Blood coagulation disorders

Non-arteritic anterior ischemic optic neuropathy is caused by a transient optic nerve ischemia and results in permanent vision loss. Currently, there is no effective treatment for this ischemic optic nerve injury. This study characterized the duration and extent of ischemia induced after a coagulopathy injury to the optic nerve of adult rats. Acute ischemia was induced in adult rats by intravenous injection of Rose Bengal dye, followed by argon green laser treatment of the vessels at the optic disc. Rats were assessed in the short-term for hypoxyprobe-1 binding and expression of hypoxia inducible factor-1α (HIF-1 α) and fractin, markers of neuronal injury. Five months after injury, optic axon number was quantified. The coagulopathy injury resulted in short-term hypoxia in the optic nerve and retina. Tissues were hypoxic within 15 min of the coagulopathy injury, but normoxic by 24 h as measured by hypoxyprobe-1 staining. Both HIF-1α and fractin were upregulated in ganglion cells variably across the retina. Five months after the ischemic injury, there was a 71% reduction in optic axon number compared to controls. It is critical to have a reproducible and relevant method for producing transient hypoxia in order to test therapeutic strategies for rescuing injured neurons. The coagulopathy induced in this study resulted in a reproducible and transient ischemic optic nerve injury and long-term axonal loss. This ischemia shows similar, although not identical, morphological and physiological changes to those seen in the human eye after optic nerve ischemia. We are currently testing therapeutic strategies to protect ganglion cells from degeneration after this ischemic injury.

Autism, archetype of the autistic spectrum disorders (ASD), is a neurodevelopmental disorder characterized by socially aloof behavior and impairment of language and social interaction. Its prevalence has surged in recent years. Advanced functional brain imaging has confirmed pervasive neurologic involvement. Parent involvement in autism management has accelerated understanding and treatment. Often accompanied by epilepsy, cognitive deficits, or other neurologic impairment, autism manifests in the first three years of life and persists into adulthood. Its etiopathology is poorly defined but likely multifactorial with heritability playing a major role. Prenatal toxic exposures (teratogens) are consistent with autism spectrum symptomatology. Frequent vaccinations with live virus and toxic mercurial content (thimerosal) are a plausible etiologic factor. Autistic children frequently have abnormalities of sulfoxidation and sulfation that compromise liver detoxification, which may contribu...

Introduction. The routine pre-operative evaluation of children undergoing elective tonsillectomy and/or adenoidectomy includes coagulation screening tests. The purpose of the study: detection of coagulation defects in children with planned tonsillectomy and/or adenoidectomy. Material and methods. In our study we examined 68 children with abnormal coagulation profile, age 1-17 (average 7,5), 43 male and 25 female. All children underwent coagulation tests (APTT, PT, INR, D-dimer, fibrynogen). In case of twice indicated coagulopathy we diagnosed the levels of the coagulation protein factors. Results. After second verification 15/68 (22%) patients presented prolonged APTT and/or PT. The most common disorder was isolated prolongation of APTT-47/53(89%), 3/53 (5,5%) had prolonged PT and 3/53 (5,5%) had both disorders in the same time. After vitamin K admission in 19/53 (36%) coagulation tests returned to normal. 13/53 (24%) patients had the factor XII deficiency, 1 patient had a low activity of von Willebrand factor and temporary deficient of factor VIII. In one case we found temporary deficiency of factors VIII and IX and one boy had isolated, temporary deficiency of factor IX. Rest of patients 21/53 (40%), in which the activity of coagulation factors were normal, underwent surgery despite prolonged APTT without any bleeding during or after surgery. Conclusions. The coagulation disorders in analized group of children were unstable or inessential, but in a group of 3/68 (4%) nondiagnosed disorders of coagulation tests, may due to heavy bleeding during or after surgery.

Thromboelastography (TEG) in venous air embolism (VAE) has been poorly studied. We induced coagulation abnormalities by VAE in a rat model, assessed by TEG with and without mexiletine, a lidocaine analogue local anesthetic. Twenty-three Sprague Dawley rats instrumented under isoflurane anesthesia and allowed to recover five days prior to the experiments were randomized into three experimental groups: 1) VAE (n = 6); 2) VAE and mexiletine (n = 9); and 3) normal saline (NS) alone (control group, n = 8). Blood samples were collected at baseline, one hour (h) and 24 h in all groups and analyzed by TEG to record the R, K, angle α and MA parameters. In Group 1, VAE decreased significantly R at 1 h (31%), K at 1 h (59%) and 24 h (34%); α increased significantly at 1 h (30%) and 24 h (22%). While R returned to baseline values within 24 h, K, MA and α did not. In group-2 (Mexiletine + VAE), K and R decreased at 1 h (48% and 29%, respectively) and at 24 h the changes were non-significant. Ang...

