ALBERT

Description: Abstract 4742 The MC-SAT program is a telemedicine system developed for the management of patients under oral anticoagulant treatment (OAT). The program constitutes the natural evolution of an original research project, which assessed the capability of a telematic system in managing different chronic patients access flow to health care services. In particular, for patients on oral anticoagulation we planned a direct access to a call center server and a pre-process of the INR data obtained through self-testing with portable prothrombin time (PT) monitor. The original project performed the technology assessment of all the devices and procedures able to automatically drive international normalization ratio (INR) data from patients to specialists in a hospital anticoagulation clinic and to get patients able to read the medical answer. The ability of patients and/or general practitioners to self-determine INR without specific training and the integration of a portable PT monitor for home use into routine patient care in anticoagulation clinics was subsequently successfully evaluated. After a pilot phase of the project, during which the feasibility of the MC-SAT telemedicine service was assessed, we started the enrollment of consecutive patients. Controls matched by age (+/− 5 years), sex and therapeutic range with the cases, were selected among those who attended our anticoagulation clinic (whose population reaches 3,557 individuals) and were managed by usual care. At the beginning of the program, which is still ongoing, a portable monitor (Coagucheck®, Roche Diagnostics, Germany) has been given to 40 patients and to 10 general practitioners (GPs) provided with portable monitors and Internet access. Each GP had the task to follow 5 patients on chronic OAT. Subsequently, additional 40 patients joined, referring to the preferred community laboratory to perform the prothrombin time and subsequently send the INR results through MC-SAT. To date, the system works like this: the INR data, obtained through the portable monitor or through a local laboratory, is sent by GPRS cellular phone or by Internet computer. When an alert output is detected, an automatic message is sent to the specialist. GPRS services are implemented in order to connect the specialist to the database containing the clinical history of the patient. The specialist is able to monitor, from any location, by means of smartphone or tablet PC, all INR values recorded by the system, all the previous patient accesses to the hospital and the last weekly OAT dose. On these basis, if necessary, a change of the weekly OAT doses is made and transferred to the GP's or patients' computer. Since the start of this project in its definitive shape in june 2009, we enrolled 130 patients allocated to prolonged oral anticoagulant treatment. Of these, 80 were directly assisted by our clinic. The remaining 50 patients were assigned to the GPs. Of the 130 patients originally enrolled, 39 never provided any data. These 39 patients were among those assigned to the GPs. Even if periodically urged to do so, GPs sent data on 11 patiens only. Of the 80 patients directly assisted by our clinic, who utilized either the given portable monitor or referred to a community laboratory, 69 showed great interest to the program, did send their results and continue to do so, utilizing the system 1104 times during the period july 2010-june 2011, with a mean of 16 prescription/year/patient. No significant differences were recorded in the TTR (time in therapeutic range) between the patients enrolled and the controls. More than 80% of the answers were given before 9 hours from the request. After two years, we confirm that the use of the system represents an improvement in the management of patients under oral anticoagulant treatment, by favouring communications and, potentially, clinical outcomes. The program showed to work better when it involves the individual patient rather than GPs. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1072 Poster Board I-94 Introduction: Heparin-induced thrombocytopenia (HIT), alone or associated with thrombosis (HITT), may develop during anticoagulant treatment with unfractionated heparin (UFH) or low-molecular weight heparin (LWMH). Fondaparinux is a selective inhibitor of coagulation factor Xa which apparently does not react with anti-PF4/heparin antibodies in in vitro testing. Methods: From january 2005 to december 2007 we treated 44 patients who had strong suspect of HIT (12 patients) or HITT (32 patients, of whom 12 had both DVT and PE). Of these, 30 patients were previously exposed to unfractionated heparin (UFH) for major cardiac surgery. The remaining patients were admitted to medical or general surgery wards. In the 32 patients who developed HITT, we applied therapeutic dosages of fondaparinux, i.e. 7.5 mg QD or lower, in accordance with their bleeding risk. The remaining patients were treated with prophylactic dosages of fondaparinux, i.e. 2.5 mg QD. Switch to warfarin was performed as soon as possible. The mean of our patients 4T's score was 6.2, corresponding to high risk patients; the