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Stüve-Wiedemann syndrome (SWS) is a rare, autosomal recessive disorder, causing dysautonomia and multisystem failure. Symptoms include skeletal malformations, restricted joint mobility and desensitisation to pain. Patients with SWS presenting with intraoral lesions are extremely rare and this is probably due to their shortened lifespan. We present a case of a 9-month-old patient who presented to our Oral and Maxillofacial Surgery (OMFS)Unit with a chronic inflamed ulcer affecting the tongue, secondary to trauma from erupting central incisors. We believe that depapillation in conjunction with an increased pain threshold contributed to its development. The patient was successfully treated by extraction of the lower central incisors and intralesional steroid injections under general anaesthetic. This case highlights that patients with SWS can present to the OMFS clinician with oral lesions and that they can be safely managed under general anaesthesia.

Introduction The mandible is the most common bone to develop complications following treatment of facial fractures. This is due to a complex interaction of both fracture specific and patient factors. Our aim was to identify those patient factors, with a specific focus on those that may be potentially modifiable to reduce the incidence of complications. Method A systematic review of the literature was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology to identify patient factors ascribed to an increased risk of complications following mandible fracture treatment. These were divided non- modifiable and potentially modifiable factors. A meta-analysis was performed to weight those factors for which statistical analysis had been performed. Results 22 pertinent papers were identified, of which 8 described non-modifiable and 7 potentially modifiable factors. The most common potentially modifiable factor identified was smoking. Meta-analysis established that tobacco smoking demonstrated an increased risk of complications in three studies (OR: 4.04 – 8.09). Conclusions Division of patient factors into those that are potentially modifiable and those that are not will enable clinicians to focus on those in which change within the immediate post-operative period can be instigated. This includes smoking cessation assistance, education as to the need for a soft diet and facilitating post- operative clinic attendance. It also enables stratification of risk in terms of consent, and choice of treatment. Further research should use standardised terminology, particularly in stopping the use of generalizable terms such as patient compliance and instead describing its individual components.

BACKGROUND: Diabetic ketoacidosis (DKA) is a medical emergency with a high mortality rate and is associated with severe metabolic acidosis and dehydration. DKA patients have an increased risk of arterial and venous thromboembolism, however little is known about this metabolic derangement in the first 24 hours of admission and to assess its effect on coagulation. We therefore utilised a novel functional marker of clot microstructure (fractal dimension - df) to assess these changes within the first 24 hours. METHODS: Prospective single centre observational study to demonstrate whether the tendency of blood clot formation differs in DKA patients. RESULTS: 15 DKA patients and 15 healthy matched controls were recruited. Mean df in the healthy control group was 1.74±0.03. An elevated df of 1.78±0.07 was observed in patients with DKA on admission. The mean pH on admission was 7.14±0.13 and the lactate was 3.6±2.0. df changed significantly in response to standard treatment and was significantly reduced to 1.68±0.09 (2–6& h) and to 1.66±0.08 at 24& h (p

Measures of patient-reported quality of life (QoL) are increasingly being used to tailor services that are funded by Clinical Commissioning Groups (CCG) in England. Mandibular osteotomies may result in altered sensation of the lower lip, but we know of limited evidence about the resulting effect on QoL. The modified Bristol orthognathic patient outcomes questionnaire was given to patients who had mandibular osteotomies at the Queen Elizabeth Hospital, Birmingham, between March 2006 and April 2016. Questionnaires were collected at the final orthognathic postoperative appointment. The significance of the difference in QoL between those who had altered sensation of the lower lip and those who did not was compared using a two-tailed t test. During this period 170 patients had mandibular orthognathic operations. Completed questionnaires were received from 117 of those patients (69%) during this period, after a follow up of about six months. We found no significant difference between the perceived benefits of treatment between the 41 who had altered sensation and the 74 who did not (p=0.30). Only 5/41 who reported residual numbness six months postoperatively stated that they would not choose to have the same treatment again. In conclusion, orthognathic surgery results in an appreciable improvement in QoL and should continue to be funded by CCG in England. Contrary to the perception of some clinicians, those patients with residual numbness of the lip did not have significantly poorer QoL. Future interpretation of the data will be improved if they are collected both before and after the operation.

Autogenous bone remains the gold standard for augmentation of the alveolar ridge in congenital hypodontia and appreciable post-traumatic deformity. This generally reflects the volume of material required for such defects and the osteogenic potential of the grafts. Morbidity at the donor site and success rates may lead to autogenous grafts being superseded by xenografts or alloplastic materials in the future, but we know of little evidence to confirm this. All patients having augmentation of the alveolar ridge or sinus lift to enable subsequent placement of implants between 01 January 2009 and 31 December 2016 were identified from a prospectively-gathered database held at the Queen Elizabeth Hospital, Birmingham. Morbidity was recorded, with overall success defined as a graft that enabled subsequent placement of an implant. During this period the following grafts: calvarial (n=4), iliac crest (n=4), and ramus (n=149) were recorded, as well as 53 sinus lifts. Sinus lift augmentation with BioOss® had the highest success rate (51/53). Calvarial and iliac crest grafts had higher failure rates (2/4 and 3/4, respectively) than those from the mandibular ramus (6/149, 4%). Fifteen of 149 (10%) ramus grafts resulted in transient anaesthesia of the inferior alveolar nerve but no patients developed any permanent morbidity at the donor or recipient sites. Ramus grafts are a predictable method of bone augmentation with only transient morbidity at the donor site. Higher failure rates for extraoral grafts probably reflect their use in more challenging cases when more bone is required. Bilateral ramus grafts are an alternative to extraoral grafts and may be supplemented by bovine-derived particulate grafts with no appreciable increase in complications.

