Treament with oral anticoagulation is highly effective in reducing the burden of thromboembolic complications in several clinical conditions. The number of patients receiving oral anticoagulation is growing steadily. InSwedenabout 1.5 percent of the population receives treatment. Although the treatment is highly effective in preventing thromboembolic complications, it is also associated with a substantial increase in the risk of bleeding. In clinical practice every physician has to balance the potential benefit of treatment against the risk of bleeding complications in the individual patient. To aid in this decision making, risk scores addressing the likelihood of thromboembolic events, as well as the risk of bleeding complications, have been developed. These scores are imperfect and, to some degree limited by the fact that the risk factors predictive of thromboembolic events are also often associated with bleeding complications. The addition of biomarkers has the potential to increase the predictive ability of risk scores and further enhance the net benefit of oral anticoagulant treatment in the individual patient. In this thesis several potential biomarkers for thromoboembolic and haemorrhagic complications of anticoagulant therapy have been investigated in a longitudinal cohort study of 719 patients with a median follow-up time of 4.2 years. Thrombomodulin is a key component in the generation of activated protein C and hence, a coagulation inhibitor. Conversely, it is also a key component in the inhibition of fibrinolysis by activation of trombin-activated fibrinolysis inhibitor. In warfarin-treated patients we demonstrate that thrombomodulin predicts an increased risk of bleeding complications, but not cardiovascular events. Thus, thrombomodulin has potential as a biomarker specifically for bleeding complications. Von Willebrand factor plays a central and intricate role in the aggregation of platelets and low levels of VWF have been associated with bleeding as a manifestation of von Willebrand’s disease. In our study we noted that high levels of von Willebrand factor predict an increased risk of cardiovascular as well as all-cause mortality, possibly as an expression of endothelial dysfunction. We also noted that high levels of WVF seem to be associated with serious bleeding complications. Decreased renal function is usually measured by an increase in the levels of creatinine and cystatin C, or a decrease in the calculated glomerular filtration rate. A decrease in kidney function is regarded as a marker of an increased risk of bleeding complications. We investigated all the mentioned markers of kidney function and no association with bleeding complications became apparent. However, a clear association between a decrease in kidney function and mortality was noted. Our findings indicate that the emphasis on impaired kidney function as a risk marker needs to be shifted from bleeding complications toward thromboembolic events. Fibrinolysis is important in containing coagulation and several constituents of the fibrinolytic pathway have been shown to predict cardiovascular events and mortality. We found that fibrinolytic factors seem to predict cardiovascular events in patients with oral anticoagulation and that D-dimer also predicts bleeding complications. In conclusion, we have found several biomarkers which exhibit different predictive abilities in patients with oral anticoagulation. It is likely that biomarkers, either alone, in combination, or as ancillary components of risk scores, can contribute to improved risk stratification in patients with oral anticoagulation.

No description available.

