Thrombotic History Research Articles

Incidence and Timing of Thromboembolism in Pediatric Patients with Congenital Heart Disease Undergoing Cardiac Surgery: A Single Center Retrospective Study

Background Thromboembolism (TE) is a complication in pediatric patients with congenital heart disease (CHD) due to disrupted blood flow, inflammation, foreign materials and cardiac surgery. Reported rates of TE in pediatric patients with CHD vary. Furthermore, most studies report TE rates following cardiac surgery, but there is a scarcity of data describing TE rates prior to cardiac surgery, the timing of these events, as well as the rates of post-operative TE recurrence in this population Given the limited information available describing the incidence and timing of TE both before and after cardiac surgery, the primary aim of this study was to describe the rate of TE 12 months before and 12 months after cardiac surgery in pediatric pts with CHD. Methods This was a single center retrospective study from October 2020 to June 2023 (inclusive). Patients were eligible for inclusion if they were <18 years of age, underwent cardiac surgery for congenital heart disease, and had a radiologic confirmed diagnosis of a thrombus either 12 months before or 12 months after CHD surgery. Data collection was conducted using the institution's surgical database and through electronic medical record chart review. Variables included age (neonates: <28 days of age, infants: 1 month to <12 months of age, children: 1 year to <12 years of age, and adolescents: 12 to 18 years of age), surgical procedure, administration of prothrombin complex concentrate, thrombotic history, cardiac catheterization ≤30 days of TE, lines at time of TE, treatment agents, and TE recurrence rates. Data analysis was conducted using descriptive statistics. Results A total of 260 children underwent cardiac surgery during the study period, of these, 36 patients (14%) had a TE and were eligible for inclusion. Four patients had 2 operations during the study period for a total of 40 surgical encounters. The majority of patients were neonates and infants (85%) at the time of cardiac surgery (Table 1). Of the 36 (patients who had a TE, 6 (16.7%) patients had a TE prior to cardiac surgery, 23 (63.9%) had a TE after cardiac surgery, and 7 (19.4%) had a TE both before and after cardiac surgery. The median (range) time of TE occurring prior to or after cardiac surgery was 86 (2-277) days and 17 (1-335) days, respectively. Thromboembolism types included: 8 (22.2%) patients with arterial, 25 (69.4%) with venous, and 3 (8.3%) patients with both arterial and venous. Of note, 11 (20.5%) patients who developed thromboembolism had a history of prior TE >12 months prior to surgery. Twenty-four (62.5%) patients received prothrombin complex concentrate intra-op, and 16 (44.4%) patients had cardiac catheterization 30 days prior to the documented TE (Table 1). With regards to lines, 75% of TE were associated with a central venous/arterial catheter (Table 2). Treatment agents in the acute period included: no agent (6, 16.6%), unfractionated heparin (5, 13.9%), enoxaparin (21, 58.3%), bivalirudin (2, 5.6%), and new/increased antiplatelet therapy (2, 5.6%). Treatment agents in the subacute period included: no agent (10, 27.8%), enoxaparin (17, 47.2%), bivalirudin (2, 5.6%), unfractionated heparin (1, 2.8%), rivaroxaban (2, 5.6%), and new/increased antiplatelet therapy (4, 11.1%%). Overall median (range) duration of treatment was 49 (3-182) days. Of the 36 patients, 8 (21.2%) patients had at least 1 recurrent thromboembolism (Table 2). Conclusions We report in this single center retrospective study a high incidence of TE in children with CHD not only after cardiac surgery but also prior to surgery. Awareness of TE prior to cardiac surgery may be beneficial for optimizing post-operative prevention strategies to minimize the recurrence of TE. Future multicenter prospective studies are needed to validate these findings and evaluate risks factors for TE in pediatric patients with CHD both before and after cardiac surgery.

ELN Criteria for Cytoreduction Start Identify Patients with Polycythemia Vera at Higher Thrombotic Risk

