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1.  Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate 
BJA: British Journal of Anaesthesia  2014;113(4):585-595.
Background
We aimed to create a theoretical tool to model the effect of three haemostatic agents containing fibrinogen (therapeutic plasma, cryoprecipitate, and fibrinogen concentrate) on the patient's plasma fibrinogen level.
Methods
A mathematical model was developed step-wise. The relationship between the amount of haemostatic agent and plasma fibrinogen level was plotted for each agent. A fibrinogen concentration simulator (FCSamount) was developed, where the amount of haemostatic agent was calculated from patient characteristics, agent characteristics, and target plasma fibrinogen level. Refinements were introduced so that (i) FCSamount would account for in vivo fibrinogen recovery, (ii) circulatory volume would not increase ad infinitum with increasing amounts, and (iii) red blood cells would be included in the simulation if haematocrit decreased below a certain level. A second FCS (FCSlevel) was created to calculate fibrinogen levels resulting from specified amounts of haemostatic agents.
Results
Fibrinogen concentration in haemostatic agents has a critical impact on their ability to increase patients' fibrinogen levels. If the target plasma fibrinogen level approaches the concentration of the fibrinogen source, the required amounts increase exponentially; it is impossible to achieve a target above the concentration of the fibrinogen source.
Conclusions
We successfully developed two theoretical tools answering the questions: ‘How much therapeutic plasma, cryoprecipitate, or fibrinogen concentrate would be needed to achieve a specified target fibrinogen level?’ and ‘What would be the resultant fibrinogen level for a specified amount of haemostatic agent?’ The current tools are not intended for clinical application, but they are potentially useful for educational purposes.
doi:10.1093/bja/aeu086
PMCID: PMC4166889  PMID: 25064078
computer simulation; cryoprecipitate; drug dosage calculations; fibrinogen; plasma
2.  Reply from the authors 
BJA: British Journal of Anaesthesia  2014;112(6):1121-1123.
doi:10.1093/bja/aeu173
PMCID: PMC4020385  PMID: 24829427
3.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
Background
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
Methods
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Results
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Conclusions
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
doi:10.1093/bja/aes576
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
4.  Haemostatic monitoring during postpartum haemorrhage and implications for management 
BJA: British Journal of Anaesthesia  2012;109(6):851-863.
Summary
Postpartum haemorrhage (PPH) is a major risk factor for maternal morbidity and mortality. PPH has numerous causative factors, which makes its occurrence and severity difficult to predict. Underlying haemostatic imbalances such as consumptive and dilutional coagulopathies may develop during PPH, and can exacerbate bleeding and lead to progression to severe PPH. Monitoring coagulation status in patients with PPH may be crucial for effective haemostatic management, goal-directed therapy, and improved outcomes. However, current PPH management guidelines do not account for the altered baseline coagulation status observed in pregnant patients, and the appropriate transfusion triggers to use in PPH are unknown, due to a lack of high-quality studies specific to this area. In this review, we consider the evidence for the use of standard laboratory-based coagulation tests and point-of-care viscoelastic coagulation monitoring in PPH. Many laboratory-based tests are unsuitable for emergency use due to their long turnaround times, so have limited value for the management of PPH. Emerging evidence suggests that viscoelastic monitoring, using thrombelastography- or thromboelastometry-based tests, may be useful for rapid assessment and for guiding haemostatic therapy during PPH. However, further studies are needed to define the ranges of reference values that should be considered ‘normal’ in this setting. Improving awareness of the correct application and interpretation of viscoelastic coagulation monitoring techniques may be critical in realizing their emergency diagnostic potential.
doi:10.1093/bja/aes361
PMCID: PMC3498756  PMID: 23075633
blood coagulation tests; point-of-care systems; postpartum haemorrhage; thrombelastography
5.  Life Course Weight Characteristics and the Risk of Gestational Diabetes 
Diabetologia  2009;53(4):668-678.
Aims/hypothesis
To prospectively determine the risk of gestational diabetes (GDM) in association with life-course weight characteristics and adult abdominal adiposity.
Methods
We investigated the joint and independent impact of birth weight, childhood size by somatotypes, adolescent and adult body mass index (BMI) and abdominal adiposity on GDM risk among 21,647 women in the Nurses’ Health Study II who reported a singleton pregnancy between 1989 and 2001. 1,386 incident GDM cases were reported. Relative risk (RR) was estimated by pooled logistic regression adjusting for age, prematurity, race, smoking status, parental history of diabetes, age of first birth, parity, and physical activity.