Η οξεία αιμορραγία ανώτερου πεπτικού (ΟΑΑΠ) παραμένει ένα από τα πιο συχνά και επείγοντα περιστατικά που συνοδεύεται με αυξημένη νοσηρότητα και θνητότητα. Σκοπός της μελέτης είναι να δειχθούν αλλαγές στα κλινικο-επιδημιολογικά χαρακτηριστικά των ασθενών με ΟΑΑΠ την τελευταία δεκαετία. Συλλέχθηκαν δεδομένα από όλους τους ασθενείς που εισήχθησαν στα νοσοκομεία του Νομού Αχαΐας με ΟΑΑΠ από 1η Ιανουαρίου ως την 31η Δεκεμβρίου 2005 και έγινε αναδρομική σύγκριση με δεδομένα από ασθενείς που εισήχθησαν πριν 10 έτη στην ίδια περιοχή την περίοδο από 1η Ιανουαρίου ως τη 31η Δεκεμβρίου 1995. Η επίπτωση των ασθενών με ΟΑΑΠ και των πεπτικών ελκών και στις δυο περιόδους υπολογίσθηκε με βάση δεδομένων στοιχείων από την Εθνική Στατιστική Υπηρεσία. Παρατηρήθηκε μείωση στην επίπτωση των ασθενών με ΟΑΑΠ από 162,9/100.000 πληθυσμού το 1995, σε 108,2 /100.000 πληθυσμού (RR=0,49, CI 95%=0,37-0,63) το 2005 και στην επίπτωση των ασθενών με αιμορραγία από πεπτικό έλκος (ΑΠΕ) από 104,8 /100.000 πληθυσμού σε 72,5 /100000 (RR=0,49, CI 95%=0,35-0,68). Η μείωση αυτή οφειλόταν κυρίως στη μείωση της επίπτωσης των ασθενών με αιμορραγία από δωδεκαδακτυλικό έλκος (ΑΔΕ)(από 66,7ασθενείς/100.000 σε 35,5/100.000 πληθυσμού), ενώ η επίπτωση της αιμορραγίας από γαστρικά έλκη παρέμεινε στα ίδια επίπεδα (από 33,1 /100.000 σε 34,4 /100.000). Η μέση ηλικία των ασθενών αυξήθηκε από 59,4±17,1 έτη σε 66,1±16,1, p<0.0001, όπως και η συν-νοσηρότητα των ασθενών. Το ποσοστό χρήσης μη στεροειδών αντιφλεγμονωδών φαρμάκων (ΜΣΑΦ) σε αυτούς τους ασθενείς παρέμεινε σταθερό (49,3% vs 48,2%), ενώ η χρήση από του στόματος αντιπηκτικών και αντιαιμοπεταλιακών φαρμάκων αυξήθηκε σημαντικά (από 2,2% σε 6,8%, p=0,001 και από 1,2% σε 10,8%, p<0,0001 αντίστοιχα). Η συχνότητα υποτροπής αιμορραγίας σε ασθενείς με ΑΠΕ ,καθώς και η συχνότητα της επείγουσας χειρουργικής αιμόστασής τους μειώθηκαν σημαντικά (από 12% σε 5,9%, p=0,02 και από 8,9% σε 3,4%, p=0,009, αντίστοιχα). Δεν ανεβρέθηκε στατιστικά σημαντική διαφορά στην συνολική θνητότητα (3,9% το 1995 vs 6,5 % το 2005). Η επίπτωση της ΟΑΑΠ κατά την τελευταία δεκαετία μειώθηκε σημαντικά κυρίως λόγω της μείωσης της επίπτωσης των ασθενών με ΑΔΕ. Οι ασθενείς αυτοί είναι πιο ηλικιωμένοι με αυξημένα συνοδά νοσήματα, αλλά χωρίς να έχει μεταβληθεί στατιστικά η θνητότητά τους τα τελευταία δέκα έτη. / Acute upper gastrointestinal bleeding (AUGIB) remains a common medical emergency and an important cause of morbidity and mortality. The aim of this study was to evaluate changes in clinico-epidemiologic characteristics of patients who presented with AUGIB during the last 10 years. Data from all patients admitted with AUGIB in a defined geographical area in Greece from January 1 to December 31, 2005 (period B) were compared with retrospectively collected data from all patients admitted with AUGIB in the same area 10 years ago, from January 1 to December 31, 1995 (period A). The estimated incidence of AUGIB and peptic ulcer bleeding (PUB) in both periods was calculated using data from the population of this area according to the National Statistical Service. A reduction in the incidence of AUGIB from 162.9/100,000 population in 1995, to 108.2/100,000 population (rate ratio=0.49, confidence interval 95%=0.37-0.63) in 2005 and in the incidence of PUB from 104.8/100,000 population to 72.5/100,000 (rate ratio=0.49, confidence interval 95%=0.35-0.68) were, respectively, observed. This reduction was mainly due to the reduction in the incidence of duodenal ulcer bleeding (from 66.7 cases/100,000 to 35.5/100,000 population), whereas gastric ulcer bleeding incidence remained unchanged (33.1/100,000 vs. 34.4/100,000 cases). Mean age of patients increased from 59.4+/-17.1 years to 66.1+/-16.1, P<0.0001, and the patients' comorbidity. The percentage of NSAIDs' use remained stable (49.3% vs. 48.2%), whereas the use of oral anticoagulants and antiplatelets drugs increased significantly (from 2.2% to 6.8%, P=0.001 and from 1.2% to 10.8%, P<0.0001, respectively). Blood transfusion requirements per patient significantly decreased (from 2.5+/-2 to 2+/-2.4, P=0.009). The rate of rebleeding in PUB patients and emergency surgical hemostasis statistically decreased (from 12% to 5.9%, P=0.02 and from 8.9% to 3.4%, P=0.009, respectively). No significant difference in the overall mortality was observed (3.9% in 1995 vs. 6.5% in 2005). The incidence of AUGIB during the past 10 years significantly decreased, mainly due to the decline in the incidence of bleeding duodenal ulcers. Nowadays, patients are older with more comorbidities, but mortality remains unchanged.