Introduction Recently, the European Leukemia Net (ELN) recommended cytoreduction in patients (pts) with Polycythemia Vera (PV) at low risk (LR) (age <60 yrs & no previous thromboses) but carrying additional criteria for therapy start (CTS) ( Marchetti M et al, Lancet Haematol 2022). Little is known about: 1] efficacy of hydroxyurea (HU) in LR pts, high risk due to age >60 yrs (HR-AGE) or high risk due to previous thrombosis regardless of age (HR-THRO); 2] impact of CTS on thrombotic risk. Aims In a large cohort of HU-treated PV pts, we investigated if thrombotic risk was influenced by: 1] conventional risk factors for thrombosis; 2] ELN-defined complete response (CR) at 12 mos; 3] presence of CTS. Methods After IRB approval, data of 961 WHO2016-defined PV pts were retrospectively collected by 21 Hematology Centers. In April 2023, an update was performed in 10 participating Centers with specific focus on CTS at diagnosis and HU start; 504 HU-treated pts resulted eligible for this analysis. Therapy was at discretion of the treating hematologist. Pts were followed until death or data cut-off date. CTS evaluated for association with thrombosis included: persistent/progressive leukocytosis (100% increase if white blood cells (WBC) <10 x10 9/L or 50% increase if WBC>10 or WBC>15 at diagnosis and HU start); extreme persistent thrombocytosis (>1000 x10 9/L platelets (PLT) at diagnosis and HU start); progressive splenomegaly (increase of >5 cm from diagnosis); inadequate hematocrit (Hct) control (>6 PHL/yr; HCT >53% at diagnosis and HU start; PHL intolerance); uncontrolled cardiovascular risk factors (CVRF). Symptoms were present as the only ELN criterion in 40 patients, of whom none had thrombosis; therefore, they were not included in the analysis. Results 504 pts received HU: 81 pts were at LR and 423 (83.9%) were at HR (HR-AGE, no. 290, 57.5%; HR-THRO, no. 133, 26.4%). Median time on HU was 11.6 yrs (0.1-23.1). During HU, 53 pts had 69 thromboses (35 arterial) for an incidence rate of thrombosis (IR-thro) of 1.5 %p-y, comparably in LR and HR ( Table 1). Notably, IR-thro was equal in LR and HR-AGE (p=0.94), but significantly higher in HR-THRO pts (p=0.005 vs LR and p=0.009 vs HR-AGE). At 12 months, CR was achieved by 8.2%, 23% and 25% of LR, HR-AGE and HR-THRO pts, respectively (LR vs HR-AGE and HR-THRO, p<0.001 and p=0.003). Thrombosis-free survival (TFS) by landmark analysis at 12 months was significantly better in CR pts (p=0.01). Specifically, best TFS was observed in LR and HR-AGE pts with CR, while HR-THRO pts without CR had the worst TFR (p=0.009). CTS were observed in 255 (50.6%) pts: 48 LR (59.3%), 139 HR-AGE (47.9%) and 68 HR-THRO (51.1%). In the remaining LR pts, HU was triggered by mild thrombocytosis (<1000 x10 9/L) and/or mild leukocytosis (<15 x10 9/L) and/or mild splenomegaly (<5 cm from costal margin) and/or persistent systemic symptoms. CTS were associated to significantly increased of IR-thro in the overall cohort (p<0.001), in LR pts (p=0.04), in HR-AGE pts (p=0.02) and in HR-THRO pts (p=0.03) ( Table 1) . The impact of CTS was confirmed in the overall cohort both for arterial (1.30 vs 0.44 %p-y, p=0.01) and venous thrombosis (1.37 vs 0.44 %p-y, p=0.007). TFS at 5 yrs was 87% and 95% in pts with or without CTS (p<0.001) ( Fig.1a). In presence of CTS, TFS of LR and HR-AGE pts were comparable to HR-THRO pts without CTS ( Fig. 1b). In multivariate Cox analysis considering age>60 yrs, previous thrombosis, CTS, and CR to HU at 12 months, CTS and previous thrombosis remained associated with thrombotic risk (HR: 2.7, 95% CI: 1.4-5, p =0.002; HR: 2.4, 95% CI: 1.4-4.2, p =0.001). Finally, in 59 additional LR pts untreated with HU, IR-thro was 0.78 in absence of CTS, and 1.57 %p-y in presence of such criteria. Conclusions Albeit retrospective, this study shows for the first time that ELN criteria for therapy start including splenomegaly, leukocytosis, thrombocytosis, uncontrolled Hct and CVRF, identified an increased risk phenotype either in LR and HR pts treated with HU. This was confirmed also in HU-untreated pts. Also, lack of CR at 12 months was detrimental on TFS particularly in HR-THRO pts, and less significantly than CTS. These findings, that complement data from the Majic-PV trial ( Harrison CN et al, J Clin Oncol 2023), dictate better management of HU therapy, and call for greater attention to CTS and their integration into prognostic models that go beyond the two categories related only to age and thrombotic history.

Impact of Cytoreductive Drugs upon Outcomes in a Contemporary Cohort of Adolescent and Young Adults with Essential Thrombocythemia and Polycythemia Vera

Introduction Essential thrombocythemia (ET) and polycythemia vera (PV) are well described in adolescent and young adults (AYA) patients (pts); the most prevalent complications are thrombotic events, but progression to myelofibrosis (MF) is also associated with significant morbidity and mortality and this risk is time-dependent. Here we investigated the impact of cytoreductive drugs on outcomes in a well-defined cohort of AYA pts. Method and objectives Patients with a diagnosis (Dx) of ET or PV established at less than 25 years (yrs) of age and having known driver mutation status were included from a collaborative group of centers within the EHA MPN special working group. Patients were classified by the first cytoreductive treatment they received or no cytoreduction (NoCYTO). Main endpoints were thrombosis free survival (TFS) and, for those who received a minimum of 2 years of treatment, myelofibrosis free survival (MFS). Kaplan-Meier and log-rank tests were used to compare groups. Results Overall we included 348 pts (278 ET, 70 PV) with median age 20 yrs at Dx (IQR: 18-23). Median age at Dx for ET was 21 yrs (18-23) and for PV 20 yrs (16-23). 249 pts were female (216 ET, 33 PV). Median follow-up was 9 yrs (4-15). Overall, 237/348 (68%) started a cytoreductive therapy. First treatment was hydroxycarbamide (HU) in 126 pts (100 ET, 26 PV), IFN in 55 pts (33 ET, 22 PV), anagrelide (ANA) in 52 pts (51 ET, 1 PV) and other in 4 pts (1 ET, 3 PV). 111 pts (32 %) did not receive cytoreduction (93 ET, 18 PV) deemed NoCYTO. According to ELN risk group at Dx, 39/43 pts (26 ET, 13 PV) receiving a cytoreductive drug were high-risk and 197/304 pts (159 ET, 38 PV) were low-risk. Reason for treatment initiation was thrombotic event in 32 pts (24 ET, 8 PV), platelets >1000x10 9/L in 96 pts (87 ET, 9 PV), MPN-related symptoms 12 pts (7 ET, 5 PV), and other/unknown for 97 pts (67 ET, 30 PV). Ten year TFS was 87% (95%CI: 82-91%) overall, 87% (82-92%) for ET and 86% (77-96%) for PV. In multivariate analysis, elevated WBC (>11x10 9/L) was associated with higher thrombosis risk (HR: 2.8, 95%CI: 1.2-6.2, p=0.01) and splenomegaly with a lower risk (HR: 0.2, 95%CI: 0.1-0.9, p=0.04). In the ELN low-risk group, 10yrs TFS was 82% (73-90%) for HU, 84% (70-98%) for IFN, 93% (84-100%) for ANA and 94% (88-100%) for noCYTO, suggesting no benefit for cytoreduction, p=0.04. For high-risk patients, 10yrs TFS was 78% (56-100%) for HU, 67% (35-98%) for IFN, and 86% (59-100%) for ANA, p=0.689 (Fig 1A). Ten year MFS was 95% (92-98%) overall, 95% (91-98%) for ET, 93% (85-100%) for PV. On multivariate analysis, CALR mutation (HR: 6.0, 95%CI: 2.3-16.1, p<0.05) and interestingly thrombotic history at Dx (HR 3.8, 95%CI: 1.3-11, p=0.02) were associated with increased risk of MF progression overall. For ET: CALR mutation (HR 4.1, 95%CI: 1.6-10.5, p <0.05) and splenomegaly (HR: 2.9, 95% CI: 1.1-7.7, p=0.03) were associated with MF progression, but only CALR mutation was significant on multivariate analysis (HR: 4.2, 95% CI: 1.6-11.6, p<0.05). For PV, we did not identify risk factors associated with MF progression. Finally, we investigated the impact of cytoreductive therapy on MF progression. Overall, 10yrs and 20yrs MFS for IFN was 100%, for HU 10yrs and 20yrs MFS were 93% (86-99%) and 74% (57-92%), for ANA 10yrs and 20yrs MFS were 92% (82-100%) and 73% (40-100%), and for NoCYTO patients 10yrs and 20yrs MFS were 94% (88-100%) and 74% (47-100%), respectively (Fig 1b). Log-rank test comparing IFN vs. other management (HU, ANA or NoCYTO) was significantly in favour of IFN (p=0.046). Finally, during the follow-up there was only one MDS-progression and four deaths (1 of GVHD following HSCT 34 yrs after Dx, 1 of CMV disease 15 yrs after Dx, 2 of unknown cause, 4 yrs and 41 yrs after Dx). Discussion This study is the largest of its kind in contemporary young ET and PV patients focusing on specifically upon the impact of treatment. We demonstrate that early initiation of cytoreduction in low-risk patients does not impact TFS and that the choice of drug does not impact TFS in high-risk patients. In addition, importantly our data demonstrate that IFN specifically compared to other cytoreductive agents yields significantly better MFS compared to other treatments. These results support the use of IFN as a currently available disease-modifying agent to improve long-term MFS and also warrant reconsideration of earlier treatment in patients with ET and PV with IFN to improve MFS potentially as a primary aim.

