Kreuziger, Lisa Baumann

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are at risk of splanchnic vein thrombosis (SVT). Prior studies failed to demonstrate a benefit of hydroxyurea in preventing SVT extension/recurrence, but these were limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. We therefore investigated the role of cytoreduction as a time-dependent covariate on thrombosis recurrence in a large, international cohort of MPN-SVT patients. Methods We performed a retrospective cohort study of MPN-SVT patients included in the international GASTRO-MPN consortium. Patients diagnosed with MPN at any time before, concurrently with, or up to 60 days after initial SVT were included. Primary outcome was time from initial SVT to first thrombosis recurrence, defined as the composite of SVT extension/recurrence, transjugular intrahepatic portosystemic shunt (TIPS) thrombosis, or venous/arterial thrombosis outside the splanchnic veins. Secondary outcomes included SVT extension/recurrence, TIPS thrombosis or extra-SVT thrombosis individually, clinically relevant bleeding (composite of major and clinically relevant non-major bleeding), MPN progression to myelofibrosis or blast phase, and death. Cytoreductive therapy was treated as a time-dependent covariate to account for discontinuation and therapy changes. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results A total of 757 patients were included for this analysis. Median age was 51 years (IQR 38-62), 59% were female. SVT involved the portomesenteric veins in 558 (77%) patients, hepatic veins in 95 (13%), and both in 54 (7.4%). MPN was known prior to initial SVT in 316 patients (42%) and diagnosed concurrently or up to 60 days after SVT in 441 (58%). Polycythemia vera (PV) was the most common MPN subtype (43%), followed by essential thrombocythemia (ET) in 24%, and primary myelofibrosis in 14%. JAK2V617F mutation was present in 86% and CALR in 2.9%. 13% had prior non-SVT thrombosis. 607 patients (83%) were treated with cytoreduction. At time of SVT, 131 patients (17%) were already on cytoreduction; in those who started after SVT, median time to initiation was 54 days after SVT, and median duration of cytoreduction per patient was 63 months. Cytoreductive therapies used at any point in treatment included hydroxyurea in 504 (69%), ruxolitinib in 182 (25%), and interferon-based in 85 (12%) patients. Anticoagulation (AC) was started within 30 days after SVT in 504 (68%) patients. Median duration of any AC per patient was 24.6 months. During a median follow up of 7.4 years, 245 patients (33%) had thrombosis recurrence; 143 (20%) had SVT extension/recurrence/TIPS thrombosis, 129 (18%) extra-SVT thrombosis (of which 74% venous), 237 patients (32%) experienced clinically relevant bleeding, and 163 (22%) died. After adjusting for age, sex, timing of MPN diagnosis relative to SVT diagnosis, AC within 30 days of SVT, PV/ET vs other MPN, JAK2 mutation, previous thrombosis, non-MPN cancer, and cirrhosis, cytoreductive therapy was associated with a significantly decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). Age was associated with an increased risk of recurrent thrombosis (p=0.01). When considering types of recurrent thrombosis, cytoreduction was associated with a decreased risk of SVT extension/recurrence/TIPS thrombosis (HR 0.62 95%CI 0.42-0.90, p=0.01), but not thrombosis outside the splanchnic veins (HR 0.97 95%CI 0.72-1.30, p=0.82). There was no association between cytoreduction and bleeding (HR 1.10 95%CI 0.82-1.47, p=0.52). Similarly, there was no association between cytoreduction and time to MPN progression (p=0.24) or overall survival (p=0.30). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=271), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.10, p=0.09) for recurrent thrombosis. Limited sample size and low event-rate precluded evaluation of the impact of individual cytoreductive therapies. Conclusions In the largest cohort of MPN-SVT patients to date, we show for the first time that cytoreductive therapy is associated with a decreased risk of thrombosis recurrence, driven largely by decreased SVT extension/recurrence/TIPS thrombosis. Collectively, these findings support use of cytoreductive therapy in individuals with MPN-SVT to prevent recurrent thrombosis.

