Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer.

In 2 double-blind studies, ambulatory patients with objectively proven, disseminated metastatic breast carcinoma (TOPIC-1) or stage III/IV non-small-cell lung carcinoma (TOPIC-2) were randomized to certoparin 3000 IU or placebo subcutaneously once daily, for 6 months. Primary efficacy outcome was objectively confirmed symptomatic or asymptomatic venous thromboembolism (VTE). Safety outcomes included bleeding (major and minor), and thrombocytopenia. TOPIC-1 was halted after an interim analysis. Venous thromboembolism occurrence was not different between treatment groups in TOPIC-1 (4% treated with certoparin, 7 of 174 vs 4% receiving placebo, 7 of 177, odds ratio [OR] 1.02; 95% confidence interval [CI] 0.30-3.48) and in TOPIC-2 (4.5%, 12 of 268) vs 8.3%, 22 of 264, respectively, OR 0.52; CI 0.23-1.12). Mortality was not different between groups. A post hoc analysis showed certoparin significantly reduced VTE in stage IV lung carcinoma (3.5% vs 10.2%; P = .032) without increased bleeding. In conclusion, thrombosis risk and prophylactic benefit was highest in stage IV lung carcinoma patients.

Antiphospholipid syndrome and pre-eclampsia.

Antiphospholipid syndrome (APS) is defined as an autoimmune disorder characterized by recurrent thrombosis or obstetrical morbidity. These features are linked to the presence in blood of autoantibodies against negatively charged phospholipids or phospholipid-binding proteins. Obstetric morbidity includes recurrent abortion (early and late) and severe pre-eclampsia (P-EC)/hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, and/or severe placental insufficiency. Criteria that define the major clinical and laboratory events were published in revised forms in the Sydney recommendations in 2006. We analyzed the blood of patients with severe P-EC according to the subgroups based on the 2006 revised criteria definition and compared these results with women after uncomplicated pregnancy and delivery. We found 20% elevated antiphospholipid antibodies (APAs) in women with severe P-EC (group I, 7.5%; group IIa, 5.0%; group IIb, 5.0%; group IIc, 2.5%). The increased APAs were observed only in women with severe P-EC (odds ratio: 2.45; 95% confidence interval, 1.01 to 4.3) and not in patients with severe P-EC at >34 weeks of gestation. According to our retrospective observation, we recommend the determination of anticardiolipin antibodies, lupus anticoagulant, and ß-2 glycoprotein-1 antibodies in patients with severe P-EC at <34 weeks of gestation.

CD3-CD56+CD16+ natural killer cells and improvement of pregnancy outcome in IVF/ICSI failure after additional IVIG-treatment.

PROBLEM: The purpose of this retrospective, observational study was to investigate whether additional treatment with intravenous immunoglobulin (IVIG) increased the rate of successful pregnancies after repeated implantation failure (RIF). The retrospective data were compared with data of patients without IVIG-therapy from the meta-analysis of Clark et al. METHOD OF STUDY: A total of 188 women with 226 treatment cycles between 2007 and 2009 were evaluated for IVIG therapy. The percentage of NK cells was measured two times before a new embryo transfer (only women with NK cell percentages >12% were included) and after embryo transfer at a positive pregnancy test. RESULTS: In comparison with the meta-analysis of Clark et al., we observed a pregnancy rate of 50.5%, an implantation rate of 21% and a miscarriage rate of 16.8%. In 42%/IVIG- patient or 34.9%/embryo transfer, we observed a live born baby. The live born rate per embryo was 16.6%. In accordance with the study of Kwak et al., we indicate a decrease in the NK cells in patients with improved pregnancy outcome. CONCLUSION: In a subgroup of RIF-patients with high level of CD56(+) CD16(+) NK-cells the additional application of IVIG leads to a favourable pregnancy outcome.

Blood rheology at term in normal pregnancy and in patients with adverse outcome events.

