Evidence of maternal platelet activation, excessive thrombin generation, and high amniotic fluid tissue factor immunoreactivity and functional activity in patients with fetal death.

OBJECTIVE: Fetal death can lead to disseminated intravascular coagulation or fetal death syndrome. However, currently it is not clear what are the changes in the coagulation system in patients with a fetal death without the fetal death syndrome. This study was undertaken to determine: (1) whether fetal death in the absence of fetal death syndrome is associated with changes in hemostatic markers in maternal plasma and amniotic fluid; and (2) whether maternal hypertension or placental abruption are associated with further changes in the hemostatic profile of these patients. METHODS: A cross-sectional study included the following: (1) determination of changes in markers of coagulation and platelet activation in patients with a normal pregnancy (n = 71) and patients with fetal demise (FD) without disseminated intravascular coagulation (n = 65); (2) determination of the amniotic fluid (AF)-tissue factor concentration and activity, as well as the concentrations of thrombin-antithrombin III (TAT) complexes in patients with a normal pregnancy (n = 25) and those with a FD (n = 36) who underwent amniocentesis. Plasma and AF concentrations of TAT complexes and TF (an index of thrombin generation), as well as maternal plasma concentrations of sCD40L (a marker of platelet activation), tissue factor pathway inhibitor (TFPI) and prothrombin fragments (PF) 1 + 2 (also an indicator of in vivo thrombin generation) were measured by ELISA. TF and TFPI activity were measured using chromogenic assays. RESULTS: (1) patients with FD without hypertension had a higher median maternal plasma sCD40L concentration than normal pregnant women (P < 0.001); (2) patients with FD had a higher median maternal plasma TAT III complexes than women with a normal pregnancy (P < 0.001); (3) the median AF-TF concentration and activity were higher in the FD group than in the normal pregnancy group (P < 0.001 for both); (4) patients with preeclampsia and FD had a higher median maternal plasma immunoreactive TF concentration than both normotensive patients with FD and women with normal pregnancies (P < 0.001 and P = 0.001, respectively); (5) the median plasma TF activity was higher in patients with preeclampsia and FD than that of women with normal pregnancies (P = 0.003); (6) among patients with a FD, those with placental abruption had a higher median AF-TAT complexes concentration than those without abruption (P = 0.0004). CONCLUSIONS: Our findings indicate that: (1) mothers with a FD have evidence of increased in vivo thrombin generation and platelet activation than women with normal pregnancies; (2) patients with a FD and hypertension had a higher degree of TF activation than those with fetal death but without hypertension; (3) the AF of women with a FD had a higher median TF concentration and activity than that of normal pregnant women. AF can be a potential source for tissue factor and it participates in the development of fetal death syndrome in patients with a retained dead fetus.

Unfractionated heparin, low molecular weight heparins, and pentasaccharide: basic mechanism of actions, pharmacology, and clinical use.

During the past decade, a large number of new anticoagulant and antithrombotic drugs have been developed. These agents represent a wide variety of substances that are derived using natural sources, biotechnology-based methods, and synthetic approaches. Because of the structural and molecular characteristics, these agents exhibit physicochemical and functional diversities. Thus, each of these classes of drugs controls thrombogenesis by way of distinct mechanisms. The main classes of these new drugs include peptides, peptidomimetics, heparinomimetics, and recombinant proteins. Despite these significant developments, heparin and heparin-derived drugs have continued to play a major role in the management of thrombotic and cardiovascular disorders.

Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome.

Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.