Median Nadir Platelet Count Research Articles

Prognostic significance of nadir platelet count in patients with heatstroke: A multi-center retrospective study

BackgroundHeatstroke (HS), associated with the early activation of the coagulation system and frequently presenting with thrombocytopenia, poses a significant healthcare challenge. Understanding the relationship of nadir platelet count (PLT) within 24 h for adverse outcomes in HS patients is crucial for optimizing management strategies. MethodsThis retrospective cohort study, conducted in six tertiary care hospitals, involved patients diagnosed with HS and admitted to the emergency departments. The primary and secondary outcomes included in-hospital mortality and various acute complications, respectively, with logistic regression models utilized for assessing associations between nadir PLT and outcomes. The PLT count change curve was described using a generalized additive mixed model (GAMM), with additional analyses involving body temperature (BT) at 2 h also conducted. ResultsOf the 152 patients included, 19 (12.5%) died in-hospital. The median nadir PLT within 24 h was 99.5 (58.8–145.0)*10^9/L. Notably, as a continuous variable (10*10^9/L), nadir PLT was significantly associated with in-hospital mortality (OR 0.76; 95% CI 0.64–0.91; P = 0.003) and other adverse outcomes like acute kidney and liver injury, even after adjustment for confounders. GAMM revealed a more rapid and significant PLT decline in the non-survival group over 24 h, with differential PLT dynamics also observed based on BT at 2 h. ConclusionsNadir PLT within 24 h were tied to in-hospital mortality and various adverse outcomes in HS patients. Early effective cooling measures demonstrated a positive impact on these associations, underscoring their importance in patient management.

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure

AbstractPlatelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.

Significance of heparin induced thrombocytopenia (HIT) in COVID-19: a systematic review and meta-analysis.

Heparin-induced thrombocytopenia (HIT) occurs in approximately 3% of patients receiving heparinoids. About 30-75% of patients with type 2 of HIT develop thrombosis as a result of platelet activation. The most important clinical symptom is thrombocytopenia. Patients with severe COVID-19 are among those receiving heparinoids. This meta-analysis performed to picture the current knowledge and results of published studies in this field. Three search engines were searched and 575 papers were found. After evaluation, 37 articles were finally selected of which 13 studies were quantitatively analyzed. The pooled frequency rate of suspected cases with HIT in 13 studies with 11,241 patients was 1.7%. The frequency of HIT was 8.2% in the extracorporeal membrane oxygenation subgroup with 268 patients and 0.8% in the hospitalization subgroup with 10,887 patients. The coincidence of these two conditions may increase the risk of thrombosis. Of the 37 patients with COVID-19 and confirmed HIT, 30 patients (81%) were treated in the intensive care unit or had severe COVID-19. The most commonly used anticoagulants were UFH in 22 cases (59.4%). The median platelet count before treatment was 237 (176-290) x 103/µl and the median nadir platelet count was 52 (31-90.5) x 103/µl.

