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Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determined that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (∼26%), while erythroblasts contribute 1-4% of cfDNA in healthy individuals. Surprisingly, we discovered that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with Thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as novel biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.GRAPHICAL ABSTRACT

OBJECTIVE: To explore the indirect impact of the COVID-19 pandemic on patterns of pregnancy-related venous thromboembolism (VTE) events, mediated by population mobility restrictions during lockdown periods. METHODS: Pregnancy-related VTE hospitalizations were identified through a code-targeted search of the Hadassah Medical Center's computerized database. A manual analysis of relevant medical records was performed, and cases diagnosed throughout the year 2020 were compared to those diagnosed during 2019 and 2018. Statistical analyses studied obstetrical outcomes, as well as the extent and treatment of VTE events during the COVID-19 pandemic compared to those of preceding years, stratified by pre-, intra-, and post-lockdown periods. RESULTS: The incidence of pregnancy-related thromboembolic events during 2020 was 0.16% of all deliveries, significantly higher than in 2018 and 2019 (0.06% and 0.1%, respectively; P

Background: Venous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy. Objectives: We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL. Patients: All patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005–2017 were included. Results: There were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0–1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event. Conclusions: Among our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL.

Oral anticoagulants (AC) and antiplatelet (AP) agents are increasingly prescribed to prevent and treat acute and chronic thrombotic conditions. The direct oral anticoagulants (DOAC), a newer class of AC, raise concerns in the trauma setting. Our study aims to compare the mortality rates and other outcomes among adult trauma patients based on pre-admission AC/AP status. We conducted a retrospective cohort study of a prospectively collected database of trauma patients previously on DOAC, warfarin, aspirin or clopidogrel. A matched control group of trauma patients not receiving AC/AP was used for comparison. Our primary endpoint was in-hospital mortality according to antithrombotic medication class. Secondary endpoints included length of stay (LOS), intensive care unit (ICU) admission, need for blood transfusion, and discharge to a dependent setting. Univariate and multivariate analyses were conducted. There were 996 exposed patients and 234 controls, with no major clinically significant difference among study groups in terms of gender, injury site, injury severity, mechanism, and comorbidities. The mortality rates were 2.14% (control, 5/234), 2.88% (DOAC, 3/104), 3.34% (aspirin, 17/509), 7.63% (warfarin, 18/236), 9% (clopidogrel, 8/89), and 13.79% (aspirin + clopidogrel, 8/58) (p

To collect and summarize pregnancy outcomes among women with a history of cerebral sinus vein thrombosis (CSVT). A retrospective multicenter case–control study. The study group comprised all women diagnosed with CSVT during 2004–2018 at four university hospitals, and with follow-up data of pregnancy. A control group of women with a singleton pregnancy was established by matching, four-to-one, according to maternal age. The data of 74 pregnancies of 65 women with CSVT were analyzed. The median time-to-pregnancy interval from the CSVT was 4.2 [2.7–6.8] years. Anticoagulation therapy in the form of enoxaparin was administered in 68 (91.9%) pregnancies. Adjunctive low-dose aspirin was used throughout 12 (16.2%) pregnancies. Overall, 54 (73.0%) of the pregnancies ended in live births and 20 (27.0%) in miscarriage. The use of anticoagulation therapy during pregnancy was positively associated with live birth outcome (P

Postpartum low-molecular-weight heparin (LMWH) thromboprophylaxis is indicated for a substantial proportion of women. We assessed women’s adherence to postpartum thromboprophylaxis and the factors associated with adherence. This retrospective cohort study was conducted at a university hospital during 2018. Parturients for whom a recommendation for LMWH prophylaxis was given at discharge from the maternity ward were contacted at the end of the recommended post-discharge course of LMWH, and were invited to participate in a telephone survey. The main outcome measures were optimal (> 80%) and suboptimal adherence (

The efficacy of pharmacomechanical catheter-directed thrombolysis (PCDT) in preventing post thrombotic syndrome (PTS) for pregnancy related deep vein thrombosis (DVT) is unknown.An observational cross section study of women with pregnancy related proximal (femoral/iliofemoral) DVT who underwent PCDT followed by anticoagulation (study group), and women who were treated with anticoagulation alone (control group). Women were evaluated for PTS using the Villalta scale (primary outcome) and VEINES-QOL/Sym questionnaires.Eleven women with iliofemoral DVT underwent PCDT, two during their first trimester and nine postpartum; 18 women were treated with anticoagulation only. There were no significant differences in age, number of previous pregnancies, and duration of anticoagulation or thrombophilia between the groups. The time between DVT diagnosis and study inclusion was longer in the study group [median 50.5 (range 16-120) months] compared to the control group [median 27 (range 11-64) months],This study suggests that PCDT may reduce the incidence of PTS in women with pregnancy related proximal DVT.Bullet pointsDVT involving the iliofemoral veins and development of post thrombotic syndrome is frequent among pregnant or postpartum womenStudies of pharmacomechanical catheter-directed thrombolysis (PCDT) for deep vein thrombosis did not include pregnant or postpartum womenIn our observational cross section study women who underwent PCDT (mainly in the postpartum period) had reduced frequency of post-thrombotic syndrome compared to women who received anticoagulation onlyLarger studies are required to confirm the use of PCDT for prevention of PTS in this population.

