Activated protein C has a regulatory role in factor VIII function.

Mechanisms thought to regulate activated factor VIII (FVIIIa) cofactor function include A2-domain dissociation and activated protein C (APC) cleavage. Unlike A2-domain dissociation, there is no known phenotype associated with altered APC cleavage of FVIII, and biochemical studies have suggested APC plays a marginal role in FVIIIa regulation. However, the in vivo contribution of FVIIIa inactivation by APC is unexplored. Here we compared wild-type B-domainless FVIII (FVIII-WT) recombinant protein with an APC-resistant FVIII variant (FVIII-R336Q/R562Q; FVIII-QQ). FVIII-QQ demonstrated expected APC resistance without other changes in procoagulant function or A2-domain dissociation. In plasma-based studies, FVIII-WT/FVIIIa-WT demonstrated dose-dependent sensitivity to APC with or without protein S, whereas FVIII-QQ/FVIIIa-QQ did not. Importantly, FVIII-QQ demonstrated approximately fivefold increased procoagulant function relative to FVIII-WT in the tail clip and ferric chloride injury models in hemophilia A (HA) mice. To minimize the contribution of FV inactivation by APC in vivo, a tail clip assay was performed in homozygous HA/FV Leiden (FVL) mice infused with FVIII-QQ or FVIII-WT in the presence or absence of monoclonal antibody 1609, an antibody that blocks murine PC/APC hemostatic function. FVIII-QQ again demonstrated enhanced hemostatic function in HA/FVL mice; however, FVIII-QQ and FVIII-WT performed analogously in the presence of the PC/APC inhibitory antibody, indicating the increased hemostatic effect of FVIII-QQ was APC specific. Our data demonstrate APC contributes to the in vivo regulation of FVIIIa, which has the potential to be exploited to develop novel HA therapeutics.

Predicting the need for nonstandard tracheostomy tubes in critically ill patients.

PURPOSE: Few guidelines exist regarding the selection of a particular type or size of tracheostomy tube. Although nonstandard tubes can be placed over the percutaneous kit dilator, clinicians often place standard tracheostomy tubes and change to nonstandard tubes only after problems arise. This practice risks early tracheostomy tube change, possible bleeding, or loss of the airway. We sought to identify predictors of nonstandard tracheostomy tubes. MATERIALS AND METHODS: In this matched case-control study at an urban, academic, tertiary care medical center, we reviewed 1220 records of patients who received a tracheostomy. Seventy-seven patients received nonstandard tracheostomy tubes (cases), and 154 received standard tracheostomy tubes (controls). RESULTS: Sex, endotracheal tube size, severity of illness, and computed tomography scan measurement of the distance from the trachea to the skin at the level of the superior aspect of the anterior clavicle were significant predictors of nonstandard tracheostomy tubes. Specifically, trachea-to-skin distance >4.4 cm and endotracheal tube sizes ≥8.0 were associated with nonstandard tracheostomy. CONCLUSIONS: The findings suggest that clinicians should consider using nonstandard tracheostomy tubes as the first choice if the patient is male with an endotracheal tube size ≥8.0 and has a trachea-to-skin distance >4.4 cm on the computed tomography scan.