5599228 PITFALLS IN DIAGNOSING THROMBOTIC THROMBOCYTOPENIC PURPURA IN SICKLE CELL DISEASE

Background: Thrombotic microangiopathies are diagnosed by thrombocytopenia, microangiopathic haemolytic anaemia and evidence of end organ damage. In TTP this includes neurological symptoms, renal impairment and cardiac microthrombi. Confirmation of the diagnosis is severe deficiency (<10%) of the metalloproteinase ADAMTS13 and/or the presence of an inhibitor. The diagnosis of TTP in sickle cell disease (SCD) can be challenging as SCD is characterised by a chronic state of haemolysis often with very abnormal peripheral blood morphology so clinical features suggestive of TTP can be due to complications of SCD. More specifically, the coexistence of neurological impairment and thrombocytopenia seen in fat embolism syndrome (FES) complicating SCD can lead to an erroneous diagnosis of TTP. FES typically affects non-homozygous patients and those with a previously mild course of their illness manifesting with respiratory failure, neurological signs, thrombocytopenia and potential involvement of any system leading to high morbidity and mortality. Peripheral blood morphology typically shows very high number of nucleated red blood cells (nRBC). Aims: To identify published cases of TTP in patients with SCD and review the diagnostic approach. Methods: A PubMed literature search was performed using the terms “sickle cell” and “thrombotic thrombocytopenic purpura”/”TTP”. Results: Of 19 cases identified, 9 were individual case reports and a case series of 10. All patients had very mild course of their SCD. The median nadir platelet count was 38 x 109/L (7-70). 84% had neurological involvement either at presentation or shortly afterwards; primarily altered sensorium/drop in GCS. 79% patients also had severe type I respiratory failure either preceding or occurring simultaneously with the development of neurological signs and associated with extensive changes on chest imaging. Schistocytes were identified in all cases but in the vast majority at relatively low levels; at the same time, all showed large numbers of nRBCs. 18 of the 19 cases were published after 1998; in 15 there was no mention of ADAMTS13 testing at all. In the 3 cases with ADAMTS13 levels, all were normal; 2 samples were obtained before therapeutic plasma exchange (TPE) and 1 after. 18 patients received TPE and 1 an infusion of donor plasma. However, prior to TPE, all patients had already received red cell transfusion achieving Hb S levels of 30% or less. There were 2 (11%) deaths while the remainder of patients achieved complete recovery. One due to intracranial haemorrhage and the other, sepsis in the context of immunosuppression for prevention of TTP recurrence. The presence of early respiratory failure, the inconclusive morphological findings, the degree of thrombocytopenia, and the complete absence of confirmatory ADAMTS13 results bring the diagnosis of TTP to question in all cases. Given the clinical presentations, we suspect that some of these patients had FES. The positive outcomes may be explained by the fact that all patients received adequate red cell transfusion, but also the possible beneficial effect of TPE in acute complications of SCD with a hyper inflammatory component such as FES. Conclusion: The diagnosis of TTP in patients with SCD is challenging due to many overlapping features. It should not be made without confirmatory ADAMTS13 results and the possibility of alternative diagnoses should be explored.

Abstract 112: Cerebral Venous Sinus Thrombosis Due To Vaccine-induced Immune Thrombotic Thrombocytopenia In Middle-Income Countries

Introduction: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). In India alone, 1.67 billion ChAdOx1 nCoV-19 vaccines have been administered by August 23, 2022. Surprisingly however, there are only few reports of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) from LMICs. We aimed to gain insight into the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. Methods: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared characteristics of CVST-VITT cases from LMICs to cases from high-income countries (HICs). Results: By August 15, 2022, 228 CVST cases after vaccination were reported, of which 63 cases from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, and Turkiye). Of these, 32/63 (51%) met the criteria for definite, probable or possible VITT. Only 5/32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-PF4 antibodies were not tested in 21/32 (66%) cases. Patients from MICs were diagnosed in a later time period than patients from HICs (1/32 [3%] vs 65/103 [63%] cases diagnosed before May 2021, respectively). Median age was 26 (IQR 20-37) vs 47 (IQR 32-58) years, and proportion of women was 25/32 (78%) vs 77/103 (75%) in MICs vs HICs, respectively. Clinical manifestations, such as focal neurologic deficits, coma, seizures, and intracranial hemorrhages, were similar. Concomitant venous thromboembolism was less frequent in MICs (3/31 [10%] vs 26/97 [27%]). Median platelet count nadir was higher in the MICs than the HICs group (65 x10 9 /L [IQR 36-115] vs 33 x10 9 /L [IQR 18-55], p =0.001). Intravenous immunoglobulin use was similar (19/30 [63%] vs 63/99 [64%]). In-hospital mortality was lower in the MICs than the HICs group (7/32 [22%, 95%CI 11-39] vs 44/102 [43%, 95%CI 34-53], p =0.031). Conclusions: The absolute number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines in these countries. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.

