, 7, 10, before each of six cycles of Cisplatinum/ Epirubicin/Cyclophosphamide chemotherapy, during follow-up and in the post-operative period of second look surgery. In addition, blood coagulation tests results were determined prospectively. Two patients were excluded from these calculations due to previous DVT 5 to 6 weeks before the diagnosis of ovarian cancer but all patients were eligible for surgery and randomized to receive either daily low molecular weight heparin (LMWH) (n = 28) or unfractionated heparin (UFH) (n = 32) for perioperative thrombosis prophylaxis until the 7th post-operative day. According to the FIGO stage, patients were equally distributed in the 2 heparin treatment groups. The predictive value of pre-operative coagulation test results, clinical parameters, and type of heparin used were tested in univariate and multivariate analysis for development of post-operative DVT and overall patients survival. Impedance plethysmography for DVT screening was used. The presence of DVT was then confirmed by phlebography. Only D-dimer and fibrinogen levels were correlated significantly with the FIGO stage while antithrombin, protein C, and plasminogen activator inhibitor activity were not. The incidence of DVT was 6.7% (4/60) up to the 7th and 8.3% (5/60) between the 8th and 29th post-operative day. DVT occurred in 10.6% (5/47) during chemotherapy. Pre-operative coagulation test results, the type of heparin used, and clinical parameters were not significant risk factors for post-operative DVT development in univariate analysis. The D-dimer and fibrinogen levels were significant risk factors for reduced overall survival in univariate analysis but only the FIGO stage was an independent predictor (in multivariate analysis). After a median follow up of 26.5 months (min. 8 months, max. 41 months), 21.4% of LMWH treated and 37.5% of UFH-treated patients died of cancer (p = 0.26). Pre-operative test results were neither predictive for DVT nor the outcome of cancer but patients showed an improved though not statistically significant overall survival after LMWH treatment.

Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial.

Recent studies suggest that low molecular weight heparin (LMW heparin) therapy in malignancy may improve cancer survival following surgical resection. We studied prospectively whether cancer mortality during follow-up in women with previously untreated breast, and pelvic cancer is reduced in those who randomly received LMW heparin (Certoparin) compared to patients given unfractionated heparin (UF heparin) for thrombosis prophylaxis during primary surgery. In a prospective, randomized, double-blind clinical trial, 160 patients received Certoparin and 164 UF heparin until post-operatively day 7. Survival estimations are based on the outcome data from a subset of 140 LMW heparin - and 147 UF heparin recipients. Long-term survival in the Certoparin group compared to the UF heparin group was significantly improved after 650 days (P=0. 0066) but not thereafter when analysis was performed on all cancer cell types combined. In the probability estimates survival benefit within this time was restricted to patients with pelvic cancer but was not observed in breast cancer. However, in breast cancer patients who received LMW heparin the impact of classical tumor prognostic markers was statistically significant after 1,050 days but not after 650 days. Thus, breast cancer patients with unfavorable prognosis seem to benefit in terms of survival advantage from LMW heparin within the 650 days after surgery. These results suggest that improvement in cancer survival can be achieved after even a short course of treatment with LMWH (compared to UFH) given for DVT prophylaxis in the post-operative period. An effect of UFH on disease outcome is not excluded. Further definitive trials of LMWH vs. placebo for cancer outcome (rather then DVT) using doses and schedules that may be more optimal are indicated.

Antithrombotic therapy in gynecologic surgery and gynecologic oncology.

The European Consensus Conference has assessed the risk for thrombotic complications for most women undergoing gynecologic surgery and found it to be moderate. Nonetheless, it is important to analyze a patient's individual risk before surgery so that appropriate thrombosis prophylaxis can be given if increased risk is determined. Malignancy accounts for most thrombotic complications among gynecologic patients. Patients with known malignancies should receive prophylaxis during surgery, and some patients with breast cancer should receive prophylaxis during chemotherapy. Heparin, and low-molecular-weight heparin in particular, may favorably influence the outcome of cancer in some patients and treatment with these agents is currently under investigation in a number of trials as a new approach to anticancer therapy.

Antithrombotic therapy in high-risk pregnancy.

