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.