mean of anticorpal optical density (GTI Enhanced®) was 1.4; the mean platelet number was 45 × 109/L. Results: All patients but four showed sustained normalization of the platelet number. All patients but four showed a significant reduction of their thromboembolic burden. No death related to severe bleeding was recorded. Two episodes of major bleeding were recorded in post-surgical patients (4,5%); 4 episodes of minor bleeding were recorded (9,1%). Four patients underwent dialysis during fondaparinux without bleeding complications. One patient developed acute coronary syndrome during treatment with fondaparinux. Nine patients did not survive (20,5%), with a key role of primitive diseases (i.e. sepsis) causing delay in the diagnostic process of HIT (four of them had a diagnosis of HIT with a mean delay of 7 days). In 16 patients submitted to therapeutic dosages of fondaparinux, anti-PF4/heparin antibody titers were followed over time showing a constant decrease: in one case antibody levels did not decrease up to 6 months after stopping both heparin and fondaparinux. Thirty patients were easily switched from fondaparinux to VKAs without problems in reaching the appropriate INR target. Conclusions: This report provides further evidence supporting the safety and efficacy of fondaparinux in the treatment of HIT and underlines the importance of an early diagnosis. However, it shows the need of a randomized controlled study between fondaparinux and a registered comparator drug. Disclosures: Piovella: GlaxoSmithKline: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Boehringer Ingelheim: Honoraria, Speakers Bureau. Off Label Use: fondaparinux in the treatment of heparin-induced thrombocytopenia.

Description: Introduction. Prekallikrein (PK) and high-molecular-weight kininogen (HK) deficiencies are ultra-rare, autosomal-recessive defects of the contact system caused by biallelic mutations in the KLKB1 and KNG1 genes, respectively. Since affected subjects do not manifest a bleeding phenotype, a correct diagnosis is essential to prevent the administration of prohemostatic agents or plasma and to avoid delay of surgery. We describe a new case of PK deficiency identified at UMC Mainz. In addition, we performed a systematic review of the literature in order to i) collect blood material for genetic studies of reported PK deficient cases lacking this information, and ii) perform a comprehensive individual patient analysis for studying the clinical course and diagnostic criteria (analysis ongoing). Methods. MEDLINE and EMBASE were searched without time and language restrictions. Reference lists of retrieved articles, abstract books of hematology congresses, theses, and grey literature were manually reviewed. All the authors of recent articles on PK deficient cases not assessed for genetic defects, were contacted in order to retrieve blood samples. Clotting activities of PK and HK (PK:C and HK:C) were measured using PK and HK deficient plasmas, respectively. PK and HK antigens (PK:Ag and HK:Ag) were determined by ELISA. Routine aPTT and coagulation factor measurements were performed using an ACL TOP (IL). Genetic testing was performed by Sanger-, Pyrosequencing and/or NGS. Results. Our patient was a 69-year-old woman of African descent referred for preoperative evaluation of an isolated aPTT prolongation. Diagnosis of PK deficiency was based on absent PK:C and PK:Ag (≤1% of normal, each). The homozygous KLKB1 mutation p.Ser151Phefs*34 was found, which was not yet described as a cause of PK deficiency, but had been detected in the African sub-collective (MAF 1.3%) of the 1000 Genomes cohort. A total of 1,913 studies were identified by systematic literature review. Eleven studies with genetic data were found. Blood from 4 unrelated European families without previous genetic testing was analysed, including 3 index cases and 5 relatives. The KLKB1 mutation p.Cys548Tyr was found in 2 families with one index patient being homozygous. This data and the literature suggest that p.Cys548Tyr may be the most frequent KLKB1 mutation in Caucasians, associated with lacking PK:C but low amount of PK:Ag. One patient erroneously diagnosed with PK deficiency based on (incomplete) normalization of aPTT with increased preincubation time and low PK:C (7%) was found to carry compound heterozygous mutations in KNG1 (c.1038+1G〉A and c.1165C〉T, p.Arg389*) but no mutations in KLKB1. His low PK:C was explained by severe HK deficiency. Conclusions. PK deficiency may not be as rare as previously thought, especially in subjects of African origin. Incomplete normalization of severely prolonged aPTT upon prolonged preincubation and low PK levels are not sufficient for the diagnosis of PK deficiency. Our latter case and data from literature suggest that patients with HK deficiency usually present with moderately low PK levels: therefore, PK:C, PK:Ag, HK:C, and HK:Ag should be determined for proper diagnosis. Disclosures Kremer Hovinga: Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Lammle:Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support ; Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support .

