Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels.

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 determine 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 discover 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 biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.

Effects of anti-Xa activity monitoring on the outcome of high-risk pregnancies treated with a prophylactic dose of low-molecular-weight heparin.

OBJECTIVE: To evaluate if anti-Xa level monitoring and dose adjustment in women using a prophylactic dose of enoxaparin can decrease placenta-mediated pregnancy complications. METHODS: This retrospective observational cohort study included pregnant women receiving enoxaparin prophylaxis, who were followed at the Thrombosis and Hemostasis Outpatient clinic between 2010 and 2017. The dose was adjusted according to enoxaparin anti-Xa levels in the study group or the weight of individuals in the control group. RESULTS: Of 585 women surveyed, 110 met the inclusion criteria; 63 of them were included in the study group and 47 in the control group. Mean starting dose was 46 versus 43 mg (p = .25), mean final dose was 52 mg versus 45 mg (p = .03) and dose adjustment was required in 37% versus 11% (p = .002) in the study and control groups, respectively. Twenty-eight percent of anti-Xa measurements in the second trimester were beneath the prophylactic threshold, compared to 11% and 16% in the first and third trimesters, respectively (p = .02). Labors ended with live birth in 91% versus 94% of cases (p = .5), 85% versus 68% of pregnancies were term (p = .05), 11% versus 23% of newborns were low birth weight (p = .1) and placenta-mediated pregnancy complications were documented in 9% versus 19%, (p = .17) in the study group relative to controls, respectively. CONCLUSIONS: The most prominent decrease in anti-Xa levels was observed in the second trimester. Monitored women had significantly more term deliveries and demonstrated a trend toward higher birth weight and fewer placenta-mediated pregnancy complications. Larger studies are needed to confirm improved pregnancy outcome in monitored women.

The procoagulant potential before and after surgery for endometriosis and its association with disease severity.

OBJECTIVES: Previous studies have suggested that endometriosis is associated with increased hypercoagulable state. We aimed to determine the procoagulant potential among women with endometriosis before and after surgery. METHODS: A prospective longitudinal study performed during 2020-2021 at a university hospital. Women undergoing laparoscopic surgery for endometriosis served as the study group. Blood samples were taken preoperatively and 3 months after surgery. The degree of hypercoagulability was assessed by thrombin generation, a global marker of the activation of the coagulation system, expressed as the endogenous thrombin potential (ETP). Healthy volunteers, without any medical condition or medications use, matched for age and weight of the study group, served as a control group. RESULTS: Thirty women with histologically-proven endometriosis and thirty healthy control subjects were enrolled in this study. Median preoperative ETP was significantly higher in women with moderate-to-severe endometriosis (3313 [interquartile range, IQR 3067-3632] nM) as compared to those with minimal-to-mild disease (2368 [IQR 1850-2621] nM) and the control group (2451 [2096-2617] nM) ( P  < 0.001 for both comparisons). Following surgery, the ETP significantly decreased in those with moderate-to-severe endometriosis (postoperative: 2368 vs. preoperative: 3313 nM, P  < 0.001) and was comparable to the ETP in the control group ( P  = 0.35). In multivariate analysis, moderate-to-severe endometriosis was the only independent predictor of the preoperative ETP level ( P  < 0.001), with a direct positive correlation between disease revised American Society for Reproductive Medicine severity score and the preoperative ETP level ( rs  = 0.67; P  < 0.0001). CONCLUSION: Moderate-to-severe endometriosis is associated with enhanced hypercoagulable state, which decreases significantly after surgery. Disease severity was independently associated with the degree of hypercoagulability.

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.

OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. INTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.

Mortality in relation to presence and type of oral antithrombotic agent among adult trauma patients: a single-center retrospective cohort study.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001). In multivariate analyses, there was no difference regarding mortality between DOAC and reference groups. Blood transfusion was more likely in patients receiving warfarin or AP than those prescribed DOAC. CONCLUSION: There was no evidence of increased mortality or blood transfusion requirement among trauma patients on DOAC, including head trauma patients. Further studies on head trauma and specific subgroups of DOAC are recommended.

Factors associated with postcesarean blood transfusion: a case control study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 < .001), lower predelivery hemoglobin level (aOR [95% CI]: 0.43 (0.34, 0.54), p < .001), and major placental abnormalities (aOR [95% CI]: 2.74 (1.04, 7.18), 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 < .001), prolonged second stage of labor (aOR [95% CI]: 5.50 (2.57, 11.78), p < .001), longer duration of surgery (aOR [95% CI]: 1.03 (1.02, 1.04), p < .001), general anesthesia (aOR [95% CI]: 2.11 (1.14, 3.91), p = .02), and greater estimated operative blood loss (aOR [95% CI]: 5.72 (3.15, 10.36), p < .001). CONCLUSIONS: 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.

Thromboembolic events in pregnant and puerperal women after COVID-19 lockdowns: A retrospective cohort study.

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 < 0.05). Higher rates of VTE events were found during post-lockdown periods in 2020, compared with corresponding time periods in 2019 and 2018. CONCLUSION: The present data suggest that lockdown periods impact pregnancy-related VTE hospitalizations, possibly as a result of restricted population mobility. Increased awareness of this undesirable outcome may aid health policymakers in the continuing struggle with epidemics.

Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pathway for the Diagnosis and Management of Pulmonary Embolism.

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 healthcare 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 healthcare systems around the globe. Our pathway for the diagnosis and management of PE is divided into 3 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 text 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.

Pharmacomechanical catheter thrombolysis for pregnancy-related proximal deep venous thrombosis: prevention of post-thrombotic syndrome.

