Efficacy of Platelet-Rich Plasma in Women with a History of Embryo Transfer Failure: A Systematic Review and Meta-Analysis with Trial Sequential Analysis.

Assisted reproductive technology (ART) is used to enhance pregnancy in infertile women. In this technique, the eggs are removed from the ovary and fertilized and injected with sperm to make embryos. Unfortunately, embryo implantation failures still occur in many of these women. Platelet-rich plasma (PRP) therapies use a patient's own platelets to promote tissue healing and growth, including endometrium. The growth factors provided by the platelets play a criterial role on the regenerative ability of PRP. In the last years, PRP treatments have been gaining a lot of popularity to treat women with repeated ART failures. In this study, we collected and summarized all information published in the scientific literature to assess the evidence of the PRP effect on pregnancy. We only considered randomized controlled trials (RCT), a type of study designed to be unbiased and considered at the highest level of evidence. Our analysis indicates that PRP therapies might be an effective treatment in cases of poor responsiveness to conventional ART. However, additional studies (well-designed) are necessary to confirm this beneficial effect of PRP.

Unravelling Alveolar Bone Regeneration Ability of Platelet-Rich Plasma: A Systematic Review with Meta-Analysis.

BACKGROUND: This systematic review aims to evaluate the efficacy of the available platelet-rich plasma (PRP) products and composition to regenerate alveolar bone after tooth extraction. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and EBSCO databases were searched up to 2 July 2021. Only randomized clinical trials using leukocyte-rich plasma (L-PRP) or pure-platelet rich plasma (P-PRP) for bone regeneration in alveolar ridge preservation were selected. The following outcomes were considered: (1) new bone formation (primary outcome) and (2) bone density (secondary outcome). A meta-analysis for PRP, P-PRP, and L-PRP using a fixed effect model was performed with Review Manager 5.4 software. Overall evidence was qualified using GRADE. RESULTS: Six randomized clinical trials from 2639 unique articles initially identified met the inclusion criteria. The meta-analysis showed a significant effect of the P-PRP on the outcome of new bone formation (SMD, 1.44; 95% CI, 0.84 to 2.03) for P-PRP treatment. No information was retrieved for L-PRP. A statistically significant difference was also observed in the P-PRP group for bone density outcome (SMD, 1.24; 95% CI, 0.81 to 1.68). The L-PRP treated sockets also showed higher bone density (SMD, 0.88; 95% CI, 0.31 to 1.45) in comparison to control sockets. The quality of evidence was moderate for both outcomes in the P-PRP group and low for the L-PRP group. CONCLUSIONS: Despite the limitations of the included studies, our data suggest that P-PRP, in comparison to unassisted healing, can improve alveolar bone regenerative potential. However, more high-quality clinical studies are needed.

Bone-Regenerative Ability of Platelet-Rich Plasma Following Sinus Augmentation with Anorganic Bovine Bone: A Systematic Review with Meta-Analysis.

BACKGROUND: The objective of this systematic review is to assess the effect of the adjuvant use of platelet-rich plasma (PRP) and its type on new bone formation by anorganic bovine bone during maxillary sinus floor augmentation procedure. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and Ovid databases were searched for relevant studies published up to 16 September 2021. Randomized clinical trials (RCTs) and non-randomized controlled clinical trials (CCTs) that reported data on the new bone formation (measured by histomorphometric analysis) were considered. Risk of bias and quality assessment of included studies were evaluated following the Cochrane Handbook for Systematic Reviews of Interventions and the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. Strength of evidence was assessed following the approach of the Agency for Healthcare Research and Quality (AHRQ) through its evidence-based practice center (AHRQ EPC). The meta-analysis was based on the primary outcome of newly formed bone, for which the standard mean difference was calculated. RESULTS: After the application of eligibility criteria, six clinical trials (three RCTs and three CCTs) covering 85 maxillary sinus floor elevation procedures were included. The pooled new bone formation value for PRP was 1.67 (95% CI: -0.15 to 3.49; I2: 86%), indicating the absence of significant effect. Plasma rich in growth factors (PRGF) was the pure PRP tested in five of the included studies. When sub-group (type of PRP) meta-analysis was performed, significantly higher new bone formation was observed in the PRGF group [2.85 (95% CI: 0.07 to 5.64; I2: 88%)] in comparison to the control group. CONCLUSIONS: A beneficial effect on new bone formation after maxillary sinus floor elevation can be obtained when anorganic bovine bone is mixed with PRGF.

Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate.

Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis.

Polyphosphate as a Target for Interference With Inflammation and Thrombosis.