Direct oral anticoagulants (DOACs) are commonly administered at a level that is lower than that recommended by dose reduction criteria. This raises concern regarding the adequacy of anticoagulation achieved. To evaluate the relationship between inappropriate dosing and DOAC levels. Medical records of atrial fibrillation patients who underwent DOAC level testing during 2013-2017 were reviewed. The primary outcomes were drug levels under and above the expected steady-state range, and in the lowest and highest quartiles. Of 143 patients who underwent DOAC measurements, only 87 (60.8%) received the appropriate dose. Levels under the expected range and in the lowest quartile were found in 11.9% and 15.0% of patients treated with appropriate dosing compared to 21% and 41.5% of patients treated with inappropriately low dose. DOAC levels were above the expected range and in the highest quartile in 23.8% and 32.5% of patients treated with the appropriate dose compared to 7.1% and 9.4% treated with inappropriately low dose. In multivariate analysis, the administration of an appropriate DOAC dose was associated with a lower rate of DOAC in the lowest level (adjusted odds ratio [95% CI] 0.30 (0.12, 0.76), P = 0.011). On the other hand, appropriate dose was associated with drug levels in the highest quartile (odds ratio [95% CI] 3.77 (0.12, 0.76), P = 0.011). Treatment with inappropriately low DOAC dosing compared to appropriate dose is associated with lower DOAC levels. However, among those treated with appropriate dosing, a higher proportion had high DOAC levels above the expected range.

Little is known regarding the management of direct oral anticoagulants (DOACs) in patients with enzyme-inducing drugs (EID). The use of EID may lead to sub-therapeutic concentrations of DOACs and to treatment failure. Thus, many patients on EIDs cannot benefit from the advantages of DOACs. This was a retrospective study, evaluating the management of hospitalized patients with DOACs. Characteristics of hospitalized patients with a prescription for DOACs, with and without EIDs, were summarized and evaluated, and management strategies addressing the potential interaction were documented, including the use of DOAC concentration monitoring. During the period evaluated, 1596 hospitalized patients with prescriptions for DOACs were identified. Most patients received apixaban (n = 1227, 77%), followed by rivaroxaban (240, 15%), and dabigatran (129, 8%). Twenty-two patients (1.4%) had concomitant EIDs. Demographic and clinical characteristics of hospitalized patients with DOACs were similar in those receiving EID and those not. Management strategies included stopping DOAC or EID (41%), and DOAC dose increase (14%). During management of these interactions, DOAC concentrations were measured for 11 of 22 patients and were below the 5th percentile of expected concentration for six of these patients. The management of patients with DOAC concentration measurement differed significantly from those without (p = 0.005), as they were much less likely to have one of the medications stopped and more often had the DOACs' dose increased. Among hospitalized patients with DOACs, EIDs are not rare. DOAC concentrations are often low in the presence of EIDs. DOAC concentration monitoring may be useful in settings requiring both DOAC and EIDs.

Venous thromboembolism (VTE), the combined syndromes of deep vein thrombosis (DVT) and pulmonary embolism (PE), is currently the third most frequent acute cardiovascular syndrome globally behind myocardial infarction and stroke. PE carries substantial mortality. In the past decade we have seen a remarkable improvement in new diagnostic tools as well as advances in therapeutic options to manage patients with PE. Still, even with recently updated society guidelines, the management of intermediate and high-risk PE requires clinician expertise and judgment. To aid health care providers caring for patients with acute PE, we have developed a novel, comprehensive yet straightforward, pathway for the management of patients with PE. We believe this pathway can be used in many health care systems around the globe. Our pathway for the diagnosis and management of PE is divided into three steps: the diagnosis of PE, the acute management of patients with PE, and recommendations for chronic management. The pathway requires classification of the PE by the risk of mortality and thus leads to the appropriate intensity of initial care, intervention and monitoring. The Pulmonary Embolism Response Team (PERT) is a multispecialty team designed to guide the decision-making for the individual patient with intermediate-high or high-risk PE. The PERT team brings together specialists from different disciplines. The team convenes in real time via a platform such as WhatsApp or texts messages to communicate clinical data, discuss the options and provide consensus for a course of management. The success of this pathway to manage PE depends heavily on developing a collaborative group of specialists dedicated to provide care at each stage to patients with PE.

Pregnancy is a precipitating factor for immune thrombotic thrombocytopenic purpura (iTTP). We compared the clinical course and outcomes of iTTP in women of reproductive age, between those with pregnancy- and non-pregnancy-related iTTP. A review of all reproductive-aged women diagnosed with iTTP during 2010-2019 in seven university hospitals in Israel. Of 42 cases of iTTP, 12 (28.6%) were pregnancy-related. At presentation, the laboratory profiles did not differ significantly between those with pregnancy- and non-pregnancy-related iTTP, including hemoglobin (median 8.4 vs 8.0 g/dL), platelet count (12.5 vs. 11.5 X 10

OBJECTIVES To examine the outcomes of planned induction of labour versus spontaneous onset of labour among women using prophylactic-dose low-molecular weight heparin (LMWH) therapy. DESIGN Retrospective cohort study. SETTING University hospital. POPULATION Women receiving antepartum prophylactic LMWH therapy undergoing a trial of vaginal delivery. METHODS Charts from 2018-2019 were reviewed. MAIN OUTCOME MEASURES Duration of anticoagulation interruption and eligibility to receive neuraxial anaesthesia. RESULTS Data from 199 women were analysed; 78 (39.2%) were admitted following spontaneous onset of labour and 121 (60.8%) underwent planned induction of labour. Compared to women who underwent planned induction of labour, women who presented with spontaneous onset of labour had a shorter median admission-to-delivery interval (4.7 versus 29.3 hours, P