Autologous Breast Reconstruction Success Rates in Hypercoagulable Patients.

Hypercoagulable disorders may adversely affect microsurgical outcomes, including increased flap failure and complication rates. Outcomes specific to autologous breast reconstruction are not well described. A retrospective review was performed of autologous breast reconstructions between 2009 and 2020. Patients with either a thrombophilic disorder (TD) diagnosis or a previous thrombotic event (TE) were identified. The analysis compared perioperative complications and flap success rates. In this series, 23 patients with a TD underwent 39 flaps, and 78 patients who had experienced a TE underwent 126 flaps, compared with 815 control patients, who underwent 1300 flaps. In logistic regression models, a TD diagnosis was an independent predictor of early total flap loss [OR, 8.42 (95% CI, 1.59 to 44.47); P = 0.01], late partial flap loss [OR, 3.9 (95% CI, 1.0 to 15.22); P = 0.05], and delayed healing [OR, 2.26 (95% CI, 1.02 to 5.04); P = 0.04]. TE history trended toward an association only with late partial flap loss ( P = 0.057). Flap salvage rates (25%) and flap success rates (92.3%) were statistically lower in patients with a TD but normal in patients who had experienced a TE. Microsurgical breast reconstruction is a reasonable option for patients with hypercoagulation disorders. No increased risk of flap complications was associated with a previous TE; however, TDs carried increased risk. Risk, II.

Assessment-based management of placenta-mediated pregnancy complications: Pragmatism until a precision medicine approach evolves.

The management of pregnant women with thrombophilia and a history of gestational vascular complications remains debatable. Treatment of the latter is often based on clinical outcome rather than disease mechanism. While the use of venous thromboembolism prophylaxis in pregnancy is recommended for those at increased risk, the ability of anticoagulant and/or antiplatelet agents to lower the risk of placenta-mediated complications in this clinical setting remains controversial. The available guidelines are inconsistent in some situations, which reflects the limited evidence base. This review critically discusses risk assessment models (RAMs) and management strategies of women with thrombophilia and pregnancy complications, using clinical vignettes. RAMs, taking into account obstetric and thrombotic history as well as thrombophilia status, could drive a precision medicine approach, based on disease mechanism, and guide individual therapeutic interventions in high-risk clinical settings.

A case-report of the unprovoked thrombotic event in a patient with thymoma and severe FVII deficiency

BackgroundFactor VII deficiency is a rare bleeding disorder caused by a deficiency of clotting factor VII. However, there have been some case reports of venous thrombosis in patients with factor VII deficiency, especially underlying the prothrombotic risk factors exposure. Patients with factor VII deficiency require special considerations before undergoing surgery to minimize the risk of bleeding or thrombogenesis.Case presentationHere, we described a patient with early-stage thymoma and severe factor VII deficiency who experienced an unprovoked thrombotic episode before thymectomy and a fatal thrombotic event after surgery. By adopting gene screening, a reported homozygous F7 mutation (p.His408Gln) and a novel heterozygous PROS1 mutation (p.Pro147Ala) were identified. The former resulted in severe factor VII deficiency but did not protect against thrombosis, and the latter was correlated with normal expression and cofactor activities of protein S through the thrombin generation test. The perioperative infusion of recombinant factor VII concentrate and the absence of antithrombotic prophylaxis may collectively contribute to her fatal thrombotic event after surgery.ConclusionsFor the patients with severe factor VII deficiency undergoing surgery, uniform replacement therapy may not be recommended, and antithrombotic prophylaxis should be used in the case with thrombotic history to minimize the risk of bleeding and thrombogenesis.

Readmission After COVID-19 for Late Acute Venous Thrombosis; CASE SERIES and Systematic Review of the Literature.

