Background: Uncontrolled bleeding accounts for the majority of preventable deaths in the severely injured in both the civilian and military settings. Trauma induced coagulopathy (TIC) is now widely accepted as a major contributing factor to worsening bleeding in these patients. A quarter of severe trauma patients present with coagulopathy on admission and remain a group with high morbidity and mortality. Objectives: To describe the spectrum of coagulation profiles amongst severely injured patients presenting to an urban level-one trauma centre at Groote Schuur Hospital and to correlate these with blood product requirements, morbidity and mortality. Method: This is a retrospective study of all patients with complete baseline TEG coagulation parameters collected prior to randomization in the FIRST (Fluids In Resuscitation of Severe Trauma) trial between January 2007 and December 2009. Parameters recorded for this study included patient demographics, mechanism of injury, admission vital signs, lactate, base excess, coagulation studies PT, INR, TEG parameters, volume and type of fluids administered, volume of blood products administered, length of ICU stay, and major outcomes. Injury severity was categorized according to the Injury Severity Score (ISS) and New Injury Severity Score (NISS). Results: A total of 87 patients were included in this study, with a median ISS of 20 and 57.5% had a penetrating injury mechanism. Coagulopathy was highly prevalent in this cohort, of which a majority (69%) was diagnosed with hypercoagulopathy and 24% had a hypocoagulopathy status on admission. There was no difference in age, gender and amount 9 of pre-hospital fluids administered across the three groups (normal v/s hyper v/s hypo). Median volume of blood products was higher in the hypocoagulopathy group, although not statistically significant. Overall, 30-day mortality rate was 13%, with case fatalities occurring in only coagulopathic patients; hypercoagulopathy (15%) and hypocoagulopathy (10%). Conclusion: Trauma induced coagulopathy is not an infrequent diagnosis and remains a challenging clinical entity to manage in severely injured patients resulting in increased morbidity and mortality. Determining the coagulation profile using TEG at presentation in this group of patients may guide appropriate management guidelines in order to improve outcome. Hypercoagulable patients need to be recognised amongst the TIC patients as it results in different sequelae and impacts on clinical decision in the use of antifibrinolytic agents as compared to hypocoagulopathy.

Spontaneous foetal loss is the most common complication of pregnancy, affecting up to 20% of recognized pregnancies and recurring in 1-3% of cases. Abnormal maternal inflammation and systemic maternal coagulopathies are associated with foetal loss; however, the causal role of inflammation in the development of obstetric coagulopathies has not been determined. Further, questions remain as to whether maternal systemic coagulopathies are associated with placental haemostatic alterations and what role these local alterations play in foetal outcome. We hypothesized that abnormal maternal inflammation during pregnancy is causally linked to maternal coagulopathies and that these coagulopathies are associated with impaired utero-placental blood flow preceding foetal death. To induce inflammation-mediated fetal death, we administered lipopolysaccharide (LPS; 100-µg/kg) to Wistar rats on gestational day 14.5 and characterized the systemic maternal coagulation status 1hr post LPS administration using thromboelastograpy. Utero-placental haemostatic alterations were analyzed by periodic acid Schiff staining (PAS) and immunohistochemistry for fibrin/fibrinogen. Spiral arteriole peak flow velocity was determined by Doppler ultrasound. To determine causality between abnormal maternal inflammation, coagulopathies, and placental hemodynamics, the TNF -inhibitor etanercept (Enbrel®) was administered six hours prior to LPS administration. Systemic maternal coagulopathies were evident in 82% of LPS-treated dams and were associated with specific placental haemostatic alterations as well as reduced utero-placental blood flow. Etanercept administration prevented the development of systemic coagulopathies and placental haemostatic alterations. Furthermore, etanercept maintained normal spiral arteriole peak flow velocity. This study demonstrated that abnormal maternal inflammation is causally linked to systemic coagulopathies specific to pregnancy. Moreover, we showed that inflammation-induced systemic coagulopathies are associated with placental haemostatic alterations and reduced utero-placental blood flow preceding foetal death. Modulation of maternal inflammation may thus be useful in the prevention of coagulopathies associated with complications of pregnancy. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2011-08-01 14:29:12.489

