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Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia

Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia
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  ORIGINAL ARTICLE Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia L. JOSEPH,* A. I. CASANEGRA, †  M. DHARIWAL, ‡  M. A. SMITH, §  M. G. RAJU,  ¶   M. A. MILITELLO,**M. P. GOMES, ††  H. L. GORNIK ††  and J. R. BARTHOLOMEW †† * Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA; † Cardiovascular Section, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK;  ‡ IndianaUniversity, Indianapolis, IN;  § Department of Internal Medicine, Cleveland Clinic, Cleveland, OH;  ¶  Division of Cardiology, Department of  Medicine, Michigan State University, East Lansing, MI;  ** Department of Pharmacy, Cleveland Clinic; and   ††  Section of Vascular Medicine,Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA To cite this article:  Joseph L, Casanegra AI, Dhariwal M, Smith MA, Raju MG, Militello MA, Gomes MP, Gornik HL, Bartholomew JR.Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia.  J Thromb Haemost   2014;  12 :1044  –  53. Summary.  Background:  Heparin-induced thrombocytope-nia (HIT) is an adverse immune-mediated response tounfractionated heparin and, less commonly, lowmolecular weight heparin. It is associated with a highthrombotic risk and the potential for limb and life-threatening complications. Argatroban is the onlyapproved and currently available anticoagulant for HITtreatment in the USA.  Objectives:  To report safety andefficacy outcomes with bivalirudin for HIT treatment. Methods:  We retrospectively examined records from ourregistry of patients with a suspected, confirmed or pre-vious history of HIT and who had received bivalirudinfor anticoagulation in a single tertiary-care center overa 9-year period.  Results:  We identified 461 patients whoreceived bivalirudin: 220 (47.7%) were surgical patients,and 241 (52.3%) were medical patients. Of this popula-tion, 107 (23.2%) were critically ill, and 109 (23.6%)were dialysis-dependent. Suspected, confirmed and previ-ous history of HIT were reported in 262, 124 and 75patients, respectively. Of 386 patients with suspected orconfirmed HIT, 223 patients (57.8%) had thrombosisat HIT diagnosis. New thrombosis was identified in21 patients (4.6%) while they were on treatmentwith therapeutic doses of bivalirudin. No patientrequired HIT-related amputation. Major bleedingoccurred in 35 patients (7.6%). We found a signifi-cant increase in major bleeding risk in the criticallyill population (13.1%; odds ratio 2.4, 95% confi-dence interval 1.2  –  4.9,  P  =  0.014). The 30-day all-cause mortality rate was 14.5% (67 patients), andeight of 67 (1.7%) deaths were HIT-related.  Conclu-sion:  Bivalirudin may be an effective and safe alterna-tive option for the treatment of both suspected andconfirmed HIT, and appears to reduce the rate of HIT-related amputation. Keywords : amputation; antithrombins; death; heparin;thrombocytopenia; thrombosis. Introduction Heparin-induced thrombocytopenia (HIT) is a highly pro-thrombotic, potentially lethal adverse immunogenic reac-tion to unfractionated heparin (UFH) or low molecularweight heparin (LMWH) [1]. It is triggered by the releaseof procoagulant microparticles from platelet  a -granulesresulting from activation of platelets by means of an inter-action between their Fc c IIa receptors and immune com-plexes consisting of heparin-dependent IgG antibodies [2].These antibodies are bound to multimolecular heparin  –  platelet factor 4 (PF4) complexes. Rapidly acting non-hep-arin anticoagulants that inhibit thrombin or its generationconstitute the mainstay for treatment of HIT [2].Because the production of the direct thrombin inhibitor(DTI) lepirudin was discontinued in 2012, and the hepari-noid danaparoid is not available in the USA, argatrobanis the only available Food and Drug