Venous thromboembolism remains a major cause of morbidity and mortality associated with pregnancy and puerperium. Specific risk factors for this disorder can be identified before or during pregnancy and delivery. The heritable defects believed to be associated with venous thrombosis are factor V Leiden mutation; elevated antiphospholipid antibodies; and deficiencies of antithrombin, protein C, and protein S. Women with a history of thromboembolism and thrombophilia should receive antenatal and postpartum thrombosis prophylaxis.

A whole blood flow cytometric determination of platelet activation by unfractionated and low molecular weight heparin in vitro.

The influence of unfractionated (Heparin-Natrium) and low-molecular heparin (Fragmin(R)) on platelet activation in whole blood was investigated by FACS analysis in vitro using antibodies against glycoprotein (gp) IIb/IIIa (CD 41), GMP 140 (CD 62P), gp 53 (CD 63) and fibrinogen. Samples were also labeled with anti-gp Ib (CD 42b). Neither unfractionated heparin (UFH) nor low molecular weight heparin (LMWH) led to significant (i.e., p<0.05) changes in fluorescence intensities of platelets labeled with anti-gp IIb/IIIa or anti-gp 53. Significant platelet activation due to unfractionated heparin could be observed by labeling with anti-GMP 140 (UFH: p=0.009; LMWH: p=0.16). The proportion of platelets with surface-bound fibrinogen was significantly increased (UFH: p=0.00006; LMWH: p=0.008). After incubation with heparins, activation ability of platelets by adenosine diphosphate (ADP) was significantly increased. The potentiating action of unfractionated heparin was larger. Therefore, flow cytometric results of platelet activation in patients receiving heparin should be interpreted carefully.

Blood rheology during chemotherapy in patients with ovarian cancer.

The use of platinum based chemotherapy in ovarian malignancy and other cancer types is known to be associated with deep vein thrombosis. In a prospective study of 47 patients with ovarian cancer of International Federation of Gynecology and Obstetrics stage Ib-IV, serial rheological parameters were determined (plasma viscosity, red blood cell aggregation under conditions of stasis and low shear) in addition to hemoglobin, hematocrit, leukocytes, platelets, and fibrinogen. At the same time the incidence of deep vein thrombosis was recorded before, during six cycles of first line cisplatinum/epirubicin/cyclophosphamide chemotherapy, and 2 months thereafter (two-months check-up). Only six patients with previous deep vein thrombosis concomitantly received thrombosis prophylaxis once with 3000 anti Xa Units/day subcutaneously low molecular weight heparin (Certoparin, NOVARTIS) throughout chemotherapy. Before each cycle of chemotherapy impedance plethysmography was used for deep vein thrombosis screening and when this was suspected on the basis of physical examination or a pathological result of impedance plethysmography, ascending venography of both legs was performed. During chemotherapy, the venographically proven deep vein thrombosis incidence was 10.6%; (95% CI: 3.5-23.1) with no differences in occurrence between FIGO stages. Before operation mean plasma viscosity was higher in patients who developed deep vein thrombosis postoperatively (n = 5; 1.46 +/- 0.2 mPas) and during chemotherapy (n = 5; 1.49 +/- 0.1 mPas) as compared to those without deep vein thrombosis (1.38 +/- 0.2 mPas; p = 0.04). Postoperatively (before chemotherapy) none of the rheological variables were significantly different in patients with versus those without deep vein thrombosis during chemotherapy. Leukocyte and platelet counts decreased significantly during chemotherapy until the two-months check-up after chemotherapy while red blood cell aggregation (stasis & low shear), hemoglobin, and hematocrit showed a continuous but nonsignificant increase. The mean plasma viscosity, instead, declined into the normal range after the 4th cycle of chemotherapy (1.33 +/- 0.1 mPas) in patients without thrombosis. In contrast, mean plasma viscosity was increased to 1.48 +/- 0.1 mPas at the time of deep vein thrombosis diagnosis during chemotherapy. In the ovarian cancer patients of this study, the development of deep vein thrombosis postoperatively and during chemotherapy was associated with a hematocrit-independent increase in blood viscosity characterized by a high plasma viscosity and normal or low hematocrit, which was present before primary surgery as well as at the time of deep vein thrombosis diagnosis.

The influence of antiphospholipid antibodies on the pregnancy outcome of patients with recurrent spontaneous abortion.