Cesarean delivery (CD) is a known risk factor for postpartum hemorrhage. However, the characteristics associated with post-CD transfusion are not well-established. We aimed to assess blood transfusion rates and associated factors following CD. A retrospective case-control study of women who underwent CD at a university hospital. The study group comprised all women who received blood transfusion following surgery. A control group of women who did not receive postoperative blood transfusion was assigned in a two-to-one ratio. During study period, the overall post-CD blood transfusion rate was 4.7%. The study group comprised 170 women, and the control group 340. Maternal age (aOR [95% CI]: 1.07 (1.03, 1.11), p = .001), parity (aOR [95% CI]: 1.26 (1.09, 1.47), p = .002), gestational hypertensive disorders (aOR [95% CI]: 4.07 (1.52, 10.91), p = .005), maternal comorbidities (aOR [95% CI]: 4.16 (1.88, 9.1), p p p = .04) were independently associated with blood transfusion requirement. Intrapartum characteristics associated with blood transfusion requirement included nonelective procedure (aOR [95% CI]: 3.21 (1.72, 5.99), p p p p = .02), and greater estimated operative blood loss (aOR [95% CI]: 5.72 (3.15, 10.36), p Among women who underwent CD, we identified 11 factors associated with blood transfusion following surgery. Prospective studies are warranted to assess the implementations of prophylactic interventions to reduce transfusion rates among those deemed at high risk for CD-related bleeding.

Objective Gestational thrombocytopenia (GT) accounts for 75% of cases of thrombocytopenia in pregnancy. In most cases of GT, thrombocytopenia is mild (100–150 × 109/L) and has no consequences for either the mother or the fetus. We aimed to investigate the characteristics, neonatal risk and recurrence rate of GT with a platelet count Study Design We reviewed the records of women who delivered during 2006–2016 at a large tertiary care university hospital, and who had platelet count Results Of 97 pregnancies in which platelet count lower than 100 × 109/L was encountered, 66 (68%) were diagnosed as GT and 31 (32%) as new-onset immune-thrombocytopenic purpura (ITP). The proportions of women with onset of thrombocytopenia in early pregnancy (P = 0.004) and a lower maternal nadir platelet count (P = 0.01) were higher among those with new-onset ITP than GT. There was no difference in the rate of neonatal thrombocytopenia ( Conclusion The risk of neonatal thrombocytopenia was substantial, with no difference found between those with GT and new-onset ITP. The recurrence rate of GT was high in subsequent pregnancies.

Objectives: To characterize the risk factors associated with neonatal thrombocytopenia among pregnant women with immune thrombocytopenic purpura (ITP).Methods: We reviewed the records of ITP patien...

To examine the laboratory anticoagulant effect of two thromboprophylactic low-molecular weight heparin (LMWH) regimens in post-cesarean obese patients.A prospective cohort study, performed during 2017-2018 at a university hospital, of post-cesarean obese (90 kg) patients receiving 40 mg/day (n = 30) or 60 mg/day (n = 30) enoxaparin, and a control group of non-obese (n = 30) post-cesarean patients receiving 40 mg/day enoxaparin. Thrombin generation and anti-Xa were measured twice on the third postoperative day: prior to and 3.5-4 h following the third LMWH dose.Age, parity, weight and body mass index were comparable between the obese study groups. Compared to the control non-obese group, the 40 mg obese and 60 mg obese groups showed increased baseline thrombin generation: medians 491, 581, 571 nM, respectively (P = 0.001 and P = 0.04, respectively). At peak LMWH activity, thrombin generation was higher in the 40 mg than in the 60 mg obese and control groups: medians 2599, 2391, 2229 nM, respectively (P = 0.01 and P 0.0001, respectively); and thrombin generation was comparable between the 60 mg obese and the control groups (P = 0.58). Similarly, a significantly lower proportion of patients in the 40 mg obese group (10%) had anti-Xa levels within the recommended prophylactic range (0.2-0.5 IU/mL) than in the other groups (P 0.0001 for both comparisons).As determined by thrombin generation and anti-Xa testing, post-cesarean obese patients have an increased procoagulant potential, which was diminished only in those receiving higher dosages of LMWH. These findings support the need for clinical evaluation of LMWH dose adjustment in this setting.

Antiphospholipid syndrome (APLS) is caused by antiphospholipid autoantibodies, and manifests with vascular and/or obstetric complications. The factors associated with initial disease presentation and course are unknown. We assessed the antibody profile associated with disease presentation and with the development of vascular and obstetric complications in women with initially vascular or initially obstetric APLS. A review of records of APLS women at childbearing age followed at one center during 2006-2015. Of 126 women, median age at diagnosis 29 [23-37] years, 62 were initially diagnosed with purely obstetric APLS and 64 with purely vascular APLS. Baseline characteristics and antibody profile did not differ according to the initial diagnosis. At a mean follow-up duration of 61 ± 23 months, 19 (30.6%) with initially obstetric disease, and 20 (31.3%) with initially vascular disease, developed vascular and obstetric complications, respectively (P = 1.0). Among those with triple positivity [lupus anticoagulant (LAC)+, anticardiolipin (ACL)+, anti beta2-glycoprotein I (AB2GPI)+], a higher proportion developed both obstetric and vascular complications, compared to those with single or double positivity (42.3 vs. 16.4%, P = 0.002). In multivariate analysis, the presence of LAC (P = 0.008), ACL IgG (P = 0.009) or AB2GPI IgG (P = 0.01) was the only independent predictor of the development of both obstetric and vascular complications. Almost one-third of women with initially vascular or initially obstetric APLS developed mixed disease. The antibody profile was the only prognostic marker for disease course. The association found between LAC, ACL IgG or AB2GPI IgG, and patient outcomes could contribute to risk stratification and individualized patient management.

