Left ventricular assist devices (LVAD) provide cardiac support for patients with end-stage heart disease as either bridge or destination therapy, and have significantly improved the survival of these patients. Whereas earlier models were designed to mimic the human heart by producing a pulsatile flow in parallel with the patient’s heart, newer devices, which are smaller and more durable, provide continuous blood flow along an axial path using an internal rotor in the blood. However, device-related hemostatic complications remain common and have negatively affected patients’ recovery and quality of life. In most patients, the von Willebrand factor (VWF) rapidly loses large multimers and binds poorly to platelets and subendothelial collagen upon LVAD implantation, leading to the term acquired von Willebrand syndrome (AVWS). These changes in VWF structure and adhesive activity recover quickly upon LVAD explantation and are not observed in patients with heart transplant. The VWF defects are believed to be caused by excessive cleavage of large VWF multimers by the metalloprotease ADAMTS-13 in an LVAD-driven circulation. However, evidence that this mechanism could be the primary cause for the loss of large VWF multimers and LVAD-associated bleeding remains circumstantial. This review discusses changes in VWF reactivity found in patients on LVAD support. It specifically focuses on impacts of LVAD-related mechanical stress on VWF structural stability and adhesive reactivity in exploring multiple causes of AVWS and LVAD-associated hemostatic complications.

Preeclampsia is a pregnancy-induced condition that impairs mother9s health and results in pregnancy termination or premature delivery. Elevated levels of placenta-derived extracellular vesicles in the circulation have been consistently associated with preeclampsia, but whether placenta-derived extracellular vesicles induce preeclampsia or are merely the product of preeclampsia is not known. Guided by a small cohort study of preeclampsia patients, we examined the impact of placenta-derived extracellular vesicles on the pathogenesis of preeclampsia in mouse models. We found that placenta-derived extracellular vesicles were detected in pregnant C56BL/6J mice with a peak level of 3.8+/-0.9x107/ml in 17-18 days post-coitum. However, these pregnant mice developed hypertension and proteinuria only after being infused with these vesicles purified from injured placenta. These injured placenta-released extracellular vesicles disrupted the endothelial integrity and induced vasoconstriction. Enhancing the clearance of extracellular vesicles prevented the development of the extracellular vesicle-induced preeclampsia in mice. Our results demonstrate a causal role of placenta-derived extracellular vesicles in preeclampsia and identify microvesicle clearance as a new therapeutic target for the treatment of this pregnancy-associated complication.

Key Points: Mitochondria were released from traumatically injured brain into systemic circulation and exposed CL on their surface. CL-exposed mitochondria are highly procoagulant and induced traumatic brain injury–associated coagulopathy.

Traumatic brain injury (TBI) has high morbidity and mortality rates. The mechanisms underlying the TBI are unclear and may include the change in biological material in exosomes. Circular RNAs (circRNAs) are enriched and stable in exosomes, which can function as microRNA (miRNA) sponges to regulate gene expression levels. Therefore, we speculated that circRNAs in exosomes might play an important role in regulating gene expression after TBI and then regulate specific signaling pathways, which may protect the brain. We first isolated exosomes from the brain extracellular space in TBI mice by digestion. We then investigated the alterations in circRNA expression in exosomes by high-throughput whole transcriptome sequencing, analyzed the data by gene ontology (GO) and pathway analysis, and constructed the circRNA-miRNA network. In this study, we identified 231 significantly and differentially expressed circRNAs, including 155 that were up-regulated and 76 that were down-regulated. GO analysis showed that these differentially expressed circRNAs might be related to the growth and repair of neurons, the development of the nervous system, and the transmission of nerve signals. The most highly correlated pathways that we identified were primarily involved with glutamatergic synapse and the cGMP-PKG signaling pathway. The circRNA-miRNA network predicted the potential roles of these differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our study broadens the horizon of research on gene regulation in exosomes from the brain extracellular space after TBI and provides novel targets for further research on both the molecular mechanisms of TBI and the potential intervention therapy targets.

Cancer prognosis is poor for patients with blood-borne metastasis. Platelets are known to assist cancer cells in transmigrating through the endothelium, but ligands for the platelet-mediated cancer metastasis remain poorly defined. von Willebrand factor (vWF) is a major platelet ligand that has been widely used as a biomarker in cancer and associated inflammation. However, its functional role in cancer growth and metastasis is largely unknown. Here we report that gastric cancer cells from patients and cells from two well-established gastric cancer lines express vWF and secrete it into the circulation, upon which it rapidly becomes cell-bound to mediate cancer-cell aggregation and interaction with platelets and endothelial cells. The vWF-mediated homotypic and heterotypic cell–cell interactions promote the pulmonary graft of vWF-overexpressing gastric cancer BGC823 cells in a mouse model. The metastasis-promoting activity of vWF was blocked by antibodies against vWF and its platelet receptor GP Ibα. It was also reduced by an inhibitory siRNA that suppresses vWF expression. These findings demonstrate a causal role of cancer-cell-derived vWF in mediating gastric cancer metastasis and identify vWF as a new therapeutic target.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. The finding that cellular microparticles (MPs) generated by injured cells profoundly impact on pathological courses of TBI has paved the way for new diagnostic and therapeutic strategies. MPs are subcellular fragments or organelles that serve as carriers of lipids, adhesive receptors, cytokines, nucleic acids, and tissue-degrading enzymes that are unique to the parental cells. Their sub-micron sizes allow MPs to travel to areas that parental cells are unable to reach to exercise diverse biological functions. In this review, we summarize recent developments in identifying a casual role of MPs in the pathologies of TBI and suggest that MPs serve as a new class of therapeutic targets for the prevention and treatment of TBI and associated systemic complications.