ADAMTS13 Biomarkers in Management of Immune Thrombotic Thrombocytopenic Purpura.

CONTEXT.­: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13, a metalloprotease that cleaves endothelium-derived ultralarge von Willebrand factor. Standard of care for iTTP including therapeutic plasma exchange, caplacizumab, and immunosuppressives, known as triple therapy, has led to a significant reduction in the disease-related mortality rate. The first International Society of Thrombosis and Haemostasis TTP guideline stresses the importance of having plasma ADAMTS13 activity testing in the algorithm for diagnosis and management of iTTP. However, the predictive role of assessing plasma ADAMTS13 activity and inhibitors or other ADAMTS13-related parameters in patients with acute iTTP and during remission has not been systematically evaluated. OBJECTIVE.­: To review and assess the predictive values of testing plasma ADAMTS13 activity, antigen, and inhibitors or anti-ADAMTS13 immunoglobulin G at various stages of disease in outcomes of iTTP. DATA SOURCES.­: Peer-reviewed publications and personal experience. CONCLUSIONS.­: We conclude that assessing ADAMTS13 biomarkers is not only essential for establishing the initial diagnosis, but also crucial for risk stratification and the early detection of disease recurrence. This may guide therapeutic interventions during acute episodes and for long-term follow-up of iTTP patients.

Acute Respiratory Distress Syndrome in a Patient With Acute Promyelocytic Leukemia: Overlapping Between Differentiation Syndrome and COVID-19.

Differentiation syndrome (DS) is a relatively common and severe complication in acute promyelocytic leukemia (APL) patients undergoing induction therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). DS is a multisystem disorder with pulmonary involvement. The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is also a systemic disorder with similar pulmonary and other clinical manifestations as DS. Here, we report an APL case with overlapping between DS and COVID-19. After admission to the hospital, the patient was diagnosed with APL and underwent differentiation therapy with ATRA/ATO. In the meantime, COVID-19 was diagnosed with a positive polymerase chain reaction test of SARS-CoV-2 from an oropharyngeal swab. The patient developed acute respiratory distress syndrome, coagulopathy, and acute kidney injury, which fit the clinical pictures of both DS and COVID-19. The patient died at last and this complicate case imposed big challenges for clinicians due to the laboratory and imaging findings of DS disguised in the context of COVID-19. Therefore, comprehensive treatment strategy should be considered to balance the risk and benefit of differentiation therapy in the context of COVID-19.

Elevated Plasma Fibrinogen Is Associated With Excessive Inflammation and Disease Severity in COVID-19 Patients.

Background: The coronavirus disease-19 (COVID-19) is characterized with intense inflammatory response, cardiac involvement, and coagulopathy. Fibrinogen, as a biomarker for inflammation, cardiovascular disease, and coagulation, has not been fully investigated yet. The aim of this study was to assess the clinical application of fibrinogen in COVID-19 patients. Methods: We retrospectively analyzed the demographic and laboratory characteristics of 119 COVID-19 patients in the University of Alabama of Birmingham Medical Center. Correlations of fibrinogen on admission with intensive care unit (ICU) admission, disease severity, and laboratory parameters were analyzed. Results: Among the 119 COVID-19 patients, 77.3% (92/119) had severe disease, and 59.5% (71/119) patients were admitted to the ICU. Elevated fibrinogen was detected in 67.2% (80/119) of the patients. Fibrinogen levels were significantly associated with inflammatory markers and disease severity, but not with cardiac injury biomarker high sensitivity troponin I. Patients with severe disease had increased fibrinogen levels upon admission compared to patients with non-severe disease (P = 0.001). Fibrinogen level at 528.0 mg/dl was the optimal cutoff to predict disease severity, with a sensitivity and specificity of 66.7% and 70.3% (area undty -60er the curve [AUC] 0.72, P = 0.0006). Conclusions: Fibrinogen is commonly elevated in COVID-19 patients, especially in those with severe disease. Elevated fibrinogen correlates with excessive inflammation, disease severity, and ICU admission in COVID-19 patients.