Assess heterogeneity within patients with resolved COVID-19 to broaden the vision about post-discharge thrombotic cases and postulate possible related mechanisms in search of better anticoagulation guidelines. This study details patients' characteristics, medical history, treatment, and outcomes of readmitted patients with late acute thrombosis through a systematic review of the literature and patients from our academic center database. We extracted the records of patients readmitted for venous thrombosis complications after discharge from the database of the first 2000 patients admitted with COVID-19 in our academic center; we also performed a systematic review of the literature using the Medical Subject Headings terms "late thrombosis," "COVID-19," + "venous thrombosis" in PubMed and Google Scholar according to PRISMA guideline. The literature review found 20 patients suitable for review matching the inclusion criteria. These patients were added to those in our database, summing up a total of 26 patients. The median age was 50 years old, 76.9% were male, and most were overweight or had grade 1 obesity (n = 11, 42.3%). None had a previous thrombotic history, but 50% had an underlying comorbidity. Thrombotic events presented on a median of 20 days (range: 4-150 days) from discharge. Pulmonary embolisms occurred in 23 patients (88.46%), deep vein thrombosis in 4, mesenteric thrombosis, and cerebral venous thrombosis in 1, respectively. This study found that most patients readmitted for thrombotic events after COVID-19 discharge were middle-aged men with Venous Thrombo Embolism events.

Screening of thrombogenic risk factors in children in the Altai krai

Introduction. One of the urgent problems of modern pediatrics is the risk of developing vascular complications in children, among which thrombosis is not uncommon. For early diagnosis and thromboprophylaxis of strokes and other vascular complications, the identification of thrombogenic risk factors is indicated.
 The purpose of the study. Based on the screening, to establish predictors of thrombogenic risk in children living in urban and rural areas of the Altai Territory for the timely prevention of vascular complications.
 Materials and methods. The results of a screening study of two hundred seventeen aged 12–17 years children living in the city of Barnaul, Zarinsk and Klyuchevsk districts of the Altai Territory, were analyzed. Screening examination of children without signs of thrombosis and bleeding was carried out at an outpatient appointment with a pediatrician in random sampling. The questionnaire included questions to clarify the family thrombotic history, personal thrombotic history, background somatic diseases. Clinical examination was performed for all interviewed patients.
 Results. According to the results of the study, it was revealed that in 65 (30%) of the 217 children surveyed, the closest relatives had thrombogenic risk factors, such as heart attacks, strokes, hypertension, coronary heart disease (CHD). After analyzing the personal thrombotic history, it was found that in the general group of patients, myocardial infarction was observed in 2 (0.9%) children. Strokes were noted in 5 (2.3%) respondents, and thrombosis and TIA in 2 (0.9%) subjects. When analyzing the results, it was found that a significant proportion of children had the following conditions, such as vegetative-vascular dystonia (VVD) of the hypertensive type, the presence of signs of undifferentiated connective tissue dysplasia (UCTD), smoking, obesity.
 Conclusion. According to screening data in children, the main predisposing factors in the development of thrombosis, strokes and heart attacks are a burdened family, thrombotic history, the presence of some somatic diseases. The combination of these factors justifies the need for additional examination for the prevention of vascular thrombosis.

Proteomic-Based Platelet Activation-Associated Protein SELP May Be a Novel Biomarker for Coagulation and Prognostic in Essential Thrombocythemia.

Abnormal platelet activation can lead to thrombosis in essential thrombocythemia (ET) and thus impact patient prognosis. Platelet activation-associated proteins are key molecules for platelet activation. However, it is unclear which proteins are most closely associated with the disease's prognosis. To determine which platelet activation-related proteins can be employed as ET patient prognosis predictors, we used label-free quantification (LFQ) and parallel reaction monitoring (PRM) technology and first determined the serum proteomic expression levels and the differential proteins of ET patients. Then, based on the IPSET (International Prognostic Score for ET), the differential protein associated with the prognostic score was found. To investigate potential processes affecting prognosis, the connection of this protein with prognostic markers, such as thrombotic history, age, white blood cell count, coagulation factors, and inflammatory factors, were further examined. The levels of platelet activation-related proteins GPIbα, SELP, PF4, MMP1, and FLNA were significantly higher in ET patients, according to LFQ and PRM analyses (p < 0.01). Based on regression analysis of the IPSET prognostic score, it is suggested that the SELP level was positively correlated with the prognostic score and prognostic risk factor analysis (p < 0.05). Further regression analysis of SELP with coagulation factors showed that antithrombin (AT-III) was negatively correlated with SELP levels (p < 0.05). Further regression analysis of the inflammatory factors with AT-III and SELP revealed that IL-10, IL-12P70, and IL-31 were negatively correlated with AT-III and SELP (p < 0.01). Platelet activation pathway-related proteins are expressed more frequently in ET patients, and serum SELP may be a prognostic marker for these individuals by encouraging leukocyte increase and inflammatory factor expression and causing aberrant coagulation.

Real-world treatments and thrombotic events in polycythemia vera patients in the USA

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased risk of thrombotic events (TE) and death. Therapeutic interventions, phlebotomy and cytoreductive medications, are targeted to maintain hematocrit levels < 45% to prevent adverse outcomes. This retrospective observational study examined medical and pharmacy claims of 28,306 PV patients initiating treatment for PV in a data period inclusive of 2011 to 2019. Study inclusion required ≥ 2 PV diagnosis codes in the full data period, at least 1 year of PV treatment history, and ≥ 1 prescription claim and medical claim in both 2018 and 2019. Patients having ≥ 2 hematocrit (HCT) test results in linked outpatient laboratory data (2018–2019) were designated as the HCT subgroup (N = 4246). Patients were characterized as high- or low-risk at treatment initiation based on age and prior thrombotic history. The majority of patients in both risk groups (60% of high-risk and 83% of low-risk) initiated treatment with phlebotomy monotherapy, and during a median follow-up period of 808 days, the vast majority (81% low-risk, 74% high-risk) maintained their original therapy during the follow-up period. Hematocrit control was suboptimal in both risk groups; 54% of high-risk patients initiating with phlebotomy monotherapy sometimes/always had HCT levels > 50%; among low-risk patients, 64% sometimes/always had HCT levels above 50%. Overall, 16% of individuals experienced at least 1 TE subsequent to treatment initiation, 20% (n = 3920) among high-risk and 8% (n = 629) among low-risk patients. This real-world study suggests that currently available PV treatments may not be used to full advantage.