Background: The use of validated risk stratification tools for the workup of suspected pulmonary embolism (PE) is a recommendation of the American Society of Hematology and the American College of Emergency Physicians. Methods: We designed and implemented electronic clinical pretest probability (PTP) tools for use in emergency departments (ED). Overall, 38 EDs (tertiary and regional EDs) in the United States were involved across three health systems. PTP use was analyzed between September 12, 2022 and January 11, 2023 in 270,247 ED visits. PTP use was examined in terms of the percentage of visits for which patients underwent computed tomography pulmonary angiography (CTPA). Each site chose the 3-tier Wells’ score for implementation and Site 2 designed a combined Wells’, pulmonary embolism rule-out criteria (PERC), and YEARS score. Results: At Site 3, forced use resulted in documented PTP scores in 49–53% of ordered CTPAs. At Sites 1 and 2, where PTP scores were optional, documented PTP scores occurred in 2–3% and 1–3% of CTPA orders, respectively. At Site 1, the use of PTP increased slightly over the study period, with signs that PE yield on imaging was also increasing (3.4–5.9%). At Site 2, PE yield on imaging was 9–10%, and it remained similar, with similar use of PTP tools over the study period. PE yield (6–8%) on imaging also remained similar throughout the study at Site 3. Conclusions: Guideline-endorsed PTP scores for PE at three independent health systems in the United States did not increase PE yield on imaging. Novel implementation strategies involving interdisciplinary teams are urgently needed.

Guidelines for diagnosing pulmonary embolism (PE) start with a risk assessment using a pretest probability (PTP) tool, followed by D-dimer testing or computed tomography pulmonary angiography (CTPA) depending on risk. The project aimed to develop an electronic clinical quality measure (eCQM) to encourage broader use of a validated PTP scoring tool in emergency departments (EDs) to more accurately diagnose PE and to reduce unnecessary CTPAs. To identify a value set to accurately identify CTPA and abnormal D-dimer tests using standard classification systems and clinical vocabularies (ie, Current Procedural Terminology [CPT], Logical Observation Identifiers Names and Codes [LOINC], systematized nomenclature of medicine clinical terms [SNOMED CT]) across 3 academic United States health care systems. A comprehensive value set to identify CTPAs was selected, which contained 31 codes. Additionally, each health care system had unique, site-specific codes to more granularly identify CTPAs. Three health care systems representing 38 EDs from across the country submitted data from all ED encounters between September 12, 2022, and January 11, 2023. Imaging types were reviewed from each of the CPT codes and LOINC. The project evaluated whether a D-dimer was obtained using CPT and LOINC and whether the D-dimer result was elevated using SNOMED CT. The number of ED encounters, PTP use, and diagnosis of PE using different codes were determined. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for selected codes were calculated. Over a 4-month study period, 270,214 encounters were included from 38 EDs. 11,794 ED encounters with CTPAs during the study period, using the site-specific codes were identified. The comprehensive value set had a PPV of 63.4%. Restricting the CTPA value set to CPT code 71275 or LOINC 88322-3 improved the PPV to 82% with 100% sensitivity and 99% specificity. The restricted value set captured the highest proportion of relevant site-specific codes. D-dimer values were identified using LOINC codes 48065-7 and 91556-1 at Site 1 and 48067-3 at Site 2. SNOMED CT codes were not used at any site to identify elevated D-dimer results. Different D-dimer tests with different normal ranges were used at each site, and only one site provided an abnormal flag for D-dimer results. Heterogeneity in the use of nationally standardized codes for labs and imaging tests limits the ability to measure and compare quality across health care organizations for CTPA and D-dimer results. Restricting the identification of CTPA to CPT Code 71275 or LOINC 88322-3 resulted in high sensitivity and specificity, but false positives remain. Additionally, coding for an abnormal D-dimer test result is not standardized across institutions. Therefore, the currently available value sets cannot be used to develop eCQMs whose aim is to evaluate whether CTPA is ordered appropriately based on the PTP risk level and laboratory testing.

