Avatrombopag for adults with early versus chronic immune thrombocytopenia.

Avatrombopag is a newer thrombopoietin receptor agonist (TPO-RA) currently approved to treat chronic ITP (duration >12 months). No studies have yet evaluated the safety and effectiveness of avatrombopag in newly diagnosed ITP (duration <3 months) or persistent ITP (duration 3-12 months), and so its use in these populations is presently off-label worldwide. We hypothesize that avatrombopag has similar safety and effectiveness irrespective of ITP disease phase. To evaluate this, we performed a multicenter observational cohort study of adults with ITP treated with avatrombopag, comparing patient outcomes by disease phase (newly diagnosed/persistent versus chronic). Seventy-five patients were included, 23 with newly diagnosed/persistent ITP (17.7 patient-years of avatrombopag treatment) and 52 with chronic ITP (65.3 patient-years of avatrombopag treatment). On avatrombopag, 91% of newly diagnosed/persistent patients versus 96% of chronic patients (p = .58) achieved a platelet response (≥50 × 109 /L) and 86% versus 81% of patients (p = .78) achieved a complete response (≥100 × 109 /L). Median platelet counts on avatrombopag were similar between the two groups (165 × 109 /L vs. 129 × 109 /L, p = .57). Response durability was high and similar in both groups. No patients in the newly diagnosed/persistent group had a major bleeding event, thromboembolic event or avatrombopag discontinuation for adverse events, compared with 4, 1, and 2, respectively, in the chronic group. Thrombocytosis (platelets ≥400 × 109 /L) incidence was similar in the two groups. No other drug-related adverse events occurred in either group. Avatrombopag was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving avatrombopag for chronic ITP.

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection.

Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.

A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies.

Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy delays, dose reductions, and discontinuation. There is no FDA-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at 4 U.S. centers. The primary outcome was achievement of a romiplostim response [median on-romiplostim platelet count (Plt) ≥75x109/L and ≥30x109/L above baseline]. Secondary outcomes included time to Plt≥100x109/L and rates of the following: Plt<100x109/L, Plt<75x109/L, Plt<50x109/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of 4 (range, 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays and 89% avoided platelet transfusions. Median per-patient Plt on romiplostim was significantly higher than baseline (116x109/L vs. 60x109/L, P<0.001). Bone marrow tumor invasion, prior pelvic irradiation, and prior temozolomide predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays (IRR 3.00, 95% CI 1.30-6.91, P=0.010) or bleeding (IRR 4.84, 95% CI 1.18-19.89, P=0.029). Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with bone marrow involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.

Thrombopoietin level predicts response to treatment with romiplostim in chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer treatment. Evidence has emerged supporting use of romiplostim to treat CIT but predicting clinical response to romiplostim is not possible. To determine utility of endogenous thrombopoietin (TPO) as a biomarker of romiplostim response, we performed an observational cohort study of patients with CIT and known baseline TPO levels receiving romiplostim. For weekly on-romiplostim platelet (Plt) count assessment, clinical response was defined as Plt ≥ 75 × 109 /L and ≥ 30 × 109 /L above pretreatment baseline. Overall, moderate, and superior classes of treatment response were defined based on fraction of Plt assessments meeting clinical response criteria (> 0, ≥ 0.6, and ≥ 0.8, respectively). Sixty-three patients with CIT were included; median age was 62 years, 41.3% were female, and median (IQR) romiplostim treatment duration was 14 (4-38) weeks. Median (IQR) TPO was lower in patients achieving moderate response to romiplostim vs those who did not, 234 (135-1085) pg/mL vs 665 (244-1970) pg/mL (p = .034) and lower still in patients achieving superior response vs those who did not, 212 (91-690) pg/mL versus 559 (173-1851) pg/mL (p = .023). Negative correlations were found between TPO level and baseline Plt and TPO level and response fraction. A positive correlation was found between TPO level and lowest effective romiplostim dose. In receiver operating characteristic (ROC) analysis, optimally discriminant TPO level thresholds (as defined by Youden's Index) were ≤ 457 pg/mL for moderate response and ≤ 260 pg/mL for superior response. In conclusion, TPO levels predict response to romiplostim in CIT, with lower levels predicting improved probability and depth of response.

An Eltrombopag Red (Plasma) Alert.