Cardiac myxoma misdiagnose as infective endocarditis in a patient with acute limb ischemia and cardioembolic cerebral stroke: a case report

Introduction: Fever, systemic embolism, and intra-cardiac masses are all symptoms of Infective Endocarditis (IE) and Cardiac Myxoma (CM)1. As a result, despite proper imaging studies, these diseases are frequently misdiagnosed one for the other.2 Case description: A 23-years-old female patient was admitted to emergency department of Zainoel Abidin General Hospital with acute onset right lower extremity pain for the last few hours and presented roth spots of the retina. The next day after admission, she presented fever. The patient denied having chronic disease, drug abuse, and thrombotic history. Tooth decay were found. Transthoracic Echocardiography (TTE) were obtained due to concern of infective endocarditis. Head CT-scan revealed cardioembolic cerebral stroke. TTE showed ejection fraction 56%, severe mitral regurgitation, and a mobile mass size 3.1x2.4 cm in mitral valve, attached to anterior mitral leaflet. The patient underwent thrombectomy, stroke therapy, dental tooth decay treatment, and lower limb rehabilitation at that moment, before having Mitral Valve Replacement (MVR) surgery. Six months afterward MVR surgery was done, rather than vegetation, we found a 50cc cardiac myxoma in anterior mitral valve leaflet. A 27mm bioprosthetic valve was installed. The patient was recovered quickly and she was able to discharge from hospital in the next 7 days after procedure without any further issue. Conclusion: In order to effectively manage the patients, it is crucial to distinguish between IE and cardiac myxoma. The mainstay of treatment for cardiac myxoma cases is surgery, which has an excellent prognosis. To evaluate for recurrence, long-term follow-up is frequently required.

Профілактика і прогнозування розвитку плацента-асоційованих ускладнень у пацієнтки з обтяженим тромботичним та акушерським анамнезом (клінічний випадок)

Purpose - to analyze the effectiveness of the timely appointment of pathogenetically justified secondary prevention in a patient with a burdened thrombotic and obstetric anamnesis based on the assessment of the course of pregnancy and the postpartum period in this woman. Clinical case. A woman with fetal loss syndrome and recurrent venous thrombosis applied for a consultation to plan pregnancy. The examination revealed a homozygous polymorphism of the F2-prothrombin gene (-20210 G&gt;A), a decrease in protein S activity to the level of 35%, which indicated an extremely high risk of thromboembolic complications. Pregnancy occurred on the background of anticoagulant therapy in combination with pregravid cofactor vitamin therapy. During pregnancy, the patient received low molecular weight heparins in therapeutic doses in combination with acetylsalicylic acid at a dose of 150 mg per day, diosmin 600 mg and cofactor vitamin therapy. According to the results of combined screening in the I trimester, with the calculation of the risks of preeclampsia, the woman was classified as a high risk group for its development. At 23-24 and 32-33 weeks of gestation, an analysis was performed to calculate the risk of perinatal complications in the II-III trimesters by determining the ratio of water-soluble tyrosine kinase-1 / placental growth factor (Sflt-1/PlGF). The data obtained indicated that the preventive therapy prescribed to the patient was adequate and effective. The pregnancy was completed at the full 37 weeks of gestation by spontaneous delivery in cephalic presentation without complications. A boy was born weighing 2950 g, Apgar score - 7/8. Conclusions. The clinical case is a vivid example of how well-timed, adequate prophylactic therapy can work efficiently and effectively, even in women with a rather burdensome thrombotic and obstetric history. This case confirms the necessity and expediency of using the entire modern diagnostic arsenal that exists in Ukraine to predict the occurrence of «Great» obstetric syndromes, which to this day occupy one of the leading places in the structure of maternal and perinatal losses. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Anticoagulation Practice, Recurrent Thrombosis, and Major Bleeding in Antiphospholipid Syndrome- a Multicentre Observational Study in the United Kingdom

Background Antiphospholipid syndrome (APS) is a highly prothrombotic acquired autoimmune disease characterised by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPL).Anticoagulation is the mainstay of treatment for APS however risk of recurrence remains high especially in triple antibody positive patients. Recent clinical studies demonstrated that DOACs are not as effective as Vitamin K Antagonists (VKA) in patients with APS especially those who are triple positive. However, the use of DOACs in patients without triple positive aPL remains variable. Aims 1)To assess real-life anticoagulation practice in the UK 2)To assess the rates of recurrent thrombosis, major bleeding and minor bleeding (as per International Society of Thrombosis and Haemostasis) in patients with thrombotic APS Methods This was a multicentre observational study. Data was collected using a pre-designed standardised case record form via a secure online data entry platform (REDCap). Only patients age ≥18 years with confirmed diagnosis of APS were included in the study. Results The study included 500 patients with APS from 15 National Health Service (NHS) Trusts across the UK. The mean age was 52.9 (-/+ 15.94) years and 66.6% (333/500) were male. Frequency of single, double, and triple positivity for aPL were 36.4%, 32.6% and 31% respectively. Almost 40% of patients (37.3% , 187/500) had underlying autoimmune disease in addition to APS. Of the 500 patients, 92.2% (461/500) had at least one thrombotic event, 13.8% (69/500) had obstetric complications and 4.6% (23/500) had both thrombotic and obstetric complications. In patients with thrombotic APS, venous thrombosis occurred in 65.9% (304/461) patients, arterial thrombosis in 41.6% (192/461), and microvascular thrombosis in 4.8% (22/461) respectively. Almost all patients (99.8%; 460/461) with a thrombotic history were on anticoagulants (460/461). Of these 76.5% (352/460) were on VKAs whilst only 18.7% (86/460) were on DOACs. The rest of the patients were on low molecular weight heparin (3.5%) and fondaparinux (1.3%). Of the 342 patients on warfarin 207 patients 61% (207/342) had an INR target of 2.5 (2.0-3.0) , 10.5% (36/342) had a target of 3.0 (2.5-3.5) and 28.9% (99/343) had target INR of 4.0 (3.5-4.5). Additionally, 29.8% (102/342) of patients on anticoagulation were on antiplatelet treatment and 31.9% (109/342) patients were on Hydroxychloroquine (HCQ). Of the 155 patients with triple positive APS, 64.5% (100/155) were on warfarin and 20.6% (32/500) were on DOACs and the remainder on LMWH or fondaparinux. In those with arterial thrombosis, the vast majority were on warfarin 82.8% (159/192) with 5.2% (10/192) on a DOAC and a small minority on LMWH or fondaparinux. Of the 192 patients with arterial thrombus, 68 (19.8%) were triple positive aPL and of these 7.4% (5/68) were on a DOAC. Table 1 shows the baseline characteristics of the study group. Recurrence of thrombosis occurred in 41.6% (192/461), most frequently within 3 years of diagnosis (65.1%, 125/192). The frequency of major (Figure 1) and minor bleeding were 2.8% (13/461) and 3.2% (16/461) respectively. Dual or triple aPL status, smoking, hypertension, and ischaemic heart disease were significantly associated with recurrent thrombosis on univariate but not multivariate analysis, confirming a multifactorial contribution for thrombosis. In both univariate and multivariate analysis, increasing age was significantly associated with major bleeding [hazard ratio (HR) 1·05, 95% confidence interval (CI) 1.01-1·10; P = 0·022]. Notably, a higher target INR was associated with major bleeding. Conclusions In the largest UK study of APS to date we assessed anticoagulation practice, recurrent thrombosis rate and bleeding rate in this cohort. The frequency of recurrence of thrombosis in APS was as high as 41.6% (192/461) with most patients developing recurrence within the first 3 years of diagnosis. Frequency of major and minor bleeding were 2.8% (13/461) and 3.2% (16/461) respectively. Age was a significant contributor for major bleeding whilst thrombosis was multifactorial. Although VKA remains the main anticoagulant of use in patients with thrombotic APS, there are wide variations in the practice within the UK which are mostly, but not wholly, adherent to national guidelines especially in the context of triple positive thrombotic disease and arterial thrombosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anticoagulation and/or Antiplatelet in Thrombotic Antiphospholipid Syndrome with Previous Arterial Thromboembolism: A Retrospective Cohort