To investigate the course of acquired type 2A von Willebrand syndrome (AVWS) in relation to patient management and outcomes among pregnant patients with essential thrombocytosis (ET). A review of pregnant women with ET evaluated for AVWS at the beginning of pregnancy and at the third trimester. Eighteen women with 24 pregnancies were included in this study. A history of bleeding was noted in 8 (44%) patients. In 20 (83%) pregnancies AVWS was evident at the initial testing. Following initial testing, antithrombotic therapy was administered in 22 (92%) pregnancies (aspirin, n = 20 and low-molecular-weight heparin, n = 2). In the remaining two pregnancies, VWF:RCo levels were below 30%; thus, aspirin was given only after repeat testing at 14–16 weeks. At third trimester testing, median VWF:RCo levels were significantly higher than at the initial testing (86 vs. 48%, P

The role of drug-level monitoring among patients using direct-acting oral anticoagulant (DOAC) is unclear. We aimed to investigate its ‘real-life’ utilization and effect on clinical management. A review of records of patients who underwent DOAC level testing during 2013–2017. Overall, 212 patients (median age 77 years) underwent 292 DOAC measurements [apixaban (n = 147), rivaroxaban (n = 102), dabigatran (n = 43)]. Monitoring volume increased by 460% during study period. DOAC level testing was performed during routine follow-up in 51 (17.5%) cases, whereas the remaining 241 (82.5%) measurements were performed due to selected clinical circumstances, most commonly: bleeding (n = 60), perioperative status (n = 45), breakthrough thrombosis (n = 37) and renal failure (n = 35). Drug levels were within the expected range in 210 (71.9%), above the expected range in 62 (21.2%) and lower than expected range in 20 (6.8%). In multivariate analysis, older age (P = 0.005), lower glomerular filtration rate (P = 0.001) and lower body mass index (P = 0.006) were associated with DOAC levels above the expected range. Clinical decisions were affected by DOAC monitoring following most (140/241, 58.1%) measurements for which we identified an indication for testing; yet only rarely when monitoring was performed during routine follow-up (7.8%, 4/51) (P

Objective To determine direct-acting oral anticoagulant (DOAC) blood levels in post-bariatric surgery (BS) patients treated with long-term anticoagulation therapy. Methods We identified from medical records patients who underwent BS during 2005–2016 and who were treated with DOACs. We offered testing DOAC blood levels to these patients and to age, sex, body mass index, and serum creatinine-matched individuals treated by DOACs who did not undergo BS. Results Overall, 36 individuals were enrolled, 18 post-BS patients and 18 control subjects. Of the post-BS patients, 12 underwent laparoscopic sleeve gastrectomy, 4 laparoscopic adjustable gastric banding and 2 laparoscopic Roux-en-Y gastric bypass surgery. Median time lapsed from surgery until study inclusion was 4.9 years. Five post-BS patients had peak drug levels below expected levels compared to none of the control subjects (P = 0.05). For patients who used apixaban (n = 9) and dabigatran (n = 2), peak drug levels were within the expected range. In contrast, for the 7 patients who used rivaroxaban, levels were below the expected range in 5, including all four who underwent sleeve gastrectomy and one following adjustable gastric banding. Peak rivaroxaban levels were significantly lower in the post-BS than the control group (P = 0.02). Conclusion This preliminary study suggests that all DOACs, particularly rivaroxaban, be cautiously used following BS, if used at all. Given that vitamin-K antagonists can be easily monitored, they may be a better choice, until more data on DOAC use in this patient population are available.

OBJECTIVE We aimed to determine hemostatic changes and characterize the procoagulant potential among patients with reactive thrombocytosis (RT). METHODS Sixty patients with RT (median platelet count 718 × 109 /L) and 20 healthy persons were tested for complete blood count, C-reactive protein, von Willebrand factor (VWF), factor VIII and fibrinogen, and thrombin generation. Platelet studies, including light transmission aggregometry and Cone and Plate(let) Analyzer, were also conducted. Reticulated platelets and platelet P-selectin expression were measured using flow cytometry. RESULTS Compared to patients with mild thrombocytosis (platelet count 500-700 × 109 /L; n = 27), those with moderate-to-severe thrombocytosis (platelet count >700 × 109 /L; n = 33) had significantly higher fibrinogen, factor VIII, and VWF antigen and activity levels; higher endogenous thrombin potential, peak thrombin generation and velocity index levels, and shorter time-to-peak thrombin level. VWF antigen and activity, fibrinogen, and factor VIII were positively associated with platelet count, whereas VWF activity/antigen ratio was inversely correlated. In a multivariate analysis of RT and control participants, only platelet count predicted endogenous thrombin potential with a positive-linear correlation. No patients developed acquired von Willebrand syndrome. CONCLUSIONS As determined by thrombin generation, RT was associated with in vitro prothrombotic tendency, which correlated with platelet count. This may explain the increased thromboembolic risk previously reported in patients with RT.

Background Bariatric surgery is associated with increased thromboembolic risk, which may extend well beyond hospital stay. The hemostatic mechanisms implicated in this risk are not well established. Objectives We aimed to determine the dynamics of hemostatic changes and procoagulant potential among patients undergoing laparoscopic sleeve gastrectomy, during both the early and late postoperative periods. Setting A university hospital. Methods Patients who underwent laparoscopic sleeve gastrectomy were recruited consecutively to this study. Blood samples were taken preoperatively, before discharge (postoperative day [POD] 3), and at the first follow-up visit (POD10). All samples were tested for complete blood count, C-reactive protein, von Willebrand factor, factor VIII, fibrinogen, and thrombin generation. Results The median preoperative body mass index of the 26 participants was 41.3 (38.7–43.3) kg/m 2 . Compared with preoperative evaluation, fibrinogen, von Willebrand factor antigen and activity, and factor VIII levels were significantly higher at POD3 and POD10 ( P P = .005 for both comparisons) and POD10 ( P = .0009 and P = .007). Conclusions As determined by thrombin generation, laparoscopic sleeve gastrectomy was associated with hypercoagulability, which persisted during POD10. This finding suggests a possible benefit of extended thromboprophylaxis. Nevertheless, our results should be interpreted with caution due to the lack of a control group.