Eltrombopag is a thrombopoietin receptor agonist frequently used to manage immune thrombocytopenia and aplastic anemia. At the high doses used for aplastic anemia, but not the doses used for immune thrombocytopenia, eltrombopag can cause reddish-brown discoloration of plasma, which can interfere with bilirubin measurement and cause false clinical alarm. This case report and clinical image describes a patient with aplastic anemia managed with eltrombopag who developed reddish-brown plasma initially concerning for possible hemolysis or rhabdomyolysis.

Romiplostim for the management of perioperative thrombocytopenia.

Thrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single-centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty-seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug-related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47 × 109 /l (9-120 × 109 /l) at romiplostim initiation to 164 × 109 /l (28-603 × 109 /l) at the time of surgery (P < 0·0001). A dose of 3 µg/kg per week for 2 doses increased the platelet count to >100 × 109 /l in 79% of patients within 14 days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population.

Romiplostim in the management of the thrombocytopenic surgical patient.

BACKGROUND: Thrombopoietin receptor agonists increase platelet (PLT) counts and are approved for the treatment of chronic immune thrombocytopenia (ITP). These agents may also be useful for the management of thrombocytopenia in patients requiring surgical procedures. STUDY DESIGN AND METHODS: We conducted a retrospective review of patients with thrombocytopenia (baseline PLT count, <150 × 10(9) /L) who received romiplostim before planned operative procedures. We characterized patient demographics, dosing and duration of romiplostim use, success in achieving PLT counts high enough for surgery, and clinical outcomes. RESULTS: Eighteen patients underwent a total of 22 operative procedures, including three Jehovah's Witnesses who underwent five procedures. Etiologies of thrombocytopenia included mild ITP (not on romiplostim at baseline), liver disease, hematologic malignancy, and drug-related thrombocytopenia. Median PLT count at romiplostim initiation was 47 × 10(9) /L (range, 11 × 10(9) -120 × 10(9) /L). All patients experienced a PLT count increase over a median of 4 weeks; median PLT count at surgery was 144 × 10(9) /L (range, 28 × 10(9) -370 × 10(9) /L). PLT counts increase to more than 150 × 10(9) /L in four of five Jehovah's Witness patients by the time of surgery. There were no surgical delays or cancellations due to thrombocytopenia. Four bleeding events occurred; none were fatal and none occurred at a PLT count of fewer than 80 × 10(9) /L. No definitive thromboembolic events occurred. CONCLUSION: Romiplostim successfully increased preoperative PLT counts allowing operative interventions, was well tolerated, did not lead to any significant thromboembolic events, and avoided the need for transfusion. Romiplostim may be of clinical utility in the preoperative management of thrombocytopenic patients, especially those unable to receive or unresponsive to PLT transfusion.

Risk Factors for Death or Cardiovascular Events after Acute Coronary Syndrome in Patients with Myeloproliferative Neoplasms.

Patients with myeloproliferative neoplasms (MPNs) are at increased risk of cardiovascular disease (CVD), including acute coronary syndrome (ACS). However, data on long-term outcomes of patients with MPN who have had ACS and risk factors for all-cause death or CV events post-ACS hospitalization are lacking. We conducted a single-center study of 41 consecutive patients with MPN with ACS hospitalization after MPN diagnosis. After a median follow-up of 80 months after ACS hospitalization, 31 (76%) experienced death or a CV event (myocardial infarction, ischemic stroke, or heart failure hospitalization). After multivariable Cox proportional hazards regression, index ACS within 12 months of MPN diagnosis (HR 3.84, 95% CI 1.44-10.19), WBC ≥ 20 K/µL (HR 9.10, 95% CI 2.71-30.52), JAK2 mutation (HR 3.71, 95% CI 1.22-11.22), and prior CVD (HR 2.60, 95% CI 1.12-6.08) were associated with increased death or CV events. Further studies are warranted to improve cardiovascular outcomes in this patient population.

