Calciphylaxis is a late complication of end-stage renal disease (ESRD) affecting ~1–4% patients on hemodialysis, with a mortality rate of >50%. Cutaneous manifestations include necrotic, non-healing ulcers most commonly in the lower extremities. Visceral organ vasculopathy often occurs as well. Warfarin is a possible risk factor due to its effect on the inhibition of Matrix GLa protein. Under the influence of hyperphosphatemia, vascular smooth muscle cells can undergo ectopic calcification in absence of the MGLa protein. The issue of anticoagulation in dialysis patients has therefore been debated, as Warfarin may potentially induce vasculopathy and increase risk of bleeding, such as hemorrhagic strokes and GI bleeds. A 64-year-old male with ESRD, non-compliant with dialysis, presented with lower extremity pain. Patient was noted to have large, malodorous, bilateral lower extremity ulcers with necrosis and eschars. Punch biopsy of the ulcers demonstrated acute inflammation with calcium deposits and thrombi within the blood vessels, suggestive of Calciphylaxis. Patient was started on Sodium Thiosulfate and Sevelamer for hyperphosphatemia. Atrial fibrillation was incidentally found on EKG, and due to high risk of stroke based on the CHA2DS-VASc score, patient was started on Heparin and bridged to Warfarin on discharge. Patient was readmitted 3 months later to the ICU with septic shock. Lower extremity ulcers appeared to be healing, but he reported several episodes of hematochezia (INR=2.0, hemoglobin=5.2). Warfarin was therefore held and patient was transfused. EGD showed no evidence of upper GI bleed, however patient refused colonoscopy. Patients on dialysis are at increased risk of bleeding due to defective primary hemostasis. The most serious source of bleeding is gastrointestinal, which accounts for 3–7% of all deaths in the dialysis population. Current guidelines for management of atrial fibrillation by the American Heart Association recommend warfarin for oral anticoagulation in patients with ESRD who have a CHA2DS2-VASc score of 2 or greater to prevent thromboembolic events. Our patient with ESRD and Calciphylaxis presented with new-onset atrial fibrillation and therefore started on Warfarin due to high CHA2DS2-VASc score. However patient developed a GI bleed with worsening anemia requiring transfusion, prompting discontinuation of Warfarin. It is therefore questionable whether the risk-benefit assessment based on CHA2DS2-VASc is appropriate for dialysis patients. Unfortunately, all the data available on the subject of Warfarin in ESRD patients are observational without any randomized-clinical trials. Therefore no objective criteria exist to modify the anticoagulation guidelines in dialysis patients.

Atrial fibrillation is the most common type of serious dysrhythmia, with increasing prevalence in older age groups. Thromboembolism is a serious complication seen with atrial fibrillation and can range from ischemic stroke, mesenteric ischemia to acute limb ischemia. The annual incidence of acute limb ischemia secondary to atrial fibrillation is 0.14%[1]. Here we report a case of critical limb ischemia with brachial artery occlusion due to an embolus in a patient with new onset atrial fibrillation. A 90 year-old female patient presented to the hospital with complaints of shortness of breath on exertion, orthopnea and palpitations of one week duration. She denied any chest pain, dizziness, or syncope. Past medical history was significant for longstanding hypertension well controlled with amlodipine and a provoked deep vein thrombosis of the leg 40 years prior to presentation complicated by heparin-induced thrombocytopenia. On examination, she had an irregularly irregular rhythm and an HR in 120s, no murmurs or gallops were appreciated. 12 lead EKG was suggestive of atrial fibrillation with rapid ventricular response. She was started on metoprolol tartrate for rate control and Apixaban for anticoagulation. TSH was normal and serial troponins returned negative. A Transthoracic echocardiogram was obtained and showed an ejection fraction of 55-60%, mildly dilated left atrium, mild MR, there was no evidence of a thrombus or patent foramen ovale. Three hours after the first dose of Apixaban, and right prior to discharge, the patient started complainig of sudden onset sharp pain and paresthesia of the left upper extremity below the elbow. On Inspection, the left upper extremity was pale and cold to touch. Radial and ulnar pulses were absent, confirmed by doppler ultrasound. A stat computed tomography angiography of the left upper extremity showed complete occlusion of the brachial artery at the level of the elbow joint. She was started on Argatroban drip en route for emergent brachial embolectomy after Vascular Surgery consultation. Blood circulation to the arm was fully restored. Apixaban was resumed post-operatively and with clinical improvement, the patient was safely discharged home. Atrial fibrillation, irrespective of the type (persistent, paroxysmal, permanent or silent) leads to increased risk of thromboembolism owing to atrial clot formation[2]. However, the timing of initiation of antithrombotic therapy has been widely discussed and needs to be individualized based on the presence of risk factors for thromboembolism and bleeding. Acute limb ischemia may be defined as sudden loss of blood flow to the limb. The cause being either thrombotic (60%) or embolic (30%). It has been noted that 80% of peripheral emboli originate in the heart secondary to atrial fibrillation[3]. A timely diagnosis and treatment is of utmost importance to decrease morbidity and mortality and to salvage the limb’s functionality. References 1.Thromboembolism in atrial fibrillation Menke J1, Lüthje L, Kastrup A, Larsen J. 2.Writing Committee Members, January CT, Wann LS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-e267. doi:10.1161/CIR.0000000000000041. 3.Callum K, Bradbury A. Acute limb ischaemia. BMJ : British Medical Journal. 2000;320(7237):764-767.