Management of women after mechanical heart valve replacement throughout gestation is one of the most high-risk challenging conditions (Arya 2019). In recent decades, improvements in the field of me...

Stroke and thromboembolic events occurring among patients taking direct oral anticoagulants (DOACs) have been associated with low concentrations of DOACs. Enzyme-inducing antiseizure medications (EI-ASMs) are associated with enhanced cytochrome-P450-mediated metabolism and enhanced P-glycoprotein-mediated transport.The aim of this study was to evaluate the effect of concomitant EI-ASM use on DOAC peak concentrations in patients treated in clinical care.We performed a retrospective cohort study of patients treated with DOACs for atrial fibrillation and venous thromboembolic disease in an academic general hospital. In total, 307 patients treated with DOACs between August 2015 and January 2020 were reviewed. Clinical characteristics and peak DOAC plasma concentrations of patients co-treated with an EI-ASM were compared with those of patients not treated with an EI-ASM. An apixaban dose score (ADS) was defined to account for apixaban dosage and the number of apixaban dose-reduction criteria.In total, 177 peak DOAC plasma concentrations (including apixaban, rivaroxaban, and dabigatran) from 131 patients were measured, including 24 patients co-treated with an EI-ASM and 107 controls not treated with an EI-ASM. The proportion of patients with DOAC concentrations below the expected range was significantly higher among EI-ASM users than among patients not taking an EI-ASM (37.5 vs. 9.3%, respectively; p = 0.0004; odds ratio 5.82; 95% confidence interval [CI] 2.03-16.66). Most of these patients were treated with apixaban (85%); however, sensitivity analysis results were also significant (p = 0.031) for patients with non-apixaban DOACs. In patients co-treated with apixaban and an EI-ASM, median apixaban peak concentration was 106 ng/mL (interquartile range [IQR] 71-181) compared with 150 ng/mL (IQR 94-222) in controls (p = 0.019). In multivariable analysis, EI-ASM use was associated with 6.26-fold increased odds for apixaban concentration below the expected range (95% CI 2.19-17.90; p = 0.001). Apixaban concentrations were significantly associated with EI-ASM use, moderate enzyme inhibitor use, and ADS.Concurrent EI-ASM and DOAC use presents a possible risk for DOAC concentrations below the expected range. The clinical significance of the interaction is currently unclear.

We aimed to determine the outcome of threatened abortion in women treated with low-molecular weight heparin (LMWH) for recurrent pregnancy loss (RPL). Data of women with RPL who experienced threatened abortion while taking LMWH between 2007 and 2016 were retrospectively reviewed. All patients received the LMWH, enoxaparin (40 mg). Thrombophilia was present in 38 (33.3%) women, including 11 (9.6%) with antiphospholipid syndrome (APLS). The overall live birth rate was 58.8% (67/114). Live birth rates were 87.2% (41/47 patients) and 38.8% (26/67 patients) among those who discontinued versus those who continued LMWH treatment, respectively (P < 0.0001). Among APLS patients, live births resulted in eight of the nine women who continued LMWH. In multivariate analysis, discontinuation of LMWH was the only significant predictor of live birth outcome (P < 0.0001). Thrombophilia, presence of subchorionic haematoma, and severity of bleeding were not found to be associated with live birth outcomes. For women with threatened abortions, continuation of LMWH indicated to prevent RPL was negatively associated with live birth rates. Therefore, we support its discontinuation in this setting. Among women with APLS, LMWH continuation resulted in a relatively high live birth rate; we advocate against its withdrawal in this subset of patients.

To evaluate the impact of an institutional protocol on patterns of use and outcomes of inferior vena cava filters (IVCF). Following a multidisciplinary effort, an institutional protocol involving dedicated follow-up of patients receiving IVCF and a physician education program regarding IVCF utilization, was established. We prospectively collected data of patients who received IVCF during 2015–2016, following protocol implementation (POST group). For comparison, we reviewed records of patients who received IVCF during 2009–2014, before implementation of the institutional protocol (PRE group). In the PRE and POST groups, 76 and 38 IVCF per year were inserted respectively, with an overall decrease of 50%. IVCF were more likely to be placed for therapeutic rather than prophylactic indications in the POST compared to the PRE group (P = 0.003). Follow-up rates at our coagulation clinic were significantly higher in the POST than the PRE group (100 vs. 22.9%, P

Objective: We characterized acquired von Willebrand syndrome (AVWS) among essential thrombocythemia (ET) and polycythemia vera (PV) patients. Methods: A review of patients with ET or PV evaluated for AVWS. Results: Of 116 patients with ET, 64 (55%) developed AVWS; of 57 with PV, 28 (49%) developed AVWS. Median platelet counts of ET and PV patients who developed AVWS were 920 X 109/L and 679 X 109/L, respectively (P=0.01). Of patients who developed AVWS, 69.5% had platelet counts below 1000 X 109/L. Bleeding was more common in patients with AVWS, among both ET and PV patients (P Conclusion: Among ET and PV patients, AVWS was common and associated with higher bleeding rates and higher platelet count; nonetheless, most AVWS patients had platelet counts under 1000 X 109/L. Thus, AVWS screening should be included in routine assessment of ET and PV patients. Among ET patients, JAK2 V617F was a main driver for the development of AVWS. Disclosures No relevant conflicts of interest to declare.