INTRODUCTION Thrombosis is a severe and frequent complication of heparin-induced thrombocytopenia (HIT). However, there is currently no knowledge of the effects of HIT-like antibodies on the resulting microstructure of the formed clot, despite such information being linked to thrombotic events. We evaluate the effect of the addition of pathogenic HIT-like antibodies to blood on the resulting microstructure of the formed clot. MATERIALS AND METHODS Pathogenic HIT-like antibodies (KKO) and control antibodies (RTO) were added to samples of whole blood containing Unfractionated Heparin and Platelet Factor 4. The formed clot microstructure was investigated by rheological measurements (fractal dimension; df) and scanning electron microscopy (SEM), and platelet activation was measured by flow cytometry. RESULTS AND CONCLUSIONS Our results revealed striking effects of KKO on clot microstructure. A significant difference in df was found between samples containing KKO (df = 1.80) versus RTO (df = 1.74; p

INTRODUCTION This aim of this study is to investigate the individual effects of varying concentrations of thrombin and fibrinogen on clot microstructure (characterised through the fractal dimension of the incipient clot network, df) and clot formation time (TGP) using a fibrin-thrombin clot model. df and TGP markers are measured using a haemorheological method that has already been investigated for whole blood. METHODS This is an in vitro study using three thrombin concentrations (0.1, 0.05 and 0.02 NIH/ml) and two fibrinogen concentrations (8 mg/ml and 12 mg/ml) to investigate a fibrin-thrombin clot model. The haemorheological changes were measured at the gel point using df and TGP. RESULTS Fractal dimension (df) increased with increasing concentrations of thrombin both at 8 mg/ml (1.60±0.024, 1.67±0.022, 1.74±0.079) and 12 mg/ml fibrinogen concentrations (1.63±0.02, 1.87±0.019, 1.95±0.014). On the other hand, TGP decreased for both 8 mg/ml (1089±265, 637±80, 223±22 seconds) and 12 mg/ml fibrinogen concentrations (2008±247, 776±20, 410±20 seconds). In contrast to previous studies investigating whole blood, TGP increased with higher fibrinogen levels. CONCLUSIONS The findings from this fibrin-thrombin clot model confirmed that df and TGP can detect changes in the incipient clot following manipulation of fibrinogen and thrombin concentration. df increases (indicating stronger clot) with higher concentrations of thrombin and fibrinogen. On the other hand, TGP decreased as expected with higher thrombin level but not with higher fibrinogen concentrations.

Malignant infantile osteopetrosis (MIOP), an autosomal-recessive disorder, is extremely rare, presenting early in life with extreme sclerosis of the skeleton and reduced activity of osteoclasts. It was first described by Albers Schonberg in 1904. Disease manifestations include compensatory extramedullary haematopoiesis at sites such as the liver and spleen, hepatosplenomegaly, anaemia and thrombocytopaenia. Neurological manifestations can also occur due to narrowing of osseous foramina resulting in visual impairment, hearing loss, facial palsy and hydrocephalus. In addition, growth retardation and recurrent infections requiring long-term antibiotic use are common. The incidence of MIOP is 1/2 000 000 and if untreated, then it has a fatal outcome, with the majority of cases occurring within the first 5 years of life. At present, the only potentially curative option is a haematopoietic stem cell transplant. We present a 21-year-old woman, diagnosed with malignant infantile osteopetrosis, due to a mutation in the T-cell immune regulator 1 gene when aged 6 weeks, presenting with chronic osteomyelitis of her left mandible. As malignant infantile osteopetrosis has a high mortality in infancy, we felt it prudent to report this rare case in a patient surviving to adulthood.

It is important at the outset to distinguish the two main groups of vascular anomalies: vascular malformations and vascular tumours (e.g. haemangiomas). Vascular malformations are localized errors of angiogenic development, which should be distinguished from haemangiomas. They may involve any portion of the vascular system—arteries, veins, capillaries and lymphatics. Vascular malformations are therefore structural anomalies present at birth, which may or may not be clinically evident. Haemangiomas by contrast are tumorous growths, with increased endothelial cell proliferation as a distinguishing hallmark [1].