Administration(FDA)-approved anticoagulant for the prevention andtreatment of HIT. Argatroban, a hepatically cleared DTI, Correspondence: John R. Bartholomew, Cleveland Clinic LernerCollege of Medicine, Section Head, Vascular Medicine, Departmentof Cardiovascular Medicine, Sydell and Arnold Miller Family Heartand Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue/J3-5,Cleveland, OH 44195, USA.Tel.: +1 216 444 0825; fax: +1 216 444 7370.E-mail: barthoj@ccf.orgReceived 6 December 2014Manuscript handled by: I. PabingerFinal decision: F. R. Rosendaal, 14 April 2014 ©  2014 International Society on Thrombosis and Haemostasis Journal of Thrombosis and Haemostasis ,  12 : 1044–1053 DOI: 10.1111/jth.12592  has a half-life of 40  –  50 min, and requires dose reductionboth in patients with hepatic impairment and in the criti-cally ill [3]. It also has a significant effect on the pro-thrombin time (PT)/International Normalized Ratio(INR), which makes bridging to warfarin more complex[4]. Two drugs used off-label for the treatment or preven-tion of HIT in the USA include the DTI bivalirudin andthe indirect factor Xa inhibitor fondaparinux.Bivalirudin has US FDA approval as an alternativeanticoagulant for patients undergoing percutaneous coro-nary intervention (PCI), and is recommended over arg-atroban in patients with HIT by the American College of Chest Physicians (ACCP) for this indication [5]. It is the-oretically an attractive anticoagulant for HIT therapy,given its favorable pharmacologic profile, which includes:predominantly proteolytic elimination (only 20% renalclearance), immediate action, lack of the need for an ini-tial bolus, a low risk for immunogenicity, a short half-lifeof   ~   25 min, the potential for rapid dose titration, andminimal interference with the PT/INR [5]. We have usedbivalirudin almost exclusively at our tertiary-care institu-tion as an alternative to argatroban since 2002, and pres-ent our 9-year experience demonstrating it to be a safeand effective alternative treatment for HIT. Materials and methods  Study design and patients We examined 461 consecutive patient records identifiedfrom the Department of Pharmacy Registry of all hospi-talized patients who received bivalirudin for a suspected,confirmed or previous history of HIT at the ClevelandClinic from 1 January 2002 to 31 December 2010. Exclu-sion criteria included bivalirudin for indications otherthan HIT. We performed a retrospective review of thepatients’ demographic, clinical, laboratory and radiologiccharacteristics and outcomes for up to 30 days followingbivalirudin treatment, utilizing the method of Feinstein et al. , and recorded the data on a standardized form withREDCap (Research Electronic Data Capture) electronicdata capture tools, a secure, web-based application,hosted at our institution [6,7]. The study was approvedby our institutional review board.  Management of HIT  At our institution, acute HIT was suspected on the basisof the presence of well-defined clinical features asdescribed by King, Kelton, and Warkentin, and con-firmed by vascular medicine consultative services [8  –  10].According to our protocol, venous duplex ultrasoundscans of both upper and lower limbs were obtained formost patients with suspected or confirmed HIT. Pretestprobability scores were calculated by use of one of thefollowing clinical scoring systems: Lillo-Le Louet  et al. ,Lo  et al. , or Cuker  et al.  [11  –  13]. Serologic testing forPF4  –  heparin antibodies was obtained, UFH (or LMWH)was discontinued, and an alternative anticoagulant wasstarted in patients with an intermediate to high clinicalsuspicion of HIT. Functional assays (serotonin releaseassay [SRA] and/or heparin-induced platelet aggregation[HIPA] tests) were performed in most patients with a highclinical suspicion and/or positive immunogenic assayresult. Bivalirudin was initiated at doses of 0.05  –  0.1 mg kg  1 h  1 and titrated upwards or downwards by10  –  20% increments to obtain an activated partial throm-boplastin time (APTT) target of 1.5  –  2.5 times thepatient’s baseline. The starting dose was further reducedin the setting of renal insufficiency. If HIT was excluded,we stopped bivalirudin and reintroduced UFH orLMWH. If HIT was confirmed or considered to be inde-terminate, on the basis of laboratory testing or clinicalsuspicion, we transitioned patients to warfarin after plate-let recovery by using bivalirudin bridging. In addition,bivalirudin was administered to hospitalized patients witha previous history of HIT who required parenteral antico-agulation. Laboratory testing for HIT  We used two types of assay to aid in the diagnosis of HIT: immunogenic and functional.Immunogenic assays utilized anti-PF4  –  heparin ELISA,and were performed in all patients with suspected HIT.From 2002 until 2005, we used the GTI PF4 polyspecifickit (currently Lifecodes PF4 enhanced ELISA; Lifecodes,Waukesha, WI, USA), and from 2005 on, the GenProbeLifecodes PF4 IgG ELISA kit. Tests showing an ODvalue of   ≥  0.400 and inhibition of a positive reaction by ≥  50% in the presence of excess heparin were interpretedas positive in our laboratory.Functional assays measure platelet activation in thepatient’s serum in the presence of heparin. Most patientswith a high clinical suspicion for HIT or a positive immu-nogenic assay result underwent either HIPA or SRA, orboth. HIPA is an in-house test that uses donor platelets.Aggregation of normal platelets in the patient’s plasmaassessed by turbidimetry at 0.3 U mL  1 and 0.5 U mL  1 heparin is interpreted as positive. The SRA was sent to acentralized outside referral laboratory (Blood Center of Wisconsin, Milwaukee, WI, USA), and  ≥  20% release of serotonin with low-dose heparin plus  <  20% release inthe presence of a high concentration of heparin wasconsidered to be positive. Data collection We abstracted age, gender, body mass index (BMI),length of hospitalization, clinical setting, concomitant ill-nesses, dialysis dependence, concomitant/recent use of other antithrombotic agents, UFH or LMWH exposure ©  2014 International Society on Thrombosis and Haemostasis Bivalirudin for the treatment of heparin-induced thrombocytopenia  1045  details (type, dosage, duration, and indication) and labo-ratory values, including renal and liver function, esti-mated creatinine clearance (Cockcroft  –  Gault formula),platelet counts (baseline, nadir, and recovery time) andimmunogenic and functional assay results for HIT, fromthe medical records. We recorded patients’ outcomes,including thrombosis, bleeding, amputation, and death.For patients with suspected HIT, we retrospectively calcu-lated the 4Ts score (thrombocytopenia, timing, newthrombosis or alternative diagnosis) [12]. We obtainedavailable data for follow-up from the index hospitaliza-tion up to 30 days following the diagnosis and treatmentof HIT. Definitions We defined confirmed HIT according to the ISTH Plate-let Immunology SSC Working Group recommendation asthe presence of both a positive immunogenic assay resultand functional assay result (either SRA or HIPA) in apatient with suspected acute HIT [14]. A patient withacute HIT suspected but not confirmed according to theabove definition was classified into the suspected HITgroup. A thrombotic event was defined as any newvenous or arterial thrombus that developed during orafter UFH or LMWH exposure, in a patient with clinicalsuspicion of HIT. New thrombosis (while the patient wason bivalirudin) was defined as any different venous orarterial thrombosis or progression of a pre-existingthrombosis that occurred after the patient had received48 h of therapeutic doses of bivalirudin. Objective confir-mation by means of the available corresponding imagingstudy was required in either case.We classified bleeding according to the modified ISTHcriteria [15  –  17]. We defined major bleeding as overt bleed-ing associated