Background The rate of preterm births in Germany is 8.6%, which is very high compared to other European countries. As preterm birth contributes significantly to perinatal morbidity and mortality rates, the existing prevention strategies need to be optimized and expanded further. About ⅔ of all women with preterm birth have preterm labor or premature rupture of membranes. They are bracketed together under the term “spontaneous preterm birth” as opposed to iatrogenic preterm birth, for example as a consequence of preeclampsia or fetal growth retardation. Recent studies suggest that low-dose aspirin does not just reduce the rate of iatrogenic preterm births but can also further reduce the rate of spontaneous preterm births. This review article presents the current state of knowledge.
Method A selective literature search up until April 2020 was done in PubMed, using the terms “randomized trial”, “randomized study”, “spontaneous preterm birth”, and “aspirin”.
Results Secondary analyses of prospective randomized studies on the prevention of preeclampsia with low-dose aspirin show that this intervention also significantly reduced the rate of spontaneous preterm births in both high-risk and low-risk patient populations. The results of the ASPIRIN trial, a prospective, randomized, double-blinded multicenter study carried out in six developing countries, also point in this direction, with the figures showing that the daily administration of 81 mg aspirin starting before 14 weeks of gestation lowered the preterm birth rate of nulliparous women without prior medical conditions by around 11% (11.6 vs. 13.1%; RR 0.89; 95% CI: 0.81 – 0.98, p = 0.012).
Conclusion Further studies on this issue are urgently needed. If these confirm the currently available results, then it would be worth discussing whether general aspirin prophylaxis for all pregnant women starting at the latest in 12 weeks of gestation is indicated.
Introduction: Thalidomide and the IMiDs are rapidly becoming mainstays in the treatment of multiple myeloma. To improve the efficacy of thalidomide (T) or Revlimid (lenalidomide) (R), we have developed the BLT-D (Biaxin® (clarithromycin) (B), low dose T, and dexamethasone (D)), and the BiRD (B, R, D) regimens. These regimens have produced remarkably high responses, including complete and near complete remissions, with almost every patient not previously exposed to thalidomide. When the BLT-D regimen was initiated, an excessive number of thrombotic episodes were noted. Subsequent to this initial observation, others have also reported an inordinate number of thrombotic events, usually when T was combined with other biological or chemotherapy agents. Given the putative antiangiogenic properties of T or R, we postulated that endothelial damage may be responsible for the enhanced thrombosis and thus, subsequently initiated low dose aspirin (ASA), 81mgs, as prophylaxis in patients (pts) undergoing treatment. We report the effect of low dose ASA as a prophylactic treatment when given to pts receiving L/T containing regimens as follows:
A retrospective analysis of pts receiving BLT-D before ASA prophylaxis compared to a similar group after ASA was instituted; An examination of the incidence of thromboembolic phenomena in pts receiving either D alone, not receiving ASA, compared to combined D and low dose T, receiving ASA, as part of a prospective sequential randomized study also studying the impact of subsequent B and 3) An evaluation of thrombosis in pts receiving the BiRD regimen with mandated low dose ASA.
Low dose ASA significantly reduced the incidence of thrombosis in pts receiving BLT-D. Of the 60 pts studied, 5 (8%) developed grade 1–2 thrombosis, primarily thrombophlebitis (DVT), and 9 pts (15%) developed grade ≥3 thrombosis, primarily pulmonary embolism (PE) and coronary thrombosis. All episodes of thrombosis occurred prior to the institution of ASA. Slightly less thrombotic events were recorded in pts receiving low dose ASA and the T-D combination with or without B (1/12) when compared to pts not receiving ASA and D with or without B (3/11). 3) Three of 22 pts treated with the BiRD regimen have developed thromboembolic complications, all while off the prescribed ASA. Patient 1, a 44 yo male discontinued (d/c’ed) ASA due to epistaxis. Exactly 7 days after d/c’ing ASA, and while remaining on BiRD, he developed a DVT and PE. Patient 2 underwent exploratory laparotomy to investigate a renal mass. ASA and BiRD were discontinued 7 days prior to surgery. Ten days after surgery, the patient developed DVT. Patient 3 underwent closure of a colostomy; ASA and BiRD were d/c’ed 7 days prior surgery. Two days after the surgery, despite low dose heparin, he suffered a fatal massive PE. No thrombotic episodes with BiRD have not occurred with pts remaining on ASA.
Conclusions: Low dose ASA appears to reduce the incidence of thrombosis in pts receiving combination T or R therapy. Endothelial damage may persist beyond the residual salutary effects of discontinued ASA.
SummaryIn 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B2 (TxB2) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB2 and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg-1.day-1 for 7 days) caused >90% inhibition of TxB2formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.
SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.