Anesthesia, critical illness, and trauma are known to alter thermoregulation, which can potentially affect coagulation and clinical outcome. This in vitro preclinical study explores the relationship between temperature change and hemostasis using a recently validated viscoelastic technique. We hypothesize that temperature change will cause significant alterations in the microstructural properties of clot.We used a novel viscoelastic technique to identify the gel point of the blood. The gel point identifies the transition of the blood from a viscoelastic liquid to a viscoelastic solid state. Furthermore, identification of the gel point provides 3 related biomarkers: the elastic modulus at the gel point, which is a measure of clot elasticity; the time to the gel point (TGP), which is a measure of the time required to form the clot; and the fractal dimension of the clot at the gel point, df, which quantifies the microstructure of the clot. The gel point measurements were performed in vitro on whole blood samples from 136 healthy volunteers over a temperature range of 27°C to 43°C.There was a significant negative correlation between increases in temperature, from 27°C to 43°C, and TGP (r = -0.641, P0.0005). Conversely, significant positive correlations were observed for both the elastic modulus at the gel point (r = 0.513, P = 0.0008) and df (r = 0.777, P0.0005) across the range of 27°C to 43°C. When temperature was reduced below 37°C, significant reductions in df and TGP occurred at ≤32°C (Bonferroni-corrected P = 0.0093) and ≤29°C (Bonferroni-corrected P = 0.0317), respectively. No significant changes were observed when temperature was increased to37°C.This study demonstrates that the gel point technique can identify alterations in clot microstructure because of changes in temperature. This was demonstrated in slower-forming clots with less structural complexity as temperature is decreased. We also found that significant changes in clot microstructure occurred when the temperature was ≤32°C.

Background Stroke is the second largest cause of death worldwide. Abnormalities in hemostasis play an important role in the pathophysiology of ischemic stroke (IS). These hemostatic defects can be detected using rotational thromboelastometry (ROTEM) as a global method of measuring coagulation.This study assessed the effects of IS on blood hypercoagulability using ROTEM method, before and subsequent to therapeutic interventions. Methods In a prospective observational cohort study, whole blood coagulation using ROTEM, along with full blood count and standard coagulation tests, were compared between patients with IS and an age-matched control group of healthy volunteers. Further assessment took place at 2-4 hours and at 24 hours in the stroke group after therapy to assess the effects of therapeutic intervention. Results Seventy-two patients with IS were age-matched to 71 healthy subjects. Clotting time (CT) INTEM (P = .01) and maximum clot firmness (MCF) INTEM (P = .02) were significantly different between stroke patients at baseline and healthy subjects, but this difference disappeared when controlled for by smoking status. There was no association between ROTEM parameters and time from stroke symptom onset or stroke severity as reflected in The National Institute of Health Stroke Scale score. Significant but small changes in the values of MCF-EXTEM, clot formation time (CFT) EXTEM, and alpha-EXTEM CT were observed after therapeutic intervention (thrombolysis or aspirin treatment). Conclusions ROTEM testing does not seem to detect a hypercoagulable state in patients with IS. Nonetheless, some ROTEM parameters had a small change after antiplatelet therapy or thrombolysis.

Background Antithrombotics are the mainstay of management in coronary artery disease (CAD). However, no biomarker is available to assess their global effect on clot formation and structure. We validated a novel biomarker that measures clot microstructure, fractal dimension of incipient blood clot (df), in healthy volunteers, stroke, lung cancer and sepsis. Aims To validate df in both acute and stable CAD, and assess the effect of therapeutic intervention. Methods We prospectively recruited 2 groups: serial venous blood samples were collected on admission, after primary percutaneous coronary intervention (pPCI) and 24 hours in patients with STEMI, and a blood sample prior to angiography was obtained from 251 consecutive patients undergoing diagnostic coronary angiography. Patients were categorised based on angiographic findings as presence or absence of obstructive CAD (stenosis ≥50%). Results In 38 STEMI patients, df after pPCI was lower than df on admission (mean 1.631±0.063 vs 1.751±0.052, p Conclusions We characterise clot microstructure, as measured by df, in patients with STEMI and stable CAD. df can potentially be used to risk-stratify patients with stable CAD and assess the efficacy of therapeutic interventions by measuring changes in clot microstructure.

Background The rheological properties of sputum may influence lung function and become modified in disease. Objective This study aimed to correlate the viscoelastic properties of sputum with clinical data on the severity of disease in patients with chronic obstructive pulmonary disease (COPD). Methods Sputum samples from COPD patients were investigated using rheology, simple mathematical modelling and Scanning Electron Microscopy (SEM). The samples were all collected from patients within two days of their admission to Prince Philip Hospital due to an exacerbation of their COPD. Oscillatory and creep rheological techniques were used to measure changes in viscoelastic properties at different frequencies over time. Results COPD sputum was observed to behave as a viscoelastic solid at all frequencies studied. Comparing the rheology of exacerbated COPD sputum with healthy sputum (not diagnosed with a respiratory disease) revealed significant differences in response to oscillatory shear and creep-recovery experiments, which highlights the potential clinical benefits of better understanding sputum viscoelasticity. A common power law model G(t)=G0(tτ0)-m was successfully fitted to experimental rheology data over the range of frequencies studied. Conclusions A comparison between clinical data and the power law index m obtained from rheology, suggested that an important possible future application of this parameter is as a potential biomarker for COPD severity.