Predictors of increased risk of adverse cardiovascular outcomes among patients with myeloproliferative neoplasms and atrial fibrillation.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), have increased risk of cardiovascular (CV) disease. Atrial fibrillation (AF) is associated with adverse CV outcomes including arterial thrombosis, heart failure (HF), and CV death and coexists with MPN. Traditional risk scores (CHA2DS2-VASC and HAS-BLED) for estimating risks/benefits of anticoagulation to prevent thrombotic events in AF do not include MPN status. Therefore, we aimed to investigate CV outcomes in patients with MPN and AF and evaluate the predictive ability of traditional risk scores. METHODS: We conducted a single-center, retrospective cohort study of patients with MPN and AF. Primary outcome was composite of CV death and arterial thromboembolism; secondary outcomes were bleeding requiring emergency department visit or hospitalization, hospitalization for HF, and all-cause death. Multivariable competing-risk and Cox proportional hazards regression models were used to estimate risk of outcomes. Receiver operating characteristic (ROC) curve used to evaluate predictive ability of CHA2DS2-VASC and HAS-BLED of composite outcome and bleeding, respectively. RESULTS: A total 142 patients was included (62 ET, 54 PV, 26 MF). Composite outcome, bleeding, HF hospitalization and all-cause death occurred in 39 %, 30 %, 34 %, and 48 %, of patients respectively. After multivariable modeling, MF was associated with increased risk of composite outcome (SHR 2.70, 95 % CI 1.38-5.27) and all-cause mortality (HR 9.77, 95 % CI 4.88-19.54) but not bleeding (SHR 1.19, 95 % CI 0.51-2.80) or HF admissions (SHR 0.57, 95 % CI 0.19-1.72). CHA2DS2-VASC and HAS-BLED were poor predictors of composite outcome (C-statistic 0.52, 95 % CI 0.43-0.62) and bleeding (C-statistic 0.49, 95 % CI 0.40-0.58), respectively. CONCLUSION: In patients with MPN and AF, MF is associated with increased risk of CV death and arterial thrombosis and traditional risk scores do not accurately predict outcomes in this patient population. Further investigation is needed to refine risk scores in this patient population.

Pulmonary hypertension is associated with poor cardiovascular and hematologic outcomes in patients with myeloproliferative neoplasms and cardiovascular disease.

Cardiovascular events and hematologic progression to myelofibrosis or leukemia are leading causes of morbidity and mortality among patients with myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is also associated with MPN and cardiovascular disease (CVD), though its prognostic significance in MPN is not well characterized. Our primary objective was to investigate the effect of PH, defined as right-ventricular systolic pressure (RVSP) ≥ 50 mmHg on echocardiogram or mean pulmonary artery pressure (mPAP) ≥ 20 on right heart catheterization, on cardiovascular and all-cause mortality and hematologic progression in patients with MPN and CVD (atrial fibrillation, heart failure hospitalization, and myocardial infarction after MPN diagnosis). Of the 197 patients included (86 ET, 80 PV, 31 PMF), 92 (47%) had PH and 98 (50%) were male. All-cause mortality (58 vs 37%, p = 0.004), cardiovascular death (35 vs 9%, p < 0.0001), and hematologic progression (23 vs 11%, p = 0.037) occurred more frequently in patients with PH. Multivariable competing-risk and proportional hazards regression showed that PH was associated with increased risk of all-cause death (adjusted hazard ratio [HR], 1.80, 95% CI 1.10-2.93), CV death (adjusted subdistribution HR 3.71, 95% CI 1.58-8.73), and hematologic progression (adjusted subdistribution HR 1.99, 95% CI 1.21-3.27).

Patients with myeloproliferative neoplasms and COVID-19 have increased rates of arterial thrombosis.

Background: Both coronavirus disease-2019 (COVID-19) and myeloproliferative neoplasms (MPNs) are associated with systemic inflammation and risk of thrombosis. Risk of thrombosis in patients with COVID with and without MPNs has not been extensively studied. Methods: Retrospective cohort study of 44 patients with MPNs and 1114 patients without MPNs positive for SARS-COV-2. Outcomes were arterial thrombosis (AT), venous thromboembolism (VTE), bleeding, and death. Time-to-event analysis was performed using competing risk regression model and Cox proportional hazards. Results: AT occurred more frequently in patients with MPN (7% vs. 1%, p = 0.03). Rates of VTE (7% vs. 5%, p = 0.73), bleeding (7% vs. 2%, p = 0.06), and death (9% vs. 6%, p = 0.32) were similar. MPN patients were older and had more cardiovascular comorbidities. After time-to-event competing-risk regression adjusting for age, MPN patients had higher risk of AT (subdivision hazards ratio 3.95, 95% CI 1.09-14.39) but not VTE, bleeding, or death. Conclusions: Among patients with COVID-19, MPN patients had higher risk of arterial thrombosis but not VTE, bleeding, and death compared with non-MPN patients. Larger studies are needed to confirm our findings given the limited sample size.