A report on the creation of a new program to improve family medicine residents' understanding, and quality of care, of anticoagulation patients. Patients requiring anticoagulation therapy pose unique issues requiring a systematic approach to their care, balancing the potential benefit from therapy with possible adverse events. Here, we describe a model that helps to standardize both the care received by patients on anticoagulation therapy as well as the training of family medicine residents caring for those patients. A team-based model of care (family medicine residents, clinical pharmacists, and nurses) is used to achieve the goals of improved care and education. Clinical pharmacists are used in concert with family medicine residents and attendings to assess patients' medication profiles and help direct patient care and resident learning. Both the idea itself and the formal structure are presented in a model for possible adaptation to other programs

Objective: To document maternal and foetal morbidity and mortality in anticoagulated, pregnant patients with mechanical heart valves until 42 days postpartum. Methods: In a tertiary single-centre, prospective cohort, 178 consecutive patients at the cardiac-obstetric clinic were screened for warfarin use between 1 July 2010 and 31 December 2015. Of 33 pregnancies identified, 29 were included. Patients received intravenous unfractionated heparin from six to 12 weeks’ gestation and peripartum, and warfarin from 12 to 36 weeks. Maternal outcomes including death, major haemorrhage and thrombosis, and foetal outcomes were documented. Results: There were two maternal deaths, five returns to theatre post-delivery, eight patients transfused, six major haemorrhages, one case of infective endocarditis and three ischaemic strokes. Ten pregnancies had poor foetal outcomes (six miscarriages, three terminations, one early neonatal death). Twenty patients required more than 30 days’ hospitalisation, and 15 required three or more admissions. HIV positivity was associated with surgical delivery (p = 0.0017). Conclusions: Complication rates were high despite centralized care.

A 41‐year‐old man presenting with unstable angina was found to have diffuse coronary ectasia with a partially occluding thrombus in the proximal left anterior descending artery. Anticoagulation with heparin followed by warfarin resulted in relief of angina and resolution of thrombosis at follow‐up angiography 3.5 months later. The patient remains well after three years. Nonatherosclerotic ectatic coronary arteries are prone to thrombosis possibly because of spasm, intimal damage, and blood current eddies. We believe that chronic warfarin therapy may be indicated in many patients with coronary ectasia.

INTRODUCTION Apixaban has revolutionized anticoagulation in patients with atrial fibrillation in preventing strokes. Anticoagulant-induced nephropathy with warfarin is well known, but nephropathy with apixaban is a rare entity, and here we present a case of Apixaban-induced nephropathy. Case Description A 71-year-old patient with a medical history of persistent atrial fibrillation on apixaban, Ischemic cardiomyopathy, and chronic kidney disease stage (CKD) IIIa presented to the hospital with complaints of dyspnea and hemoptysis and tea-colored urine of three-day duration. On admission, the patient had acute kidney injury (AKI) on CKD, Methicillin sensitive Staphylococcus aureus (MSSA) bacteremia, and elevated international normalized ratio (INR) and apixaban were held. The hemoptysis worsened and prompted bronchoscopy revealing diffuse alveolar hemorrhage. The urinalysis showed gross hematuria with high red blood cell (RBC) count and 1+ proteinuria presumed secondary to MSSA associated glomerulonephritis. Evaluation for coagulopathy with serum mixing studies and autoimmune workup has been unremarkable. The patient's coagulopathy was considered secondary to decreased clearance of apixaban with AKI on CKD. However, the patient's kidney function continued to worsen, needing continuous renal replacement therapy and a kidney biopsy for a definitive diagnosis for his decline in kidney function. Kidney biopsy revealed IgA dominant infection associated glomerulitis with one out of hundred glomeruli with the crescent formation and signs of anticoagulant induced nephropathy with several intratubular RBC casts out of proportion to the degree of glomerular injury causing acute tubular damage. The patient's INR improved on dialysis. However, he continued to be oliguric before being terminally extubated. DISCUSSION With the increasing incidence of atrial fibrillation and the use of oral anticoagulants, it is vital to have anticoagulant induced as a differential in patients presenting with supra therapeutic INR and AKI. Apixaban-induced nephropathy is a subset of anticoagulant-induced nephropathy and an uncommon cause of the acute decline in kidney function needing dialysis. Prompt recognition and treatment will prevent further deterioration in kidney function and possible improvement.