To evaluate if elevated D-dimer level is specific for venous malformations (VMs) and thus useful for differential diagnosis, which can be problematic even in specialized interdisciplinary centers. Localized intravascular coagulopathy, characterized by elevated D-dimer levels, has been observed in approximately 40% of patients with VMs. Design: Prospective convenience sample accrued from 2 interdisciplinary sites. Setting: Two interdisciplinary centers for vascular anomalies in Brussels, Belgium, and Caen, France Participants: The study population comprised 280 patients with clinical data, Doppler ultrasonograms (for 251 patients), and coagulation parameter measurements. Main Outcome Measure: Measurement of D-dimer levels. Results: A VM was diagnosed in 195 of 280 patients (69.6%), and 83 of them had elevated D-dimer levels; the sensitivity of D-dimer dosage was 42.6% (95% confidence interval, 35.6%-49.5%). Among the 85 patients without VM, D-dimer levels were elevated only in 3 patients; the specificity of the dosage was 96.5% (95% confidence interval, 92.5%-100%). Conclusions: Elevated D-dimer level is highly specific for VMs (pure, combined, or syndromic), and therefore this easy and inexpensive biomarker test should become part of the clinical evaluation of vascular anomalies. It can detect hidden VMs and help differentiate glomuvenous malformation (normal D-dimer levels) from other multifocal venous lesions. Elevated D-dimer level also differentiates a VM from a lymphatic malformation. Moreover, slow-flow Klippel-Trenaunay syndrome (capillaro-lymphatico-venous malformation with limb hypertrophy) can be distinguished from fast-flow Parkes Weber syndrome (capillary malformation with underlying multiple microfistulas and limb hypertrophy). For these reasons, D-dimer level measurement is a useful complementary tool for diagnosing vascular anomalies in everyday practice.

Severe trauma continues to represent a global public health issue and mortality and morbidity in trauma patients remains substantial. A number of initiatives have aimed to provide guidance on the management of trauma patients. This document focuses on the management of major bleeding and coagulopathy following trauma and encourages adaptation of the guiding principles to each local situation and implementation within each institution. The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies. The group used a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were reconsidered and rev...

A bleeding child is a cause of great concern and often, panic, for parents and pediatricians alike. Causes of bleeding could be trivial or secondary to an underlying bleeding disorder or a potentially serious systemic illness. Based on etiology, they can be categorized into disorders affecting platelets or the coagulation cascade and can be inherited or acquired. A systematic approach with relevant clinical history and examination along with appropriate laboratory investigations aid in reaching the diagnosis promptly. Indication and administration of blood products including fresh frozen plasma, cryoprecipitate, random donor and single donor apheresis platelets is elaborated. Management of hemophilia, Von Willebrand disease, disseminated intravascular coagulation and bleeding in cyanotic congenital heart disease, among other causes is outlined. Role of antifibrinolytic therapy, desmopressin and recombinant factor VIIa is briefly described. The review outlines the approach to a bleeding child in the emergency room. Practical points in history, examination, investigations and management are discussed. Management in resource constraint setting of developing countries is addressed.

Autism and allied autistic spectrum disorders (ASD) present myriad behavioral, clinical, and biochemical abnormalities. Parental participation, advanced testing protocols, and eclectic treatment strategies have driven progress toward cure. Behavioral modification and structured education are beneficial but insufficient. Dietary restrictions, including removal of milk and other casein dairy products, wheat and other gluten sources, sugar, chocolate, preservatives, and food coloring are beneficial and prerequisite to benefit from other interventions. Individualized IgG or IgE testing can identify other troublesome foods but not non-immune mediated food sensitivities. Gastrointestinal improvement rests on controlling Candida and other parasites, and using probiotic bacteria and nutrients to correct dysbiosis and decrease gut permeability. Detoxification of mercury and other heavy metals by DMSA/DMPS chelation can have marked benefit. Documented sulfoxidation-sulfation inadequacies call...

The pathogenesis of diabetic retinopathy (DR) is insufficiently understood but may possibly involve chronic, low-grade inflammation. The aim of this cross-sectional study was to investigate the relationship between inflammatory and haemostatic markers, other markers of endothelial dysfunction and anthropometric parameters, and their association with DR in patients with type 2 diabetes. Methods. According to the DR status patients were divided into three groups: no retinopathy, mild/moderate nonproliferative (NPDR), and severe NPDR/proliferative retinopathy (PDR). Results. The groups did not differ in the levels of inflammatory and haemostatic markers, other markers of endothelial dysfunction, and anthropometric parameters. After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (= 0.0265) and in fibrinogen according to the WHR (= 0.0102) as well as in total cholesterol (= 0.0109) and triglycerides (= 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes. Conclusion. Interrelations between obesity, inflammation, haemostatic disturbance, and other risk factors may possibly play an important additional role in endothelial dysfunction involved in the pathogenesis of diabetic retinopathy.

Video 1: Platelet aggregometry using ROTEM Color coded graph for interpretation Reference values of INTEM, HEPTEM, EXTEM, and FIBTEM The ROTEM platelet system is a new module that can be added to the ROTEM, enabling simultaneous analysis of thromboelastometry measurements and platelet aggregation using impedance aggregometry.

The liver plays a central role in the maintenance of haemostasis. It serves as the site of synthesis of all clotting factors and their inhibitors. Thus liver damage from chronic liver disease can develop multiple coagulation abnormalities that disturb the balance between clotting and ...