Class of 2008 Abstract / Objectives: To determine the ecomomic impact of recurrent coagulopathy with crotaline envenomation, using the current standard of care (crotalinae polyvalent immune Fab antivenom), and establish a model of pharmacoeconmic assessment for future studies. Methods: Design of recurrent coagulopathy cost assessment tool including payor costs and patient costs. Using medical and medical billing references, government websites, business websites, and published studies, determine average costs for major variables affecting the cost of recurrent coagulopathy to the payor and the patient. Results: A prospective study has been designed to take place during the historic height of Arizona snake bite season in 2008. Conclusions: Based on previous studies of recurrent coagulopathy an estimated 45-53% of crotaline envenomation patients can expect to experience recurrent coagulopathy after treatment with crotalinae polyvalent immune Fab antivenom. The economic impact to the payor is expected to be high with laboratory costs of $49.45 each, doctor visits costing $66.02, emergency room visits costing $351, and $3563.75 per vial of crotalinae polyvalent immune Fab antivenom. Historically the cost of recurrent coagulopathy to the patient has not been evaluated. Considering lost wages, transportation to and from medical care, and the cost of additional household help and child care, this cost is expected to be great enough to adversely impact individuals and families.

Physical trauma is responsible for over six million deaths annually, and of these roughly 40 percent result from acute traumatic coagulopathy (ATC) occurring in the first few hours of incidence. Patients who have developed ATC have significantly improved survivability when treated with tranexamic acid (TXA), a chemical inhibitor of the clot lysing enzyme plasmin. Current methods of detecting ATC are inadequate, lacking in either efficient speed, sensitivity, or cost. Hyperfibrinolysis (HF) is a key component of ATC and can be a result of excess plasmin activity. The following study observes effects of plasmin on hemostasis, and explores the use of silicon-based polydimethylsiloxane (PDMS) microfluidics measuring changes in electrical resistance as a method to detect HF. Coagulation was characterized by measuring turbidity of solutions containing fibrinogen and thrombin, and plasmin was incorporated to observe fibrinolysis and other plasmin-induced effects. It was found that high concentrations of plasmin caused a delay in the turbidity increase during coagulation. This lag phase may be a contributing factor to HF and ultimately ATC. Finally, the use of PDMS microfluidics to measure changes in electrical resistance to detect coagulation and fibrinolysis activity was supported. Resistance change adhered closely to traditional substrate-enzyme kinetics and plasmin-induced effects mimicked those which were observed in turbidity measurements. Further investment and development of this method of measurement could provide a faster, more accurate, and more inexpensive alternative to current techniques for measuring fibrinolysis.

Class of 2009 Abstract / OBJECTIVES: The study’s purpose was determining the economic impact of recurrent coagulopathy with crotaline envenomation using the current standard of care, crotalinae polyvalent immune Fab antivenom (CroFab), and to establish a model of pharmacoeconomic assessment for future studies. METHODS: A recurrent coagulopathy cost assessment tool was designed that included payer and patient costs. This system used medical and billing references, government and business websites, published studies, and average costs for major variables affecting costs of recurrent coagulopathy to the payer and patient. RESULTS: Of the 42 subjects screened during the study period, 13 were eligible, and 5 chose to participate. On average, lab results were the most significant cost to payers ($247.25). No subject required additional vials of CroFab as a result of recurrent coagulopathy and therefore this was the least costly parameter. There were no correlation between lab costs, doctor visits, or ER visits. Lost wages were the highest cost to patients, with an average of $880.85. Household help and child care were the least costly parameters in this study group. The loss to follow-up was a substantial barrier to obtaining the projected number of study subjects. CONCLUSIONS: A major limitation of this study is the small sample size. Therefore, only generalizations can be made by analyzing the data in regards to the true costs of recurrent coagulopathy to patients and payers. Future pharmacoeconomic studies regarding average costs related to crotaline envenomation should consider experimental mortality a significant barrier to obtaining significant results.