OBJECTIVE: The efficacy of pharmacomechanical catheter-directed thrombolysis (PCDT) in preventing post thrombotic syndrome (PTS) for pregnancy related deep vein thrombosis (DVT) is unknown. STUDY DESIGN: 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. RESULTS: 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], p = .4. None of the women in the PCDT group developed PTS, compared to six (33.3%, p = .03) in the control group, four of whom developed severe PTS. One patient in each group developed recurrent DVT, and one patient in the study group developed a calf hematoma. A reduced frequency of lower extremity symptoms was observed in the PCDT group (VEINES-Sym questionnaire), but no differences in quality of life (VEINES-QOL questionnaire) were reported. CONCLUSION: 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.

Pregnancy and non-pregnancy related immune thrombotic thrombocytopenic purpura in women of reproductive age.

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 109/L); and levels of bilirubin (1.23 vs. 1.82 mg/dL), lactate dehydrogenase (1615 vs. 1701 U/L), creatinine (0.61 vs. 0.79 mg/dL) and anti-ADAMTS13 antibodies titer (75 vs. 82 U/mL). The proportions of women with renal, neurologic, or hepatic involvement were similar between the groups. Cardiac involvement was more common among those with pregnancy-related disease (25.0% vs. 3.3%, P = 0.06). The median number of courses of plasma-exchange therapy was 11 for both groups. All the women were treated with parenteral corticosteroids and the rate of adjunctive treatments did not differ between the groups (P = 0.30). Four women (one-third) with pregnancy-related disease had preeclampsia. Two women (16.7%) with pregnancy-related iTTP died during the acute episode (P = 0.07); no deaths were observed in the non-pregnancy-related group. Among reproductive-aged women with iTTP, most clinical and laboratory profiles were similar between those with pregnancy- and non-pregnancy-related disease. However, the higher rates of cardiac involvement and mortality among women with pregnancy-related iTTP highlight its challenging management.

Venous Thromboembolism Prophylaxis with Low-Molecular-Weight Heparin in Primary Central Nervous System Lymphoma.

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.

Factors associated with women's adherence to postpartum thromboprophylaxis.

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 (< 80%) to LMWH administration, reasons for nonadherence, and views regarding LMWH, as assessed by an adapted Beliefs about Medication Questionnaire. Overall, 250 women completed the questionnaire. The median recommended duration of post-discharge LMWH was 7 [5-8] days. Suboptimal adherence was reported by 82 (32.8%); 45 (18.0%) women did not administer any LMWH dose following discharge and only 147 (58.8%) completed the full LMWH course. In multivariate analysis, patients' perceptions of the necessity of LMWH [odds ratio (95% CI): 3.50 (2.12, 9.53), P = 0.002] and of the adequacy of the explanation given prior to discharge regarding LMWH technical administration [odds ratio (95% CI): 5.0 (2.33, 11.11), P < 0.001] were positively associated with optimal adherence. Nearly one-third of women prescribed postpartum LMWH thromboprophylaxis reported suboptimal adherence. Patients' perceptions of the necessity of the treatment and their opinion of the adequacy of explanation regarding LMWH technical administration were identified as predictors of treatment compliance, and thus represent potential areas for improvement.

Risk factors associated with neonatal thrombocytopenia in pregnant women with immune thrombocytopenic purpura.

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 patients who delivered during 2006-2016 at our medical center.Results: Of 253 pregnancies, median maternal age at diagnosis was 29 [25-33] years, 222 (87.7%) had previously-diagnosed ITP and 31 (12.3%) were diagnosed with new-onset ITP during pregnancy. Baseline characteristics were comparable between the groups except for a higher proportion of nulliparity among those with new-onset disease (p = .002). Maternal nadir platelet count was significantly lower among those with new-onset compared to previously diagnosed ITP (median 62 × 109/L versus 81 × 109/L, p = .005). Neonatal thrombocytopenia (<150 × 109/L) was encountered in 24 (9.5%) pregnancies and required treatment in 12 (50%) of them. Neonatal platelet count was directly correlated with maternal platelet count at delivery (r = 0.23, p = .01), with significantly lower maternal platelet count among those whose newborns experienced thrombocytopenia (p < .001). Neonatal thrombocytopenia followed a higher proportion of pregnancies of women with new-onset than previously diagnosed ITP (22.6 versus 7.7%, p = .02). In multivariate analysis, the presence of new-onset ITP (odds ratio [95% CI]: 4.88 (1.68, 14.16), p = .004) was the only independent predictor of the development of neonatal thrombocytopenia.Conclusion: Neonatal thrombocytopenia presented following almost one-tenth of pregnancies with ITP. New pregnancy-onset disease was the only prognostic marker for neonatal thrombocytopenia. This finding could contribute to risk stratification and individualized patient management.

Factors associated with pregnancy outcomes in women with a history of cerebral sinus venous thrombosis.

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.

Assessment of the procoagulant potential and associated risk factors in pregnant patients with inflammatory bowel diseases.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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 (ß = 0.20, P = .009), gestational age (ß = 0.45, P < .0001), extra-intestinal involvement (ß = 0.17, P = .02) and BMI (ß = 0.15, P = .05) retained independent predictors of high ETP levels. CONCLUSION: As determined by thrombin generation, the procoagulant potential among IBD pregnant patients was independently associated with disease activity, BMI and extra-intestinal disease involvement.

[RISK FACTORS ASSOCIATED WITH THE DEVELOPMENT OF UPPER EXTREMITY DEEP VEIN THROMBOSIS FOLLOWING PERIPHERALLY INSERTED CENTRAL CATHETER INSERTION].

BACKGROUND: 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. METHODS: A review of the medical records of all patients who underwent PICC insertion during 2016 at the Hadassah Medical Center. RESULTS: 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). CONCLUSIONS: 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.

Clinical pharmacist led hospital-wide direct oral anticoagulant stewardship program.

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 .