Cognitive Impairment in Patients with Immune Thrombocytopenia

Background Immune thrombocytopenia (ITP) is an autoimmune condition characterized by a low platelet count (<100 x 109/L). Patients with ITP have an increased risk of bruising and bleeding (mainly skin and mucosal). A study by Cooper et al published in 2020 showed that 43% of adult ITP patients have occult cerebral microbleeds (CMBs) on susceptibility-weighted magnetic resonance imaging (SW-MRI). The clinical and prognostic significance of CMBs has not been established but some studies have shown they are associated with cognitive impairment. ITP was believed to be an isolated blood disease, but more recent studies demonstrate impaired quality of life with symptoms including fatigue, memory and concentration problems. This may be suggestive of cognitive impairment. There is only one study by Frith et al that has reported cognitive impairment in adult patients with ITP. The findings of this study are important, although cognitive impairment was measured using a self-reported cognitive failures questionnaire, which may be less robust. Aims The primary objectives of the study were to establish the prevalence of cognitive impairment and which cognitive domains are impaired in patients with ITP. The secondary objective was to investigate any link between ITP disease parameters, presence of CMBs and cognitive impairment. Methods Ethical approval was granted by the London-Surrey Borders Health Research Authority (reference number: 13/LO/1365). Patients with ITP who attend the Imperial College Healthcare NHS ITP center and who had a nadir platelet count ≤ 30 x 109/L at any time during their disease course were recruited to the study. Patients underwent cognitive testing using an automated neuropsychological test battery (CANTAB), completion of SMOG (skin, mucosae, organs) bleeding questionnaire, cerebral SW-MRI to identify CMBs and a full blood count. CANTAB is a validated and automated software tool used in clinical practice and research to assess cognitive impairment. Five key cognitive domains (episodic memory, executive function, processing speed, working memory and attention) were assessed using different tasks. Z-scores standardized for age, sex and education level were generated. Based on the z-scores, the patients' cognitive performance was categorized as impaired or not impaired. Clinical data (including date of diagnosis, nadir platelet count, number of ITP treatments received and co-morbidities) was collected from medical records. One sample T-Tests were used for continuous data while Pearson's Chi Square Test and Fisher's Exact Test were used for categorical data. Multiple comparisons corrections were not performed. Results A total of 69 patients completed CANTAB cognitive testing and MRI. The median age was 40 years (range 19-88), median age at diagnosis was 31 years (range 4-83), median duration of disease was 69 months (range 5-535), median nadir platelet count was 5 x 109/L (range 0-30), median platelet count at time of test was 95 x 109/L (range 4-653) and median ITP treatments received were 4 (range 0-14). Forty-six percent of patients had other co-morbidities, 65% were female and 52% of patients were receiving ITP treatment at the time of cognitive testing. Of the 69 patients tested, 50% (95% CI [37, 62]) had at least one impaired cognitive domain (Figure 1a). The percentage of patients with impairment per domain were 22% episodic memory, 19% executive function, 16% processing speed, 13% working memory and 3% attention. Two patients could not finish the episodic memory CANTAB task; therefore, their score for this domain could not be generated. Higher organ bleeding score was associated with impaired episodic memory (p=0.048) (Figure 1b). Older age at diagnosis, age at time of cognitive test and number of ITP treatments received were associated with impaired episodic memory (p=0.03, p=0.08 and p=0.04 respectively). There was no correlation between the presence or number of CMBs and impaired cognition. Conclusion This is the first study to objectively measure cognitive impairment in patients with ITP. It showed that a significant proportion (50%) of patients with ITP suffer from cognitive impairment, with episodic memory being most affected. These results suggest that ITP is not just a 'low platelet' disease. Correlation between ITP disease parameters and impaired cognition requires further investigation in a larger cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Secondary Hemophagocytic Lymphohistiocytosis in Adults: Experience from a Safety Net Hospital Serving an Underserved Population