Identification of Biomarkers in Patients with Thrombotic Thrombocytopenic Purpura Presenting with Large and Small Ischemic Stroke.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder resulting in organ damage including ischemic strokes. We sought to characterize the neuroimaging patterns of stroke in a large cohort of patients with immune-mediated TTP (iTTP) and determined their associations with clinical and laboratory parameters and outcomes. METHODS: We analyzed the Alabama TTP Registry who had laboratory confirmation of acute iTTP. We reviewed the neuroimaging patterns of those with ischemic stroke on MRI, clinical information, and laboratory results. Small ischemic strokes were ≤20 mm in their maximum diameter in the axial plane. Large ischemic strokes were >20 mm. Student t test, Mann-Whitney U test, and χ2 test were all used for data analysis. RESULTS: Of 108 iTTP patients, 21 had ischemic stroke on neuroimaging. The median platelet count in these patients was 12 × 109/L (interquartile range, IQR, 8.8-21 × 109/L), plasma ADAMTS13 activity 1.8 U/dL (IQR 0-4.5 U/dL), and the mean plasma level of anti-ADAMTS13 IgG was 6,595.8 U/mL (SD 3,448.9 U/mL). Comparison between patients with large ischemic strokes (n = 10) and small ischemic strokes (n = 11) revealed that patients with small stroke were older (p = 0.043) and had higher plasma levels of citrullinated histone 3 (p = 0.006) and histone/DNA complex (p = 0.014) than those with large strokes. There were no significant differences between 2 stroke groups in mortality or exacerbation. CONCLUSIONS: iTTP patients can present with large ischemic strokes and are usually younger. Further research should be performed in assessing different etiologies of iTTP-associated stroke based on neutrophil extracellular trap formation biomarkers (e.g., histone markers) seen in small ischemic stroke.

Cerebral Infarction in Immune Thrombotic Thrombocytopenic Purpura Is Associated with Old Age, Hypertension, Smoking, and Anti-ADAMTS13 Ig, But Not with Mortality.

Background Neurological involvement is common in patients with immune thrombotic thrombocytopenic purpura (iTTP), but the frequency, risk factors, and outcomes of these with imaging-confirmed stroke in iTTP are not known. Methods We selected 66 out of 109 iTTP patients with neurological signs and symptoms and reviewed their CT/MRI (computed tomography/magnetic resonance imaging) findings for the evidence of stroke and other clinical information in Alabama TTP Registry. Results Of these, 52 (78.8%) had their CT/MRI done on admission in whom 22 (42.3%) were positive for multiple acute or chronic infarcts. The patients with image-confirmed ischemic stroke were older, and appeared to be associated with a history of hypertension and smoking. Additionally, patients with imaging-confirmed stroke showed higher plasma concentrations of anti-ADAMTS13 IgG than those without stroke. More interestingly, there was no statistically significant difference in the rate of exacerbation and 60-day mortality between those with and without stroke. Conclusion Ischemic cerebral infarcts are common findings in brain imaging studies of patients with acute iTTP; old age, chronic hypertension, and smoking, as well as high plasma concentrations of anti-ADAMTS13 IgG may be the potential risk factors for cerebral infarction in these patients. The presence of image-confirmed ischemic stroke, however, does not predict exacerbation and 60-day mortality, although the long-term effect of such ischemic brain damage on cognitive function and quality of life remains to be determined.

Plasma levels of S100A8/A9, histone/DNA complexes, and cell-free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening blood disorder, primarily resulting from autoantibodies against ADAMTS13. Infection or inflammation often precedes acute iTTP. However, the association of inflammation and inflammatory mediators with disease severity and outcome of acute iTTP is not fully assessed. OBJECTIVES: Here, we determined plasma levels of S100A8/A9, histone/DNA complexes, citrullinated histone H3 (CitH3), and cell-free DNA (cfDNA) in a cohort of 108 acute episodes from 94 unique iTTP patients and healthy controls, and assessed the association of each of these biomarkers with the disease severity and mortality. RESULTS: All acute iTTP patients had significantly increased plasma levels of S100A8/A9 (median 84.8, interquartile range [IQR] 31.2-157.4 µg/mL), histone/DNA complexes (median 55.7, IQR 35.8-130.8 U/mL), CitH3 (median 3.8, IQR 2.2-6.4 ng/mL), and cfDNA (median 937.7, IQR 781.3-1420.0 ng/mL) on the admission blood samples when compared with healthy controls. An increased plasma level of S100A8/A9, histone/DNA complex and cfDNA was associated with organ damage, coagulopathy, and mortality in iTTP. After being adjusted for age and history of hypertension, Cox proportional hazard regression analysis demonstrated that a hazard ratio (95% confidence interval) for an elevated plasma level of S100A8/A9, histone/DNA complexes, and cfDNA was 11.5 (1.4-90.9) (P = .021), 10.3 (2.7-38.5) (P = .001), and 12.8 (3.9-42.0) (P = .014), respectively. CONCLUSION: These results indicate that inflammation or plasma inflammatory mediators such as S100A8/A9 or NETosis markers such as histone/DNA complexes and cfDNA may play a role in pathogenesis of iTTP, which may help stratify patients with a high risk of death during acute iTTP episodes.