A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia.

Platelet autoantibody (PA) testing has previously shown poor sensitivity for immune thrombocytopenia (ITP) diagnosis, but no previous study used both 2011 American Society of Hematology (ASH) guidelines for ITP diagnosis and 2012 International Society on Thrombosis and Haemostasis (ISTH) PA testing recommendations. We therefore performed a comprehensive retrospective study of PA testing in adult patients with ITP strictly applying these criteria. Of 986 PA assays performed, 485 assays in 368 patients met criteria and were included. Sensitivity and specificity of a positive test result for diagnosis of active ITP (n = 228 patients) were 90% and 78%, respectively. Sensitivity and specificity of a negative test result for clinical remission (n = 61 assays) were 87% and 91%. Antibodies against both glycoprotein IIb (GPIIb)/IIIa and GPIb/IX were required for the presence of antibodies against GPIa/IIa in patients with ITP. Logistic regression analysis revealed that more positive autoantibodies predicted more severe disease (relative to nonsevere ITP, relative risk ratio for severe ITP and refractory ITP was 2.27 [P < .001] and 3.09 [P < .001], respectively, per additional autoantibody); however, serologic testing did not meaningfully predict treatment response to glucocorticoids, intravenous immunoglobulin, or thrombopoietin receptor agonists. Sixty-four patients with ITP had multiple PA assays performed longitudinally: all 10 patients achieving remission converted from positive to negative serologic results, and evidence for epitope spreading was observed in 35% of patients with ongoing active disease. In conclusion, glycoprotein-specific direct PA testing performed using ISTH recommendations in patients meeting ASH diagnostic criteria is sensitive and specific for ITP diagnosis and reliably confirms clinical remission. More glycoproteins targeted by autoantibodies predicts for more severe disease.

Improved strategy for mononuclear cell collection for donor lymphocyte infusions.

BACKGROUND: To improve donor management for donor lymphocyte collections, a protocol was established to tailor the amount of whole blood processed during leukapheresis to achieve the requested cellular dose. STUDY DESIGN AND METHODS: A retrospective review of donor and product records of all donors who provided donor lymphocytes during the period October 27, 1999, to March 2, 2005, was performed (25 donors, 54 collections). Data on product total CD3+ T cells collected and total blood volume (TBV) processed were used to establish a correlation between the two variables. The resultant correlation from the reference group (8 donors, 13 collections) was then used to prospectively determine the TBV to be processed in a subsequent series of collections ("prospective group": 18 donors, 41 collections). Donor charts were also reviewed to determine leukapheresis-associated adverse events. RESULTS: The application of the correlation data between TBV processed and CD3+ T-cell yields from the initial reference group to the prospective group yielded 92 percent successful collections; in 3 of the 4 inadequate collections, the predefined maximum of three times their TBV was processed. Compared to the reference group, the TBV processed in the prospective group was decreased from 12,598+/-4007 to 7942+/-5079 mL; the length of procedure was decreased from 208+/-53 to 146+/-79 minutes. Adverse event data were reviewed for 51 collections; the percentage of procedures without adverse events increased from 23 percent in the reference group to 37 percent in the prospective group. CONCLUSION: Application of correlation data between TBV processed and CD3+ T-cell yield was useful to predict efficient and successful donor lymphocyte collections.

Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues.

Leukotriene B4 (LTB4) is a potent chemoattractant for myeloid leukocytes, which express BLT1, the high-affinity receptor for LTB4. We report here that BLT1 is induced substantially in CD8+ effector T cells and at lower amounts in CD8+ central memory T cells. LTB4 elicited BLT1-dependent chemotaxis in effector cells, but not in naive or central memory cells. Intravital microscopy showed that BLT1 signaling induced rapid integrin-mediated arrest of rolling effector and central memory cells in postcapillary venules. In competitive homing experiments, wild-type effector cells were three times more efficient at migrating to the inflamed peritoneal cavity than were BLT-deficient effector cells. These results identify LTB4-BLT1 as a potent nonchemokine pathway for cytotoxic effector cell traffic.