Background Coronary artery disease (CAD) is associated with an increased prothrombotic tendency and is also linked to unfavourably altered clot microstructure. We have previously described a biomarker of clot microstructure (d f ) that is unfavourably altered in acute myocardial infarction. The d f biomarker assesses whether the blood will form denser or looser microstructures when it clots. In this study we assessed in patients with stable chest pain whether d f can differentiate between obstructed and unobstructed CAD. Methods A blood sample prior to angiography was obtained from 251 consecutive patients undergoing diagnostic coronary angiography. Patients were categorised based on angiographic findings as presence or absence of obstructive CAD (stenosis ≥50%). The blood sample was assessed using the d f biomarker, standard laboratory markers and platelet aggregometry (Multiplate). Results A significant difference (p=0.028) in d f was observed between obstructive CAD (1.748±0.057, n=83) and unobstructive CAD (1.732±0.052, n=168), where patients with significant CAD produce denser, more tightly packed clots. d f was also raised in men with obstructive CAD compared with women (1.745±0.055 vs 1.723±0.052, p=0.007). Additionally d f significantly correlated with the platelets response to arachidonic acid as measured by the ASPItest area under the curve readings from platelet aggregometry (correlation coefficient=0.166, p=0.008), a low value of the ASPItest indicating effective aspirin use was associated with looser, less dense clots. Conclusions For the first time, we characterise clot microstructure, as measured by d f , in patients with stable CAD. d f can potentially be used to risk-stratify patients with stable CAD and assess the efficacy of therapeutic interventions by measuring changes in clot microstructure.

AIMS: To examine the nature of maxillofacial injuries that presented to the Birmingham Children's Hospital according to aetiology, incidence and characteristics of patients. METHODS: The maxillofacial unit at Diana Princess of Wales Birmingham Children's Hospital serves a catchment area of 5.2 million. We examined all children who presented with maxillofacial trauma from 2002 to 2006. Details including characteristics of patients and aetiology and nature of injury, were entered prospectively into a database. RESULTS: The total number of patients who presented was 1062. The ratio of boys to girls was 2:1. The main reason for attendance was a fall (70%). 149 (17%) patients presented after interpersonal violence. Soft tissue injuries accounted for 70% of injuries and 14% presented with a maxillofacial fracture. CONCLUSIONS: Our data indicate that the range and mechanism of presenting injuries have not changed within the time frame. Despite public perception of increasing interpersonal violence, this was not reflected in our series of patients. Language: en

Background Exercise is well established to lead to exercise-induced hypercoagulability, as demonstrated by kinetic coagulation markers. It remains unclear as to whether exercise-induces changes lead in clot development and increased polymerisation. Fractal dimension ( d f ) has been shown to act as a marker of clot microstructure and mechanical properties, and may provide a more meaningful method of determining the relationship between exercise-induced hypercoagulability and potential clot development. Methods d f was measured in 24 healthy individuals prior to, after 5min of submaximal exercise, following maximal exercise, 45min of passive recovery and following 60min of recovery. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Results Significantly increased d f was observed following exercise, returning to resting values following 60min of recovery. The relationship between d f and mature clot microstructure was confirmed by SEM: higher d f was associated with dense clots formed of smaller fibrin fibres immediately following exercise compared to at rest. Conventional markers of coagulation confirmed findings of previous studies. Conclusion This study demonstrates that d f is a sensitive technique which quantifies the structure and properties of blood clots following exercise. In healthy individuals, the haemostatic balance between coagulation and fibrinolysis is maintained in equilibrium following exercise. In individuals with underlying vascular damage who participate in exercise, this equilibrium may be displaced and lead to enhanced clot formation and a prothrombotic state. d f may therefore have the potential to not only quantify hypercoagulability, but may also be useful in screening these individuals.

Balancing the beneficial effects of resuscitation fluids against their detrimental effect on hemostasis is an important clinical issue. We aim to compare the in vitro effects of 3 different colloid resuscitation fluids (4.5% albumin, hydroxyethyl starch [Voluven 6%], and gelatin [Geloplasma]) on clot microstructure formation using a novel viscoelastic technique, the gel point. This novel hemorheologic technique measures the biophysical properties of the clot and provides an assessment of clot microstructure from its viscoelastic properties. Importantly, in contrast to many assays in routine clinical use, the measurement is performed using unadulterated whole blood in a near-patient setting and provides rapid assessment of coagulation. We hypothesized that different colloids will have a lesser or greater detrimental effect on clot microstructure formation when compared against each other.Healthy volunteers were recruited into the study (n = 104), and a 20-mL sample of whole blood was obtained. Each volunteer was assigned to 1 of the 3 fluids, and the sample was diluted to 1 of 5 different dilutions (baseline, 10%, 20%, 40%, and 60%). The blood was tested using the gel point technique, which measures clot mechanical strength and quantifies clot microstructure (df) at the incipient stages of fibrin formation.df and clot mechanical strength decrease with progressive dilution for all 3 fluids. A significant reduction in df from baseline was recorded at dilutions of 20% for albumin (P.0001), 40% for starch (P.0001), and 60% for gelatin (P.0001). We also observed significant differences, in terms of df, when comparing the different types of colloid (P.0001). We found that albumin dilution produced the largest changes in clot microstructure, providing the lowest values of df (= 1.41 ± 0.061 at 60% dilution) compared with starch (1.52 ± 0.081) and gelatin (1.58 ± 0.063).We show that dilution with all 3 fluids has a significant effect on coagulation at even relatively low dilution volumes (20% and 40%). Furthermore, we quantify, using a novel viscoelastic technique, how the physiochemical properties of the 3 colloids exert individual changes on clot microstructure.