Results
Birth weight was inversely associated with GDM risk (P-trend 0.02). Childhood somatotypes at ages 5 and 10 years were not associated with risk. U-shaped associations were found for BMI at age 18 and somatotype at age 20 years. Weight gain between adolescence and adulthood, pre-gravid BMI and abdominal adiposity were positively associated with risk (p-trends all<0.01). Multivariate adjusted RR for GDM from lowest to highest quintile of waist-to-hip ratio were 1.00, 1.50, 1.51, 2.03, 2.12 (P-trend 0.0003). Lower birth weight (<7 pounds) without adulthood overweight (BMI>25 kg/m2) was associated with 20% increased risk (95% CI: 1.02–1.41). However, adulthood overweight alone was related to 2.36 times greater GDM risk (95% CI: 2.12–3.77).
Conclusions/Interpretation
Although lower birth weight is an independent risk factor for GDM, weight gain since early adulthood, and overall and central obesity in adulthood were more strongly associated with elevated GDM risk independent of other known risk factors.
doi:10.1007/s00125-009-1634-y
PMCID: PMC2901841  PMID: 20043144
birth weight; body mass index; gestational diabetes; life-course weight; waist
6.  Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery 
BJA: British Journal of Anaesthesia  2010;104(5):555-562.
Background
Normalization of plasma fibrinogen levels may be associated with satisfactory haemostasis and reduced bleeding. The aim of this retrospective study was to assess fibrinogen recovery parameters after administration of fibrinogen concentrate (Haemocomplettan® P) to patients with diffuse bleeding in cardiovascular surgery. Data on transfusion and patient outcomes were also collected.
Methods
Patient characteristic and clinical data were obtained from patient records. Results of the thromboelastometry (FIBTEM®) and of the standard coagulation tests, including plasma fibrinogen level, measured before surgery, before and after haemostatic therapy, and on the following day, were retrieved from laboratory records.
Results
Thirty-nine patients receiving fibrinogen concentrate for diffuse bleeding requiring haemostatic therapy after cardiopulmonary bypass were identified. The mean fibrinogen concentrate dose administered was 6.5 g. The mean fibrinogen level increased from 1.9 to 3.6 g litre−1 (mean increment of 0.28 g litre−1 per gram of concentrate administered); maximum clot firmness increased from 10 to 21 mm. The mean fibrinogen increase was 2.29 (sd 0.7) mg dl−1 per mg kg−1 bodyweight of concentrate administered. Thirty-five patients received no transfusion of fresh-frozen plasma (FFP) or platelet concentrate after receiving fibrinogen concentrate; the remaining four patients received platelet concentrate intraoperatively. Eleven patients received platelets, FFP, or both during the first postoperative day. No venous thromboses, arterial ischaemic events, or deaths were registered during hospitalization.
Conclusions
In this retrospective study, fibrinogen concentrate was effective in increasing plasma fibrinogen level, and contributed to the correction of bleeding after cardiovascular surgery.
doi:10.1093/bja/aeq058
PMCID: PMC2855672  PMID: 20348140
blood, coagulation; fibrinogen concentrate; pharmacokinetics, uptake; surgery, cardiovascular
7.  Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study 
BJA: British Journal of Anaesthesia  2009;102(6):785-792.
Background
Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV–AA) is managed with fresh-frozen plasma (FFP) and platelet concentrates. The aim was to compare haemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration.
Methods
A blood products transfusion algorithm was developed using retrospective data from 42 elective patients (Group A). Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 u of FFP if bleeding persisted, if platelet count was ≤100×103 µl−1 when removing the aortic clamp, and vice versa if platelet count was >100×103 µl−1. The trigger for each therapy step was ≥60 g blood absorbed from the mediastinal wound area by dry swabs in 5 min. Assignment to two prospective groups was neither randomized nor blinded; Group B (n=5) was treated according to the algorithm, Group C (n=10) received fibrinogen concentrate (Haemocomplettan® P/Riastap, CSL Behring, Marburg, Germany) before the algorithm-based therapy.
Results
A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all Group C patients. Group C had reduced transfusion [mean 0.7 (range 0–4) u vs 8.5 (5.3) in Group A and 8.2 (2.3) in Group B] and reduced postoperative bleeding [366 (199) ml vs 793 (560) in Group A and 716 (219) in Group B].
