Vitamin K Effects on Gas6 and Soluble Axl Receptors in Intensive Care Patients: An Observational Screening Study.

Growth arrest-specific gene 6 protein (Gas6) is avitamin K-dependent tissue bound protein. Gas6 has been shown to promote growth and therapy resistance among different types of cancer as well as thromboembolism. The aim of this prospective screening study: ClinicalTrials.gov; Identifier: NTC3782025, was to evaluate the effects of intravenously administered vitamin K1 on Gas6 and its soluble (s)Axl receptor plasma levels in intensive care patients. Vitamin K1 was intravenously injected in non-warfarin treated patients with prolonged Owren prothrombin time international normalized ratio (PT-INR) > 1.2 and blood samples were retrieved before and 20-28 h after injection. Citrate plasma samples from 52 intensive care patients were analysed for different vitamin K dependent proteins. There was a significant, but small increase in median Gas6. Only one patient had a large increase in sAxl, but overall, no significant changes in sAxl Gas6 did not correlate to PT-INR, thrombin generation assay, coagulation factors II, VII, IX and X, but to protein S and decarboxylated matrix Gla protein (dp-ucMGP). In conclusion, there was a small increase in Gas6 over 20-28 h. The pathophysiology and clinical importance of this remains to be investigated. To verify a true vitamin K effect, improvement of Gas6 carboxylation defects needs to be studied.

Mortality and morbidity of low-grade red blood cell transfusions in septic patients: a propensity score-matched observational study of a liberal transfusion strategy.

BACKGROUND: Red blood cell (RBC) transfusions are associated with risks including immunological reactions and volume overload. Current guidelines suggest a restrictive transfusion strategy in most patients with sepsis but based on previous randomized controlled trials and observational studies, there are still uncertainties about the safety in giving low-grade RBC transfusions to patients with sepsis. METHODS: Critically ill patients with severe sepsis or septic shock admitted to a university hospital intensive care unit between 2007 and 2018 that received less or equal to 2 units of RBCs during the first 5 days of admission were propensity score matched to controls. Outcomes were 90- and 180-day mortality, highest acute kidney injury network (AKIN) score the first 10 days, days alive and free of organ support the first 28 days after admission to the intensive care unit and highest sequential organ failure assessment score (SOFA-max). RESULTS: Of 9490 admissions, 1347 were diagnosed with severe sepsis or septic shock. Propensity-score matching resulted in two well-matched groups with 237 patients in each. The annual inclusion rate in both groups was similar. The median hemoglobin level before RBC transfusion was 95 g/L (interquartile range 88-104) and the majority of the patients were transfused in first 2 days of admission. Low-grade RBC transfusion was associated with increased 90- and 180-day mortality with an absolute risk increase for death 9.3% (95% confidence interval: 0.6-18%, P = 0.032) and 11% (95% confidence interval: 1.7-19%, P = 0.018), respectively. Low-grade RBC transfusion also correlated with increased kidney, circulatory and respiratory failure and higher SOFA-max score. CONCLUSIONS: Low-grade RBC transfusion during the first 5 days of admission was associated with increased mortality and morbidity in a liberal transfusion setting. The results support the current practice of a restrictive transfusion strategy in septic critically ill patients.

Detection of subclinical vitamin K deficiency in neurosurgery with PIVKA-II.

Vitamin K is known for supporting the carboxylation of hepatic coagulation proteins. Levels of proteins induced by vitamin K absence for factor II (PIVKA-II) reflect hypocarboxylated prothrombin and can be used to detect subclinical vitamin K deficiency. The aim of this study was to determine the prevalence of perioperative subclinical vitamin K deficiency among neurosurgical patients using PIVKA-II and investigate the existence of any correlation to standard coagulation assays. Also, the antitumor effects of vitamin K were reviewed. Thirty-five patients undergoing brain tumor resection were included. Blood samples were drawn preoperatively, at the end of surgery and in the morning after surgery. In addition to PIVKA-II, factor II and the Owren and Quick prothrombin times were analyzed. Seventeen of 35 patients had elevated PIVKA-II levels before surgery, which continued to be above normal range postoperatively. Median PIVKA-II and Owren prothrombin time (PT-INR) were increased on the morning day 1 postoperatively compared to before surgery, whereas Quick end-stage prothrombin time (EPT) decreased and factor II was unaffected. Postoperative complications were connected to high PIVKA-II increases. Positive correlations between PIVKA-II and factor II and body mass index (BMI) were found. In conclusion, PIVKA-II was increased in many patients preoperatively and then increased by the morning following surgery. Standard coagulation assays were largely non-pathological. Correlations were demonstrated between PIVKA-II and factor II and BMI. The effect of perioperative treatment with different vitamin K supplements should be investigated in future studies, as well as clinical trials evaluating their antitumor effects.

Coagulation during elective neurosurgery with hydroxyethyl starch fluid therapy: an observational study with thromboelastometry, fibrinogen and factor XIII.

BACKGROUND: Several studies have described hypercoagulability in neurosurgery with craniotomy for brain tumor resection. In this study, hydroxyethyl starch (HES) 130/0.42 was used for hemodynamic stabilization and initial blood loss replacement. HES can induce coagulopathy with thromboelastographic signs of decreased clot strength. The aim of this study was to prospectively describe perioperative changes in coagulation during elective craniotomy for brain tumor resection with the present fluid regimen. METHODS: Forty patients were included. Perioperative whole-blood samples were collected for EXTEM and FIBTEM assays on rotational thromboelastometry (ROTEM) and plasma fibrinogen analysis immediately before surgery, after 1 L of HES infusion, at the end of surgery and in the morning after surgery. Factor (F)XIII activity, thrombin-antithrombin complex (TAT) and plasmin-α2-antiplasmin complex (PAP) were analysed in the 25 patients receiving ≥1 L of HES. RESULTS: Most patients (37 of 40) received HES infusion (0.5-2 L) during surgery. Preoperative ROTEM clot formation/structure, plasma fibrinogen and FXIII levels were generally within normal range but approached a hypocoagulant state during and at end of surgery. ROTEM variables and fibrinogen levels, but not FXIII, returned to baseline levels in the morning after surgery. Low perioperative fibrinogen levels were common. TAT levels were increased during and after surgery. PAP levels mostly remained within the reference ranges, not indicating excessive fibrinolysis. There were no differences in ROTEM results and fibrinogen levels in patients receiving <1 L HES and ≥1 L HES. CONCLUSIONS: Only the increased TAT levels indicated an intra- and postoperative activation of coagulation. On the contrary, all other variables deteriorated towards hypocoagulation but were mainly normalized in the morning after surgery. Although this might be an effect of colloid-induced coagulopathy, we found no dose-dependent effect of HES. The unactivated fibrinolysis indicates that prophylactic use of tranexamic acid does not seem warranted under normal circumstances in elective neurosurgery. Individualized fluid therapy and coagulation factor substitution is of interest for future studies.