SummaryVenous thromboembolism (VTE) is common in cancer patients, and is the second commonest cause of death associated with the disease. Patients with chronic inflammation, such as cancer, have been shown to have pathological clot structures with modulated mechanical properties. Fractal dimension (df) is a new technique which has been shown to act as a marker of the microstructure and mechanical properties of blood clots, and can be performed more readily than current methods such as scanning electron microscopy (SEM). We measured df in 87 consecutive patients with newly diagnosed lung cancer prior to treatment and 47 matched-controls. Mean group values were compared for all patients with lung cancer vs controls and for limited disease vs extensive disease. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Significantly higher values of df were observed in lung cancer patients compared with controls and patients with extensive disease had higher values than those with limited disease (p< 0.05), whilst conventional markers failed to distinguish between these groups. The relationship between df of the incipient clot and mature clot microstructure was confirmed by SEM and computational modelling: higher df was associated with highly dense clots formed of smaller fibrin fibres in lung cancer patients compared to controls. This study demonstrates that df is a sensitive technique which quantifies the structure and mechanical properties of blood clots in patients with lung cancer. Our data suggests that df has the potential to identify patients with an abnormal clot micro-structure and greatest VTE risk.

Objectives Changes in clot microstructure are increasingly implicated in the pathology of atherosclerosis although most data are from techniques in the remote laboratory using altered blood. We validate the novel biomarker Gel Point in STEMI patients and assess therapeutic interventions. Gel Point marks the transition of blood from a visco-elastic liquid to visco-elastic solid and is rapidly measured using unadulterated blood. The Gel Point provides measurements of three parameters to reflect clot microstructure (fractal dimension ( d f )), real-time clot formation time ( T GP ) and blood clot strength (elasticity at the Gel Point ( G ′ GP )). Methods We prospectively recruited 38 consecutive patients with STEMI undergoing primary percutaneous coronary intervention (pPCI). Venous blood samples were collected on admission, after pPCI and 24 h after admission for assessment of the new biomarkers, standard coagulation tests and scanning electron microscopy (SEM). Results d f after pPCI was lower than d f on admission (mean 1.631 [SD 0.063] vs 1.751 [0.052], p d f at 24 h was similar to that on admission. G ′ GP also showed similar trend to d f (p T GP was prolonged at after-PCI measurement compared with admission (median 854 s [IQR 581–1801] vs 217 [179–305], p d f and G ′ GP were consistent with changes in the SEM images of the mature clot. Conclusions We characterise Gel Point derived markers of clot microstructure in patients admitted with emergency arterial thrombosis. This point of care test can potentially be used to assess the efficacy of therapeutic interventions by measuring changes in clot microstructure.

Background Venous thromboembolism (VTE) is common in patients with cancer, contributing significantly to morbidity and mortality Currently, no test reliably identifies patients at increased risk of developing VTE who would therefore benefit from prophylactic intervention. The aim of the current study was to evaluate rotational thromboelastometry (ROTEM) in identifying VTE risk in patients with lung cancer. We also compared parameters of ROTEM in patients with limited and extensive disease. Methods Parameters of ROTEM were measured in 67 patients with lung cancer and 72 age-matched healthy controls and compared with conventional markers of haemostasis. Patients were followed up for 12 months and VTE incidence recorded. Results Lung cancer patients had a reduced clotting time (CT), increased maximum clot firmness (MCF) and increased alpha angle compared with controls. Patients also had significantly higher levels of fibrinogen and PAI-1 than controls and in the former group there was a strong correlation between fibrinogen and both MCF and alpha angle. Six patients developed a VTE during the follow-up period and all had values for MCF at or above the upper limit of normal for EXTEM. Conclusions This study demonstrates that several ROTEM parameters are significantly different in lung cancer patients compared to healthy age-matched controls, whereas only one of the parameters measured is significantly different between extensive compared to limited disease. No differences were observed between patients who developed a VTE compared to those who did not, highlighting the limitations of ROTEM use in patients with lung cancer.

This study compared patients with venous thromboembolism (VTE) to non-VTE patients using a biomarker of clot microstructure (df ) and clot formation time (TGP ). df was the only marker that identified a significant difference (P < 0·001) between the VTE (n = 60) and non-VTE cohorts (n = 69). The 'abnormal' clot microstructures in the VTE patients suggests either inadequate response to anticoagulant therapy or the presence of a procoagulant state not detected by other markers of coagulation (i.e., International Normalized Ratio). Furthermore, elevated values of df in first time VTE patients who later develop a secondary event indicates that df may identify those at risk of recurrence.