To collect and summarize pregnancy outcomes among women with a history of cerebral sinus vein thrombosis (CSVT). A retrospective multicenter case-control study. The study group comprised all women diagnosed with CSVT during 2004-2018 at four university hospitals, and with follow-up data of pregnancy. A control group of women with a singleton pregnancy was established by matching, four-to-one, according to maternal age. The data of 74 pregnancies of 65 women with CSVT were analyzed. The median time-to-pregnancy interval from the CSVT was 4.2 [2.7-6.8] years. Anticoagulation therapy in the form of enoxaparin was administered in 68 (91.9%) pregnancies. Adjunctive low-dose aspirin was used throughout 12 (16.2%) pregnancies. Overall, 54 (73.0%) of the pregnancies ended in live births and 20 (27.0%) in miscarriage. The use of anticoagulation therapy during pregnancy was positively associated with live birth outcome (P 0.001). Late adverse outcomes were encountered in 19 (25.7%) pregnancies, including the delivery of a small for gestational age infant (n = 12), gestational hypertensive disorders (n = 6) and placental abruption (n = 3). The use of adjunctive aspirin was associated with a lower rate of late adverse pregnancy outcomes (P = 0.03). No recurrent CSVT, thrombosis at other sites, and major bleeding episodes were observed during pregnancy. Live-birth rate was higher (P = 0.007) and the rate of late adverse outcome was lower (P = 0.01) for the control (n = 296) than the study group. Among pregnant women with a prior CSVT, no recurrent thrombosis events were observed during gestation. The use of prophylactic anticoagulation was associated with live birth. The use of adjunctive aspirin should be further studied in this setting, as its utilization correlated with a lower rate of late pregnancy complications.

The occurrence of upper extremity deep vein thrombosis (UEDVT) is not uncommon following peripherally inserted central catheter (PICC) insertion. However, the risk factors associated with this condition are unknown. Moreover, the role of prophylactic anticoagulation in the prevention of PICC-related UEDVT is not well established.A review of the medical records of all patients who underwent PICC insertion during 2016 at the Hadassah Medical Center.Overall, 500 patients underwent PICC insertion during the study period. Of them, 199 (39.8%) received prophylactic anticoagulation following insertion. Patients with active cancer were less likely to receive prophylactic anticoagulation. Twenty-five (5.0%) patients experienced PICC-related UEDVT, which occurred after a median of 8 days following PICC placement. The only factors associated with the development of UEDVT were the presence of active cancer (P=0.04) and higher C-reactive protein level (P=0.02). The rate of UEDVT was comparable between those who received prophylactic anticoagulation and those who did not (P=0.98).PICC-related UEDVT is a common complication. Active cancer and higher baseline C-reactive protein level were associated with the occurrence of this condition. Future studies are warranted to confirm our findings and further assess the role of prophylactic anticoagulation in this setting.

Both inflammatory bowel diseases (IBDs) and pregnancy are established risk factors for thrombotic complications, thus IBD pregnant patients can be considered at even greater risk for thrombosis as compared to non IBD pregnant women. We aimed to evaluate the risk factors associated with this prothrombotic tendency among IBD women throughout gestation.Women with IBD attending a multidisciplinary clinic for the preconception,antenatal and postnatal treatment were prospectively recruited during 2017-2018. Prothrombotic tendency was assessed by thrombin generation, a global marker of the activation of the coagulation system, expressed as the endogenous thrombin potential (ETP).Overall, 145 IBD women and 50 healthy control subjects were enrolled in this study. Body mass index (BMI) and gestational age were comparable between the groups. ETP level was significantly higher in women with IBD compared to control subjects in all time period (P .0001). Among women with IBD, ETP level positively correlated with disease activity, as assessed by physician global assessment (P = .005), gestational age (P .0001), extra-intestinal involvement (P = .04), C-reactive protein level (P .0001), erythrocyte sedimentation rate (P .0001), white blood cell count (P = .008), BMI (P = .02) and was inversely correlated with hemoglobin level (P .0001). ETP level did not correlate with the occurrence of adverse pregnancy outcomes. In a multivariate analysis, active disease (β = 0.20, P = .009), gestational age (β = 0.45, P .0001), extra-intestinal involvement (β = 0.17, P = .02) and BMI (β = 0.15, P = .05) retained independent predictors of high ETP levels.As determined by thrombin generation, the procoagulant potential among IBD pregnant patients was independently associated with disease activity, BMI and extra-intestinal disease involvement.

Introduction In the past decade, direct-acting oral anticoagulants (DOAC) have been introduced to medical practice for several indications, with a wide range of dosing regimens. As both over- and under-dosing might lead to life-threatening events, development of methods promoting safe and effective utilization of these agents is imperative. The Hadassah Clinical Pharmacy team initiated a hospital-wide program, for monitoring and promoting safe and effective prescription of DOAC during hospitalization. This study describes the types of drug related problems addressed and the program’s performance in terms of consultation rates and physician acceptance. Methods Electronic medical records throughout the hospital were screened for DOAC orders. All DOAC orders were assessed by a clinical pharmacist for potentially-inappropriate prescribing. When potentially-inappropriate prescribing or a drug-related problem was identified, the clinical pharmacist provided consultation on management options. In specific cases, additional guidance was provided by coagulation and pharmacology specialists. Data on patient characteristics, clinical pharmacist consultations, and physician response was retrospectively retrieved for the first six months of 2017. Characteristics of patients with and without consultations were compared, consultations were categorized by the recommended management of the drug related problem, and physician acceptance rates were evaluated by category. Results During the evaluated period, 585 patients with DOAC orders were identified. Patients were evenly distributed by gender, and age averaged 78 years. Most patients received apixaban (75%) followed by rivaroxaban (14%) and dabigatran (11%), and most (63%) received “reduced dose” regimens. Clinical pharmacists provided 258 consultations for 210 patients, regarding anticoagulation management, such that more than one in three patients on DOAC had potentially inappropriate prescribing or drug related problems. Consultations included alerts regarding potentially inappropriate DOAC doses and recommendations to increase (29%) or decrease (5%) the dose, potentially inappropriate concomitant antiplatelet agents (20%), need for DOAC level monitoring (23%), and alerts regarding other drug related problems (23%). More than 70% of recommendations were accepted by the attending physician. Conclusion Due to the complexity of DOAC management, potentially-inappropriate prescribing and drug related problems are common. Multidisciplinary collaborative projects including review and consultation by clinical pharmacists are an effective method of improving management of patients on DOAC. Trial registration Retrospectively registered at clinicaltrials.gov, NCT03527615.