Plasma volume expansion of more than 1.5 l and sustainable activation of the hemostatic system that results in a steady rise of the fibrinogen/fibrin turnover are contemporary physiological events during normal pregnancy. In contrast, adverse outcome of pregnancy i.e. pre-eclampsia commonly coincide with hemo concentration and over activation of blood coagulation both of which alter blood rheology. On the basis of 4,985 consecutively recorded singleton pregnancies values range of blood rheological parameters in women with normal and complicated outcome of pregnancy at the time of their delivery were compared. Plasma viscosity (pv) was determined using KSPV 1 Fresenius and RBC aggregation (stasis: E0 and low shear: E1) using MA1-Aggregometer; Myrenne. Seventy-nine point four percent (n=3,959) had normal pregnancy outcome and 1,026 with adverse outcome of pregnancy had pre-eclampsia (8.4%; n=423), had newborn with a birth-weight < 2,500 g (9.5%; n=473), had early-birth before week 37 (9.3%; n=464), and/or were diagnosed with intra uterine growth retardation (IUGR) (5.0%; n=250). In women with normal pregnancy outcome mean (+/-SD) of pv was 1.31+/-0.09 mPa s, of E0 was 21.6+/-5.3, and of E1 was 38.4+/-7.9 while in women with adverse outcome means for rheological parameters were statistically significantly different i.e. pv: 1.32+/-0.08 mPa s; p=0.006, E0: 22.1+/-5.5; p=0.002 and E1: 39.5+/-8.5; p=0.0006. Subgroup analysis revealed statistical significant lower pv in women who either had pre term delivery or a low birth-weight child (p<0.005) as compared to women who had normal pregnancy outcome while patients with pre-eclampsia had markedly higher low shear and stasis RBC aggregation (p<0.0001). None of the rheological results at term were correlated with either maternal age (r<0.04), BMI (r<0.09), maternal weight gain until delivery (r<0.04), or fetal outcome such as APGAR-score (r<0.09) art. pH in the umbilical cord (-0.05

Mean maternal second-trimester hemoglobin concentration and outcome of pregnancy: a population-based study.

Both anemia and the lack of physiological maternal plasma volume expansion during the second trimester are associated with higher maternal morbidity and poor fetal outcome. Mean hemoglobin levels between the 14th and 30th gestational weeks were calculated in 4985 consecutive pregnant women and were correlated with outcome data of pregnancy. It was found that 9.4% of participants (n=3959) had normal pregnancy outcome. Mean maternal hemoglobin levels were significantly lower in women with a normal pregnancy (11.96+/-0.94 g/dL) compared with women who had adverse outcome events (preeclampsia, n=423, 12.5 +/- 1.0 g/dL, P< .0001; early birth, n=464, 12.2+/-1.01 g/dL, P< .0001; low birth weight newborn, n=473, 12.2+/-1.10 g/dL, P< .0001; intrauterine growth retardation, n=250, 12.2+/-1.0 g/dL, P< .0001). The risk for any adverse outcome event was lowest with a mean hemoglobin between 11.0 and 12.0 g/dL (odds ratio, 0.625; 95% confidence interval, 0.43-0.89) and highest between 13.0 and 15.0 g/dL (odds ratio, 2.24; 95% confidence interval, 1.54-3.31). In this population-based study from a community in Western Germany, impaired plasma volume expansion was an independent risk factor for the development of an adverse outcome of pregnancy.

Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study.

Antiphospholipid syndrome (APS) represents a serious risk factor in pregnancy resulting in several complications, leading to fetal loss and hemostatic complications. In this dedicated report, we describe our experiences in the treatment of pregnancies in patients with APS. The retrospective data from 140 pregnant women were investigated, and the treatment results of 121 patients were recorded. We studied two groups of patients receiving different treatment. The first group (N = 78) received the standard therapy with low-weight-molecular heparin (dalteparin 5000 U or certoparin 3000 U daily) and aspirin (100 mg daily) and in the second group (N = 43) an additional 0.2 g/kg intravenous immunoglobulin (IVIG). Outcomes were 74.3% and 83.7% live births in the first group and in the second group, respectively. The abortion rate was similar in both groups (11.5% vs. 11.6%). The late complication rate was lower in the second group (5.8% vs. 14.1%, P < 0.05) than in the group with standard therapy. Interestingly, we found a trend to higher percentage (> 12%) of natural killer (NK) cells in patients with pregnancy complications (60% vs. 12%, P < 0.05). Our retrospective data shows an improvement of late pregnancy complications by additional use of IVIG. It is possible that IVIG influences higher NK cell activity in patients with previous pregnancy complications.

Hemostatic abnormalities in patients with severe preeclampsia.

Preeclampsia is the most common medical disorder of pregnancy. Early onset preeclampsia is defined as presentation of hypertension and proteinuria before 34 weeks of gestation. Alterations of endothelial cells and fibrin deposition in microvasculature lead to enhanced activation of the coagulation cascade and impaired fibrinolysis associated with multiple organ dysfunctions. Plasma samples were obtained from 50 patients with severe preeclampsia before 34 weeks of gestation and in 61 patients with late preeclampsia. Factor VIIIR:Ag, fibrinogen, D-dimer, and thrombomodulin increased with advanced pregnancy. The platelet count is very important because of the close correlation with the activations parameters of D-dimer and antithrombin. Our results were consistent with activated coagulation and lowering of platelet count in severe cases with early onset preeclampsia. Women who develop early onset preeclampsia characterized a subgroup of patients with more and severe hematologic abnormalities than women with late preeclampsia (after 34 weeks of gestation).