Patients with atrial fibrillation (AF) are at increased risk of stroke. Warfarin anticoagulation therapy reduces the incidence of stroke and increases the incidence of hemorrhagic events. This dissertation further informs the decision to use anticoagulation therapy in AF patients by examining outcomes in patients with major hemorrhages, further examination of stroke risk in diabetic patients with AF, and by evaluating the association between warfarin and stroke while accounting for competing risk events. These studies utilized data from the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) and ATRIA-CVRN (Cardiovascular Research Network) (Study 1 only) studies which consist of patients from Kaiser Permanente Northern and Southern California. Study 1 examined short and long-term mortality in patients who experienced major gastrointestinal (GI) hemorrhages. In the ATRIA cohort, patients using and not using warfarin at the time of GI hemorrhage were equally likely to die within 30-days, while in ATRIA-CVRN, patients using warfarin were much less likely to die within 30-days (adjusted mortality rate ratio (aMRR): 0.33, 95% CI: 0.16-0.70). For longer-term mortality, both cohorts were consistent with a reduced mortality rate among patients whose GI hemorrhage occurred while using warfarin. Study 2 assessed the association between diabetes characteristics (duration of diabetes and glycemic control) and incidence of ischemic stroke among patients with AF and diabetes. Duration ≥ 3 years was associated with a large increase in rate of stroke (adjusted hazard ratio (aHR): 2.04, 95% CI: 1.27-3.26) compared to patients with duration < 3 years. Patients with the poorest glycemic control (hemoglobin A1c (HbA1c) values ≥ 9.0%) did not have an increased rate of ischemic stroke compared to patients with HbA1c < 7.0%. Study 3 evaluated the association between warfarin and thromboembolism in analyses that did and did not account for competing death events. In analyses not accounting for competing events, the adjusted HR was 0.61 (95% CI: 0.54-0.69), and after accounting for competing death events this association was attenuated (aHR: 0.87, 95% CI: 0.77-0.99). In summary, these studies add to the literature about the benefits of warfarin therapy and risk of stroke in patients with AF, findings that can improve decisions about use of anticoagulants in patients with AF.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18868号 / 医博第3979号 / 新制||医||1008(附属図書館) / 31819 / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 坂田 隆造, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Surface-induced thrombosis is a continuing issue in the development of biomaterials for blood contacting applications. Protein adsorption is a key factor in thrombosis since it occurs rapidly upon contact of a material with blood, initiating coagulation and other adverse reactions including platelet adhesion. The research presented in this thesis explores the use of a unique antithrombin-heparin covalent complex (ATH) for surface modification to provide antithrombogenicity. ATH was tethered to surfaces by various methods. Polyethylene oxide (PEO) was investigated as a linker-spacer molecule for surface attachment of ATH as well as for its antifouling properties.</p> <p>In the first phase of the work gold was used as a model substrate. ATH was attached by three different methods: direct attachment, attachment via a short chain linker, and attachment via PEO. Analogous heparin-modified surfaces were prepared for comparison. Surfaces were characterized using contact angle measurements, x-ray photoelectron spectroscopy (XPS), ellipsometry and quartz-crystal microbalance (QCM). The data suggested that the heparin moiety of ATH was directed away from the surface, in an orientation allowing ready interaction with blood components. The ATH-modified surfaces showed greater antithrombin binding than the heparin-modified surfaces as measured by radioactive labelling and Western blotting analysis. Antithrombin binding was found to occur predominantly through the active pentasaccharide sequence of the heparin moiety of ATH, demonstrating the potential of the ATH for catalytic anticoagulant function. From measurements of the ratio of total heparin to active heparin (anti-factor Xa assay), ATH-modified surfaces were shown to have greater bioactivity than heparin-modified surfaces. The adhesion of platelets to gold and modified gold surfaces was measured from flowing whole blood <em>in vitro</em> using a cone-and-plate device and was lower on all of the modified surfaces compared to bare gold. PEO-ATH surfaces were also shown to prolong plasma clotting times compared to control and heparinized surfaces.