Aim The utilization of inferior vena cava filter placement for pulmonary embolism prevention in elderly patients has not been well characterized. The present study aimed to review indications, complications and follow-up data of elderly patients undergoing inferior vena cava filter placement. Methods A retrospective review was carried out of consecutive admitted patients who underwent inferior vena cava filter insertion at a large university hospital with a level I trauma center. Results Overall, 455 retrievable filters were inserted between 2009 and 2014. A total of 133 patients (29.2%) were aged ≥70 years. Elderly patients were less likely to have their filter retrieved compared with non-elderly patients (5.3% vs 21.4%, P

Data are limited on the effects of drug interactions on direct-acting oral anticoagulant (DOAC) levels. We evaluated the effects of the use of interacting drugs on DOAC levels in patients with atrial fibrillation (AF). We reviewed data of AF patients tested for DOAC levels in 2013–2017. The primary outcomes were drug levels exceeding the expected steady-state range, and in the highest quartile. A multivariate analysis was performed to evaluate the correlation of treatment by the use of interacting drugs, CYP3A4 and P-glycoprotein (P-gp) inhibitors, with the primary outcomes. Overall, 147 patients underwent DOAC level measurement [dabigatran (n = 31), rivaroxaban (n = 29), apixaban (n = 87)]. Thirty-three (22.4%) had drug levels exceeding the expected range. Seventy-nine (53.7%) patients were treated with at least one interacting drug. In multivariate analysis, the concomitant use of interacting drugs was an independent predictor for drug levels exceeding the expected range (OR 3.3, 95% CI 1.20–9.05). The defined daily dose of the interacting drug correlated positively with DOAC levels (r = 0.29, P = 0.001). Co-treatment with interacting drugs was associated with extremely high levels of dabigatran, (OR 16.6, 95% CI 1.29–215.18) but not of the other DOAC examined. Concomitant use of interacting drugs is associated with high DOAC levels in patients with AF. Further investigation is warranted to establish the differences between specific DOAC, evaluate the effect on patient outcomes, and characterize the role of DOAC monitoring in this setting.

Gestational thrombocytopenia (GT) accounts for 75% of cases of thrombocytopenia in pregnancy. In most cases of GT, thrombocytopenia is mild (100-150 × 10We reviewed the records of women who delivered during 2006-2016 at a large tertiary care university hospital, and who had platelet count100 × 10Of 97 pregnancies in which platelet count lower than 100 × 10The risk of neonatal thrombocytopenia was substantial, with no difference found between those with GT and new-onset ITP. The recurrence rate of GT was high in subsequent pregnancies.

Current guidance recommends avoiding concomitant use of direct-acting oral anticoagulants and enzyme-inducing antiepileptic drugs because of theoretical drug interactions potentially leading to subtherapeutic drug concentrations and treatment failure. We describe a case documenting a significant interaction between phenobarbital and rivaroxaban, and then apixaban. This case illustrates and supports the concerns regarding concomitant use of these medications. Additionally, in this case the interaction was managed with concentration-guided dosing of apixaban, suggesting this approach may represent a feasible strategy for managing patients requiring treatment with direct-acting oral anticoagulants and enzyme-inducing antiepileptic drugs.

Objectives: The objective of this study is to evaluate patterns of use and outcomes of retrievable inferior vena cava filters (rIVCF) in obstetric patients. Methods: A single center review of consecutive patients who underwent rIVCF placement during pregnancy/postpartum in 2005–2016. A pooled analysis of the relevant cases in the English literature was conducted. Results: The current cohort comprised 24 women, median age 27 [interquartile range 24–30] years. Among 10 filters placed during pregnancy, the most common indication (n = 4) was the need to withhold anticoagulation therapy before delivery, in the presence of acute thrombosis. In the postpartum period, most filters (64%, 9/14) were an adjunct to catheter-directed thrombolytic therapy. Inferior vena cava filters (IVCF)-related complications occurred in seven (29.2%). Retrieval was attempted in 21 patients (87.5%), and was technically successful in 19 (90.5%), for an overall removal rate of 79.1%. Pooled analysis of the literature (n = 98) showed comparable rates for filter removal and complications (81.6%, p = .78 and 24.2%, p = .60, respectively). Suprarenal placement (p = .12) and elective cesarean section (p = .19) did not reduce overall complication and retrieval rates. The estimated radiation dose among pregnant patients who underwent rIVCF placement without adjunct catheter directed thrombolysis (CDT) (mean 695 Gy cm2) was significantly lower than the radiation dose used in postpartum patients (1863 Gy cm2) or in pregnant patients in whom adjunct CDT was utilized (4059 Gy cm2) (p = .001 for both comparisons). Conclusions: Frequent rIVCF-related complications, radiation exposure, and removal failure call for their cautious utilization in obstetric patients. The role of suprarenal placement and elective cesarean section to improve outcomes has yet to be established.