Une coagulopathie aigüe traumatique est constatée chez environ un tiers des patients traumatisés sévères. Ce trouble précoce, endogène et spécifique nécessite l’association d’importantes lésions tissulaires et d’une hémorragie. La phase initiale est caractérisée par l’expression d’un phénotype hémorragique responsable d’une mortalité précoce, la phase tardive par l’expression d’un profil pro-thrombotique responsable d’une mortalité retardée. La physiopathologie de ce phénomène est encore mal comprise. Celle-ci pourrait impliquer une dysrégulation de la voie de la protéine C, une CIVD fibrinolytique, une diminution des stocks en fibrinogène, une altération de la fonction plaquettaire et une agression endothéliale. Plusieurs auteurs ont relevé l’absence de modèle animal pertinent pour vérifier ces hypothèses. Les objectifs de ce travail de thèse ont été la mise au point d’un modèle animal de coagulopathie aigüe traumatique et l’étude de sa physiopathologie. Une première étude a été réalisée, permettant la mise au point d’un modèle murin de coagulopathie traumatique. Celle-ci a mis en évidence un trouble de la coagulation précoce, endogène et spécifique associé à l’expression d’un phénotype hémorragique et répondant à tous les critères clinico-biologiques d’une coagulopathie aigue traumatique. Une deuxième étude basée sur ce modèle a été réalisée afin de mettre en évidence les mécanismes généraux intervenant dans la physiopathologie de la coagulopathie aigüe traumatique. Le rôle protecteur du fibrinogène a été confirmé dans cette étude. Le profil clinicobiologique observé associait une génération de thrombine normale, une discrète thrombopénie et un phénotype hémorragique. Celui-ci infirmait l’hypothèse d’une CIVD mais était compatible avec celle d’une fibrinolyse médiée par une production accrue de protéine C activée. / An acute traumatic coagulopathy is observed in about one-third of severely traumatized patients. This early, endogenous and specific disorder occurs when tissue damages are combined with hemorrhage. The early phase of this condition is characterized by the expression of a bleeding phenotype and a lengthening in prothrombin time.The late phase is characterized by a pro-thrombotic profile leading to multiple organ failure. The physiopathology of this phenomenon is still poorly understood. This could involve a dysregulation of the protein C pathway, fibrinolytic DIC, a decrease in fibrinogen, impairment in platelet function and endothelial damages. Various authors have emphasized the lack of relevant animal model to study this phenomenon.The objective of this work was to develop an animal model of acute traumatic coagulopathy to study its pathophysiology. A first study was performed and led to the development of a murine model of traumatic coagulopathy. This study revealed a hemostasis disorder that meets all the criteria of acute traumatic coagulopathy. Then, a second study based on this model was performed to observe general hemostasis disorders occurring in the context of traumaassociated hemorrhage. This study confirmed the protective role of fibrinogen against ATC. The clinicalbiological profile observed in the case of ATC combining normal thrombin generation, subtle thrombocytopenia and hemorrhagic phenotype observed in the case of ATC invalidated the hypothesis of DIC but was compatible with fibrinolysis mediated by an increase in activated protein C.

A hypercoagulable state has been demonstrated in human falciparum malaria in mild and complicated forms of the disease. Disseminated intravascular coagulation (DIC) was implicated by some authors, but deemed a rare occurrence by others. The possibility of coagulopathy in Babesia canis rossi infections in the canine patient has also been suggested in the literature, but minimal work has been done to evaluate the clinicopathological nature of it in further detail. In the canine babesiosis (CB) pathogenesis thought-process, DIC has been implicated. A DIC-like syndrome, as evidenced by intravascular fibrin deposition and haemorrhage into muscles and tissues was found at post mortem in one study. On the basis of these findings, it was postulated that DIC might be a serious complication of severe Babesia infection in the dog. Clinical DIC (haemorrhagic diathesis) is however seldom seen. It was also hypothesised in the literature that the multiple organ dysfunction syndrome (MODS) demonstrated in the complicated form of Babesia was caused, in addition to tissue damage due to local hypoxia, by microthrombi as a result of a coagulopathy. This needs to be further investigated. Pulmonary thromboembolism (PTE) has not been implicated in CB, however thromboemboli in the lungs were found in dogs with immune-mediated haemolytic anaemia (IMHA) for which a similar mechanism of venous stasis, hypercoagulability and endothelial damage (as found in CB) is proposed. In humans, PTE is believed to be a major underdiagnosed contributor to mortality in 5 to 15% of hospitalised adults. If early diagnosis of PTE can be achieved, the mortality rate can certainly be decreased. A similar situation with resultant serious implications in complicated CB cases may exist. Clinically, PTE is suspected if a patient with a known prothrombotic condition develops sudden dyspnoea and tachypnoea. These clinical symptoms are frequently seen in complicated CB patients and may, in addition to being a compensatory mechanism for the metabolic acidosis and anaemia, be attributed to thrombus-induced mechanical changes in lung function. Pulmonary scintigraphy provides a sensitive means of diagnosing PTE. It was (and some authors still do) believed that a ventilation scintigraphic scan should be done in association with a perfusion scan to increase the specificity and accuracy of diagnoses. However, authors of the recent PISA-PED study in humans proposed that the sensitivity and specificity of a perfusion scan, without a ventilation scan, in patients with suspected PTE was sufficient. The incidence of PTE or the use of pulmonary perfusion scintigraphy in CB dogs has never been studied. The objective of this study was to prospectively evaluate the scintigraphic pulmonary perfusion pattern in hospitalised Babesia dogs in an attempt to ascertain whether a scintigraphic pattern consistent with PTE does indeed occur in these patients. The study consisted of a normal control group of nine mature healthy Beagle dogs aged 36 – 43 months and weighing 9.9 – 15kg and a Babesia group with 14 dogs of a variety of breeds that were naturally infected with Babesia, aged 6 – 103 months and weighing 6.3 – 25.5kg. Pulmonary perfusion scintigraphy was performed after making thoracic radiographs and performing a blood gas analysis in both groups. The scintigraphic images were visually inspected for changes suggestive of PTE. Surprisingly, not a single dog in the Babesia group had segmental or wedge-shaped perfusion defects which would have resulted in a high probability for PTE. The scintigraphic pulmonary perfusion pattern demonstrated was not significantly different between the two groups (p = 1.00). Many dogs in both groups had a mottled appearance on the right and left dorsal oblique images, which was not believed to be consistent with clinically relevant PTE. This study provides baseline data that may be used to further investigate the pulmonary perfusion pattern in Babesia dogs. / Dissertation (MMedVet (Diagnostic Imaging))--University of Pretoria, 2007. / Companion Animal Clinical Studies / unrestricted