OBJECTIVE-To define the frequency, risk factors, and outcomes of massive transfusion in obstetrics. METHODS-The State Inpatient Dataset for New York (1998-2007) was used to identify all delivery hospitalizations for hospitals that reported at least one delivery-related transfusion per year. Multivariable logistic regression analysis was performed to examine the relationship between maternal age, race, and relevant clinical variables and the risk of massive blood transfusion defined as 10 or more units of blood recorded. RESULTS-Massive blood transfusion complicated 6 of every 10,000 deliveries with cases observed even in the smallest facilities. Risk factors with the strongest independent associations with massive blood transfusion included abnormal placentation (1.6/10,000 deliveries, adjusted odds ratio [OR] 18.5, 95% confidence interval [CI] 14.7-23.3), placental abruption (1.0/10,000, adjusted OR 14.6, 95% CI 11.2-19.0), severe preeclampsia (0.8/10,000, adjusted OR 10.4, 95% CI 7.7-14.2), and intrauterine fetal demise (0.7/10,000, adjusted OR 5.5, 95% CI 3.9-7.8). The most common etiologies of massive blood transfusion were abnormal placentation (26.6% of cases), uterine atony (21.2%), placental abruption (16.7%), and postpartum hemorrhage associated with coagulopathy (15.0%). A disproportionate number of women who received a massive blood transfusion experienced severe morbidity including renal failure, acute respiratory distress syndrome, sepsis, and in-hospital death.

Disseminated intravascular coagulation (DIC) may result in hemorrhagic and thrombotic complications and is rarely associated with stable abdominal aortic aneurysms. In a retrospective review of our experience over the past 5 years, we identified only two instances of DIC-associated abdominal aortic aneurysms among a total of 67 patients who were operated on for asymptomatic aneurysms. In the first patient with DIC induced by abdominal aortic aneurysm, consumptive coagulopathy and a bleeding diathesis developed. The second patient's course was complicated by consumptive coagulopathy and migrating thrombophlebitis. In both instances coagulopathy resolved after surgical intervention. In this report we briefly discuss the pathogenesis and laboratory diagnosis of aneurysm-associated DIC and review current management strategies.

Background: Rare bleeding disorders (RBDs) are heterogeneous disorders, mostly inherited in an autosomal recessive pattern. Iran is a Mideast country with a high rate of consanguinity that has a high rate of RBDs. Objective: In this study, we present prevalence and clinical presentation as well as management and genetic defects of Iranian patients with RBDs. Methods: For this study, all relevant publications were searched in Medlin until 2015. Results and discussion: Iran has the highest global incidence of factor XIII deficiency. Factor VII deficiency also is common in Iran, while factor II deficiency, with a prevalence of 1 per ∼3 million, is the rarest form of RBDs. Factor activity is available for all RBDs except for factor XIII deficiency, in which clot solubility remains as a diagnostic test. Molecular analysis of Iranian patients with RBDs revealed a few recurrent, common mutations only in patients with factor XIII deficiency, and considerable novel mutations in other RBDs. Clinical manifestations of these patients are variable and patients with factor XIII, factor X and factor VII more commonly presented severe life-threatening bleeding, while patients with combined factor V and factor VIII presented a milder phenotype. Plasma-derived products are the most common therapeutic choice in Iran, used prophylactically or on-demand for the management of these patients. Conclusion: Since Iran has a high rate of RBDs with life-threatening bleeding, molecular studies can be used for carrier detection and, therefore, prevention of the further expansion of these disorders and their fatal consequence.

To study the relationship between hypofibrinolysis, thrombophilia, and osteonecrosis. We evaluated the frequency of abnormal concentrations of 9 coagulation factors in patients diagnosed with osteonecrosis. Blood samples were drawn from 45 patients diagnosed with osteonecrosis. Etiologic associations included systemic lupus erythematosus (n = 9), inflammatory bowel disease (n = 1), corticosteroid therapy (n = 20), or history of heavy alcohol (n = 4) or tobacco (n = 3) use. No associated risk factors were identified in 5 patients; these individuals were labeled "idiopathic." The patient cohort was matched to a similarly studied cohort of 40 healthy individuals without documented osteonecrosis. The following factors were analyzed: plasminogen activator inhibitor (PAI-Fx), stimulated tissue plasminogen activator, lipoprotein (a), resistance to activated protein C, anticardiolipin antibodies (aCL IgG, IgM), protein C, protein S (free), and homocysteine. Thirty-seven of the 45 ...

Case records of 177 patients admitted with Hodgkin's disease were reviewed to assess the frequency and significance of coagulation abnormalities. Prolongation of the prothrombin time, aclivated partial thromboplasUn time, or thrombin time occurred in 56 patients, 32 percent of all evaluable cases. The most frequent clotting abnorrealities Involved the prothrombin time, which was increased in 43 patients (24 percent). Prothrombin time prolongation correlated with bulky or advanced disease as defined by stage (p = 0.001), consti-tuUonal symptoms (p <0.0001), massive medlastinal Involvement (p = 0.02), and elevated alkaline phosphatase levels (p <0.0001). Abnormal coagulation test results followed the course of disease, normalizing with tumor regression and reappearing during relapse. Despite the surprising incidence of abnormal coagulation results, bleeding complications were reported in only two cases. Patients undergoing invaslve procedures in the presence of clotting abhormalitles fared no worse than those in whom procedures were cancelled. There is no evidence that complete staging evaluation should be compromised because of these abnormal test values. Extensive hematologic testing revealed no single mechanism to explain the coagulation factor disorders found in Hodgkin's disease.