</p> <p>In subsequent work, surface modification methods were developed for polyurethane (PU) substrates. Isocyanate groups were introduced into the PU surface for attachment of PEO and ATH was attached to the “distal” end of the PEO. Surfaces using PEO of varying molecular weight and end group were investigated to determine conditions for maximum anticoagulant activity and minimum non-specific protein adsorption. Surfaces were characterized using contact angle measurements and XPS, and protein interactions were studied using radiolabelling. The optimum balance of bioactivity and protein resistance was found to occur with PEO of low to mid range MW (ie. MW 300-600). These PU-PEO-ATH surfaces showed low fibrinogen adsorption and high selectivity for antithrombin. Consistent with results using gold substrates, platelet adhesion remained low when ATH was attached to polyurethane surfaces grafted with PEO. A hetero-bifunctional amino-carboxy-PEO (PEO-COOH surface) was compared with a “conventional” homo-bifunctional dihydroxy-PEO (PEO-OH surface) with respect to their effectiveness as linkers for attachment of ATH. The PEO-COOH-ATH surface was shown to bind slightly greater amounts of antithrombin, indicating higher catalytic anticoagulant activity. Thrombin binding was measured to determine whether the surfaces could provide direct anticoagulant activity. The PEO-OH-ATH surface bound high amounts of thrombin, indicating potential for direct thrombin inhibition. It is hypothesized that the PEO properties (MW and functional end group) may have an effect on the orientation of ATH on the surface thus influencing its "preference" for catalytic vs. direct anticoagulant function.</p> <p>This thesis provides new information regarding the interactions of proteins and platelets with ATH immobilized on biomaterials. ATH-modified surfaces were superior to analogous heparin-modified surfaces with respect to antithrombin binding and catalytic anticoagulant ability. Immobilized ATH was also shown to bind thrombin, suggesting potential for direct anticoagulant activity. It can thus be seen as a unique surface modifier with dual functioning anticoagulant activity. The modification of polyurethane with ATH using PEO as a protein resistant linker-spacer, may provide a material of improved antithrombogenicity for the construction of blood contacting devices.</p> / Doctor of Philosophy (PhD)

Background Every year about 2,500 patients in Sweden undergo surgery for heart valve disease, primarily in the aortic valve.  In contrast to the mitral valve, which can be repaired in 70% of the cases, the aortic valve is normally replaced by a mechanical or biological prosthesis. A mechanical heart valve (MHV) necessitates lifelong anticoagulation treatment with a vitamin K antagonist, most commonly warfarin, due to the high thrombogenicity of the prosthesis. The quality of the warfarin treatment is crucial in these patients. Compared to other countries, treatment quality in Sweden is very high; nonetheless, there is always room for improvement. One of the ways to achieve this improvement is to implement computerized dosing assistance. Treatment recommendations for anticoagulation intensity are based on few and old studies, making these recommendations uncertain. There is therefore a need for studies designed to establish the appropriate level of anticoagulation therapy. Aim The aim of these studies was to investigate the efficacy and safety of anticoagulation treatment among patients with mechanical heart valve prostheses in Sweden; to assess whether computerized dosing can increase the treatment quality; to investigate the influence of the treatment quality, measured by Time in Therapeutic Range (TTR) and INR variability, on the risk of complications and, finally, to establish the optimal intensity of anticoagulation treatment in this group of patients. Methods Data were obtained from AuriculA – a national quality registry established in 2006, which currently includes approximately 50% of all patients treated with oral anticoagulation in Sweden. Study II used only data from AuriculA. 769,933 warfarin-dosing suggestions proposed by the dosing algorithm in AuriculA were analysed. Accepted dose suggestions (590,939) were compared with 178,994 manually-changed doses in regard to the resultant INR value, measured as mean error (deviation from target INR) and hit rate (number of INR samples within the target range 2-3). In study III, AuriculA was used to identify patients in Sundsvall and Malmö in the period 2008 – 2011 who were receiving warfarin for a mechanical heart valve prosthesis, as well as to retrieve their INR data. Data on background characteristics and bleedings or thromboembolic complications were manually retrieved from medical records by two investigators.  