Description: Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) may develop during anticoagulant treatment in patients submitted to various regimens of unfractionated or low-molecular weight heparins. Several molecules have been studied as alternative anticoagulants in patients with HIT or HITT, including danaparoid, argatroban, lepirudin. Lepirudin requires dosage adjustments in patients with renal insufficiency and has potential for antibody formation. Argatroban requires dosage adjustments in patients with hepatic insufficiency. Argatroban increases the International Normalized Ratio (INR) when co-administered with warfarin, leading to dosage difficulties when transitioning to warfarin therapy. Anticoagulation of patients with HIT or HITT may be limited by antibodies cross-reactivity with danaparoid and by new generation of antibodies with lepirudin. Fondaparinux is the first of a new class of synthetic antithrombotics: the selective inhibitors of coagulation factor Xa. It is the most advanced competitor of low molecular weight heparins, which are the reference drugs in prophylaxis and treatment of venous thromboembolism. Fondaparinux does not bind to platelet factor 4 (PF4) and does not react with anti-PF4/heparin antibodies in in vitro testing. We treated 20 patients who develop HIT (3 patients) or HITT (17 patients, of whom 4 had both DVT and PE). Nine patients were previously submitted to extracorporeal circulation with unfractionated heparin (UFH) followed by low-molecular weight heparin (LMWH) for major cardiac surgery. The remaining patients had been previously treated with either UHF or LMWH at therapeutic or prophylactic dosage in internal medicine or surgery wards. In the 17 patients who developed HITT, we applied therapeutic dosages of fondaparinux, i.e. 7.5 mg QD or lower, accordingly with their bleeding risk. To the remaining patients with HIT we gave prophylactic dosages of fondaparinux, i.e. 2.5 mg QD. Patients with HITT were treated for 4 to 25 days before starting warfarin. Fondaparinux was stopped when INR of 2.0 or more was reached. All patients showed a significant reduction of their thromboembolic burden. One episode of major bleeding was recorded in a post-surgical patient. All patients but one showed sustained normalization of the platelet number. In the remaining patient platelet count remained unchanged. Treatment was switched from fondaparinux to lepirudin and after few days her platelets reverted to close-to-normal levels. In seven patients, submitted to therapeutic dosages of fondaparinux, anti-PF4/heparin antibody titers were determined using a PF4/heparin enzyme-linked immunosorbent assay (ELISA): in all cases antibody levels progressively decreased close to disappearance by 30–45 days. This series of cases provides further evidence for the safety and efficacy of fondaparinux in the treatment of both HIT or HITT.