Video 1: Platelet aggregometry using ROTEM Color coded graph for interpretation Reference values of INTEM, HEPTEM, EXTEM, and FIBTEM The ROTEM platelet system is a new module that can be added to the ROTEM, enabling simultaneous analysis of thromboelastometry measurements and platelet aggregation using impedance aggregometry.

BACKGROUND The pathophysiological mechanism associated with the higher prothrombotic tendency in atrial fibrillation (AF) is complex and multifactorial. However, the role of prothrombotic markers in AF remains inconclusive. MATERIAL AND METHODS We conducted a meta-analysis of observational studies evaluating the association of coagulation activation, fibrinolytic, and endothelial function with occurrence of AF and clinical adverse events. A comprehensive subgroup analysis and meta-regression was performed to explore potential sources of heterogeneity. RESULTS A literature search of major databases retrieved 1703 studies. After screening, a total of 71 studies were identified. Pooled analysis showed the association of coagulation markers (D-dimer (weighted mean difference (WMD) =197.67 and p&lt;0.001), fibrinogen (WMD=0.43 and p&lt;0.001), prothrombin fragment 1-2 (WMD=0.53 and p&lt;0.001), antithrombin III (WMD=23.90 and p=0.004), thrombin-antithrombin (WMD=5.47 and p=0.004));  fibr...

Trauma is a major cause of death, and haemorrhage represents an important target for improving outcomes after severe injury. Volume replacement with crystalloids in resuscitation might become harmful in large amounts because of coagulopathy. A fine balance must be achieved between haemodynamic and haemostatic resuscitation. Permissive hypotension refers to permitting some degree of hypotension in such adult patients in an attempt to attain this fine balance. For patients who require a significant volume of blood product resuscitation, the term &#39;massive transfusion protocol&#39; (MTP) is used. There is very little data on transfusion protocols for paediatric trauma patients, and children respond to hypovolemic shock in a different physiological manner compared to adults. Hence, concepts such as permissive hypotension may not be appropriate when treating children involved in major trauma. We recently embarked on a plan to streamline the management of blood transfusion in massive b...

Background: Thromboelastography (TEG) records the continuous profiles of whole blood coagulation by measurement of the viscoelastic changes associated with fibrin polymerization, and thereby provides a global assessment of haemostatic function. In the past decades there has been an increasing interest for TEG in clinical practice. In this paper we present the rationale for the method and a discussion of the possible application of TEG. Material and methods: This review is based on personal experience and literature retrieved from searches in PubMed. Results and interpretation: Currently TEG is used with standard coagulation tests to decrease the risk for bleeding and reduce the homologous blood transfusion in cardiac surgery with cardiopulmonary bypass and in liver surgery. Other applications are severe trauma, obstetric medicine, haemophilia and hypercoagulable conditions. Development of a modified TEG, using heparin in combination with reptilase and factor XIIIa, has the potential to monitor the effects of platelet inhibiting drugs. It should be kept in mind that the TEG is a global test of coagulation and therefore the need for additional haemostatic tests should be evaluated when applicable. The main advantage for TEG is an inexpensive patient near method for quick evaluation of the patient's global haemostatic system. Used by experienced hands, TEG is a valuable haemostatic test, the future of which is already present.

A 53 year old female who was maintained on long-term warfarin therapy due to history of pulmonary embolism, repeatedly presents with an abnormally prolonged Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). After many asymptomatic episodes were corrected with Vitamin K therapy to temporarily reverse the effects of the warfarin, the cause of the apparent coagulopathy was further investigated. Factor Activity Assays of the common pathway factors II, IX, and X all revealed critically low values; below the threshold even a loading dose of warfarin is typically capable of eliciting. The patient tested strongly positive for Tissue Transglutaminase IgA, which is highly suggestive of a gluten-sensitive enteropathy. One effect of this condition is malabsorption due to flattened intestinal villi. The patient was determined to have an acquired vitamin K deficiency secondary to gluten-sensitive enteropathy. Her condition was exacerbated by the long-term warfarin therapy, r...