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, driven by an overactivation of the immune system, which causes inflammatory tissue damage potentially leading to organ failure and death. Secondary HLH in adults is a rare clinical entity and diagnosis often is delayed due to low index of clinical suspicion or limited availability of sophisticated testing. Therefore, evidence related to overall outcomes in underserved populations remains scarce. Methods: After institutional review board approval, we retrospectively reviewed charts of patients 18 years or above, with a diagnosis of hemophagocytic lymphohistiocytosis at our institution between 2015-2021. Data on baseline characteristics, cause of HLH and overall outcomes were collected and analyzed. SAS v9.4 was used for statistical analysis. Results: A total of 17 patients were included for the analysis. Majority patients were males (10/17, 58.8%) and mean age was 41.1 ± 17.1 years. Most patients lacked insurance coverage (12/17, 70.6%); in patients with insurance coverage, Medicaid was the most common primary payer (5/6, 83.3%). 8/17 (47.1%) patients were African Americans, similarly Caucasians (8/17, 47.1%), followed by Hispanics (1/17, 5.9%). Fever was noted to be the most common presentation (12/17, 70.6%), followed by abdominal pain, vomiting and cough which were present only in 3/17 (17.6%) patients. Splenomegaly/ hepatosplenomegaly was the most common finding on imaging (7/17, 41.2%). Laboratory investigations were consistent with with cytopenias (16/17, 94.1%) and transaminitis (13/17, 76.5%) in majority of the patients. Bone marrow biopsy was performed to aid in diagnosis in 8/17 (47.1%) patients, out of which, hemophagocytosis was noted only on 4/17 (23.5%). NK- cell activity was tested in 8/17 (47.1%) patients and was noted to be low. Soluble interleukin-2 receptor-alpha/CD25 was tested in 7/17 (41.2%) patients and ranged from 345-6,029 units/ml and was helpful in diagnosis (>2400 units/ml) only in 3/7 (42.9%) patients. Underlying infection was the most common cause of HLH (8/17, 47.1%), out of which, majority had HIV (5/8, 62.5%). 4 out of 5 patients with HIV had disseminated histoplasmosis (80%). 4/17 (23.5%) patients were noted to have underlying rheumatologic disease; the cause of HLH was deemed to unknown in 4 patients (4/17, 23.5%)). One patient was diagnosed with an underlying malignancy, i.e., acute myeloid leukemia (1/17, 5.9%). Majority patients were managed in intensive care unit setting (10/17, 58.8%). Patients managed in ICU setting had a lower median platelet count nadir than those managed on the floor (40,000 cells/cu. mm vs 52,000 cells/ cu. mm, p=0.04). However, no significant difference in the median platelet count, white blood cell count or median hemoglobin levels on presentation was noted between the two groups (p>0.05). Majority patients were managed with steroids alone (9/17, 52.9%), followed by steroids+steroid-sparing agents (4/17,23.5%), anti-fungal agents alone (2/17, 11.8%) and steroids+intravenous anti-globulin and anti-fungal agent (1/17, 5.9%). One patient (1/17, 5.9%) was only conservatively managed. Complete recovery was noted in majority of the patients (13/17, 76.5%), while 4/17 (23.5%) patients died during their hospital stay. 2 out of the 4 patients (50%) who died had underlying rheumatological disease, while the remaining two patients had acute myeloid leukemia and cellulitis respectively. Conclusion: Majority of the cases of secondary HLH in our cohort of underserved adults were noted to be related to infectious causes. Contrary to existing literature, HIV was noted to be the predominant cause in these patients (as opposed to Epstein-Barr virus). HLH in patients with HIV should prompt investigation for underlying histoplasmosis. Patients with a lower platelet nadir appear to be at greater risk of escalation of level of care. HLH related to infections is associated with a relatively favorable outcome, which may explain the relatively lower overall mortality in our study population. Clinical presentation was widely non-specific, warranting a high index of suspicion for secondary HLH, to allow prompt diagnosis in these patients. Investigations such as bone marrow biopsy and interleukin-2 receptor-alpha/CD25 may not aid in diagnosis in many patients and may not be included in initial evaluation for HLH in resource-limited settings.

Early post-liver transplant thrombocytopenia in children: Clinical characteristics and significance.

Post-liver transplant thrombocytopenia is common and associated with worse outcome in adults. In children, however, the prevalence, course, and significance of post-liver transplantation thrombocytopenia are not described. Therefore, we aimed to assess this phenomenon in children. A retrospective chart review of children who underwent liver transplantation at a single tertiary center between 2004 and 2021. Overall, 130 pediatric liver transplantations were reviewed. During the first 28 POD, thrombocytopenia was evident in 116 (89%, 95% CI 83%-94%). The median nadir platelet count was 54 K/μl (IQR: 37-99). Nadir platelet count was reached in half the patients by the third POD (IQR: 1-6). In multivariate analysis, preoperative platelet count (p= .024), volume of intraoperative packed cell transfusion (p= .045), and hypersplenism (p= .007) were associated with lower postoperative platelet counts. Patients with platelet count lower than the 50th centile on the first POD suffered from a more complicated course leading to a longer PICU admission (p= .039). Early post-liver transplant thrombocytopenia appears to be common in children and associated with preoperative thrombocytopenia, hypersplenism, and higher intraoperative blood transfusion volumes. A low first POD platelet count (<86 K/μl) was found to be independently associated with a more complicated postoperative course, suggesting the need for heightened surveillance.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Clinical Characteristics of Severe Acute Chest Syndrome in Children with Sickle Cell Disease