The purpose of this study was to investigate women's experiences of pain, bleeding,to discover the fetus, hospitalization associated with medical abortion at home and toexplore differences in experiences between different groups of women, as age orprevious childbirth. The study was conducted at two gynecological clinics in Uppsalaand in Stockholm. A questionnaire was distributed and analyzed using a quantitativeanalysis method. The response rate was 30 %. Most women were satisfied with thepain relief given to them from the hospital. The group that had not given birth and theyounger women (18-28 years) experienced greater pain than the older women andthose women who had not given birth. Heat such as heating pad on the stomach wasthe most common non-pharmacological method of pain relief. A majority of thewomen in the study bled for six days, and many bled over 14 days. Many of theparticipants who felt that they noticed when the fetus descended described it as alump or a ball. Despite the low numbers of participation this study helps midwives inthe two clinics to provide better support and information to women seeking anabortion completed in the home.

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Background: Up to 40% of trauma patients die during the first 24 hours after injury due to massive hemorrhage. In patients who survive this critical time period, no information is available on rates of delayed major bleeding or factors associated with delayed major bleeding. Methods: A retrospective chart review of 150 critically ill adult trauma patients was used to determine the incidence of delayed major bleeding events. Cox proportional hazards multivariate analysis was performed to assess for risk factors associated with delayed major bleeding events. The anticipated rate of delayed major bleeding events was 10%. Results: The incidence of delayed major bleeding in this cohort of critically ill trauma patients was 44%. Predictors that were statistically significantly associated with delayed major bleeding included: male gender, pre-injury use of the antiplatelet agents aspirin and/or clopidogrel, presence of intracranial bleeding, higher injury severity scores, requirement of massive transfusion, and low pH values. Use of anticoagulant prophylaxis was not associated with delayed major bleeding. Conclusion: The rate of delayed major bleeding was higher than estimated. Larger retrospective and prospective cohorts are needed to confirm these findings.

Lower gastrointestinal bleeding (LGIB) can result in serious adverse events. Appropriate risk stratification of LGIB patients can improve their care. Previous risk scores to identify severe LGIB patients have limitations, therefore we developed clinical decision tool to accurately identify LGIB patients presenting to the emergency department (ED) who are at risk for 30-day adverse outcomes that would overcome these limitations. We conducted a health records review and compared two methods of regression analysis on our data in order to develop a clinical decision tool. We identified five risk factors that have a high sensitivity and good predictive value for identifying low risk LGIB patients: age ≥ 75 years, INR ≥2.0, hemoglobin ≤ 100 g/l, ongoing bleeding in the ED and a medical history of colorectal polyps. Future, large, prospective studies should be done to validate the results, after which implementation studies should be conducted.

Background Bleeding can be an adverse side effect from hospital treatment. The aim was to develop an electronic identification method for patients who are bleeding within The Ottawa Hospital. Methods A retrospective exploratory cohort (N=1000) was used to identify potential candidate markers for bleeding. Electronic data were extracted to evaluate candidate identifiers. Data which were associated with bleeding events were assessed in a model derivation cohort (N=700). Multivariate analysis was used to establish the best model for identifying all bleeding events and in-hospital bleeding events. Results Overall 38% of the exploratory cohort had bleeding. In the model derivation set 29% had bleeding. The model predicting all bleeding included number of transfusions, admitting specialty, re-operation and endoscopy (C-statistic 0.82, 95%CI 0.79-0.86). The model predicting in-hospital bleeding included number of transfusions, admitting specialty and re-operation (C-statistic 0.78, 95% CI 0.73-0.84). Conclusion We have developed two models for identifying hospital bleeding events from The Ottawa Hospital electronic medical records. These should be validated prospectively on the hospital-wide population.

