Coagulation, inflammation, and pregnancy complications.
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Abortion, Spontaneous↗
Biomedical subjects
Benjamin Brenner
Publications and source records attributed to Benjamin Brenner.
Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation.
Bleeding is the most serious adverse event of oral anticoagulants and is a major cause of morbidity and mortality in such patients. Rapid reversal of anticoagulation in bleeding patients or prior to urgent surgery is mandatory. The therapeutic options in these situations include administration of fresh frozen plasma (FFP), and recently of prothrombin complex concentrates (PCCs). However, viral safety and thrombogenicity of PCCs remain issues of concern. In the present study, we administered Octaplex, a new solvent/detergent (S/D) treated and nanofiltered PCC, to excessively anticoagulated bleeding patients or to anticoagulated patients facing urgent surgery. Ten excessively anticoagulated patients with major bleeding and 10 anticoagulated patients awaiting surgery (median age 72.5 (43-83) years, 9 females) received a median dose of 26.1 IU/kg body weight (BW) of Octaplex for reversal of anticoagulation. Response to Octaplex was rapid with decline of INR within 10 min after Octaplex administration (from 6.1+/-2. to 1.5+/-0.3). Clinical response was graded as good in most patients (85%) and as moderate in the rest. Octaplex administration was uneventful in all patients. Following Octaplex administration, a small increase in F1+2 levels was observed in bleeding patients, whereas D-dimer level did not change significantly. We conclude that Octaplex is effective and safe in situations where rapid reversal of anticoagulation is needed.
Administration, Oral↗
Haemostatic changes in pregnancy.
In normal pregnancy, there is a marked increase in the procoagulant activity in maternal blood characterized by elevation of factors VII, X, VIII, fibrinogen and von Willebrand factor, which is maximal around term. This is associated with an increase in prothrombin fragments (PF1+2) and thrombin-antithrombin complexes. There is a decrease in physiological anticoagulants manifested by a significant reduction in protein S activity and by acquired activated protein C (APC) resistance. The overall fibrinolytic activity is impaired during pregnancy, but returns rapidly to normal following delivery. This is largely due to placental derived plasminogen activator inhibitor type 2 (PAI-2), which is present in substantial quantities during pregnancy. D-dimer, a specific marker of fibrinolysis resulting from breakdown of cross-linked fibrin polymer by plasmin, increases as pregnancy progresses. Overall, there is a 4- to 10-fold increased thrombotic risk throughout gestation and the postpartum period. Local haemostasis at the placental throphoblast level is characterized by increased tissue factor (TF) expression and low expression of the inhibitor TFPI. Microparticles derived from maternal endothelial cells and platelets, and from placental throphoblasts may contribute to the procoagulant effect. Local anticoagulant mechanisms on placental throphoblasts are important for counterbalance of the procoagulant milieu. Disruption of anticoagulant mechanisms, for example, autoantibodies, to annexin V may increase pregnancy complications in patients with antiphospholipid antibodies (APLA).
Activated Protein C Resistance↗
IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life.
The general safety and efficacy of intravenous immunoglobulin (IGIV) as treatment for idiopathic thrombocytopenic purpura (ITP) has been well-studied. The current study compares the safety and efficacy of a novel IGIV (IGIV-C; Gamunex, 10%) with a licensed solvent/detergent-treated product (IGIV-S/D; GamimuneN, 10%) in treatment of ITP. Ninety-seven pediatric and adult patients with acute and chronic ITP were treated in a multi-center, prospective, randomized, double-blind parallel group, non-inferiority trial at 26 international sites. Baseline data (age, duration of ITP, platelet counts, previous treatment) were comparable between groups. Patients were treated with 1 g/kg/day of IGIV-C or IGIV-S/D for 2 days. The primary end-point, proportion of patients whose platelet counts increased from >/=20 x 10(9)/L to >/=50 x 10(9)/L within 7 days after dosing, was achieved by 35/39 (90%) and 35/42 (83%) of patients treated with IGIV-C and IGIV-S/D, respectively. A secondary endpoint, maintaining platelet counts >/=50 x 10(9)/L for >/=7 days, was achieved by 29/39 (74%) of IGIV-C and 25/42 (60%) IGIV-S/D treated patients. Compared with IGIV-S/D, fewer patients treated with IGIV-C received corticosteroids beyond day 7 (p = 0.02). Efficacy was independent of the presence of isoantibodies or blood type, supporting mechanisms of effect different from anti-D treatments. Adverse events were generally mild and occurred with similar frequency in each group. Viral safety monitoring for HIV, HCV, HBV and Parvovirus B19 showed no seroconversions on study. In conclusion, IGIV-C is as safe and efficacious as IGIV-S/D in treatment of ITP.