Background: This retrospective study was set to assess the influence of systemic and local bone and intra-oral factors on the occurrence of implant loss from abutment connection up to 2 years. Materials and methods: The files of 700 patients, have been collected randomly from the total patient group treated by means of endosseous Brå nemark s system implants (Nobel Biocare, Gothenburg, Sweden) at the Department of Periodontology of the University Hospital of the Catholic University of Leuven. The end point observation was evaluating the loss of the implants 2 years after abutment installation. The study involved all implants that did not encounter early loss and implants for which it was possible to evaluate its status 2 years after abutment surgery. Thus, data of 412 patients (240 females) provided with 1514 implants were analyzed. For each patient, the medical history was carefully checked. Data collection and analysis were mainly focused on endogenous factors such as hypertension, coagulation problems, osteoporosis, hypo-hyperthyroidism, chemotherapy, diabetes type I or II, Crohn's disease, some local factors [e.g. bone quality and quantity, implant (length, diameter, location), type of edentulism, PTV, radiotherapy], smoking habits, and breach of sterility during surgery. Results: Radiotherapy, implant (diameter and location), and higher PTV at implant insertion and abutment connection, all affected significantly the implant loss. Conclusion: Implant location in the oral cavity and radiotherapy seem predominant to explain the occurrence of implant loss. On the other hand, smoking and systemic health factors do not seem to be prominent players in the etiology of late implant loss.

The authors illustrate some relevant emerging topics in pediatric anesthesia. Endotracheal cuffed tubes have entered into routine clinical practice in younger patients. Concerns about tracheal stenosis were overcome when manufactures began to produce a new class of high volume, low pressure endotracheal tubes. Ultrasound-guided central venous cannulation helped anesthesiologists and intensivists to more efficaciously and safely perform the invasive monitoring required by ever more invasive surgical procedures. The utility of ultrasonography in peripheral nervous blocking has also been demonstrated. Better knowledge of the pathophysiology of both hypovolemic shock and coagulation dysfunction helped made it possible to face and successfully perform even major surgical procedures and treat more dramatic trauma. The introduction of devices to monitor anesthesia depth helped clinicians to better understand the pharmacodynamic effects of anesthetics, resulting in the maintenance of a more...

The in vitro haemostatic functions of fresh whole blood (FWB) are well preserved after cold storage. This study aimed to determine whether platelets derived from FWB and stored whole blood (SWB) contribute to clot formation in tissue injury after transfusion into coagulopathic rats with polytrauma/haemorrhage (T/H). The rats were resuscitated 1 h after trauma with FWB or SWB collected from green fluorescence protein (GFP) transgenic rats. After transfusion, a liver incision was made and the tissue was collected 10 min after injury to identify GFP(+) platelets by immunohistochemistry. In comparison to FWB, platelet aggregation to adenosine diphosphate and protease-activated receptor-4 was reduced by 35% and 20%, and clotting time was shortened by 25% in SWB. After transfusion, SWB led to a significant increase in platelet activation as measured by an elevation of CD62P and phosphatidylserine expression. The platelets from SWB were in a higher activation state, and showed higher clear...

Exchange transfusion of hepatic coma in the treatment Three children with acute in[ectious hepatitis and hepatic coma were treated by exchange blood transfusion. All recovered consciousness within twelve hours. Clinical improvement was [ollowed by return to normal of blood and spinal fluid chemical vallzes.

Objectives: To describe the epidemiological profile of children and adolescents with moderate to severe traumatic brain injury admitted to an intensive care unit; to describe the frequency of coagulation disorders in these patients; to determine the relationship between coagulopathy and trauma severity; to assess the factors associated with coagulopathy; and to assess the effect of coagulopathy on the mortality of these patients. Methods: Cross-sectional study with 301 patients aged up to 16 years admitted to an intensive care unit due to moderate to severe traumatic brain injury, carried out over a 5-year period. The coagulation profile was associated with clinical, epidemiological and CT findings. Univariate and multivariate analyses were used to check the association between coagulopathy and mortality. Results: Minimum age was 23 days, and maximum age was 16 years (mean of 7.9 years). About 77% of patients had coagulopathy, whose occurrence was directly associated with the severity of the trauma, but not with the rise in mortality. The factors associated with the presence of coagulopathy were the following: severity of the traumatic brain injury (OR = 2.83; 95%CI 1.58-5.07), diagnosis of brain swelling on cranial computed tomography (OR = 2.11; 95%CI 1.13-4.07) and occurrence of chest and/or abdominal injury (OR = 2.07; 95%CI 1.11-4.00). Approximately 35% of patients died. The multivariate analysis showed that the factors associated with an increased risk of death were presence of sodium disorders (OR = 5.56; 95%CI 2.90-10.65), hypotension in the intensive care unit (OR = 12.58; 95%CI 4.40-35.00) and acute respiratory distress syndrome (OR = 13.57; 95%CI 1.51-121.66). Conclusion: The development of coagulopathy is a frequent complication in patients with moderate to severe traumatic brain injury. Even though it is not closely associated with death in this study, it may be regarded as a marker of injury severity.