We investigated the effect of progressive haemodilution on the dynamics of fibrin clot formation and clot microstructure using a novel rheological method. The technique measures clotting time (TGP), clot strength (G`GP), and quantifies clot microstructure (df) at the incipient stages of fibrin formation. We use computational modelling to examine the relationship between structure and mass, as well as helium ion microscopy (HIM) to compare morphological changes in the fully formed clot to that of the incipient clot.This is an in vitro study; 90 healthy volunteers were recruited with informed consent and a 20ml sample of whole blood obtained from each volunteer. Five clinically relevant dilutions were investigated using 0.9w.v isotonic saline (0, 10, 20, 40 and 60%, n=18 for each dilution). The rheological method of assessing structural clot changes was compared against conventional coagulation screen and fibrinogen estimation.Fractal dimension (df) and final clot microstructure both decreased with progressive dilution (significant at a dilution of 20%) with similar relationships observed for final clot characteristics in HIM images. Significant correlations were observed between df and G`GP (clot strength) (0.345, p=0.02), as well as clotting time (PT: -0.690, p0.001; APTT: -0.672, p0.001; TGP: -0.385, p=0.006).This study provides new insight into the effects of haemodilution by isotonic saline on clotting time (TGP), clot strength (G'GP) and clot microstructure (df). Previous studies have attempted to link clot microstructure to clot quality/strength, however this study provides a significant step in quantifying these relationships.

Congenital granular cell tumour is a rare, benign, soft tissue lesion of the oral cavity. Large or multiple lesions can cause mechanical obstruction of the oral cavity and may result in prenatal polyhydramnios, and postnatal feeding and respiratory problems.We present a case in which prenatal diagnostic imaging was used in the successful management of an infant with a large congenital granular cell tumour.

OBJECTIVE: To assess the prognostic and diagnostic value of whole blood impedance aggregometry in patients with sepsis and SIRS and to compare with whole blood parameters (platelet count, haemoglobin, haematocrit and white cell count). METHODS: We performed an observational, prospective study in the acute setting. Platelet function was determined using whole blood impedance aggregometry (multiplate) on admission to the Emergency Department or Intensive Care Unit and at 6 and 24 hours post admission. Platelet count, haemoglobin, haematocrit and white cell count were also determined. RESULTS: 106 adult patients that met SIRS and sepsis criteria were included. Platelet aggregation was significantly reduced in patients with severe sepsis/septic shock when compared to SIRS/uncomplicated sepsis (ADP: 90.7±37.6 vs 61.4±40.6; p

Introduction Prevalence of OSAS in people with cardiovascular disease is much higher than in the general population. Many OSAS patients are prescribed Aspirin for secondary prevention of cardiovascular events but the effects of morning Aspirin might be attenuated by night of recurrent apnoeas and intermittent hypoxia. Therefore evening dosing might be more appropriate. Aim To assess platelets function in the afternoon and immediately post-sleep in untreated OSAS subjects who are on long term once daily 75mg Aspirin (am). Methods 11 subjects with newly diagnosed and untreated severe OSAS prescribed Aspirin by their physicians: 10 males, (mean + SD) BMI 40.8 ± 7.2 kg/m 2 , age 60.8 ± 10.02 years, 4% Desaturation rate (4% DR) 58.4 ± 40.8 events/hour. Platelet aggregation was induced in vitro by collagen (COL), adenosine-diphoshate (ADP), and arachidonic acid (ASPI). Platelet activation was measured by multiple electrode platelet aggregometry (Multiplate™). Blood samples were collected at 4pm then 7:30am the following morning, prior to the Aspirin dose. Results Platelet aggregation in response to ASPI was reduced in the presence of Aspirin as expected and the effects were the same in the afternoon (38.6 ± 44.4 units) versus morning (39.2 ± 36.2 units). There was no difference between afternoon and morning platelet function (p > 0.05 for all measures of platelet aggregation using three agonists) (Figure 1). Conclusions 75 mg of once daily (morning) Aspirin was sufficient to block in vitro platelet aggregation in untreated severe OSAS over a 24 hour period and was not influenced by recurrent apnoeas occurring just prior to blood sampling.