Inherited afibrinogenemia and hypofibrinogenemia are rare bleeding disorders characterized by markedly reduced levels of fibrinogen in blood. Thrombotic complications in these disorders have been rarely described. We performed a multicenter retrospective study and reviewed the occurrence of thrombotic complications among patients with inherited fibrinogen deficiency. Cases were identified during a review of medical records of all patients with inherited fibrinogen deficiency followed at three different university hospitals in Israel. Nine patients were included in this study: five were afibrinogenemic and four hypofibrinogenemic. There were seven thrombotic events, mostly venous, that occurred in four out of nine patients (44 %). All thrombotic events occurred in afibrinogenemic patients. Mean age at the time of thrombosis was 45 (range 28-61) years. Thrombophilic evaluation performed was negative in all cases. At the time of thrombosis in five out of seven (71.4 %) events, fibrinogen replacement therapy was concurrently given. Therapeutic approach was different among patients ranging from supportive therapy alone, antiplatelet agents and anticoagulant therapy with the concurrent administration of fibrinogen replacement therapy. This study discloses a high rate of thrombosis in patients with afibrinogenemia. Events were both venous and arterial and may be recurrent. Management is highly problematic due to the precarious balance between bleeding and thrombotic risk in these patients. Fibrinogen replacement therapy should be cautiously used in these patients as most thrombotic events followed the administration of fibrinogen replacement therapy. Larger cohorts are warranted to better characterize the best management strategy in these paradoxical events.

Background Venous thromboembolism (VTE) is an increasingly recognized problem among children and adolescents. Although inferior vena cava (IVC) filter placement for pulmonary embolism prevention is well reported in adults, data regarding safety and efficacy in the pediatric age group are lacking. Procedure At a large university hospital with a level I trauma center, medical records of children and adolescents who underwent IVC filter insertion were reviewed. Appropriateness of referral for retrieval was assessed in each case. Results Fifty-nine children and adolescents (mean age 16 years) successfully underwent IVC filter insertion. All filters placed were retrievable. In 47 patients (79.7%), prophylactic filters were placed in the absence of acute VTE in the setting of trauma. In eight patients (13.5%), filters were placed due to contraindication to anticoagulation therapy with concomitant lower extremity deep vein thrombosis or pulmonary embolism. Filters were successfully retrieved in only 12 patients (20.3%), although an attempt at removal was appropriate and feasible in over 90% of cases. Mean duration of follow-up was 2.1 (range 0.4–7.3) years. A significantly higher retrieval rate was found in patients followed at our thrombosis clinic (P

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by headaches, seizures, a confusional state and visual disturbances associated with transient predominantly bilateral posterior white mater magnetic resonance imaging lesions. It is primarily reported in the setting of hypertension, acute renal failure, peripartum eclampsia, autoimmune disease, immunosuppression and chemotherapy. Thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) has also been reported as potential PRES inducer. The present study reviews two cases of patients with PRES, associated with TMA caused by chemotherapy. Their clinical and imaging data, and the relevant literature were reviewed. Patient 1 presented with TMA-induced PRES following mitomycin-C for metastatic colon adenocarcinoma. Treatment with steroids, plasma exchange, intravenous immunoglobulins, aspirin, antihypertensive drugs, and diuretics resulted in resolution of the neurological and imaging deficits. Patient 2 presented with TMA-induced PRES following gemcitabine for metastatic breast carcinoma. Treatment was ineffective and the patient deteriorated despite verapamil, dexamethasone, and plasma exchange. In this report, the relevant literature regarding pathogenesis, treatment and prognosis of chemotherapy-induced PRES associated with TMA was reviewed. We conclude that several chemotherapy agents may cause PRES through various pathogenic mechanisms, leading to clinical variability and divergent response to therapy.

Deep vein thrombosis (DVT) is a rare disease in patients with hemophilia A. We report a case of 22-year-old male with severe hemophilia A who presented to the emergency room with 5-day history of right arm pain that was attributed initially to bleeding event. In the absence of external signs of bleeding or hematoma and normal hemoglobin level, we suspected an underlying DVT. Doppler ultrasonography of the right upper limb revealed thrombosis of the subclavian vein and this was confirmed by CT venography. The d-dimer level was normal and investigations for prothrombotic state revealed heterozygosity for prothrombin G20210A mutation. Treatment with factor VIII and low molecular weight heparin led to successful resolution and marked improvement of his clinical condition.

Thromboembolic events following splenectomy are not uncommon. However, the role of thromboprophylaxis and risk factors for thrombosis, as well as the clinical course and outcomes, are not well characterized. A retrospective review of individuals who underwent splenectomy between January 2006 and December 2015 in two university hospitals. Overall, 297 patients underwent splenectomy [open splenectomy (n = 199), laparoscopic splenectomy (n = 98)]. Mechanical (thigh-length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h after surgery until discharge) was provided for all patients. One hundred and sixteen patients (39%) also received an extended thromboprophylaxis course of enoxaparin for 2–4 weeks after discharge. Twenty-three patients (7.7%) experienced thrombotic complications following splenectomy, including 16 cases (5.4%) of portal-splenic mesenteric venous thrombosis (PSMVT), 5 (1.7%) pulmonary embolism and 2 (0.7%) deep vein thrombosis. Longer operative time (mean operative time of 405 vs. 273 min, P = 0.03) was independently associated with PSMVT. Post-splenectomy thrombocytosis was not associated with thrombosis (P = 0.41). The overall thrombosis rate was significantly lower in patients who received an extended thromboprophylaxis course following splenectomy (3.4 vs. 10.5%, P = 0.02). Complete resolution of thrombosis was observed in most cases (n = 20, 87.0%), with no recurrent thrombosis during a mean follow-up of 38 ± 25 months. Thromboembolic complications, mainly PSMVT, are common following splenectomy. Longer operative time was associated with thrombosis. Significantly lower rates of thrombosis were found in patients who received an extended thromboprophylaxis course.