Assembly of alternative prothrombinase by extracellular histones initiate and disseminate intravascular coagulation (2020)

Type of publication:
Journal article

Author(s):
Abrams, Simon Timothy; Su, Dunhao; Sahraoui, Yasmina; Lin, Ziqi; Cheng, Zhenxing; Nesbitt, Kate; *Alhamdi, Yasir; Harrasser, Micaela; Du, Min; Foley, Jonathan; Lillicrap, David; Wang, Guozheng; Toh, Cheng-Hock

Citation:
Blood; Jul 2020 [epub ahead of print]

Abstract:
Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated co-factor V (FVa) and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragments F1 and F2 specifically, to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin fragments F1+F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit (ICU) patients with sepsis (n=144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation, and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in Factor VIII and IX-deficient plasma, as well as in Factor VIII-deficient mice. In conclusion, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation as well as in correcting coagulation factor deficiency.

Preoperative anemia and outcomes in cardiovascular surgery: systematic review and meta-analysis (2019)

Type of publication:
Systematic Review

Author(s):
*Padmanabhan, Hari; Siau, Keith; *Curtis, Jason; Ng, Alex; Menon, Shyam; Luckraz, Heyman; Brookes, Matthew J

Citation:
The Annals of Thoracic Surgery. Dec 2019; vol. 108 (no. 6); p. 1840-1848

Abstract:
BACKGROUND Pre-operative anemia is common in patients scheduled for cardiac surgery. However, its effect on postoperative outcomes remains controversial. This meta-analysis aimed to clarify the impact of anemia on outcomes following cardiac surgery.METHODS A literature search was conducted on MEDLINE, Embase, Cochrane, and Web of Science databases. The primary outcome was 30-day postoperative or in-hospital mortality. Secondary outcomes included acute kidney injury (AKI), stroke, blood transfusion, and infection. A meta-analytic model was used to determine the differences in the above postoperative outcomes between anemic and non-anemic patients. RESULTS Out of 1103 studies screened, 22 met the inclusion criteria. A total of 23624 (20.6%) out of 114277 patients were anemic. Anemia was associated with increased mortality (odds ratio [OR] 2.74, 95% confidence interval [CI] 2.32-3.24; I2=69.6%; p<0?001), AKI (OR 3.13, 95% CI 2.37-4.12; I2=71.1%; p<0?001), stroke (OR 1.46, 95% CI 1.24-1.72; I2=21.6%; p<0?001), and infection (OR 2.65, 95% CI 1.98-3.55; I2=46.7%; p<0?001). More anemic patients were transfused than non-anemic (33.3 versus 11.9%). No statistically significant association was found between mortality and blood transfusion (OR 1.35, 95% CI 0.92-1.98; I2=83.7%; p=0.12) but we were not able to compare mortality with or without transfusion in those who were or were not anemic. CONCLUSIONS Preoperative anemia is associated with adverse outcomes following cardiac surgery. These findings support the addition of preoperative anemia to future risk prediction models, and as a target for risk modification.

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Anaemia and upper GI bleeding: A local experience (2017)

Type of publication:
Conference abstract

Author(s):
*Ding M.; *Prawiradiradja R.; *Arastu Z.; *Sabri H.; *Smith M.

Citation:
United European Gastroenterology Journal; Oct 2017; vol. 5 (no. 5)

Abstract:
Introduction: There has been significant research recently on the use of blood transfusions in upper GI bleeding (UGIB) [1] with recent evidence advocating a restrictive approach to blood transfusions as well as the use of iron therapy[2] for anaemia post UGIB. Our team conducted a local retrospective analysis on patients admitted with UGIB over a six month period and analysed the use of blood transfusions at our trust which consists of two District General Hospitals. Patient data over a period of up to 12 months post discharge was collected to monitor their anaemia. Aims & Methods: Our aim was to monitor the appropriateness of transfusions in Upper GI Bleeding as well as monitoring the response to iron therapy following discharge. All inpatients that had an Upper GI endoscopy for UGIB were analysed. Electronic patient records were obtained from our endoscopy software and hospital database. Patients were selected over a time period of six months from 1/ 6/2015 to 31/12/2015. A Student’s T-Test was used to compare the average increase in haemoglobin (Hb) for patients discharged with iron therapy against those who were not. Results: There were 148 patients, 81 male and 67 female. The mean age was 69.3, minimum 20 and maximum of 98. The average Hb on admission was 103 g/L (min=32 g/L, max=178 g/L). 78 out of 148 (52.7%) patients presenting with UGIB received a blood transfusion. The mean amount of blood received for those transfused was 3.7 units. 48 out of 78 (61.5%) of blood transfusions were given when Hb was below 70 g/L. 30 of 78 (38.5%) were transfused above a Hb of 70 g/L. (36.7%, n=11) of those who were transfused with Hb above 70 had cardiac risk factors. The mortality rate in those transfused above Hb of 70 was 13.3% (n=4) vs 10.4% (n=5) 41.5% (n=44) patients who were anaemic post-UGIB were discharged with iron therapy. The average rise in Hb was 26.5% for those discharged on iron vs 12.1% for those who did not. There was a statistically significant rise in Hb for those discharged with iron therapy (p<0.005) on follow-up versus those who did not receive it (n=62). The anaemia related readmission rates were similar for patients discharged on iron or not (9.1% n=4 vs 9.7% n=6). Conclusion: The data obtained supports a restrictive transfusion policy (mortality rate of 13.3% vs 10.4%). 58.5% of patients who were anaemic on discharge did not receive any iron therapy. On follow up, there was a statistically significant rise in Hb level in the group discharged on iron. Our data affirms recent evidence favouring iron therapy post UGIB. Further education is needed to improve outcome in patients presented with GI bleed.

A rare mandibular presentation in multiple myeloma (2017)

Type of publication:
Conference abstract

Author(s):
*Mihalache G.; *MacBean A.; *Bhatia S.

Citation:
British Journal of Oral and Maxillofacial Surgery; Dec 2017; vol. 55 (no. 10)

Abstract:
Introduction: Multiple myeloma(MM)is a relatively rare malignant haematological disease, a monoclonal malignant proliferation of plasma cells that causes osteolytic lesions in the vertebrae, ribs, pelvic bone, skull and jaw. This rare disease develops mainly in men aged 50 to 80 years (mean age, 60 years). Materials: We report on a clinical case of a 45-year-old female patient who presented with spinal and long bones pain to the hospital and she was diagnosed with multiple myeloma. In order to start her treatment (radiotherapy/ chemotherapy/ bisphosphonates) conform our hospital protocol, she came for a full oral and dental assessment. No intraorally abnormalities were seen. However the orthopantomogram showed multiple rounded lesions of various sizes which have little, if any, circumferential osteosclerotic bone reaction. Results: Patient was diagnosed with multiple myeloma with mandibular involvement. She will be followed up by our team and her dentist for monitoring the oral health. Conclusions: The clear and rare multilocular image of myeloma on the orthopantomogram makes our case unique. Knowledge about the maxillofacial manifestations of multiple myeloma is important for the diagnosis of the disease and treatment, also the follow up of these patients regarding their oral manifestations. In the clinical case presented here, we highlight the interdisciplinarity needed to obtain a diagnosis and treatment of multiple myeloma.