Introduction Platelets are critical drivers of thrombus formation with high on-treatment platelet reactivity despite dual antiplatelet therapy (DAPT) representing a risk factor for thrombosis. Coagulation pathways also play a central role and configuration of the fibrin network is a vital determinant of clot stability and outcome,with dense clots composed of compact thin fibres associated with thrombotic events. However, despite the interwoven nature of platelet activation and the coagulation system, studies relating both aspects of thrombosis in the same population are limited. Methods Four groups of healthy volunteers (n = 8) received single anti-platelet therapy aspirin (75 mg) or prasugrel (10 mg) or DAPT with aspirin (75 mg) plus prasugrel (10 mg) or aspirin (75mg) plus ticagrelor (90mg) for 7 days. In this study, we characterised the influences of these standard anti-platelet therapies on platelet function using standard tests of platelet activation and aggregation. We then associated platelet reactivity to fibrin clot microstructure which was determined using advanced rheological techniques to analyse the viscoelastic properties of incipient clots; fractal dimension (D f ) and mean relative mass (RM). Results Aspirin alone caused inhibition of platelet responses to arachidonic acid (AA), but did not reduce ATP release, P-selectin or PAC-1 binding. Aspirin also had no effect upon the measures of clot structure D f (1.71 ± 0.01 to 1.69 ± 0.01, p = 0.41) or RM (-8 ± 19%, p = 0.47). Prasugrel significantly reduced D f (1.72 ± 0.02 to 1.67 ± 0.01, p = 0.03) and RM(-40 ± 11%, p = 0.03), as well as caused a significant decrease in ATP release, PAC-1 and p-selectin expression (p f ; 1.73 ± 0.02 to 1.68 ± 0.02 (p = 0.03) and 1.72 ± 0.03 to 1.62 ± 0.02 (p = 0.04) by aspirin+prasugel and aspirin+ticagrelor, respectively. This corresponded to reductions in RM both for aspirin plus prasugrel (-35 ± 16% change, p = 0.04) and for aspirin plus ticagrelor (-45 ± 14% change, p = 0.04). Conclusion We demonstrate that platelets are important determinants of clot microstructure which is modifiable by anti-platelet therapies. These therapies may rely on their abilities to reduce thrombus density to exert their therapeutic effects with increased levels of platelet inhibition associated with the formation of more open, porous fibrin clots. We also suggest that it is activation of P2Y 12 receptors rather than TX (A 2 ) receptors that are key to clot formation. We conclude that there lies both diagnostic and therapeutic potential in determining the functional relationship between platelet reactivity, eventual clot quality and clinical outcome and D f could be a useful novel biomarker in risk stratification and tailored anti-platelet therapies.

Treatment for conditions of the mandible may require resection of the affected segment, and this may need reconstruction. There are case reports of spontaneous regeneration of segments of excised mandibles that resulted in reduced or no need for reconstruction, and we present four such cases. The age at presentation ranged from 6 to 12 years. In all cases the periosteum was preserved during resection. All patients showed evidence of spontaneous regeneration, both clinically and radiographically, between 3 and 5 months after resection. The planned delayed reconstruction meant that these patients either did not need any bony reconstruction, or needed less than had originally been anticipated. Such regeneration is mostly reported in children, and is thought to be the result of an intact periosteal layer. In patients having planned mandibular resections, where the periosteum is preserved, some spontaneous regeneration should be anticipated and final reconstruction delayed until this is complete.

Here we report the first application of a fractal analysis of the viscoelastic properties of incipient blood clots. We sought to ascertain whether the incipient clot's fractal dimension, Df, could be used as a functional biomarker of hemostasis. The incipient clot is formed at the gel point (GP) of coagulating blood, the GP demarcating a functional change from viscoelastic liquid to a viscoelastic solid. Incipient clots formed in whole healthy blood show a clearly defined value of Df within a narrow range that represents an index of clotting in health, where Df = 1.74 (± 0.07). A significant relationship is found between the incipient clot formation time, TGP, and the activated partial thromboplastin time, whereas the association of Df with the microstructural characteristics of the incipient clot is supported by its significant correlation with fibrinogen. Our study reveals that unfractionated heparin not only prolongs the onset of clot formation but has a significant effect on its fractal microstructure. A progressive increase in unfractionated heparin concentration results in a linear decrease in Df and a corresponding prolongation in TGP. The results represent a new, quantitative measure of clot quality derived from measurements on whole blood samples.

Background More than 200 combinations of antiplatelet and anticoagulant drugs can be given during an acute cardiac event. However, no biomarker is available to assess their global effect on clot formation and structure. Fractal dimension (D f ) and clot formation time (T GP ) are global markers of haemostasis that have been validated in healthy and anticoagulated blood. In contrast to standard coagulation assays, these biomarkers use unadulterated whole blood and are measured immediately at the bedside. D f quantifies clot microstructure whereas T GP is a real-time measure of clotting time, and both are calculated from the gel point (GP). We aimed to validate D f and T GP in ST-segment-elevation myocardial infarction (STEMI) and assess the effect of therapeutic intervention. Methods We recruited prospectively patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Venous blood samples were collected on admission (after 300 mg of aspirin), after PCI (after clopidogrel, heparin, and bivalirudin), and 24 h after admission. In addition to assessment of D f and T GP , each sample was assessed by standard coagulation tests and a full blood count. Wilcoxon signed-rank and paired t tests were used to compare changes from admission to after PCI and at 24 h. Spearman's correlation analysis was done to explore any associations. Normality was assessed with the Shapiro-Wilks test. This study was approved by the local Research Ethics Committee (REC Number 07/WMW02/34) and written informed consent was obtained from all participants. Findings 33 patients (mean age 69 years [SD 12]; 19 men, 14 women) were included. D f on admission (mean 1·75, SD 0·05) was higher than values we have previously reported in healthy individuals despite use of antiplatelet therapy. D f after PCI was significantly lower than D f on admission (mean 1·64 [SD 0·06] vs 1·75 [0·05], p f at 24 h was similar to that on admission. T GP was significantly prolonged at after-PCI measurement compared with admission (median 723 s [IQR 492–1793] vs 210 [173–314], p f correlated negatively with T GP ( r =−0·75, p r =−0·49, p r =−0·52, p r =0·36, p=0·0009). There was no significant correlation observed between D f and platelets or haematocrit. Interpretation Therapeutic manipulation in STEMI especially with drugs given during PCI had a striking effect on clot structure and rate of coagulation as measured by D f and T GP . Larger studies are in progress to evaluate potential therapeutic strategies based on these biomarkers and their accuracy in detecting hypocoagulable and hypercoagulable states, and predicting cardiovascular risk. Funding National Institute for Social Care and Health Research, Engineering and Physical Sciences Research Council.

