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Blood Dec 2023Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune...
Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.
Topics: Thrombocytopenia; Heparin; Vaccination; Humans; Platelet Factor 4; Antibodies; Male; Female; Child, Preschool; Child; Adult; Thrombosis
PubMed: 37883798
DOI: 10.1182/blood.2023022136 -
Nature Communications Aug 2023Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative...
Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.
Topics: Humans; Blood Platelets; Phosphoric Monoester Hydrolases; Thrombin; Oxidative Stress; Hemostasis; Nucleotides; Mitochondria; Thrombosis; DNA Repair Enzymes
PubMed: 37563135
DOI: 10.1038/s41467-023-40600-7 -
Advanced Science (Weinheim,... Oct 2023Epidemiological studies show an association between inflammatory bowel disease (IBD) and increased risk of thrombosis. However, how IBD influences thrombosis remains...
Epidemiological studies show an association between inflammatory bowel disease (IBD) and increased risk of thrombosis. However, how IBD influences thrombosis remains unknown. The current study shows that formation of neutrophil extracellular traps (NETs) significantly increased in the dextran sulfate sodium (DSS)-induced IBD mice, which in turn, contributes to thrombus formation in a NETs-dependent fashion. Furthermore, the exosomes isolated from the plasma of the IBD mice induce arterial and venous thrombosis in vivo. Importantly, proinflammatory factors-exposed intestinal epithelial cells (inflamed IECs) promote neutrophils to release NETs through their secreted exosomes. RNA sequencing revealed that LINC00668 is highly enriched in the inflamed IECs-derived exosomes. Mechanistically, LINC00668 facilitates the translocation of neutrophil elastase (NE) from the cytoplasmic granules to the nucleus via its interaction with NE in a sequence-specific manner, thereby inducing NETs release and thrombus formation. Importantly, berberine (BBR) suppresses the nuclear translocation of NE and subsequent NETs formation by inhibiting the interaction of LINC00668 with NE, thus exerting its antithrombotic effects. This study provides a novel pathobiological mechanism linking IBD and thrombosis by exosome-mediated NETs formation. Targeting LINC00668 can serve as a novel molecular treatment strategy to treat IBD-related thrombosis.
Topics: Animals; Mice; Extracellular Traps; Exosomes; Thrombosis; Neutrophils; Inflammatory Bowel Diseases
PubMed: 37590310
DOI: 10.1002/advs.202300560 -
The Journal of Vascular Access Jan 2024Insertion of Peripherally Inserted Central Catheters (PICCs) is potentially associated with the risk of immediate/early adverse events, some of them minimal (repeated...
The SIP protocol update: Eight strategies, incorporating Rapid Peripheral Vein Assessment (RaPeVA), to minimize complications associated with peripherally inserted central catheter insertion.
Insertion of Peripherally Inserted Central Catheters (PICCs) is potentially associated with the risk of immediate/early adverse events, some of them minimal (repeated punctures) and some relevant (accidental arterial puncture or nerve-related injury). Several strategies adopted during the insertion process may minimize the risk of such events, including late complication risks such as infection, venous thrombosis, or catheter dislodgment and/or malposition. This paper describes an update version of the SIP protocol (Safe Insertion of PICCs), an insertion bundle which includes eight effective strategies that aims to minimize immediate, early, or late insertion-associated complications. These strategies include: preprocedural ultrasound assessment utilizing the RaPeVA (Rapid Peripheral Venous Assessment) protocol; appropriate skin antiseptic technique; choice of appropriate vein, adoption of the Zone Insertion Method™; clear identification of the median nerve and brachial artery; ultrasound-guided puncture; ultrasound-guided tip navigation; intra-procedural assessment of tip location; correct securement of the catheter, and appropriate protection of the exit site. This updated version of the SIP protocol includes several novelties based on the most recent evidence-based scientific literature on PICC insertion, such as the clinical relevance of the tunneling technique, the use of ultrasound for intra-procedural tip navigation and tip location, and the new technologies for the protection of the exit site (cyanoacrylate glue) and for the securement of the catheter (subcutaneous anchorage).
Topics: Humans; Catheterization, Central Venous; Central Venous Catheters; Catheters, Indwelling; Veins; Venous Thrombosis; Catheterization, Peripheral
PubMed: 35633065
DOI: 10.1177/11297298221099838