Burkitt lymphoma is a highly aggressive B cell non-Hodgkin lymphoma characterized by the translocation t(8,14) and deregulation of the MYC gene on chromosome 8. The endemic (African) form presents classically as an expanding mass in the jaw. The nonendemic (European/North American) form often presents with an abdominal mass. We present an interesting case of Burkitt’s Lymphoma with atypical features. A thirty-five-year-old lady with no significant medical history presented to the hospital with a three week complaint of vaginal bleeding and lower abdominal pain/cramps associated with night sweats and chills. She underwent gynecologic workup with an ultrasound revealing endometrial thickening followed by a hysteroscopic Dilatation and Curettage procedure. Laboratory workup revealed direct hyperbilirubinemia and elevated liver enzymes. MRCP showed gallbladder wall thickening but no biliary obstruction. A diagnosis of acalculous cholecystitis was considered and she underwent a laproscopic cholecystectomy and liver biopsy. Her initial complete blood count revealed mild leukocytosis. Follow up lab work revealed worsening leukocytosis and a hematology consultation was sought. A peak WBC of 81,000 with peripheral blood blasts as high as 31% was noted. Peripheral smear exam revealed moderate sized immature wbc precursors/blasts with high nuclear-cytoplasmic ratio. Further hematological work up including bone marrow aspirate and biopsy was expedited. Pathology resulted positive for Burkitt's lymphoma/leukemia, positive molecular studies, t(8,14), involving bone marrow, gallbladder, liver and endometrium. Patient was emergently treated with dexamethasone and nitrogen mustard as elevated bilirubin levels precluded standard treatment. She was started on Rituxan as this neoplasm is a CD 20+ B cell malignancy but could not tolerate it. HyperCVAD multi-agent chemotherapy was subsequently initiated along with intrathecal chemotherapy (cytarabine and methotrexate). CSF cytology remained negative for lymphoma. Patient’s clinical condition has improved after 2 cycles of chemotherapy and she is currently receiving on going therapy. Burkitt’s lymphoma is one of the most aggressive neoplasms with a tumor doubling time of a few days. The usual presentation is with constitutional symptoms and adenopathy or a mass lesion, and sometimes may manifest solely in the peripheral circulation as an L3 variant of acute lymphoblastic leukemia. Hepatic parenchymal involvement is rare, but reported. Gallbladder involvement with endoluminal deposits is even rarer. Simultaneous hepatic, gallbladder, uterine, nodal and leukemic involvement at presentation is unique. Treatment is primarily with systemic chemotherapy and multi agent regimens effective in acute lymphoblastic leukemia and/or aggressive lymphomas have been used successfully in this condition with a complete response rate of 80%-90% with a long-term survival rate of approximately 60%. Therapy is fraught with risks of fatal tumor lysis syndrome, pancytopenia, infection/sepsis, and bleeding. Potential progression/relapse in the CNS with the CSF serving as a sanctuary site has been well documented necessitating prophylactic intra thecal chemotherapy administration as in our patient. Aggressive biology of this disease required urgent treatment, as delay in institution of combination chemotherapy could result in poor outcome. This case highlights the need to maintain an open mind while evaluating apparently routine symptoms and the importance of rapid diagnosis and treatment of a hematologic-oncologic emergency.

MSc (Med), Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand / Factor X deficiency is a rare bleeding disorder with an incidence of one in a million in the general population. Patients with the severe form of factor X deficiency suffer from serious bleeds occurring mainly into the joints and the muscle. In the two factor X deficient families currently looked after at the Haemophilia Comprehensive Care Centre, there are definite differences in the bleeding tendencies between and within family members. We hypothesize the differences in genetic mutations and the influence of cytokines to be responsible for these bleeding variabilities. These factors were explored in our study. The study population included a total of fourteen members of the two families with factor X deficiency. Blood for factor X measurement, cytokine studies and genetic studies was collected in the Haemophilia Comprehensive Care Centre of the Charlotte Maxeke Johannesburg Academic Hospital. Each blood was processed according to the test to be performed. Factor X activity levels were measured using the factor X assay, and the information on each patient’s bleeding episodes was obtained from the Haemophiliac Clinic database. Cytokines were analyzed in all patients using the ELISA kits from Biosource. Factor X gene was amplified using PCR and sequenced with Spectrumedix SCE 2410. iv For cytokine studies, high levels of IL-1beta and TNF-alpha were observed in frequent bleeding patients compared to infrequent bleeders. These cytokines are known to be involved in acute inflammatory process leading to cellular infiltrate and joint swelling. This results in synovitis and the creation of massive joint bleeding. The low levels of IL-1beta and TNF-alpha detected in infrequent bleeding patients appear to be related to the high levels of IL-1Ra and IL-10. These anti-inflammatory cytokines are known to inhibit the inflammatory synovitis and lessen the severity of joint bleeding. For genetic studies, differences were observed between the amino acid sequence of the three frequent bleeding patients and the consensus. In addition, a novel mutation Cys350Phe was detected in two of these patients. This mutation is characterized by very low factor X levels which sometimes are not detectable in circulation. The substituted cystine is known to cause defect in the substrate binding, leading to the lost of enzyme activity. From these findings we have concluded that the origin of the heterogeneity of bleeding in factor X deficiency is multifactorial, cytokines and genetic mutations seems to have a role in determining the clinical manifestations of the factor X deficient patients.