Conclusions
In this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 h postoperative bleeding in patients undergoing AV–AA.
doi:10.1093/bja/aep089
PMCID: PMC2683341  PMID: 19411671
blood, coagulation; measurement techniques, thrombelastograph; surgery, cardiovascular; transfusion
8.  Analysis of Michigan Medicaid costs to treat HIV infection. 
Public Health Reports  1989;104(5):416-424.
To obtain better understanding of the nature and cost of health care related to human immunodeficiency virus (HIV) infection, medical payment records were analyzed for 204 men, women, and children older than 60 months who had indications of HIV infection. The records were those of Michigan Medicaid, the General Assistance Medical Program, and the Resident County Hospitalization Program, with service dates on or after January 1, 1984, and which were processed by November 30, 1987. Patient payment records were coded according to whether the patient's condition was considered to be pre-HIV, HIV unrelated, possibly HIV related, or HIV related. Average monthly payments were found to be $150 for pre-HIV patient payment records, $114 for those HIV unrelated, $57 for those possibly related, and $1,213 for those related to HIV infection. HIV-related monthly payments rose from about $1,500 per month in the period 3 months prior to the patient's death to more than $8,000 in the last month of life. Men were found to have twice as many claims as women, and men's claims cost about three times as much. A higher percentage of women than men (91 percent versus 37 percent) received pre-HIV paid services, indicating a higher percentage of women were at least initially receiving Medicaid for reasons other than an HIV-related disability. Diagnostic categories that accounted for the bulk of the HIV-related health care utilization included infectious and parasitic diseases, acquired immunodeficiency syndrome, diseases of the respiratory system, and non-HIV-specific immunity disorders. Inpatient hospitalization accounted for more than 75 percent of the payments, followed by physician costs (11 percent), pharmacy costs (5 percent), and outpatient costs (3 percent). A total of 45, or about 22 percent of the recipients, received zidovudine (AZT) prescriptions at an average monthly cost of $404.
PMCID: PMC1579960  PMID: 2508170
9.  Effects of low temperature on in vivo and in vitro protein synthesis in Escherichia coli and Pseudomonas fluorescens. 
Journal of Bacteriology  1978;134(3):861-874.
The effects of temperature on protein synthesis by Escherichia coli, a mesophile, and Pseudomonas fluorescens, a psychotroph, were investigated by using whole-cell and cell extract preparations. After shifts to 5 degrees C, protein was synthesized at a slowly decreasing rate for 1 h by both organisms, after which P. fluorescens synthesized protein at a new rate corresponding to its 5 degrees growth rate, in contrast to E. coli which did not synthesize protein at a measurable rate. In vitro protein-synthesizing systems using MS-2 RNA, endogenous mRNA, and purified polysomes were utilized to investigate initiation of translation at 5 degrees C. In these systems, P. fluorescens cell extracts synthesized protein at linear rates for up to 2 h at 5 degrees C, whereas E. coli cell extracts synthesized protein for only 25 min at 5 degrees C. The rates of polypeptide elongation, as tested by the incorporation of phenylalanine into polyphenylalanine by cell extract protein-synthesizing systems from both organisms, were identical over the range of 25 to 0 degrees C. The polysome profiles of E. coli whole cells shifted from 37 to 5 degrees C showed accumulation of 70S ribosomal particles and ribosomal subunits at the expense of polysomes. Similar experiements done with P. fluorescens resulted in polysome reformation at 5 degrees C. In vitro experiments demonstrated that the 70S ribosomal particles, which accumulated in E. coli at 5 degrees C, were capable of synthesizing protein in vitro in the absence of added mRNA. These in vivo and in vitro results suggest that incubation of E. coli at subminimal temperatures results in a block in initiation of translation causing polysomal runoff and the accumulation of 70S particles, some of which are 70S monosomes.
PMCID: PMC222333  PMID: 96102
11.  On Antiseptic Inhalations 
British Medical Journal  1884;1(1208):353-354.
PMCID: PMC2306964  PMID: 20750832
12.  Nitrite of Amyl in Uræmic Asthma 
British Medical Journal  1883;1(1171):1115-1116.
PMCID: PMC2372585  PMID: 20750633
13.  Gout as a Tropho-Neurosis 
British Medical Journal  1881;1(1066):880.
PMCID: PMC2263806  PMID: 20749886

Results 1-13 (13)