Adolescent↗
Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis.
The placenta is a highly vascularized organ with fetal and maternal blood supply. Syncytiotrophoblasts (STB), which line the placenta villous are possibly involved in local hemostatic mechanisms. The aim of this study was to evaluate the levels of tissue factor (TF) and its inhibitors, tissue factor pathway inhibitor (TFPI, TFPI-2), in STB model within hemostatic and inflammatory environments. Human primary STB cell cultures were characterized by vascular and hormonal markers. TF and TFPI mRNA expression, protein levels and activity were determined and compared to human umbilical vein endothelial cells (HUVEC). High levels of TF were demonstrated in STB cells compared to low levels in HUVEC. In contrast, STB expressed lower TFPI levels than HUVEC. LPS and TNFalpha increased the high constitutive TF in STB, whereas LPS and IL-1alpha further reduced TFPI levels. The procoagulant tendency of STB identified by us may reflect the physiological need for immediate inhibition of hemorrhage in the placental inter-villous spaces in basal and inflammatory conditions. This hemostatic balance may be critical for normal placental function and pregnancy outcome.
Cells, Cultured↗
Thrombophilia and pregnancy complications.
The implications of currently available data on the association of gestational vascular complications with thrombophilia are presented in this consensus report. Screening is recommended for women with the following previous complications: fetal loss including three or more first trimester loss, two or more second trimester loss, or any stillbirth; early, severe or recurrent preeclampsia and severe intrauterine growth restriction. Maternal antithrombotic therapy is currently evaluated in women with thrombophilia and previous complications.
Abortion, Habitual↗
Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study.
The etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. In our multi-center case-controlled study we studied 46 patients with CSVT diagnosed from April 1996 to December 2003, consecutively referred for thrombophilia work-up. The results of thrombophilia screen were compared to 112 healthy paediatric controls. Anticoagulant therapy was applied according to treating physicians' decisions, and all cases were prospectively followed for a median of 4.1 years. Of 46 children, 8 had CSVT diagnosed in the neonatal period and therefore were analyzed separately. The prevalence of single thrombophilia markers and combinations of thrombophilic risk factors were similar among cases and controls. Among children with CSVT co-morbid systemic illness was present in most patients at diagnosis. Seven out of 8 children with idiopathic CSVT had thrombophilic risk factors as compared to 31/38 patients with co-morbid conditions. Anticoagulation was initiated in most patients, 11/46 patients continued therapy for a total of one year or more post event. Neither clinical presentation nor initial treatment decisions were affected by presence of thrombophilic risk factors in our study group. Thrombophilia prevalence was not increased in children with CSVT as compared to controls, however thrombophilia was more frequent among children with idiopathic CSVT. Thus, those selected patients would benefit most from thrombophilia work-up, required for long-term therapy considerations.
Adolescent↗
New insights into paediatric haemostasis: thrombosis and bleeding issues.
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Adult↗
Venous sonography for the diagnosis of asymptomatic deep vein thrombosis in patients with cancer undergoing chemotherapy.