Antihypertensive therapy in patients with pre-eclampsia: A prospective randomised multicentre study comparing dihydralazine with urapidil.

BACKGROUND: Drug treatment is imperative for pregnant women with pregnancy-induced hypertension (PIH) and pre-eclampsia. For more than 40 years, dihydralazine has been the drug of choice for this indication. Another particularly effective and better tolerable antihypertensive is urapidil. Yet only a few studies on limited patient collectives have been published on the clinical experience with urapidil in PIH. METHODS: Urapidil was interindividually compared to dihydralazine in a total of 42 patients, at six participating clinical centres. Patients were randomly assigned to the treatment groups. Urapidil was administered at an initial dose of 12.5-25mg, dihydralazine was administered at a uniform initial dose of 5mg. Patients were closely monitored for the initial 24h of therapy. Until delivery and in the postpartal phase, mother and baby underwent four additional follow-up checks at regular intervals. RESULTS: Either drug was effective in lowering BP. Urapidil treatment proved to be better controllable. There were clear differences as to tolerability. In the urapidil group, one patient complained of headaches. In the dihydralazine group, six patients experienced adverse occurrences. Under dihydralazine treatment, some marked HR increases occurred, interpretable as reflectory tachycardia. CONCLUSIONS: Urapidil proved to be equally effective as dihydralazine in lowering BP in patients with pre-eclampsia, but showed a better controllability and tolerability. Urapidil can hence be recommended as a promising alternative for patients with PIH.

Monitoring of rheologic variables during postoperative high-dose brachytherapy for uterine cancer.

Oxygenation of tumor tissue has recently been assed an important prerequisite for the effectiveness of radiotherapy in cervical cancer. Hyperviscosity is a common phenomenon in malignancy and a cause of reduced oxygen transport capacity that would favour tissue hypoxia. Hemorheological variables were serially tested preoperatively, during four cycles of fractionated adjuvant IR(192) HDR after loading radiation (HDR-AL) of the vaginal vault (weekly intervals), and 6 months postoperatively in patients with cervical (n=12) and endometrial cancer (n=26). Women who were scheduled for benign tumor surgery served as controls (n=29). Preoperatively, in cervical and endometrial cancer patients, mean plasma viscosity (PV: 1.31+/-0.1 mPa s; p<0.05; 1.35+/-0.13 mPa s; p<0.001) and fibrinogen levels (383+/-46 mg/dL; p<0.05; 379+/-117 mg/dL; p<0.05) were higher as compared to the controls (1.25+/-0.07 mPa s; 314+/-89 mg/dL). Red blood cell aggregation at low shear and stasis (RBC agg.: 15.7+/-5.6; p<0.05; 29.6+/-9.1; p<0.05) was higher in endometrial cancer patients as compared to the controls (13.7+/-3.4; 25.3+/-5.6). Postoperatively PV decreased in endometrial cancer patients and transiently increased in cervical cancer patients. After the third session of irradiation in both cancer groups, PV regained and at the 6-month checkup, levels were higher as compared to the values before surgery. Postoperatively fibrinogen levels increased and remained higher throughout HDR-AL and 6 months postoperatively. After surgery and during irradiation, anemia persisted in both cancer groups while hematocrit recovered after 6 months in endometrial cancer patients. Thrombosis was diagnosed in three patients postoperatively (7.9 %) but in none during HDR-AL. While a temporary reduction of hyperviscosity is found postoperatively and during HDR-AL in uterine cancer patients, 6 months after surgery RBC aggregation, PV, and hematocrit returned to the pretreatment range.

Impact of rheological variables in cancer.

Rheological alterations are commonly found in malignant disease and are most pronounced in advanced-stage cancer. Although most of these changes are caused by cancer-unspecific mechanisms, it has been shown that the extent of these changes in some cancer types is related with the stage of cancer, prognosis of disease, and the patient's risk for thrombosis. Monitoring of rheological variables during follow-up of patients has been useful in gynecologic cancer; a significant increase in the main determinants of blood viscosity was found when metastasis became clinically apparent. The most frequent constellation in newly diagnosed cancer is an increase in plasma viscosity (PV) and red blood cell (RBC) aggregation that produces hyperviscosity and is compensated for by anemia. Unconditional elevation of the hematocrit in cancer can deteriorate microcirculatory flow properties and may plunge the patient into an undesirable hemorheological condition that limits effectiveness of cytoreductive treatment and favors dissemination of cancer cells and the development of thrombosis. Modification of hyperviscosity, most likely at the plasma level, may represent a concept for cancer treatment and prevention of thrombosis. Anticoagulants and anti-inflammatory substances seem most suitable at this point, because high fibrinogen turnover is an important determinant of hyperviscosity in malignancy.