Several therapeutic regimens have been proposed for women with recurrent spontaneous abortion (RSA) and antiphospholipid antibodies (APA). Conflicting results have been reported about women with history of RSA, positive APA, and failure of standard therapy. To evaluate the use of intravenous immunoglobulin in RSA patients with APA and history of treatment failure, we initiated a study with standard therapy (aspirin and low-molecular-weight heparin) and intravenous immunoglobulin. We used an enzyme-linked immunosorbent assay (ELISA) test to screen IgG and IgM anticardiolipin antibodies, and a diluted Russel viper venom time assay for the lupus anticoagulant activity. Altogether, 66 pregnant women with positive APAs at the first visit could be included. Patients with hereditable thrombophilic factors were excluded. After confirmation of the pregnancy, women received a basis immunization of 0.3 g/kg immunoglobulin in a 4-week cycle until the 28th to 32nd week of gestation. All patients received 100 mg/d aspirin and 3,000 anti-Xa U/d certoparin. Among the 66 pregnant women, 17 were persistently autoantibody positive (25.8%), of whom 11 (16.7%) were ACA positive alone, 2 (3%) were lupus anticoagulant positive, and 4 (6.4%) had both antibody types. A total of 49 patients had positive APAs at the initial test, but were negative for ACA and lupus anticoagulant at the second test administered approximately 5 weeks after the start of therapy. We described this group in our following observation as "antibody negative." Sixteen of the 17 autoantibody-positive patients (94.1%) were delivered of live infants compared with 40 patients (81.6%) in the antibody-negative group (odds ratio [OR]: 1.2; 95% CI: 0.98 to 1.4). The overall miscarriage rate was 12.1% and the fetal loss rate was 15.2%. Four patients (25%) in the antibody-positive group developed symptoms of preeclampsia and fetal growth retardation compared with four patients (9.8%) in the antibody-negative group. In conclusion, we see a reduction of the fetal loss rate in patients with RSA and positive APA (5.8%) compared with APA-negative (18.4%) women with the same therapy (OR: 0.3; 95% CI: 0.04 to 2.3).

Chemotherapy and thrombosis in gynecologic malignancy.

Thromboembolism is a severe and frequent problem in gynecologic malignancy. The average DVT incidence during chemotherapy of 5% might represent the lower range of incidence because < 55% of thrombotic complication manifest clinical signs. However, it seems likely that in addition to chemotherapy other risk factors such as menopausal status, BMI of patients, or type of preceding surgery must coincide before thrombosis manifests. While monitoring of patients using sophisticated coagulation tests did not identify patients' risk for DVT during chemotherapy, an evaluation of the coagulation status before initiating chemotherapy is recommended. Patients with a venous access device (e.g., indwelling central venous catheter or with port cart) are at a particularly high risk for DVT. This has to be considered when cytoreductive therapy is given. Thrombosis prophylaxis, orally or subcutaneously, should only be considered in a subpopulation of patients who offer a combination of the aforementioned risk factors. Thrombosis prevention trials during chemotherapy found a significant reduction of DVT in patients treated with anticoagulants.

Neonatal platelet activation in preeclampsia.

Preeclampsia is associated with an increased platelet activation; however, there are few studies concerning platelet activation of the newborn. The aim of our study was to compare platelet activation in newborns of preeclamptic mothers to newborns of healthy mothers by using whole blood flow cytometry. Blood samples were obtained from 20 newborns (10 healthy controls, 10 cases of preeclampsia/HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome) during cesarean section. Antibodies against the following antigens were used as markers for platelet activation: CD 41, CD62P, CD 63, and platelet-bound fibrinogen. In addition to the basal platelet activation, the ability of platelets to undergo activation as a result of in vitro incubation with a weak agonist (adenosine diphosphate) was evaluated. A significant difference between the groups concerning basal platelet activation could only be seen for platelet-bound fibrinogen; the control group showed a higher extent of platelet activation (16.6 +/- 11.3 vs. 6.1 +/- 4.9; p = 0.03). Incubation with adenosine diphosphate in the control group resulted in minor increases of platelet activation, which was significant only for platelet-bound fibrinogen (16.6 +/- 11.3 vs. 42.5 +/- 22.1; p = 0.02). However, the preeclamptic group showed significantly increased levels of platelet activation for all used markers after in vitro activation (CD 41: 115.6 +/- 18.2 vs. 163.2 +/- 29.6; p = 0.002; CD62P: 2.4 +/- 0.4 vs. 3.9 +/- 0.3; p < 0.001; CD 63: 2.7 +/- 0.5 vs. 3.7 +/- 0.6; p = 0.002; platelet-bound fibrinogen: 6.1 +/- 4.9 vs. 55.1 +/- 9.1; p < 0.001). Preeclampsia or HELLP syndrome is therefore associated with an increased susceptibility to neonatal platelets, even against weak activators such as adenosine diphosphate. Whether this results from peculiarities in the fetal vascular environment or maternal influences is yet uncertain.