Multifocal or multiple osteonecrosis (ON), defined by the involvement of 3 or more anatomic sites, is unusual, being observed in only 3%Y10% of patients diagnosed with ON. We report the clinical characteristics of a cohort of 29 patients with multifocal ON from a single center and evaluate the prevalence of associated prothrombotic abnormalities in 26 of these patients. We conducted a retrospective study of all patients diagnosed with multifocal ON evaluated in our institution during the last 20 years. We recorded clinical manifestations and underlying diagnoses. A wide thrombophilic profile was performed, including antithrombin, protein C, protein S, lupus anticoagulant, anticardiolipin antibodies, activated protein C resistance, factor V Leiden, mutation G-20210-A of the prothrombin gene, and factor VIII. Coagulation test results were compared with those in a healthy control group and a group of patients with history of lower-extremity deep venous thrombosis. The mean age of the patients was 49.2 T 15 years (range, 28Y81 yr). The mean number of ON localizations per patient was 5.2 T 2.3 (range, 3Y11). Hips were the most commonly affected joint (82%), followed by knees (58%), shoulders (37%), and ankles (13%). Most patients had an underlying disease process, and 12 of 25 (48%) patients had coagulation test abnormalities. The most common alterations were high factor VIII levels and antiphospholipid antibody (aPL) positivity in 24% and 20% of cases, respectively. These abnormalities were more prevalent in patients with multifocal ON compared with patients in the control groups. Sixty-one percent of patients had a history of corticosteroid treatment. Patients with coagulation abnormalities had a higher number of ON localizations per patient (6.5 T 2.7 vs. 3.88 T 0.8; p = 0.002) and a higher prevalence of atypical ON localizations (25% vs. 0%; p = 0.05). In conclusion, in the present cohort of patients with multifocal ON, 48% of the patients had at least 1 prothrombotic factor, especially high levels of factor VIII and aPL. These findings have major implications for the diagnosis and treatment of multifocal ON and clearly indicate the need to perform a thrombophilic profile in these patients. (Medicine 2013;92: 295Y304) Abbreviations: aCL = anticardiolipin antibodies, aPL = antiphospholipid antibodies, APS = antiphospholipid syndrome, aPTT = activated partial thromboplastin time, DVT = deep venous thrombosis, ELISA = enzyme-linked immunosorbent assay, HIV = human immunodeficiency virus, LA = lupus anticoagulant, Lp(a) = lipoprotein (a), MRI = magnetic resonance imaging, MTHFR = methylenetetrahydrofolate reductase, ON = osteonecrosis, PAI-1 = plasminogen activator inhibitor, PT = prothrombin time, SLE = systemic lupus erythematosus.

H ospitalized patients frequently require central venous access for medication administration or hemodynamic monitoring. Jugular and subclavian vein approaches are frequently preferred. Patients requiring central venous access often have underlying conditions that increase the risk of bleeding complications. Many physicians are hesitant to perform these procedures because of this greater risk. Correction of bleeding disorders with blood component therapy may decrease these complications but the administration of blood products is not without risk. It *From the Division of Pulmonary/Critical Care Medicine (Drs.

Objectives-To evaluate the use of citrated recalcified (nonactivated) thromboelastography (TEG) in healthy horses and horses with colitis and suspected coagulopathies. Design-Prospective, observational study conducted between October 2007 and June 2009. Setting-Veterinary Teaching Hospital. Animals-Forty-five healthy adult horses and 12 sick adult horses with colitis and prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT). Interventions-None. Measurements and Main Results-Whole blood was collected on admission. Coagulation profile (PT, aPTT, platelet count, and fibrinogen concentration) and citrated recalcified whole blood TEG analysis (R-time [R], Ktime [K], angle [a], maximum amplitude [MA], G value [G], lysis at 60 min [LY60]) were evaluated. Mean values (SD) for TEG parameters in healthy horses were: R 5 10.4 (3.1) minutes; K 5 3.5 (1.2) minutes; a 5 46.3 (11.0)1; MA 5 55.6 (5.1) mm; G 5 6,429 (1,341) dyn/cm 2 , and LY60 5 5.1 (2.4)%. Mean coefficients of variation for intra-assay/interindividual variability in healthy horses were: R 5 4.7%/30.7%, K 5 4.8%/35.3%, a 5 4.4%/23.8%, MA 5 1.4%/9.3%, G 5 3.4%/20.8%, and LY60 5 13.1%/47.7%, respectively. Horses with colitis and prolonged PT and/or aPTT had longer mean values for R (Po0.001) and K (Po0.001), narrower mean a (Po0.001), decreased mean MA (P 5 0.001), and smaller mean G (P 5 0.02); changes consistent with hypocoagulability. Conclusions-Citrated recalcified (nonactivated) TEG demonstrated changes consistent with hypocoagulability in horses with colitis that had preidentified coagulation abnormalities. This technique has high interindividual variability and low intra-assay variability. TEG may be useful for detecting hypocoagulable states in horses with colitis and suspected coagulopathies.