Antiphospholipid syndrome in obstetrics.

Antiphospholipid syndrome (APLS) in pregnancy is characterized by the presence of autoantibodies in association with recurrent fetal loss and severe complications such as preeclampsia, fetal growth retardation, or placental insufficiency. The most clinically important serologic markers are lupus anticoagulant, anticardiolipin antibodies, and recently anti-beta-2-glycoprotein 1 antibodies. At present, standardization does not exist and a definitive association between specific clinical manifestation and antibody level is not yet known. Experimental data gave evidence that passive transfer of antiphospholipid antibodies result in clinical manifestation of APLS, that is, fetal loss and thrombocytopenia. Treatment with heparin, aspirin, or intravenous immunoglobulins decreased the fetal loss rate. Treatment regimens in human are very difficult to interpret. Evidence from two prospective studies supported treatment with heparin and aspirin to improve pregnancy outcome. The risk of preeclampsia and placental insufficiency was substantial and occurred in 50% of patients. The general failure rate of heparin/aspirin treatment is approximately 30%. In such cases intravenous immunoglobulin in combination with heparin and aspirin has been used to treat APLS.

Prognostic role of plasmaviscosity in breast cancer.

Tumor growth leads to tissue hypoxia and tissue hypoxia, in turn, is a strong stimulus for expression of genes encoding factors that promote tumor growth. Likewise, hypoxia is a key condition within the vicious cycle of autogenous neoplastic dissemination. A marker of the presence of tissue hypoxia may be the presence of high blood viscosity, which is found in a number of neoplastic diseases including gynecological cancer. At the time of diagnosis of breast cancer, patients dying of this disease had had significantly higher initial pv (1.40+/-0.18 mPa s; p<0.0001) when compared to patients not dying of cancer (1.30+/-0.10 mPa s). In multivariate proportional hazard regression analysis, next to tumor size (p=0.03) and nodal status (p=0.004), pv was found an independent prognostic marker for overall survival of breast cancer patients (RR=130.2; 95% CI: 11.6-1,460.6; p<0.0001). An optimized preoperative cut-off value above 1.40 mPa s was significantly associated with poor outcome (log-rank-test) in the Kaplan-Meier survival-estimates, even in node-negative breast cancer (n=153; 54.6%). The most likely explanation for these findings is that increased fibrinogen/fibrin turnover and breakdown products characteristically associated with tumor-cell dissemination contribute to the increased plasma viscosity while the hematocrit, leukocyte count, and platelet count contributed little to the increased blood viscosity in patients with breast cancer. These findings may constitute an approach for new strategies in cancer therapy since it might be possible that reduction of plasma viscosity by treatment improves responsiveness to radio/chemotherapy and thus survival of patients.

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.

ProC Global assay in the evaluation of women with history of severe preeclampsia or HELLP syndrome.

Preeclampsia/HELLP syndrome has been associated with a high incidence of defects in the protein C pathway and increased anticardiolipin-antibodies/lupus anticoagulants. It is also apparent that thrombophilia is responsible for other pregnancy complications, such as recurrent spontaneous abortion, fetal growth restriction, intrauterine fetal death, and abruptio placentae. ProC Global is a new global dotting assay designed to evaluate the abnormalities in the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac, to prolong an activated partial thromboplastin time. A total of 61 patients with a history of severe preeclampsia or HELLP syndrome and 61 normal pregnant women (controls) were evaluated, 15 of whom had factor V Leiden mutation, 12 had protein C/S deficiency, 30 had a repeated lupus anticoagulants, and 27 increased anticardiolipin antibodies (ACA). All carriers of factor V Leiden mutation (N=15) as well as all the patients with low activated protein C (APC) resistance ratio (N=15) had a ProC Global normalized ratio (NR) less than 0.80 (sensitivity 100%). Twenty-four patients positive for the lupus anticoagulants (LA) and 19 patients positive for ACA (>5.0 IgG U/mL) had a ProC Global NR less than 0.8, while six and eight, respectively, had a ProC Global NR greater than 0.8 (sensitivity, 70%-80%). The detection of a reduced protein C/protein S activity (<70%) was low (sensitivity, 33%-44%). In 25 cases with pathologic ProC Global results, a thrombophilic defect (protein S/LA/ACA without APC resistance) was diagnosed in 18 women; but in 7 cases, no known thrombophilic defect was present. ProC Global is a new screening test to identify patients with defects of the protein C system and an activated dotting system in preeclampsia but cannot correctly cover each thrombophilic component.