with a fall in the hemoglobin level of  ≥  2 g dL  1 , or leading to a transfusion of two or moreunits of packed red blood cells or whole blood, or bleedingthat occurred in a critical site – intracranial, intraspinal,intraocular, pericardial, intra-articular, intramuscular withcompartment syndrome, or retroperitoneal – or surgicalsite bleeding that required a second intervention, or con-tributed to death. Clinically relevant non-major bleedingwas defined as overt bleeding not meeting the criteria formajor bleeding, but associated with a medical intervention,an unscheduled contact with a physician, (temporary)cessation of anticoagulation, or discomfort for the patient,such as pain or impairment of activities of their daily life[15,16].We defined as critically ill any patient who requiredintensive care treatment for  ≥  24 h during the indexhospital stay. Chronic renal failure was defined as aglomerular filtration rate of   <  60 mL min  1 1.73 m  –  2 for >  3 months. Chronic liver disease was defined as the pres-ence of biochemical, radiologic and/or histologic featuresof cirrhosis.  Statistical analysis We examined each variable for normal distribution, pre-sented continuous variables as mean    standard deviationor as the median (25th and 75th percentiles) when appro-priate, and categorical variables as proportions. Forcontinuous variables, we used Student’s  t -test in the case of bi-level categorical independent variables, and one-way ANOVA  in the the case of multi-level categorical independentvariables. Data were analyzed with the chi-square test forcategorical variables. Variables with a skewed distributionwere logarithm-transformed before the analysis, and thenretransformed to their natural units to represent them, andwere compared by use of the Mann  –  Whitney  U  -test andthe Kruskal  –  Wallis  H  -test.  SPSS  for Windows version 20.0(SPSS, Chicago, IL, USA) was used for the analysis. Allreported  P -values were two-sided, and a  P -value of   <  0.05was considered to be statistically significant. Results Among 461 patients included in our study, 241 (52.3%)were medical and 220 (47.7%) were surgical. Among thepatients, 107 (23.2%) were critically ill, and 109 (23.6%)were dialysis-dependent. Of these, 75 (16.3%) had a previ-ous history of HIT, 262 (56.8%) had suspected HIT, and124 (26.9%) had confirmed HIT (Table 1; see Table S1for additional details).The clinical and serologic profiles of patients with sus-pected or confirmed HIT ( n  =  386) are shown in Tables 2and 3, and Fig. 1 (see Table S2 for additional details). Themost common heparin exposure was intravenous UFH(272 patients, 70.5%). The most common indication forUFH or LMWH was antithrombotic prophylaxis (153patients, 39.6%).Of the 223 patients (57.8%) who developed thromboticevents, 213 (55.2%) had venous thromboembolism(VTE), 38 (9.8%) arterial thrombosis, and four (1.0%)skin necrosis. The upper extremity was the most commonlocation for deep vein thrombosis (DVT) (106 patients,27.5%). The frequency of thrombotic events was signifi-cantly higher in patients with confirmed HIT than inthose with suspected HIT (70.2% vs. 51.9%;  P  =  0.001).Patients were treated with bivalirudin for a median of 9 days (range, 5  –  15 days), and achieved a therapeuticAPTT within a median period of 12 h (range, 5  –  23.5 h).The platelet count recovered to  >  150 000  l L  1 after amedian of 4 days of therapy (range, 2  –  7 days) in 225(58.3%) suspected or confirmed HIT patients. The plate-let count did not recover to  >  150 000  l L  1 during biva-lirudin therapy in 153 patients (39.6%; confirmed HIT[40 patients, 10.4%]), and the remaining eight patientsdid not have platelet count nadirs below 150 000  l L  1 .The outcomes of bivalirudin treatment are summarized inTable 4 (see Table S3 for additional details on bleedingevents). ©  2014 International Society on Thrombosis and Haemostasis 1046  L. Joseph  et al  There were 46 (10%) clinically relevant bleeding eventsrelated to bivalirudin: 35 were major, including sevenfatal, and 11 were non-major. New thrombosis was docu-mented in 21 (4.6%) of the patients while they werereceiving therapeutic doses of bivalirudin. There were noHIT-related amputations. During the 30-day follow-up,there were 67 all-cause deaths (14.5%), and eight (1.7%)were HIT-related. One death resulted from pulmonaryembolism, and seven were resulted from bleeding relatedto bivalirudin therapy (two intracranial hemorrhages; twogastrointestinal bleeds; and three diffuse alveolar hemor-rhages).More than half of the patients (271 of 461, 59%) werechanged to warfarin. The proportion of patients with achange to warfarin was significantly higher in the con-firmed HIT group than among patients with suspectedHIT or with a previous HIT history. The reasons for notchanging the treatment of 190 patients were as follows:exclusion of HIT (68 patients), death (57 patients), moveto a hospice (five patients), high bleeding risk (22patients), change to fondaparinux (five patients), refusal(one patient), and unclear reasons (32 patients).We examined our data to evaluate for predictors (cho-sen on the basis of on clinical significance) of treatmentoutcomes (bleeding events, new thrombosis/HIT-relatedamputation, and 30-day all-cause mortality) as summa-rized in Table 5. There were no significant differences intreatment outcomes in patients by age, BMI, gender, orthe presence of renal insufficiency, or across various HITgroups (see Table S4 for additional details). Patients inthe critical care setting had a significantly higher fre-quency of major bleeding events (odds ratio [OR] 2.4,95% confidence interval [CI] 1.2  –  4.9,  P  =  0.014) and sig-nificantly higher 30-day mortality rates (OR 1.9,95% CI 1.1  –  3.4,  P  =  0.02). A lower nadir of plateletcounts was significantly associated with all-cause 30-daymortality and major bleeding events. Discussion We have used bivalirudin almost exclusively to treatpatients with a suspected, confirmed or previous historyof HIT. Our study from a single center demonstrates thatbivalirudin may be an effective and safe alternative anti-coagulant for treating HIT (with and without associatedthrombosis).The 2012 ACCP guidelines recommend non-heparinanticoagulants (lepirudin, argatroban, or danaparoid) forthe treatment and/or prevention of HIT [18]. That docu-ment reviewed the results of pooled analyses of prospec-tive cohort studies comparing lepirudin and argatrobanwith historical controls, and found that both agents were Table 1  Demographic and clinical characteristics of patientsCharacteristicsAll patients( n  =  461)Previous history of HIT( n  =  75)Suspected HIT( n  =  262)Confirmed HIT( n  =  124) P -value for comparisonbetween HIT groupsAge (years) 62.5    14.5 61.3    14.5 61.9    14.8 64.4    13.6 0.226Males,  n  (%) 262 (56.8) 43 (57.3) 147 (56.1) 72 (58.1) 0.932Body mass index (kg m  2 ) 30.0    8.0 30.6    8.2 29.7    8.3 30.1    7.1 0.767Clinical setting,  n  (%)Intensive care 107 (23.2) 14 (18.7) 67 (25.6) 26 (21.0) 0.361Medical 241 (52.3) 40 (53.3) 140 (53.4) 61 (49.2) 0.724Surgical 220 (47.7) 35 (46.7) 122 (46.6) 63 (50.8) 0.724Comorbidities,  n  (%)Active cancer 53 (11.5) 5 (6.7) 35 (13.3) 13 (10.5) 0.254Chronic liver disease 35 (7.6) 6 (8.0) 20 (7.6) 9 (7.3) 0.981Chronic renal failure 124 (26.9) 18 (24.0) 74 (28.2) 32 (25.8) 0.727Known thrombophiliccondition27 (5.9) 11 (14.7) 12 (4.6) 4 (3.2) 0.002Dialysis dependence 109 (23.6) 11 (14.7) 69 (26.3) 29 (23.4) 0.230Patients treated with analternative anticoagulantbefore bivalirudininitiation (fondaparinux,lepirudin, or argatroban)31 (6.7) 5 (6.7) 17 (6.5) 9 (7.3)  –  Baseline laboratory parametersPlatelet count onadmission (1000  l L  1 )186.0 (135.0, 243.0) 197.5 (137.5, 276.0) 185.5 (132.8, 248.0) 179.0 (138.0, 231.0) 0.287Serum creatinine(mg dL  1 )1.1 (0.8, 1.9) 1.0 (0.8, 2.0) 1.2 (0.8, 1.8) 1.2 (0.9, 2.0) 