Elevated plasma levels of syndecan-1 and soluble thrombomodulin predict adverse outcomes in thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13 activity. Despite recent advances in early diagnosis and novel therapeutics, the mortality rate of acute iTTP remains as high as 10% to 20%. Moreover, a reliable clinical and laboratory parameter that predicts disease severity and outcomes is lacking. We show in the present study that plasma levels of syndecan-1 (Sdc-1) and soluble thrombomodulin (sTM) on admission were dramatically increased in patients with acute iTTP and remained substantially elevated in a subset of patients compared with healthy controls. The elevated admission plasma levels of Sdc-1 and sTM were associated with abnormal Glasgow coma scale scores, low estimated glomerular filtration rates, the need for intensive care, and in-hospital mortality rates. Moreover, a further simultaneous increase in plasma Sdc-1 and sTM levels at the time of clinical response/remission (eg, when normalization of platelet counts and substantial reduction of serum lactate dehydrogenase activity were achieved) was highly predictive of iTTP recurrence. These results demonstrate that endothelial injury, resulting from disseminated microvascular thromboses, is severe and persistent in patients with acute iTTP. Plasma levels of Sdc-1 and sTM on admission and in remission are predictive of in-hospital mortality and recurrence of acute iTTP, respectively. Thus, an incorporation of such novel plasma biomarkers into the risk assessment in acute iTTP may help implement a more vigorous and intensive therapeutic strategy for these patients.

Longitudinal assessments of plasma ADAMTS13 biomarkers predict recurrence of immune thrombotic thrombocytopenic purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is primarily caused by immunoglobulin G (IgG)-type autoantibodies that bind and inhibit plasma ADAMTS13 activity and/or accelerate its clearance from circulation. Approximately 50% of patients with iTTP who achieve initial clinical response to therapy experience recurrence (ie, exacerbation and/or relapse); however, a reliable biomarker that predicts such an event is currently lacking. The present study determines the role of longitudinal assessments of plasma ADAMTS13 biomarkers in predicting iTTP exacerbation/recurrence. Eighty-three unique iTTP patients with 97 episodes from the University of Alabama at Birmingham Medical Center between April 2006 and June 2019 were enrolled. Plasma levels of ADAMTS13 activity, antigen, and anti-ADAMTS13 IgG on admission showed no significant value in predicting iTTP exacerbation or recurrence. However, persistently low plasma ADAMTS13 activity (<10 U/dL; hazard ratio [HR], 4.4; 95% confidence interval [CI], 1.6-12.5; P = .005) or high anti-ADAMTS13 IgG (HR, 3.1; 95% CI, 1.2-7.8; P = .016) 3 to 7 days after the initiation of therapeutic plasma exchange was associated with an increased risk for exacerbation or recurrence. Furthermore, low plasma ADAMTS13 activity (<10 IU/dL; HR, 4.8; 95% CI, 1.8-12.8; P = .002) and low ADAMTS13 antigen (<25th percentile; HR, 3.3; 95% CI, 1.3-8.2; P = .01) or high anti-ADAMTS13 IgG (>75th percentile; HR, 2.6; 95% CI, 1.0-6.5; P = .047) at clinical response or remission was also predictive of exacerbation or recurrence. Our results suggest the potential need for a more aggressive approach to achieve biochemical remission (ie, normalization of plasma ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG) in patients with iTTP to prevent the disease recurrence.

NPM1A in Plasma is a Potential Prognostic Biomarker in Acute Myeloid Leukemia.