Background: Venom recurrence or persistence in the circulation after antivenom treatment has been documented many times in viper envenoming. However, it has not been associated with clinical recurrence for many snakes, including Russell's viper (Daboia spp.). We compare the recovery of coagulopathy to the recurrence or persistence of venom in patients with Russell's viper envenoming. Methodology/Principal Findings: The study included patients with Russell's viper (D. russelii) envenoming presenting over a 30 month period who had Russell's viper venom detected by enzyme immunoassay. Demographics, information on the snake bite, and clinical effects were collected for all patients. All patients had serum collected for venom specific enzyme immunoassay and citrate plasma to measure fibrinogen levels and prothrombin time (international normalised ratio; INR). Patients with venom recurrence/persistence were compared to those with no detectable recurrence of venom. There were 55 patients with confirmed Russell's viper envenoming and coagulopathy with low fibrinogen concentrations: 31 with venom recurrence/persistence, and 24 with no venom detected post-antivenom. Fibrinogen concentrations increased and INR decreased after antivenom in both the recurrence and non-recurrence patients. Clinical features, laboratory parameters, antivenom dose and length of hospital were similar for both groups. Pre-antivenom venom concentrations were higher in patients with venom recurrence/persistence with a median venom concentration of 385 ng/mL (16-1521 ng/mL) compared to 128 ng/mL (14-1492 ng/mL; p = 0.008). Conclusion: Recurrence of Russell's viper venom was not associated with a recurrence of coagulopathy and length of hospital stay. Further work is required to determine if the detection of venom recurrence is due to the venom specific enzyme immunoassay detecting both venom-antivenom complexes as well as free venom.

HE outcome of many childhood cancers has improved tremendously during the last four decades because of early diagnosis, improved surgical technique, and the use of cytotoxic drugs with or without radiation therapy. Among the complications of cancer therapy, hematological and vascular changes are potentially associated with ICH. Although ICH is a recognized complication of cancer and its treatment, few reports exist regarding the causes and outcome of ICH in children with cancer and those studies involve small numbers of patients. 3,7,11,12 The incidence of ICH in children during and after cancer therapy has not been established, but potential causes of ICH include transient and severe thrombocytopenia, and coagulopathy resulting from cancer or its treatment. Hemorrhage within the intracranial cavity can cause severe morbidity, including death, and survivors may sustain significant neurological deficits. Few data are available regarding the incidence of ICH, related clinical phenomena, and long-term morbidity in survivors of childhood cancer. We report the occurrence of ICH in a population of children who were undergoing cancer therapy or prolonged posttreatment follow up at the time of ICH; data were analyzed with the goal of revealing potential causes and assessing clinical outcome. Clinical Material and Methods Patient Population After approval from the Institutional Review Board had been obtained, patients with ICH were identified from hospital and neurology clinic databases. Inclusion criteria for this study consisted of a cancer diagnosis, treatment at our institution, and the development of ICH confirmed on imaging or surgically between January 1985 and January

The effectiveness of plasma exchange (PE) with continuous hemodiafiltration (CHDF) in the treatment of critically ill patients was evaluated based on changes in cytokine levels. Twenty-six patients with acute hepatic failure were treated with PE (PE group) or PE and CHDF (PE+CHDF group), and the levels of cytokines such as tumor necrosis factor (TNF)-␣, interleukin (IL)-6, and IL-8 were determined before and after treatment. Bilirubin levels were significantly lower after treatment in both the PE and PE+CHDF groups. There were no significant differences in TNF-␣ levels before and after treatment in the PE group, but the TNF-␣ level was significantly lower after treatment in the PE+CHDF group. There were no significant differences in the IL-6 levels before and after treatment in both the PE and PE+CHDF groups. There were no significant differences in IL-8 levels before and after treatment in the PE group, but the IL-8 level was significantly lower after treatment in the PE+CHDF group. PE with CHDF therapy was given to 5 patients with acutely aggravated autoimmune diseases, 2 patients with hemorrhagic shock and encephalopathy syndrome, and 3 patients with thrombotic microangiopathy. The results suggested that PE with CHDF therapy are useful in critically ill patients with suspected hypercytokinemia.

To review the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both elective surgical and trauma settings, and to recommend the most appropriate treatment strategies. M Me et th ho od ds s: : Medline was searched for articles on "massive transfusion," "transfusion," "trauma," "surgery," "coagulopathy" and "hemostatic defects." A group of experts reviewed the findings. P Pr ri in nc ci ip pa al l f fi in nd di in ng gs s: : Coagulopathy will result from hemodilution, hypothermia, the use of fractionated blood products and disseminated intravascular coagulation. The clinical significance of the effects of hydroxyethyl starch solutions on hemostasis remains unclear. Maintaining a normal body temperature is a first-line, effective strategy to improve hemostasis during massive transfusion. Red cells play an important role in coagulation and hematocrits higher than 30% may be required to sustain hemostasis. In elective surgery patients, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. In trauma patients, tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of disseminated intravascular coagulation and microvascular bleeding. The use of platelets and/or fresh frozen plasma should depend on clinical judgment as well as the results of coagulation testing and should be used mainly to treat a clinical coagulopathy. C Co on nc cl lu us si io on ns s: : Coagulopathy associated with massive transfusion remains an important clinical problem. It is an intricate, multifactorial and multicellular event. Treatment strategies include the maintenance of adequate tissue perfusion, the correction of hypothermia and anemia, and the use of hemostatic blood products to correct microvascular bleeding. Objectif : Revoir la physiopathologie de la coagulopathie chez les adultes transfusés massivement et auparavant compétents sur le plan hémostatique, à la fois dans le contexte d'une intervention chirurgicale réglée ou à la suite d'un traumatisme. Recommander les stratégies thérapeutiques les plus appropriées.