A total of 534 patients with mechanical heart valve prostheses were divided into quartiles based on TTR and were compared regarding the risk of complications. For Studies I and IV, data from AuriculA were merged with the Swedish National Patient Register, SWEDEHEART/ Heart surgery, and the Swedish Cause of Death Register, comprising in total 77,423 patients on warfarin with 217,804 treatment years. Every treatment period registered in AuriculA was given an individual identification number. During the study period a patient could have any number of treatment periods. The number of complications in total and in different patient groups within the study population was investigated. Complications were defined by ICD-10 codes. Major bleeding was defined as an event necessitating hospital treatment and given a discharge diagnosis with one of the ICD-10 codes reflecting bleeding, as listed in the Appendix. Bleeding events were divided into intracranial, gastrointestinal and other bleedings. Thromboembolic complications consist of venous events (deep vein thrombosis, pulmonary embolism, venous stroke) or arterial events (stroke, TIA, acute myocardial infarction, peripheral arterial embolism). Data were analysed using both simple, descriptive statistical methods and various tests such as Mann-Whitney (or two sample Wilcoxon), T-test, Chi 2 test, ANOVA, multivariate analysis with logistic regression and survival analysis with Cox Regression with proportional hazard assumption. Results Treatment quality  Mean TTR among all patients in Study I was 76.5% whereas patients with mechanical heart valve prostheses had a TTR of 74.5%. The annual incidence of major bleeding or thromboembolic events among all patients was 2.24% and 2.65%, respectively. The incidence of intracranial bleeding was 0.37% per year in the general population and 0.51% among patients with mechanical heart valve prostheses, who also had a higher bleeding rate in total (3.37% per year). Both the mean and median errors were smaller (0.44 vs. 0.48 and 0.3 vs. 0.4, respectively) and the hit rate was higher (0.72 vs. 0.67) when the dose suggested by the algorithm was accepted, compared to when it was manually changed. TTR  In Study III there was no significant difference in the risk of thromboembolism regardless of TTR level. Risk of bleeding in quartiles I and II was more than two times higher than in the quartile with TTR &gt;82.9. In Study IV, lower TTR (≤70%) was associated with a significantly higher rate of complications when compared with TTR &gt;70%. Bleeding risk was higher in the group with lower TTR (HR=2.43, CI 2.02-2.89, p&lt;0.001). After dividing patients into TTR quartiles, the rate of complications in total was significantly higher in quartiles I to III compared with quartile IV, which had the highest TTR. Risk of thromboembolism, major bleeding and death was higher in the first and second quartile compared to the quartile with the highest TTR. INR variability  Higher INR variability above mean (≥0.40) was related to a higher rate of complications compared with lower INR variability (&lt;0.40) as shown in Study IV. Bleeding risk was higher in the group with INR variability ≥0.40 (HR = 2.15, CI 1.75-2.61, p&lt;0.001). Comparison of quartile IV, which had the lowest INR variability, with the other three revealed that quartiles I and II, which had the highest INR variability, had significantly worse outcomes for all complications except for thromboembolic events, plus also death in quartile II. TTR and INR variability combined  High variability and low TTR combined was associated with a higher risk of bleedings (HR 2.50, CI 1.99-3.15), death (3.34, CI 2.62-4-27) and thrombosis (1.55, CI 1.21-1.99) compared to the best group. Level of anticoagulation Higher warfarin treatment intensity (mean INR 2.8-3.2 vs. 2.2-2.7) was associated with a higher rate of bleedings (HR 1.29, CI 1.06-1.58), death (1.73, CI 1.38-2.16) and complications in total (1.24, CI 1.06-1.41) after adjustment for MHV position, age and comorbidity. Conclusion Warfarin treatment quality is crucial for patients with mechanical heart valve prostheses. Computerized dosing assistance could help maintain high warfarin treatment quality. Well-managed treatment with TTR ≥70% and INR variability below mean &lt;0.40 is associated with a lower risk of serious complications compared with a lower TTR and higher INR variability. No benefit of higher warfarin treatment intensity was found for any valve type or position.