Introduction: Thrombotic antiphospholipid syndrome (TAPS) is a prothrombotic autoimmune disease associated with a high risk of arterial thromboembolism (ATE). While direct oral anticoagulants (DOAC) are inferior treatment in TAPS with ATE, the optimal antithrombotic regimen of vitamin K antagonists (VKA) and/or antiplatelet therapy (AP) remains unclear. Objectives: To assess the effectiveness and safety of VKA (target (t) international normalized ratio (INR) 2-3), VKA (t INR 2-3) with AP (including dual AP therapy), VKA (t INR >3), VKA (t INR >3) with AP, and AP alone at preventing recurrent thrombotic events in TAPS patients with previous ATE. Methods: This retrospective cohort study included adult TAPS patients with previous ATE assessed at two academic tertiary care centers in Toronto, Canada between April 1, 2011 to April 1, 2021. Included patients met Sydney criteria for TAPS and had a history of ATE (ischemic stroke (IS), transient ischemic attack (TIA), myocardial infarction (MI), or systemic embolism (SE)). At participating centers, patients with a thrombotic history suspicious for TAPS were screened for lupus anticoagulant, anti-cardiolipin antibodies, and/or anti-beta-2-glycoprotein 1 antibodies (anti-B2GP1) at the discretion of the treating physician. Testing for anti-B2GP1 was only available as a send away test. We excluded patients with a known cardioembolic source for their ATE including atrial fibrillation, patent foramen ovale, mechanical heart valves, Libman-Sacks endocarditis, those with initial ATE associated with catastrophic antiphospholipid syndrome (CAPS), and those treated with DOAC. Outcomes included both thrombotic and bleeding events. Recurrent thrombosis included both ATE and VTE. ATE included IS, TIA, MI, or SE. Bleeding events were categorized as major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) as defined by International Society on Thrombosis and Haemostasis criteria. Outcomes were assessed during the time the particular antithrombotic regimen was used. If a single patient had multiple antithrombotic regimens, they were included in multiple groups for the time they used that particular antithrombotic regimen, defined as antithrombotic trials. Outcomes were calculated as the number of events per 100 patient years by antithrombotic regimen with 95% confidence intervals (CI) using Poisson's exact test. Statistical calculations were performed using SPSS. Results: From an initial 891 patients with at least one positive antiphospholipid antibody test, 120 patients met criteria for TAPS and had a previous ATE. 62 patients were excluded for the following reasons: 47 for a cardio-embolic source of ATE, 5 for absence of any follow up, 7 for use of DOAC, and 3 for CAPS in the absence of any other ATE. After exclusions, 58 patients with a total of 89 antithrombotic trials were included in the analysis with a cumulative follow up of 248.4 years. The study population comprised of thirty-one (53.4%) women with a mean age of 51 (Standard Deviation (SD) 12.9) years at the start of their initial antithrombotic trial. Twenty-three (39.7%) patients were known to have systemic lupus erythematosus (SLE) whereas seven (12.1%) patients had non-SLE autoimmune disorders. Thirty-four (58.6%) patients had baseline hypertension. The baseline characteristics are summarized in table 1. Overall, there were a total of 7 ATE and 1 VTE recurrences with a thrombotic rate of 3.2 per 100 patient-years (95% CI 1.4 to 6.3). The recurrence rates in the VKA (t INR 2-3), VKA (t INR 2-3) with AP, VKA (t INR >3) with AP, and AP alone were 3.3 (95% CI 0.9 to 8.4), 2.6 (95% CI 0.3 to 9.3), 0 (95% CI 0 to 18.8), and 6.8 (0.8 to 24.4) per 100 patient-years respectively. There were a total of 10 MB events including 4 intracranial bleeding (ICB), 1 gastrointestinal bleeding, and 5 other types of MB. ICB occurred in 3 patients on VKA (t INR 2-3) and 1 on VKA (t INR 2-3) with AP. Outcomes are summarized in table 2. Conclusions: This retrospective cohort of 58 patients with TAPS and a previous ATE demonstrated a numerically higher risk of recurrent thrombosis with AP alone and a numerically higher risk of MB with the combination VKA and AP. Study limitations include the small sample size, risk of selection bias, and retrospective design. Larger, prospective studies are needed to confirm our observations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Antiphospholipid Antibodies in Pregnancy: Maternal and Neonatal Implications.