Severe COVID-19 is a multisystem condition with thromboinflammation as a significant driver of morbidity and mortality. Cellular components involved in inflammatory and coagulation responses include platelets, endothelium, monocytes, and neutrophils. Thrombotic manifestations, such as arterial thrombosis, venous thromboembolism, and tissue microthrombosis, occur in at least 20% of ICU COVID-19 patients, possibly more based on postmortem studies. This study investigates the presence of prothrombotic antibodies similar to those found in heparin-induced thrombocytopenia (HIT), a condition caused by platelet-activating antibodies targeting platelet factor 4 (PF4) when complexed with heparin (PF4/H). In a study of samples from 130 hospitalized patients collected on average 3.6 days after COVID-19 diagnosis, 80% were found to have IgG antibodies recognizing PF4/H. This percentage is significantly lower than in 22 HIT patients (100%) but higher than in 51 non-COVID-19 patients with acute respiratory symptoms (ARS) (25%) and 12 healthy subjects (0%). Additionally, 41% of the 130 patients had antibodies inducing PF4-dependent P-selectin expression in CpG-treated normal platelets, a rate significantly lower than in 12 HIT patients (100%) but higher than in 51 non-COVID-19 ARS patients (20%) and 12 healthy subjects (0%). Significantly, platelet-activating antibodies in COVID-19 patients were associated with a specific elevation of platelet α-granule proteins in the plasma and correlated with inflammation and tissue damage markers, suggesting these antibodies' functionality in patients. Significantly, unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in COVID-19 patients regardless of recent heparin exposure, indicating different antigenic stimuli for these antibodies in COVID-19. Notably, certain antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 possessed sequence motifs, RKH and Y5, in the heavy-chain complementarity-determining region 3 (HCDR3) resembling those in pathogenic HIT antibodies identified in our previous studies, suggesting that these antibodies can activate platelets. Introducing exogenous RBD to COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. Furthermore, immunodepleting RBD-reactive antibodies from COVID-19 plasma or IgG purified from COVID-19 plasma using RBD-coated beads significantly reduced their ability to activate platelets. These findings demonstrate that some RBD-specific plasma IgG antibodies can activate platelets. To demonstrate the presence of RBD-specific, platelet-activating antibodies at the clonal level, we produced recombinant antibodies from 42 RBD-binding IgG+ B cells, tested their ability to activate platelets, and identified four that could do so. Interestingly, three antibodies possess HCDR3 sequences resembling RKH or Y5 motifs. Additionally, we identified RKH or Y5 motifs in RBD-specific antibodies reported by other groups, produced 15 such antibodies recombinantly, tested their ability to activate platelets, and identified four more that could do so. IgG+ B cells with these HCDR3 motifs were markedly expanded in severe COVID-19 patients, suggesting an expansion of B cells producing platelet-activating antibodies. The demonstration of functional and structural similarities between certain RBD-specific antibodies in COVID-19 patients and pathogenic HIT antibodies suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