The role of intravenous volume expansion in moderate pre-eclampsia.

We examined the hemodynamic and hemorheological effects of intravenous volume expansion in women with pre-eclampsia. 20 untreated women with moderate pre-eclampsia were randomized to receive a 500 ml infusion over 4 h of either hydroxyethylstarch (HAES steril 10%, HES) or NaCl 0.9% solution. After completion of the infusion trial all patients received oral antihypertensive drugs, bed rest and free sodium and water intake. The hemodynamic responses were measured by impedance cardiography. Hemorheological parameters and blood pressure were measured before and after (24 h later) infusion. The HES infusion but not NaCl leads to a significant reduction of hematocrit and erythrocyte aggregation. In addition to that there was a nonsignificant increase of the cardiac index in the HES-group but no changes in the heart rate. Intravenous volume expansion in women with pre-eclampsia with a long acting colloid like hydroxyethylstarch is associated with a significant influence on the flow properties (hematocrit and erythrocyte aggregation) of blood.

Association between blood rheology, thrombosis and cancer survival in patients with gynecologic malignancy.

In cancer patients impaired blood rheology in the presence of coagulation activation may reduce blood flow in the vascular microcirculation that favors thrombosis but may also support tumor progression and metastasis. In 451 patients with gynecological cancer and 177 patients with corresponding benign tumor disease preoperatively, during adjuvant treatment, when venous thrombosis (VT) or cancer progression was diagnosed hematocrit (micro centrifuge), hemoglobin, leukocytes, platelets (Coulter Counter); red blood cell (RBC) aggregation (aggr.) during stasis and low shear conditions (MA 1, Myrenne), plasma viscosity (viscosimeter KSPV 1 Fresenius), and fibrinogen (Multifibren Behring Dade) were investigated. One hundred and twelve healthy women served as controls. Preoperatively, mean plasma viscosity (pv) was significantly higher in cancer patients as compared to patients with the corresponding benign tumor disease (breast cancer: n = 261; pv = 1.32 vs. 1.27 mPa s; p = 0.023; ovarian cancer: n = 68; pv = 1.39 vs. 1.31 mPa s; p < 0.001; endometrial cancer: n = 70; pv = 1.37 vs. 1.25 mPa s; p < 0.001; cervical cancer: n = 52; pv = 1.33 vs. 1.26 mPa s; p = 0.004). RBC aggr. was significantly lower in controls compared to the preoperative values in cancer patients but mean (median) values (RBC aggr. stasis < 21) were within the normal range in all. Preoperatively, plasma viscosity was a significant risk factor for the overall survival in ovarian cancer patients (p = 0.02) and for subsequent thrombosis in ovarian (p = 0.02) and cervical cancer patients (p = 0.007). In the multivariate analysis plasma viscosity was an independent prognostic marker for the overall survival of breast cancer patients (r = 99.45; 95% CI: 7.32-980.2; p < 0.0001). An optimized preoperative cut-off value above 1.40 mPa s (Log-Rank-test) was significantly associated with poor outcome in the Kaplan-Mayer survival estimates, even in node-negative breast cancer. In gynecologic cancer patients the combination of an increase in RBC aggregation and plasma viscosity impairs blood-flow-properties and may induce hypoxia in the microcirculation that favors thrombosis, settlement of tumor-cells and thus metastasis. Improvement of blood fluidity and thus oxygen transfer in the tumor-vascular-microcirculation may increase susceptibility of systemic anti-cancer therapy.