OBJECTIVE: Early detection of asymptomatic deep vein thrombosis by venous sonography may identify patients who may benefit from anticoagulant therapy and thus may prevent morbidity and mortality associated with deep vein thrombosis. The aim of this study was to examine the prevalence of deep vein thrombosis by venous sonography in asymptomatic ambulatory patients with cancer undergoing chemotherapy and to evaluate the correlation between procoagulant activity and asymptomatic deep vein thrombosis. METHODS: The study population included 62 patients (32 with lung cancer and 30 with lymphoma) receiving chemotherapy with an ambulatory performance status and without clinical evidence of deep vein thrombosis. Bilateral venous sonographic studies of the lower extremities were performed, covering the femoropopliteal venous system. The D-dimer level and acquired activated protein C resistance were determined in the patients and in 30 healthy control subjects. RESULTS: Sonographic evidence of deep vein thrombosis on the femoropopliteal axis was found in 0 (0%) of 62 patients (1-sided 95% confidence interval, 0%-4.8%). Acquired activated protein C resistance prevalence and D-dimer levels were increased in study patients compared with control subjects (34% versus 0%; P < .003; median, 0.72 versus 0.25 mg/L; P < .0001, respectively). CONCLUSIONS: Despite the procoagulant tendency, venous sonography did not detect asymptomatic deep vein thrombosis in patients with cancer undergoing chemotherapy. Thus, screening by venous sonography is not justified in this patient population.
Activated Protein C Resistance↗
[Is there an association between PUPPP and preeclampsia, abruptio placentae and fetal death?].
This is a case study of a 28-year old woman, gravida 1 para 0, presented at 37+4 weeks gestation due to purpura and fetal death. A 3700 gram dead male fetus without gross malformation was delivered by forceps. Post delivery abruptio placentae, diffuse intravascular coagulation, fulminant preeclampsia and acute renal failure followed. Skin biopsy revealed pruritic urticarial papules and plaques of pregnancy. The patient fully recovered one week postpartum. This case report discusses a possible association between pruritic urticarial papules, plaques of pregnancy and severe preeclampsia with fetal death.
Abruptio Placentae↗
Inherited thrombophilia and pregnancy loss.
A growing body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control and cross-sectional studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss. Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins (LMWH) are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.
Abortion, Habitual↗
Haemostatic mechanisms in human placenta.
The placenta is a unique organ with dual blood circulation functioning throughout fetal development. The architecture and functions of the placenta, where maternal blood flows into the intervillous space, present haemostatic problems, mainly the risk of haemorrhage. Placental trophoblasts express and produce coagulation components, participating not only in haemostasis but also in placental vascular development and differentiation. The expression of tissue factor, membrane phosphatidylserine and fibrin render the trophoblasts pro-coagulant, thus compromising the risk of bleeding while exposing the placenta to pro-thrombotic risks. Local inhibitory mechanisms-TFPI-1 and TFPI-2, thrombomodulin, annexin V and the fibrinolytic system-limit coagulation activation and fibrin deposition. Pregnancy complications have been associated with abnormalities in the functions of these inhibitors. Haemostatic processes in placental cells change throughout gestation and are affected by the changing requirements of the organ.
Animals↗
Inherited thrombophilia and poor pregnancy outcome.
Gestational vascular complications are a major cause of maternal and fetal morbidity.A growing body of evidence suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss and early-onset pre-eclampsia. Placental abruption and severe intrauterine growth restriction (IUGR) may also be associated with thrombophilia. Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary non-randomized studies suggest a benefit for prophylaxis with unfractionated and low-molecular-weight heparin (LMWH), and prospective randomized trials are in progress to define whether LMWH is effective in preventing pregnancy loss and other gestational vascular complications in women with thrombophilia and previous fetal wastage.
Abortion, Habitual↗
Thrombophilia and fetal loss.
A large body of evidence obtained during the last 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss. Other complications such as preeclampsia, placental abruption, and intrauterine growth retardation may also be associated with thrombophilia. Placental pathologic findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.
Abortion, Habitual↗
Procoagulant and anticoagulant mechanisms in human placenta.