Antiphospholipid antibodies (aPL Abs) have long been associated with the occurrence of certain specific pregnancy morbidities, affecting both mother and fetus. Antithrombotic-based prophylactic regimens are the standard of care. Their intensity is modulated by the thrombotic history and has greatly improved the prognosis related to spontaneous morbidity. Observational studies show that this treatment is still associated with the persistence of excess of late-pregnancy placental diseases, calling for new or complementary developments, yet to be validated. Rigorous prospective multicentric validation of clinical and laboratory parameters capable of identifying those women and fetuses at a risk of pejorative evolution, thus early prognosis, is a priority issue. These will make it possible to develop customized treatments and test them. Furthermore, there are still concerns, particularly neurodevelopmental ones, about children born to aPL Ab-positive mothers, and clarification based on regular, more systematic evaluations is required. Even after pregnancy, women with a pure obstetrical antiphospholipid syndrome are at a greater risk of venous and arterial thrombosis over time, and prevention needs to be improved. These women also appear to develop more psychiatric and mood disorders. Central nervous system imaging using high-resolution techniques has shown subtle impairments in the white matter, associated with the most pathogenic aPL Abs and the clinical significance of this is under investigation. These mothers also seem to develop an excess of cancers. The systemic impact of aPL Abs is gradually being suspected, although this requires further evidence, and prevention should be envisaged.

Thrombotic incidents in patients with myelofibrosis suggest to be independent of JAK2 V617f mutational status.

Myelofibrosis (MF) belongs to a group of conditions known as Philadelphia-negative myeloproliferative neoplasms (MPN). Bleeding or various vascular complications could be the main causes of morbidity and mortality in patients with MF. MPNrelated thrombosis is a multifactorial process and in the case of myelofibrosis, little is known. The risk factors for thrombotic complications in MF have been rarely assessed. The purpose of this study was to investigate the incidence of thrombotic events in MF and the role of JAK2 V617F mutation as a risk factor for thrombotic incidents in patients with MF. In our study of 37 patients, 35% had thrombotic events in the past. All patients were admitted to the Clinic of Hematology, St Ivan Rilski University Hospital, Sofia, Bulgaria between 2016 and 2019 and diagnosed based on the WHO criteria of 2016. The majority of patients (23, 62%) proved positive for JAK2 (Janus kinase) V617F mutation carrying one (16, 70%) or two (7, 30%) mutated alleles. Thirteen of the patients (35%) had a thrombotic event in the past and 9 of them (69%) were carriers of JAK2 V617F mutation. Fourteen patients of those without thrombotic history (24, 58%) were also carriers of JAK2 V617F mutation. As a whole, we did not find a statistically significant difference between JAK2 V617F mutation and the frequency of thrombotic events. Rendering an account to the possible life-threatening complications, treatment decisions should be undertaken upon possible antithrombotic prevention in MF.

P1016: POLYCYTHEMIA VERA AND IMMUNE THROMBOGENESIS

Background: Polycythemia Vera (PV) is a Ph1-negative myeloproliferative neoplasm characterized by vascular thrombosis and poor survival. The polycythemic thrombogenesis is associated with erythrocytosis and red cell adhesiveness angiopathy. Recent studies reported a JAK/STAT-mediated reduction of the regulatory T cells (Tregs) (CD4+, CD25high, CD127low, FoxP3+) and loss of self-tolerance. Aims: We investigated Tregs, anti-endothelial cell antibodies (AECA), and endothelial, platelet and coagulation activation, in Polycythemia Vera (PV) and thrombosis. Methods: We enrolled 60WHO-defined PV patients (30 men, 30 women; mean age 45±10 years) without cardiovascular risk factors, autoimmune disease or thrombotic history. Of PV patients, 40/60 had thromosis includingmyocardial infarction (MI) (10/60) according to the WHO critera, deep vein thrombosis (20/60) and pulmonary embolism (10/60) on lower-limb ultrasonography and computed tomography angiography, respectively. All patients were evaluated for JAK2V617F allele burden, Tregs, AECA,Endothelial Leukocyte Adhesion Molecule-1 (ELAM-1), Intercellular Adhesion Molecule-1 (ICAM-1),prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimer (DD). JAK2V617F allele burden were analyzed by Polymerase chain reaction, Tregs were measured by flow cytometry,AECA, ELAM-1 and ICAM-1 by ELISA, PT and APTT by coagulometric test, Fib using Clauss method, and DD using ELISA.Complete blood hemostasis was studied by PFA-100 on Collagen/ADP (CT-ADP) and Collagen/Epinephrine (CT-EPI) cartridges and Thromboelastometry method on Clotting Time (CT), Clotting Formation Time (CFT), Maximum Clot Firmness (MCF), and clot lysis at 30 minutes (LY-30). Results: The patients with thrombosis had JAK2V616F allele burden higher (> 50%) compared to patients without thrombosis (< 50Kroll%), lower Tregs (1,5±0,5% vs 3.5±1%),higher AECA (200±20% vs 110±10%), ELAM-1 (80±10 ng/ml vs 45±5 ng/ml), and ICAM (170 ng/mL±10 vs 110±10 ng/mL), longer PT (30±10 s vs 20±2 s) and PTT (60±10 s vs 38±5 s), lower Fib (90±20 mg/dl vs 120±20 mg/dl), higher DD (650±100 mg/l vs 300±50 mg/l) and shorter C/ADP and C/EPI (C/ADP, n.v. 68-121 s (40±10 s vs 55±20 s) and C/EPI n.v. 84-160 s (35±5 s vs 60±10 s). The patients with thrombosis had shorter CT (INTEM 35±20 s vs 70±20 s, EXTEM 20±10 s vs 30±5 s), shorter CFT (INTEM 15±10 s vs 25±5 s EXTEM 18±10 s vs 28±5 s), longer MCF (INTEM 130±10 mm vs 90±10 mm, EXTEM 120±10 mm vs 82±10 mm), and lower LY-30 (INTEM 0.9% vs 15%, EXTEM 0.8% vs 15%). A positive correlation there was between Tregs and AECA, ELAM-1 and ICAM-1 and thrombosis. Summary/Conclusion: These findings shed new light on thrombotic pathogenesis in patients with PV.