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23071号 / 医博第4698号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 YOUSSEFIAN Shohab, 教授 平井 豊博 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Vitamin K acts a cofactor for the gamma-carboxylation of several proteins in the coagulation cascade. The clinical spectrum of vitamin K deficiency (VKD) can be asymptomatic to a significant bleeding. VKD is classically seen in newborns. However, this can manifest later in patients with risks such as sub-optimal nutrition, fat malabsorption, medications including antibiotics. A 17-year-old male with spinal muscular atrophy (SMA) Type 1, tracheostomy with ventilator dependent, gastrostomy tube feeding was seen by the gastroenterologist following treatment for small intestinal bacterial overgrowth (SIBO). Investigations showed coagulopathy following which he was transferred to the Pediatric ICU. Labs revealed prothrombin time (PT) 114 s [Normal 9.4-12.5 s], INR (International normalized ratio) 12.6 [Normal < 1.1] and partial thromboplastin time (PTT) 90 s [Normal 25.1-36.5 s]. Mixing studies and coagulation assays were consistent with VKD (low Factor VII and Factor IX with normal Factor V). His home blenderized feeding regimen met the caloric requirement but not the adequate intake (AI) values for vitamin K and other minerals. He received intravenous vitamin K (phytonadione) for five consecutive days with resolution of the coagulopathy (PT 13.2 s, PTT 37.1 s, INR 1.2). The patient was discharged on enteral vitamin K and additional supplements following dietary review by a nutritionist. Clinicians should be cognizant of VKD in patients on blenderized tube feeds which may not meet the adequate intake (AI) goals. In patients who are not receiving nutritionally complete formulas or receiving inadequate volumes, it is important to monitor macro and micronutrients.

Trauma continues to be a major cause of death across the globe. While the exact causes of trauma differ greatly between the military and civilian lifestyles, the ability to stop bleeding after trauma is paramount for survival. Over the past decade coagulation research has transitioned from a classical understanding of plasma based protein coagulation to the current cell focused research. As part of this shift, platelets have become a central player in hemostasis. Unfortunately little is currently understood about how platelet function is affected by trauma. In an effort to better define platelet function during trauma and the resulting shock from exsanguination, a multipronged approach was developed. The hypothesis that the introduction of a state of clinical shock in a controlled environment would allow for an in-depth assessment of trauma-induced coagulopathy led to the development of a swine based model of hemorrhagic shock. In this model a composite injury consisting of soft tissue damage, long bone fracture, and controlled hemorrhage was used to induce a moderate state of hypovolemic shock. As a result of this injury the animals showed both the beginning of a plasma protein consumption coagulopathy as well as kinetic quickening in the clotting process. These surprising results show competing up-regulation and down-regulation of the coagulation system in response to trauma induced shock. To better define the effect of polytrauma on platelet function in a human population a clinical study was conducted. The hypothesis behind the development of this study was that the examination of platelet function during polytrauma would lead to a more complete understanding of the effects of trauma on hemostasis. This study resulted in the identification of two separate but not mutually exclusive coagulopathies in response to trauma. The first was the traditional consumption based coagulopathies recently suggested to be varying degrees of disseminated intravascular coagulopathy. The second was a development a hypercoagulable state that may be attributed to increased platelet function. The identification of these two competing coagulopathies in separate models highlights the inadequacies of the current plasma based clinical testing, and the need for increased whole blood testing in the trauma treatment environment.