The placenta is a highly vascularized organ functioning as the interface between fetal blood, which is confined within the villous blood vessels, and maternal blood, which flows in decidual arteries and washes the intervillous spaces in contact with syncytiotrophoblast (STB) cells. The STB adopts vascular characteristics such as the presence of von Willebrand factor (vWF), CD31 markers, adhesion molecules, and coagulation components. The special structure of the placenta requires efficient mechanisms for fast activation and localized regulation of coagulation. The presence of procoagulant and anticoagulant components on placental vascular endothelial cells (EC) and STB is essential for hemostasis. Activation of coagulation may be a favored process, as suggested by elevated fibrin depositions documented in some pathologic states. Increased localized procoagulant components such as tissue factor (TF) and plasminogen activator inhibitors (PAI-1, PAI-2), are associated with some pregnancy complications. Several anticoagulants regulate placental coagulation: tissue factor pathway inhibitor (TFPI) is primarily produced in EC; TFPI-2, a variant of TFPI, has been purified from the placenta and was identified in the STB lining the villi; thrombomodulin, a membrane glycoprotein that activates protein C, is localized in EC and apical membranes of STB; annexin V, an anticoagulant that binds to negative membrane phospholipids, is abundant on normal placental STB, whereas reduced STB annexin V was associated with the presence of antiphospholipid antibodies. The placenta is a putative source of coagulation components. However, the interplay between local procoagulant and anticoagulant mechanisms and their association with pregnancy complications need to be assessed.
Blood Coagulation↗
Thrombophilia and pregnancy.
Inherited and acquired thrombophilia are the main cause of thrombosis in pregnant women. A growing number of reports over the last 6 years suggest that these disorders are also associated with an increased incidence of vascular pathologies resulting in poor gestational outcome. This review discusses recent data on thrombophilia and vascular placental pathology, and then discusses therapies to prevent placental vascular thrombosis and to maximize successful gestational outcome.
Adult↗
Thrombophilia and pregnancy loss.
A large body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case-control studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss early onset preeclampsia, placental abruption, and severe intrauterine growth retardation (IUGR). Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary case-control studies suggest a benefit for prophylaxis with low molecular weight heparins (LMWH), and prospective randomized trials are in progress to define whether LMWH are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.
Abortion, Habitual↗
Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage.
OBJECTIVE: To describe the characteristics of thrombophilia in women with idiopathic pregnancy loss. DESIGN: Prospective observational study. SETTING: Tertiary referral center in a teaching academic hospital. PATIENT(S): One hundred forty-five patients with repeated pregnancy loss and 145 matched controls. INTERVENTION(S): Prospective assessment of thrombophilia in patients and controls. MAIN OUTCOME MEASURE(S): Prevalence of activated protein C (APC) resistance, protein C, protein S, and antithrombin III deficiencies, antiphospholipid antibodies, factor V Leiden, factor II G20210A, and MTHFR C677T mutations. RESULT(S): At least one thrombophilic defect was found in 66% of study group patients compared with 28% in control group patients. Combined thrombophilic defects were documented in 21% of women with pregnancy loss compared with 5.5% of control patients. Late pregnancy wastage occurred more frequently in women with thrombophilia compared with women without thrombophilia (160/429 [37%] vs. 39/162 [24%], respectively). APC resistance was documented in 39% of women with pregnancy loss compared with 3% of the control patients. APC resistance without factor V Leiden mutation was documented in 18% of women with pregnancy loss compared with none of the controls. While factor V Leiden mutation was more common in women with pregnancy loss (25% vs. 7.6%), factor II G20210A and homozygosity for MTHFR C677T contributed to pregnancy loss only in the presence of other thrombophilia. CONCLUSION(S): Thrombophilia was found in the majority (66%) of women with idiopathic pregnancy loss. APC resistance with or without factor V Leiden mutation is the most common thrombophilic defect, and combined thrombophilia is a frequent finding in women with pregnancy loss. Thrombophilia is associated with increased frequency of late pregnancy wastage.
Abortion, Habitual↗