Description: Abstract 4329 Chronic thromboembolic pulmonary hypertension (CTEPH) results from obstruction of the major pulmonary arteries by incompletely resolved or organized pulmonary emboli which have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistances. CTEPH is a condition that is recognised in an increased percentage of patients. Pulmonary endarterectomy (PEA) is recognized as being the only curative option for a subgroup of those patients, but anaesthesiologists and intensivists face many challenges in how they manage these patients perioperatively. Ultimately, it is the combination of skills in a multidisciplinary team that leads to a successful procedure and dramatically improves patient's quality of life and life expectancy. Careful pre- and post-operative management is therefore essential for such a successful outcome following PEA. In 1994 in Pavia was started a program in which members of a multidisciplinary team work in close interaction with the aim of increase experience in the challenging problems these patients present in the evaluative, surgical, and post-operative phases of their care. Pregnancy in women with pulmonary hypertension (PH) is reported to carry a maternal mortality rate of 30–56%. No report is available on the management of pregnancy and delivery in patients with CTPH. We report our experience of the management of a pregnancy in a patient previously submitted to PEA in whom pressures decreased significantly but remained higher than normal due to partial intervention. EFS, 29 yrs, had first hemoptysis in 2001. Since then, she suffered effort dyspnea. A second hemoptysis occurred in 2004. She was admitted to hospital as having “Multiple foci pneumonia, with pulmonary hypertension of unclear origin”. In 2005 patient was admitted to a different hospital. A CT scan showed: “Congenital right pulmonary artery agenesia associated with bilateral multiple artero-venous malformations. NYHA Class III”. Patients was transferred to our hospital. Thrombophilic workout resulted negative. PaO2: 79.9 mmHg, pulmonary artery pressures (PAP): 130/60/13 mmHg, pulmonary vascular resistances (PVR): 1.083 dynes/sec/min−5. CT angio-scan: Severe dilation of the common pulmonary artery (34 mm). Right pulmonary artery visible only at proximal level. Bronchial artery dilation, bilaterally. V/Q scan: Absent visualization of the right pulmonary artery. Perfusion absent. Arteriography: Clearcut thrombosis of the right pulmonary artery (initial tract). Multiple typical CTPH lesions of the left pulmonary artery. Lower limb compression ultrasound (CUS): No sign of deep or superficial vein thrombosis. On 11 april, 2005 PEA was performed on the left side, with an attempt on the right side. No agenesia of the right pulmonary artery was found. Probable occlusion in early age, with evolution in fibrosis. Post surgery, PaO2: 94.3 mmHg, PAP: 53/32/15 mmHg, PVR: 453 dynes/sec/min−5. On September 16, 2005 she was pregnant, seventh week. After careful multidisciplinary counseling, patient decided to continue pregnancy. Anticoagulant treatment was switched from warfarin to low molecular weight heparin (LMWH), therapeutic dosage. Two days before elective delivery, LMWH was reduced to prophylactic dosages. On march 2, 2006 after an uncomplicated Caesarean section under general anesthesia, she delivered a healthy baby girl. During the following months, PAPs and functional parameters normalized. Patient is today in relatively good health. Is under oral vitamin K antagonists treatment. In 2007, being pregnant again, opted for therapeutic abortion. Maternal mortality in parturients with PAH or CTPH remains prohibitively high, despite lower death rates than previous decades. Early advice on pregnancy risks, including contraception, remains paramount. Women with PAH or CTPH who become pregnant warrant a multidisciplinary approach with consideration of appropriate therapies. Disclosures: No relevant conflicts of interest to declare.

Description: Patients undergoing knee joint replacement (KJR) are at high risk of postoperative venous thromboembolism (VTE), but data on the time trends of VTE rate in this population are sparse. In this analysis of the German nationwide inpatient sample, we included all hospitalizations for elective primary KJR in Germany 2005–2016. Overall, 1,804,496 hospitalized patients with elective primary KJR (65.1% women, 70.0 years [IQR 63.0–76.0]) were included in the analysis. During hospitalization, VTE was documented in 23,297 (1.3%) patients. Total numbers of primary KJR increased from 129,832 in 2005 to 167,881 in 2016 (β-(slope)-estimate 1,978 [95% CI 1,951 to 2,004], P