Purpose This study aims to describe the characteristics of severe head injuries in children less than 6 years old, victims of falls from windows, and identify the main predictive factors of mortality in this population. Patients and methods A cross-sectional study was designed through data derived from medical records of less than 6year-old children victims of falls from windows presenting with a severe head injury defined by an initial Glasgow coma scale (GCS) ≤8, hospitalized at a Pediatric Trauma center level III, between January 2000 and December 2005. Statistical analysis used univariate analysis and multiple logistic regressions.

The concept of a coagulation cascade describes the biochemical interactions of the coagulation factors, but has flaws as a model of the hemostatic process in vivo. For example, the model cannot explain why hemophiliacs bleed when they have an intact factor VIIa/tissue factor ("extrinsic") pathway. Hemostasis requires the formation of an impermeable platelet and fibrin plug at the site of vessel injury, but it also requires that the powerful procoagulant substances activated in this process remain localized to the site of injury.

Dysfunctional uterine bleeding (DUB) is a gynecologic problem that occurs often during adolescence and is the most frequent cause of urgent admission to the hospital. DUB occurs in the adolescent usually because of anovulation, a result of developmental immaturity of the hypothalamic-pituitary-ovarian (HPO) axis. Diagnosis can only be confirmed when there is no other pathology present, so it is important to exclude all the other possibilities. The aim of this study was to evaluate the frequency of coagulation disorders and other underlying situations as a cause of menorrhagia in adolescents with DUB and to assess the response to the treatment(s) given.

Introduction
The debate on replacing coagulation factors and its effect on the final outcome of the patients with acute traumatic coagulopathy (ATC) in need of transfusion is still ongoing. Therefore, the present study is designed with the aim of comparing the outcome of patients with acute traumatic coagulopathies receiving fibrinogen and fresh frozen plasma (FFP).

Methods
In this quasi-experimental randomized controlled study, patients with severe blunt trauma (ISS > 16) and in need of packed cells transfusion were divided into 3 groups of receiving fibrinogen, receiving FFP, and control, and their final outcome was compared.

Results
90 patients with the mean age of 33.16 ± 16.32 years were randomly allocated to one of the 3 study groups (82.2% male). The 3 groups were similar regarding baseline characteristics. Patients receiving fibrinogen needed significantly less packed cells (p = 0.044) and intravenous fluid in the initial 24 h of hospitalization (p = 0.022). In addition, mortality rate (p = 0.029), need for admission to intensive care unit (p = 0.020) and duration of hospitalization (p = 0.045) were also lower in the group receiving fibrinogen. The number of sepsis cases in patients receiving fibrinogen and control group was lower than those who received FFP (p = 0.001). The number of multiple organ failure cases in patients receiving fibrinogen was about one fourth of the other 2 groups (p = 0.106), and a fewer number of them needed mechanical ventilation (p = 0.191). No case of venous thrombosis was detected in any of the 3 groups.

Routine preoperative blood testing has become a dogma. The general practice is to order preoperative work up as a knee jerk response rather than individualize it for each patient. The fact that the bleeding brain tends to swell, which coupled with limited options for proximal control, packing and overall hemostasis, leads to an over emphasis on preoperative coagulation profile. This is a retrospective review of the medical records of patients admitted at Aga Khan University Hospital from January 2010 to December 2015 for an elective craniotomy. The hospital registry was used to identify files for review. Data was collected on a predefined proforma. A nationwide survey was performed and 30 neurosurgery centers were contacted across Pakistan to confirm the practice of preoperative workup. The survey revealed that all centers had a similar practice of preoperative workup. This included CBC, serum electrolytes and coagulation profile; including PT, aPTT and INR. A total of 1800 files we...

The authors studied whether haemostatic abnormalities connected with the development of cerebral circulatory disturbances can be demonstrated in young stroke patients in whom Doppler and angiographic examination failed to reveal deviations indicative of stroke. They determined the in vivo activation of the coagulation system (TAT, F 1 + 2), the degree of secondary fibrinolysis (D-dimer), the plasma levels of the markers of fibrinolysis, with special regard to inhibitors: plasminogen activator inhibitor (PAI-1), alpha 2 antiplasmin (alpha 2 AP), alpha 2 macroglobulin (alpha 2 M), the frequency of pathologic serum lipoprotein (a)-Lp(a)-values and the association of PAI-1 and Lp(a) with the fibrinolytic system. They conclude that in the acute phase of the disease, the TAT and F 1 + 2 values were significantly elevated compared to the control, without change in the D-dimer value. The results suggest that in the tested period increased thrombin generation dominated and it significantly s...

This review summarizes the evolution of trauma resuscitation from a one-size-fits-all approach to one tailored to patient physiology. The most dramatic change is in the management of actively bleeding patients, with a balanced blood product-based resuscitation approach (avoiding crystalloids) and surgery focused on hemorrhage control, not definitive care. When hemostasis has been achieved, definitive resuscitation to restore organ perfusion is initiated. This approach is associated with decreased mortality, reduced duration of stay, improved coagulation profile, and reduced crystalloid/vasopressor use. This article focuses on the tools and methods used for trauma resuscitation in the acute phase of trauma care.