Nivolumab-Induced Thrombotic Thrombocytopenic Purpura in a Patient with Anal Squamous Cell Carcinoma: A Lesson on Hematologic Toxicity from Immunotherapy.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic hemolytic anemia characterized by thrombocytopenia, hemolytic anemia, and ischemic organ damage. It is mainly caused by an autoreactive antibody directed at ADAMTS13. Immunotherapy is frequently associated with autoimmune complications in patients with cancer, but only three cases of TTP have been reported, none implicating single treatment with the anti-programmed cell death receptor 1 ligand antibody nivolumab. We present the first identified and reported case of nivolumab-associated TTP in a 51-year-old woman with stage IIIc anal carcinoma who achieved complete response following chemoradiation and received adjuvant nivolumab as part of a randomized clinical trial. Twelve weeks into treatment, she presented with dark urine, progressive fatigue, and headache. TTP diagnosis was based on laboratory evidence of hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 9% associated with an inhibitor. She was treated with daily plasma exchange and oral prednisone and responded well to treatment, with platelet counts over 100 K/cmm within 4 days. We reviewed and summarized data from all reported cases of TTP associated with cancer immunotherapy. We provide guidance on identification and management of this devastating hematologic complication, focusing on the importance of early recognition, as most patients achieve complete recovery with appropriate treatment. KEY POINTS: Thrombotic thrombocytopenic purpura (TTP) was originally excluded from previous reviews of hematologic immune-related adverse events; however, several cases have been reported in the past 2 years in patients treated with either single agent or combination of cytotoxic T-lymphocyte-associated antigen 4 and the programmed cell death receptor 1 (PD-1) or the PD-1 ligand inhibitors. Although rare, TTP is a life-threatening condition that could be challenging to diagnose, and early recognition is key as delayed treatment is associated with significant increase in mortality. The pathophysiology of immunotherapy-induced TTP is likely related to autoimmune inhibition of ADAMTS13; the addition of prednisone and rituximab to urgent plasmapheresis appears to be effective and should be part of the up-front management for these patients.

Bleeding risk from anticoagulant thromboprophylaxis in patients with multiple myeloma: a MarketScan analysis.

Background: Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is frequently recommended but underutilized partly due to the absence of studies assessing bleeding risk. Objectives: To determine the rate of severe (hospitalized) bleeding from thromboprophylaxis in patients treated for MM and identify clinical risk factors for bleeding in this population. Methods: Using the MarketScan database, we analyzed 6656 patients treated for MM between 2013 and 2021. Concomitant thromboprophylaxis was defined using prescription claims. Hospitalized bleeding was identified through the Cunningham algorithm. Bleeding rates were compared by thromboprophylaxis status, and Cox regression identified risk factors for bleeding. Results: Anticoagulant thromboprophylaxis was used in 6.6% (436) patients treated for MM. Patients on thromboprophylaxis had a higher rate of immunomodulatory-based therapy (63.8% vs 46.7%; P < .01) and lower rate of antiplatelet use (2.1% vs 4.7%; P < .01). Bleeding occurred in 1.4% of them during median follow-up of 1.3 years. Rate of severe bleeding was not different between those on prophylaxis (7.8 per 1000 person-years) and those not on prophylaxis (10.1 per 1000 person-years). No association was identified between thromboprophylaxis and bleeding. Factors associated with increased bleeding included age (hazard ratio [HR], 1.38 per 10 years increase in age), comorbidity index (HR, 1.18 per SD increase), history of bleeding (HR, 1.54), hypertension (HR, 1.87), and renal disease (HR, 1.56). Conclusion: Risk of serious bleeding from thromboprophylaxis in patients treated for MM was low, and concomitant anticoagulant therapy did not result in increased bleeding risk. Clinical risk factors for bleeding included age, comorbidity index, bleeding history, hypertension, and renal disease.

Validation of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk scores for venous thromboembolism and bleeding in an independent population.

Background: Multiple guidelines recommend assessment of bleeding and venous thromboembolism (VTE) risk in adult medical inpatients to inform prevention strategies. There is no agreed-upon method for VTE and bleeding risk assessment. Objectives: To validate the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE and bleeding risk scores in an independent population. Methods: In this retrospective study, we calculated the IMPROVE VTE and bleeding risk scores in medical inpatients admitted between 2010 and 2019 at the University of Vermont Medical Center (UVMMC). Patients were followed for in-hospital bleeding events while hospitalized and VTE events while hospitalized and for 3 months after discharge. We assessed calibration of the risk models by comparing the observed incidence of events in the UVMMC and IMPROVE populations across the published risk categories. We also assessed performance of the IMPROVE risk factors after refitting the models in the UVMMC population. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC). Results: VTE occurred in 270 (1.1%) of 23,873 admissions, with 92 (34%) occurring during admission, and bleeding occurred in 712 (4.7%) of 15,240 admissions. When the IMPROVE-VTE risk factors were refitted to the UVMMC data, the AUC was 0.64. When the IMPROVE bleeding risk factors were refitted to the UVMMC data, the AUC was 0.67. The IMPROVE-VTE score tended to overestimate risk at higher scores, and the IMPROVE bleeding score underestimated risk at lower scores and overestimated risk at higher scores. Conclusion: While the refitted IMPROVE VTE and bleeding risk scores had reasonable model fit, the scores were poorly calibrated and did not reliably identify or differentiate patients at risk for VTE and bleeding. Different methods are needed for risk assessment of medical inpatients for VTE and bleeding risk.