Background: Myeloproliferative neoplasms (MPNs) are chronic leukemias with increased thrombotic risk. Venous thrombosis in MPN often occurs in atypical sites, such as splanchnic vein thrombosis (SVT), defined by thrombosis in the portal, hepatic, mesenteric, or splenic veins. Data to guide anticoagulation management of SVT in MPN patients is lacking. Objectives: The purpose of this study is to evaluate outcomes as well as the safety and efficacy of different anticoagulation strategies in MPN patients with SVT. Methods: A retrospective cohort study of MPN patients with SVT from 10 international centers was conducted. All centers performed systematic identification of adults with a World Health Organization 2016 diagnosis of an MPN (polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis [MF], prefibrotic MF, MPN-unclassifiable [MPN-U]) and confirmed SVT. Inclusion criteria were met if first SVT occurred after or within one year before MPN was diagnosed. The primary outcome was 1-year cumulative incidence of recurrent venous (VT) or arterial thrombosis (AT). Secondary outcomes included 1-year cumulative incidence of (1) major and clinically relevant non-major bleeding (CRNMB) by International Society on Thrombosis and Hemostasis criteria, (2) SVT recanalization; and (3) 1-year overall survival. Death as a competing risk was used for cumulative incidence analyses of recurrence and bleeding. Results: 486 MPN patients (median age at first SVT 51 years; 62.3% female) were identified. MPN diagnosis preceded SVT in 35.2% of patients (median time 4.8 years) and occurred simultaneously or within 1 year of first SVT in 64.8% of patients. 43.8% of patients had PV, 23.7% ET, 14.2% MF, 3.1% prefibrotic MF and 13.2% MPN-U. The most common driver mutation was in JAK2 (90.7%) followed by CALR (4.4%) and MPL (1.6%). SVT localization was isolated to portal (25.7%), hepatic (15.4%), mesenteric (1.9%), and splenic veins (4.3%), and in 51.2% of cases SVT occurred in multiple vessels. Prior VT or AT occurred in 8.8% and 4.1% of subjects, respectively. Cytoreduction (most commonly hydroxyurea [36.9%], interferon [9.6%] or JAK inhibitor [6.8%]) was started after SVT in 58.7% of newly diagnosed MPN patients and 40.6% of those with known MPN. 57.6% of patients were anticoagulated, 3.5% of patients were treated with an antiplatelet agent, and 11.7% were treated with both. The most common initial anticoagulants were vitamin K antagonists (VKA) (29.2%), direct oral anticoagulants (DOAC; 20.4%), and low-molecular-weight heparin (LMWH; 10.5%). DOACs were more commonly used in the USA and Asia than Europe (21.2%, 52%, and 13.5%; p<0.001). The median duration of anticoagulation was 23.9 months, with 62.8% still on anticoagulation after 3 years or at last follow-up. 1-year cumulative incidence of recurrent VT and AT was 14% (95% CI 11-18) (5.8% for recurrent SVT [95% CI 3.9-8.3]; 6.3% for other VT [95% CI 4.3-8.8]; 2.4% for AT [95% CI 1.3-4.2]), with an overall time to event 89 (IQR 34-193) days. Thrombosis incidence was similar in patients initially treated with VKA (13%), DOAC (15%) or LMWH (16%) (p=0.93); in comparison, individuals not treated with anticoagulation had 1-year thrombosis incidence of 13% (p=0.22). 1-year major and CRNMB cumulative incidence in all patients was 5.8% (95% CI 3.9-8.2) and 8.5% (95% CI 6.1-11), with median time to event 68 (IQR 13-150) days. Incidence of major bleeding was similar in VKA, DOAC, and LMWH-treated patients (5.9%, 6.6%, and 4.0%; p=0.89). 1-year cumulative incidence of SVT (partial) recanalization was 13% (95% CI 9.8-16) in all patients, with a median time to recanalization of 127 (IQR 40-323) days; recanalization rates were similar in anticoagulated and non-anticoagulated patients (p=0.76). There was a trend toward higher recanalization rates in patients treated with DOAC (26.9%) than with VKA (21.5%) or LMWH (13.6%; p=0.28). 1-year overall survival was 94.2% (95% CI 91.8-96.1) and similar between treatment groups (VKA 96.7%, DOAC 95.6%, LMWH 89.7%; p=0.11) and for no anticoagulation (82.3%; p=0.32). Conclusions: This is the largest contemporary cohort of MPN patients with SVT. MPN patients with SVT remain at risk for short-term thrombosis and bleeding complications regardless of treatment. We found no significant differences in outcomes between anticoagulation strategies, including in patients treated with DOACs compared to VKA or LMWH.

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

Abstract Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide–treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.