OBJECTIVE: The aim of the study was to investigate whether nucleophosmin type A mutation (NPM1A) in plasma was associated with the prognosis of patients with acute myeloid leukemia (AML). METHODS: Plasma NPM1A levels were investigated in 80 AML patients, 22 patients with benign hematopathy and 12 healthy donors by qRT-PCR. Additionally, the relationship between NPM1A levels and clinic characteristics were evaluated by Chi-square test. Kaplan-Meier method was used to analyze overall survival (OS) and relapse-free survival (RFS), and univariate and multivariate analyses were performed with Cox proportional hazard model. RESULTS: Plasma levels of NPM1A in AML patients were significantly higher than those in benign hematopathy patients and healthy controls, respectively (both P<0.001). Additionally, high NPM1A level was significantly associated with higher WBC and platelet count (both, P<0.05). Moreover, survival analysis revealed that patients with high NPM1A levels had worse OS (P<0.001) and RFS (P<0.001). Multivariate analysis identified NPM1A as an independent prognostic predictor for AML (OS: HR=8.214, 95% CI: 2.974-22.688, P<0.001; RFS: HR=4.640, 95%CI: 1.825-11.795, P=0.001). CONCLUSIONS: Results reveal that NPM1A in plasma could serve as an ideal tool for predicting the prognosis of patients with AML.

Successful treatment with rivaroxaban of cerebral venous thrombosis and bone marrow necrosis induced by pegaspargase: A case report and literature review.

RATIONALE: Pegaspargase has been used in the treatment of acute lymphoblastic leukemia with promising results. However, it has also been associated with several potentially serious complications, including thrombosis. Pegaspargase-induced cerebral venous thrombosis and bone marrow necrosis are very rare. PATIENT CONCERNS: A 50-year-old female developed headache, weakness of the right lower extremity, fever, and bone pain after chemotherapy including pegaspargase for the treatment of acute lymphoblastic leukemia. DIAGNOSES: Her imaging studies and bone marrow examinations were compatible with cerebral venous thrombosis and bone marrow necrosis. INTERVENTIONS: The patient received anticoagulation therapy with rivaroxaban. OUTCOMES: After treatment with rivaroxaban, she had a good outcome without major or minor bleeding. LESSONS: Clinicians should be aware of the very rare but possible induction of bone marrow necrosis during pegaspargase treatment when there is necrosis in other organs. Because of its greater safety and convenience, rivaroxaban gains popularity over traditional anticoagulant drugs.

Serum adiponectin levels are inversely correlated with leukemia: A meta-analysis.

OBJECT: This study is aimed at exploring the correlation between serum adiponectin (ADPN) levels and leukemia. MATERIALS AND METHODS: Eligible studies were retrieved using both computerized and manual searches. Relevant case-control studies were enrolled in strict accordance to our inclusion and exclusion criteria. RESULT: We searched 130 published studies and included 11 eligible studies for our meta-analysis according to our rigorous inclusion and exclusion criteria. The selected studies included 637 leukemia patients and 524 healthy controls. Our meta-analysis showed: (1) Serum ADPN levels of patients with leukemia were lower than healthy controls; (2) a subgroup analysis based on sample size verified that serum ADPN levels in patients with leukemia were significantly lower than that in healthy controls irrespective of a large sample size (n ≥ 80) or a small sample size (n < 80). CONCLUSION: Our meta-analysis suggested that serum ADPN levels may be inversely correlated with leukemia, and ADPN levels can be used as an effective biologic marker in early diagnosis and therapeutic monitoring of leukemia.

Analysis on 71 patients with polycythemia vera.

The aim of this study was to analyse the clinical characteristics and laboratory data, treatment and prognosis of polycythemia vera (PV). A retrospective study was performed for 71 PV patients treated in our hospital during January 2001 to July 2011 including analysis of clinical characteristics, laboratory data, myelogram chromosome karyotypes, BCR/ABL and JAK2V617F genes, as well as lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) levels in serum and so on. The results showed that 71 patients (37 males and 34 females with a average age of 57.8 years) were diagnosed. Thrombosis and embolism occurred in 34 patients (47.89%), hemorrhage in 10 patients (14.08%), splenomegaly occurred in 44 patients. The onset of the disease was insidious, 13 patients (18.31%) were found to have PV during the treatments for other diseases. The average hemoglobin at diagnosis was 206.31 (171 - 242) g/L. JAK2V617F mutation was detected in 31 (81.58%) of 38 patients studied. The average levels of serum LDH and NSE were higher than normal and both positively correlated with hemoglobin (P = 0.007, P = 0.005). The disease outcomes were myelofibrosis for 3 patients, death from cerebral hemorrhage for 1 patient, and death from ineffective chemotherapy in 1 patient with ANLL-M2. It is concluded that PV is a chronic myeloproliferative disorder characterized predominantly by thrombosis and hemorrhage. The serum LDH and NSE levels are higher than the normal values. It is inferred that the serum LDH and NSE levels can reflect the degree of malignant proliferation of bone marrow hematopoietic cells and also can be used as an indicator to judge the therapeutic effect of PV.