0.125CG GFR(mL min  1 1.73 m  –  2 )55.2 (31.2, 86.5) 55.7 (32.0, 96.6) 57.1 (31.4, 90.0) 52.0 (29.2, 73.3) 0.383CG GFR, Cockcroft  –  Gault formula-based glomerular filtration rate; HIT, heparin-induced thrombocytopenia. Continuous variables are pre-sented as mean    standard deviation or as the median (25th and 75th percentiles). ©  2014 International Society on Thrombosis and Haemostasis Bivalirudin for the treatment of heparin-induced thrombocytopenia  1047  more effective at preventing new thrombosis in patientswith HIT with thrombosis (HITT) and those with isolatedHIT [18  –  23]. Argatroban was also found to significantlyreduce the frequency of death resulting from thrombosis.Neither agent reduced the risk of limb amputation, butboth led to an increased risk of major bleeding in patients Table 3  Heparin-induced thrombocytopenia (HIT) laboratory and pretest probability scoring detailsCharacteristicsSuspected orconfirmed HIT( n  =  386)Confirmed HIT( n  =  124)Suspected HIT( n  =  262) P -value for com-parison betweensuspected andconfirmed HITgroupsPlatelet count nadir (1000  l L  1 ) 60.0 (36.0, 88.0) 51.0 (31.0, 79.0) 65.0 (41.0, 92.0) 0.003Anti-PF4 ELISA (OD) 1.3    1.1 2.2    1.1 0.8    0.8 0.000 ≥  0.4,  n  (%) 293 (75.9) 123 (99.2) 170 (64.9) 0.0000.4  –  1.0,  n  (%) 105 (27.2) 21 (16.9) 84 (32.1)  –  ≥  1.0,  n  (%) 188 (48.7) 102 (82.2) 86 (32.8)  –  Serotonin release assay,  n  (%)Positive 74 (19.2) 74 (59.7)  – –  Indeterminate 9 (2.3)  –   9 (3.4)  –  HIPA,  n  (%)Positive 71 (18.4) 71 (57.3)  – –  Indeterminate 36 (9.3) 15 (12.1) 21 (8.0)  –  4Ts score  – –   5.0 (4.0, 6.0)  –  Low probability (0  –  3),  n  (%)  – –   27 (10.3)  –  Intermediate probability (4  –  5),  n  (%)  – –   145(55.3)  –  High probability (6  –  8),  n  (%)  – –   90 (34.4)  –  HIPA, heparin-induced platelet aggregation; PF4, platelet factor 4. Continuous variables are presented as mean    standard deviation or as themedian (25th and 75th percentiles). Table 2  Clinical profile of patients with patients with suspected or confirmed heparin-induced thrombocytopenia (HIT)CharacteristicsSuspected orconfirmed HIT( n  =  386)Confirmed HIT( n  =  124)Suspected HIT( n  =  262) P -value for com-parison betweensuspected andconfirmed HITgroupsDuration of heparin exposure (days) 7.0 (4.0, 12.0) 7.0 (3.0, 10.0) 7.0 (4.0, 13.0) 0.345Type of heparin use and route of administration,  n  (%)UFH i.v. 272 (70.5) 74 (59.7) 198 (75.6) 0.001UFH s.c. 138 (35.8) 52 (41.9) 86 (32.8) 0.081LMWH s.c. 50 (13.0) 24 (19.4) 26 (9.9) 0.010UFH for cardiopulmonary bypassor during surgery123 (31.9) 44 (35.5) 79 (30.2) 0.294Indication for heparin exposure,  n  (%)DVT 74 (19.2) 22 (17.7) 52 (19.8) 0.624PE 30 (7.8) 9 (7.3) 21 (8.0) 0.795ACS 46 (11.9) 15 (12.1) 31 (11.8) 0.940Atrial fibrillation/flutter 67 (17.4) 22 (17.7) 45 (17.2) 0.891Antithrombotic prophylaxis 153 (39.6) 54 (43.5) 99 (37.8) 0.280Thromboembolic complications at thetime of diagnosis of HIT,  n  (%)223 (57.8) 87 (70.2) 136 (51.9) 0.001Venous thromboembolic events,  n  (%) 213 (55.2) 85 (68.5) 128 (48.9) 0.207DVT 182 (47.2) 73 (58.9) 109 (41.6) 0.002Proximal lower extremity DVT 69 (17.9) 27 (21.8) 42 (16.0) 0.169Distal lower extremity DVT 73 (18.9) 33 (26.6) 40 (15.3) 0.008Upper extremity DVT 106 (27.5) 41 (33.1) 65 (24.8) 0.090PE 30 (7.8) 13 (10.5) 17 (6.5) 0.171SVT 76 (19.7) 25 (20.2) 51 (19.5) 0.872Visceral 7 (1.8) 3 (2.4) 4 (1.5) 0.539Arterial thrombotic events,  n  (%) 38 (9.8) 15 (12.1) 23 (8.8) 0.878ACS, acute coronary syndrome; DVT, deep venous thrombosis; i.v., intravenous; LMWH, low molecular weight heparin; PE, pulmonaryembolism; s.c., subcutaneous; SVT, superficial vein thrombosis; UFH, unfractionated heparin. Continuous variables are presented asmean    standard deviation or as the median (25th and 75th percentiles). ©  2014 International Society on Thrombosis and Haemostasis 1048  L. Joseph  et al
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