Spleen and Liver Fibrosis Is Associated to Treatment Response and Prognosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Spleen and Liver Fibrosis Is Associated to Treatment Response and Prognosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Risk Factors for Catheter-Related Thrombosis in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

Background and Objectives: Cancer associated thrombosis (CAT) is a common complication of neoplasms. Multiple myeloma (MM) carries one of the highest risks of CAT, especially in the early phases of treatment. Autologous stem cell transplantation (ASCT) as the standard of care in transplant-eligible patients with MM carries a risk of catheter-related thrombosis (CRT). The aim of this study was identification of the risk factors of CRT in MM patients undergoing ASCT in 2009–2019. Materials and Methods: We retrospectively analyzed patients with MM undergoing ASCT. Each patient had central venous catheter (CVC) insertion before the procedure. The clinical symptoms of CRT (edema, redness, pain in the CVC insertion area) were confirmed with Doppler ultrasound examination. We examined the impacts of four groups of factors on CRT development: (1) patient-related: age, gender, Body Mass Index (BMI), obesity, Charlson comorbidity index, hematopoietic stem cell transplantation comorbidity index, renal insufficiency, and previous thrombotic history; (2) disease-related: monoclonal protein type, stage of the disease according to Salmon–Durie and International Staging System, number of prior therapy lines, and MM response before ASCT; (3) treatment-related: melphalan dose, transplant-related complications, and duration of post-ASCT neutropenia; (4) CVC-related: location, time from placement to removal. Results: Symptomatic CRT was present in 2.5% (7/276) of patients. Univariate analysis showed an increased risk of CRT in patients with a catheter-related infection (OR 2.4, 95% CI; 1.109–5.19, p = 0.026), previous thrombotic episode (OR 2.49, 95% CI; 1.15–5.39, p = 0.021), previous thrombotic episode on initial myeloma treatment (OR 2.75, 95% CI; 1.15–6.53, p = 0.022), and gastrointestinal complications of ASCT such as vomiting and diarrhea (OR 3.87, 95% CI; 1.57–9.53, p = 0.003). In multivariate analysis, noninfectious complications were associated with higher CRT incidence (OR 2.75, 95% CI; 1.10–6.19, p = 0.031). Conclusions: The incidence of symptomatic CRT in ASCT in MM was relatively low. Previous thrombotic events, especially during the induction of myeloma treatment, increased CRT risk during ASCT. Dehydration following gastrointestinal complications may predispose to higher CRT incidence.

Levels of Protein S and Risk of Thromboembolism

BACKGROUNDDeficiency of natural anticoagulants like Protein S, Protein C and Anti thrombin III can lead to increased risk of a clot. Statistically, 2.5% of the population will have the protein activity 2 standard deviations below the mean. These patients are labeled as deficient; however, this does not necessarily correlate with a phenotypic clotting disorder. We would like to determine if there is a certain protein activity level that corresponds to increased risk of clotting history, as well as increased risk of a present clot in a patient. Here we are present data on Protein S and we are currently gathering data for Protein C and ATIII. MethodsWe found 875 patient charts from our electronic medical records which were tested for protein S level. Out of those, 172 were found to have at least one incidence of Protein S deficiency (protein S functional measurement of <60). We reviewed the charts of these 172 patients and collected data on gender, race, age at the time of labs, past and present (3 months prior to labs), thrombotic history, protein C level, anticoagulant usage including warfarin and enoxaparin, pregnancy, oral contraceptive use, genetic profile for Factor V and Prothrombin gene mutation, and sickle cell disease.To determine a protein S threshold for increased risk of clotting events, confounding populations including patients who were pregnant, actively taking warfarin, under 12 months of age, or diagnosed with sickle cell disease were excluded. The total number of individuals at each protein S level was tallied, followed by the number at that level to have any previous clotting history as well as individuals with a history of a clot within the past three months. To determine if there was a threshold for increased risk of clotting, a series of chi squared tests were run for “low” versus “very low” protein S levels, with threshold protein S level between the two groups changing for each test. The most likely threshold for increased risk was concluded based on the threshold that provided the most significant chi squared test between the two groups. To supplement the findings of this approach, a classification and regression tree analysis (CART), as well as a receiver operating characteristic (ROC) curve, were run for both clotting scenarios.The threshold for increased risk of clotting history was then used to subdivide the entire, unfiltered protein S deficient population into a “low” group determined to be at lower risk and a “very low” group determined to be at higher risk. The gathered data on patient demographics and clinical history was then compiled for each subgroup. RESULTSPatients with protein S level of 38 or below have a 55.2% higher prevalence of clotting history compared to patients with protein S levels between 39 and 59 (OR = 3.65, 95% CI 1.175-11.330). The threshold for the lower protein S subgroup was set to a maximum of 38 after determining the boundary provided the most significant contrast in clotting history prevalence (Chi-squared = 5.33, P = 0.021). Both CART analysis and the ROC curve suggested a similar lower threshold of 39.Patients with protein S level of 34 or below have a 129% higher prevalence of present clots compared to patients with protein S levels between 35 and 59 (OR = 3.58, 95% CI 1.165-11.03). In this case, the threshold for “very low” protein S was set to a maximum of 34 after determining the boundary provided the most significant contrast in recent clot prevalence (Chi-squared = 5.042, P = .025). CART analysis and the ROC curve for recent clot suggest a similar threshold of 34.5. CONCLUSIONThe data suggest that patients with a functional protein S level of 38 U/dL or below have a greater risk of past clots than patients with levels between 39 and 59 U/dL, despite both groups falling under the category of “protein S deficient.” Similarly, patients with a functional protein S level of 34 or below are associated with greater risk of a present clot than patients with a level between 35 and 59 U/dL. DisclosuresNo relevant conflicts of interest to declare.