Activated platelets and mast cells expose the inorganic polymer, polyphosphate (polyP) on their surfaces. PolyP initiates procoagulant and proinflammatory reactions and the polymer has been recognized as a therapeutic target for interference with blood coagulation and vascular hyperpermeability. PolyP content and chain length depend on the specific cell type and energy status, which may affect cellular functions. PolyP metabolism has mainly been studied in bacteria and yeast, but its roles in eukaryotic cells and mammalian systems have remained enigmatic. In this review, we will present an overview of polyP functions, focusing on intra- and extracellular roles of the polymer and discuss open questions that emerge from the current knowledge on polyP regulation.

Inducing heat shock protein 70 expression provides a robust antithrombotic effect with minimal bleeding risk.

Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. The heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. By using murine models, we aimed to test the hypothesis that overexpressing Hsp70 with CM-695, a first in class dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. Intraperitoneal (i. p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [p=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs 39.0 minutes (min) in the control group (CG), p=0.008, n≥10] and ferric chloride (OT: 14.7 vs 9.2 min in the CG, p=0.032, n≥10) models. I.p. 80 mg/kg CM-695 (n≥9) and intravenous 3 mg/kg rivaroxaban (n≥8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs 7.5 min in the CG, n≥10]. However, BT was dramatically increased by rivaroxaban (30.0 vs 13.7 min in the CG, p=0.001, n=10). In conclusion, CM-695 is a new antithrombotic small molecule devoid of bleeding risk that may be envisioned as a useful clinical tool.

Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk.

AIMS: Atrial fibrillation (AF) is a major risk factor for cardio-embolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern. This study sought to identify new targets to develop safer antithrombotic therapies. METHODS AND RESULTS: Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke brought to light a stroke-related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was down-regulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. Remarkably, the tail bleeding time was unchanged. Accordingly, both TRC051384 and tubastatin A, i.e. two Hsp70 inducers via different pathways, delayed thrombus formation in WT mice, the tail bleeding time still being unaltered. Most interestingly, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression and higher circulating levels of activated protein C upon thrombotic stimulus. CONCLUSIONS: Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, and is especially promising for treating AF patients and in other situations where there is also a major bleeding hazard.

Short Leukocyte Telomere Length Is Associated With Cardioembolic Stroke Risk in Patients With Atrial Fibrillation.

BACKGROUND AND PURPOSE: The risk of cardioembolic stroke in patients with atrial fibrillation (AF) cannot be accurately assessed and novel tools are needed to improve prediction. We hypothesize that telomere shortening constitutes a novel risk factor for cardioembolic stroke in patients with AF. METHODS: The peripheral blood leukocyte telomere length (LTL) was determined by real-time polymerase chain reaction in 187 patients with AF, 93 of them without stroke history and 94 of them having suffered 1 cardioembolic stroke. Percentiles were calculated according to LTL values in the nonstroke group to estimate the cardioembolic stroke risk associated with LTL using logistic regression models. RESULTS: Short LTL values were independently and dose-dependently associated with an increased risk of cardioembolic stroke, with an odds ratio (95% confidence interval) of 2.93 (1.24-6.94) and 6.26 (2.01-19.52), respectively, for sex, hypertension, diabetes mellitus, heart failure, and age-adjusted models using the LTL 10th and 5th percentile cut-offs, respectively. CONCLUSIONS: Telomere shortening is associated with cardioembolic stroke risk in patients with AF. Prospective studies are encouraged to establish the value of LTL to improve prediction tools to categorize cardioembolic stroke risk in AF.

sPLA2-V inhibits EPCR anticoagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hydrophobic groove.

The endothelial protein C receptor (EPCR) plays an important role in cardiovascular disease by binding protein C/activated protein C (APC). EPCR structure contains a hydrophobic groove filled with an unknown phospholipid needed to perform its function. It has not been established whether lipid exchange takes place in EPCR as a regulatory mechanism of its activity. Our objective was to identify this phospholipid and to explore the possibility of lipid exchange as a regulatory mechanism of EPCR activity driven by the endothelially expressed secretory group V phospholipase A(2) (sPLA(2)-V). We identified phosphatidylcholine (PCh) as the major phospholipid bound to human soluble EPCR (sEPCR). PCh in EPCR could be exchanged for lysophosphatidylcholine (lysoPCh) and platelet activating factor (PAF). Remarkably, lysoPCh and PAF impaired the protein C binding ability of sEPCR. Inhibition of sPLA(2)-V, responsible for lysoPCh and PAF generation, improved APC binding to endothelial cells. EPCR-dependent protein C activation and APC antiapoptotic effect were thus significantly enhanced. In contrast, endothelial cell supplementation with sPLA(2)-V inhibited both APC generation and its antiapoptotic effects. We conclude that APC generation and function can be modulated by changes in phospholipid occupancy of its endothelial cell receptor.