Introduction Untreated obstructive sleep apnoea syndrome (OSAS) increases cardiovascular risk and altered haemostasis is at least partly implicated. As previously reported using fractal analysis and a new biomarker called fractal dimension (Df) it is possible to assess the microstructure of incipient clot in whole blood (1). Df relates to the kinetics of clot formation and quantifies clot fibrin network microstructure as it forms. A higher Df represents a more pro-coagulable state. Healthy volunteers have a reproducible Df of 1.74(0.07) (2). Aim To see if Df changes in OSAS after an acute and subacute treatment with CPAP. Methods 36 patients with newly diagnosed OSAS: 32 males, mean (SD), BMI = 37.1 (7.5) kg/m 2 , age 56.6 (10.2) years, 4% desaturation rate (4% DR) = 44.6 (31.1) events/hour, Epworth Sleepiness Score (ESS) 13.23 (5.0). Blood was collected at baseline prior to CPAP treatment and then after the first night and 4 weeks of CPAP. Samples were tested for fractal analysis (AR-G2 Rheometer, TA Instruments, UK). Results Patients who were commenced on CPAP were followed up within an average of 36.97(6.29) days. CPAP compliance was overall satisfactory with a mask on average time of 4.43 (1.8) hrs/night. Repeated overnight pulse oximetry while on CPAP showed a significant improvement in sleep study variables (4% DR = 7.58 (8.3) events/hr; p Conclusion As reported previously OSAS is associated with a significantly increased prothrombotic state in the morning that is detected by Df. Acute CPAP use in OSAS is sufficient to alter fibrin clot microstructure which can be quantified with Df. This preliminary data suggest Df could be used as a new sensitive biomarker to assess vascular risk. References Wilczynska M et al Thorax . 2012;67:A23-A23 Evans PA et al Blood . 2010;116:3341–3346

We have investigated the hypothesis that in whole blood the incipient clot formed at the gel point (GP) is characterised by a fractal microstructure [1,2] and that this could be detected in healthy and anticoagulated blood. We compared the gel time (GT) required to form the incipient clot and the corresponding fractal dimension (df) against laboratory markers of haemostasis and thromboelastography (TEG).

Angiogenesis is the formation of new blood vessels, a phenomenon that should be distinguished from the elongation and enlargement of existing vessels, although both frequently combine to increase the blood supply or vascularity of a tissue. Angiogenesis is indispensable for the growth of tissues and organs, and is a feature of a number of normal and pathological conditions. The term was first used to describe vascular development in the placenta. Other examples of angiogenesis include the reconstitution of the uterine lining after menstruation, wound healing, chronic inflammation, diabetic retinopathy, immunological reactions, thrombosis and neoplasia.

Stroke is the second largest cause of death worldwide. Hypercoagulability is a key feature in ischaemic stroke due to the development of an abnormally dense clot structure but techniques assessing the mechanics and quality of clot microstructure have limited clinical use. We have previously validated a new haemorheological technique using three parameters to reflect clot microstructure (Fractal Dimension (d f )) ex-vivo, real-time clot formation time (T GP ) and blood clot strength (elasticity at the gel point (G’GP)). We aimed to evaluate these novel clotting biomarkers in ischaemic stroke and changes of clot structure following therapeutic intervention. In a prospective cohort study clot microstructure was compared in ischaemic stroke patients and a control group of healthy volunteers. Further assessment took place at 2–4 hours and at 24 hours after therapeutic intervention in the stroke group to assess the effects of thrombolysis and anti-platelet therapy. 75 patients (mean age 72.8 years [SD 13.1]; 47 male, 28 female) with ischaemic stroke were recruited. Of the 75 patients, 32 were thrombolysed with t-PA and 43 were loaded with 300 mg aspirin. The following parameters were significantly different between patients with stroke and the 74 healthy subjects: d f (1.760 ± .053 versus 1.735 ± 0.048, p = 0.003), TGP (208 ± 67 versus 231 ± 75, p = 0.05), G’GP (0.056 ± 0.017 versus 0.045 ± 0.014, p