The relative risk of bleeding after medical hospitalization: the medical inpatient thrombosis and hemorrhage study.

BACKGROUND: Clinically relevant bleeding risk in discharged medical patients is underestimated and leads to rehospitalization, morbidity, and mortality. Studies assessing this risk are lacking. OBJECTIVE: The aim of this study was to develop and validate a computable phenotype for clinically relevant bleeding using electronic health record (EHR) data and quantify the relative and absolute risks of this bleeding after medical hospitalization. METHODS: We conducted an observational cohort study of people receiving their primary care at sites affiliated with an academic medical center in northwest Vermont, United States. We developed a computable phenotype using EHR data (diagnosis codes, procedure codes, laboratory, and transfusion data) and validated it by manual chart review. Cox proportional hazard models with hospitalization modeled as a time-varying covariate were used to estimate clinically relevant bleeding risk. RESULTS: The computable phenotype had a positive predictive value of 80% and a negative predictive value of 99%. The bleeding rate in individuals with no medical hospitalizations in the past 3 months was 2.9 per 1000 person-years versus 98.9 per 1000 person-years in those who were discharged in the past 3 months. This translates into a hazard ratio (95% CI) of clinically relevant bleeding of 22.9 (18.9, 27.7), 13.0 (10.0, 16.9), and 6.8 (4.7, 9.8) over the first, second, and third months after discharge, respectively. CONCLUSION: We developed and validated a computable phenotype for clinically relevant bleeding and determined its relative and absolute risk in the 3 months after medical hospitalization discharge. The high rates of bleeding observed underscore the clinical importance of capturing and further studying bleeding after medical discharge.

Viscoelastic hemostasis assays in septic, critically ill coronavirus disease 2019 patients: a practical guide for clinicians.

Coronavirus disease 2019 (COVID-19)-associated coagulopathy is unusual, poorly defined and is linked with significant hypercoagulability and microthrombotic and macrothrombotic complications leading to worse outcomes and higher mortality. Conventional coagulation assays do not always actively reflect these derangements and might fail to detect this coagulopathy. Viscoelastic hemostatic assays (VHA) provide a possible tool that adds to conventional coagulation assays in identifying this hypercoagulable state. VHA has been mostly used in surgery and trauma but it's still not well defined in sepsis patients with lack of large randomized trials. Few studies described VHA findings in patients with COVID-19 showing significant hypercoagulability and fibrinolysis shutdown. Clinicians taking care of these patients might have little experience interpreting VHA results. By reviewing the available literature on the use of VHA in sepsis, and the current knowledge on COVID-19-associated coagulopathy we provide clinicians with a practical guide on VHA utilization in patients with COVID-19.

Thrombo-inflammatory biomarkers and D-dimer in a biracial cohort study.

BACKGROUND: Higher D-dimer is a risk factor for cardiovascular diseases and venous thromboembolism. In the general population, D-dimer and other thrombo-inflammatory biomarkers are higher among Black individuals, who also have higher risk of these conditions compared to White people. OBJECTIVE: To assess whether Black individuals have an exaggerated correlation between D-dimer and thrombo-inflammatory biomarkers characteristic of cardiovascular diseases. METHODS: Linear regression was used to assess correlations of 11 thrombo-inflammatory biomarkers with D-dimer in a cross-sectional study of 1068 participants of the biracial Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. RESULTS: Adverse levels of most biomarkers, especially fibrinogen, factor VIII, C-reactive protein, N-terminal pro-B-type natriuretic peptide, and interleukin (IL)-6, were associated with higher D-dimer. Several associations with D-dimer differed significantly by race. For example, the association of factor VIII with D-dimer was more than twice as large in Black compared to White participants. Specifically, D-dimer was 26% higher per standard deviation (SD) higher factor VIII in Black adults and was only 11% higher per SD higher factor VIII in White adults. In Black but not White adults, higher IL-10 and soluble CD14 were associated with higher D-dimer. CONCLUSIONS: Findings suggest that D-dimer might relate to Black/White differences in cardiovascular diseases and venous thromboembolism because it is a marker of amplified thrombo-inflammatory response in Black people. Better understanding of contributors to higher D-dimer in the general population is needed.

Thromboinflammation response to tocilizumab in COVID-19.

Background: Coronavirus disease-19 (COVID-19) spans a wide spectrum of illness. Severe cases of COVID-19 can manifest inflammation in organs other than the lung, in tissues not known to support viral replication, and also in a hypercoagulable state. These observations have suggested that severe acute respiratory syndrome coronavirus 2 can provoke a hyperimmune response in some cases that could lead to secondary organ damage. Methods: With evidence of elevated levels of interleukin-6 (IL-6) in patients with severe COVID-19, we conducted a small pilot off-label compassionate care study of the IL-6 receptor inhibitor tocilizumab in patients with severe COVID-19. Results: A single infusion of tocilizumab in patients with severe COVID-19 manifested rapid declines in C-reactive protein and d-dimer and gradual rises in lymphocyte and platelet counts. Conclusions: These findings suggest both pathophysiological mechanisms and clinical benefit that might be seen with IL-6 inhibition in severe COVID-19.