Background: Acute chest syndrome (ACS) is a form of acute lung injury that is a leading cause of morbidity and mortality in children and adults with sickle cell disease (SCD). Despite advances in health maintenance and disease-modifying therapies for SCD, ACS remains a common and often severe complication. There is still limited understanding of why some patients suffer more severe ACS episodes. Few studies have specifically investigated clinical parameters associated with severe ACS in the pediatric population. The purpose of this study is to determine the association between hematologic and radiologic clinical findings and severe ACS in children and adolescents with SCD.Methods: We conducted a single-institution retrospective chart review of 120 pediatric patients with HbSS or HbSβ 0 thalassemia and at least one documented episode of ACS, and then further classified patients by their most severe ACS event. We extracted laboratory and radiologic data to compare clinical findings. Infections reported in patient encounters were verified by documented viral PCR and blood cultures. Continuous variables were analyzed using Welch's t-test; categorical variables were analyzed using Fisher's exact test.Results: Eighty patients in the moderate ACS group were excluded for this analysis. Twenty patients (median age 5.6 years, SD 4.20) had mild ACS defined by no supplemental oxygen requirement, only one segmental or lobar infiltrate on chest radiography, and transfusion of less than 3 units (or 15 cc/kg) of red blood cells. Twenty patients (median age 7.6 years, SD 4.01) had severe ACS characterized by acute respiratory failure requiring mechanical (invasive or non-invasive) ventilation and/or exchange transfusion. Median length of stay for patients with severe ACS was longer than for the mild cohort (mean: 8 days vs 2 days, p <0.001). The median absolute neutrophil count (ANC) was significantly higher in the severe ACS cohort (19.8 x 10 3µL vs. 9.4 x 10 3 µL, p = 0.004). The median platelet count nadir was significantly lower in the severe ACS group compared to the mild group (165 x 10 3 µL vs. 309 x 10 3 µL, p <0.001). Review of radiologic data showed that the median number of lobes affected in the severe ACS group were 3, compared to 1 lobe in the mild group (p <0.001). Approximately 65% of patients with mild ACS had left-sided disease (p = 0.18), while 85% of patients with severe ACS had bilateral disease (p = 0.002). The risk of pleural effusions was also significantly increased with severe ACS [OR 76.00 (95% CI 9.235-825.6), p <0.001]. When we analyzed infection at time of ACS, the proportion of laboratory-confirmed viral infections were twice as high in the mild ACS cohort (41.2%), compared to the severe ACS cohort (20.0%, p = 0.279). There were no bloodstream bacterial infections found in either cohort.Conclusion: Severe ACS in children is a clinically distinct phenotype associated with longer length of stay, higher ANC and lower platelet nadir counts during active ACS, increased involvement of 3 or more lung lobes, and presence of pleural effusions. A lower proportion of confirmed viral infections were found in the severe ACS cohort compared to mild ACS patients, although did not reach statistical significance. Future prospective studies investigating the utility of these specific laboratory and radiographic parameters as components of an ACS severity prediction score are warranted. DisclosuresTubman: Forma Pharmaceuticals: Consultancy; Novartis Pharmaceuticals: Honoraria, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Perkin Elmer: Honoraria. Fasipe: Emmaus: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Other: Grant Review Committee ; Novartis: Consultancy; Pfizer: Research Funding.

Bendamustine Is a Safe and Effective Regimen for Lymphodepletion before Tisagenlecleucel in Patients with Large B-Cell Lymphomas

Bendamustine Is a Safe and Effective Regimen for Lymphodepletion before Tisagenlecleucel in Patients with Large B-Cell Lymphomas

Dabigatran as first-line treatment for heparin-induced thrombocytopenia in the intensive cardiac care setting

Abstract Introduction Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated disorder related to the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) which is associated with increased risk of vascular thrombosis. HIT constitute a relevant and not so uncommon clinical issue in the intensive cardiac care unit setting. Parenteral non-heparin anticoagulants are recommended for the treatment of HIT. The efficacy of dabigatran, direct oral anticoagulant, is poorly documented in this indication. In laboratory-confirmed HIT only few cases with short-term use and early conversion to and from another anticoagulant were reported. Purpose The purpose of our study was to evaluate the efficacy and safety of dabigatran as a first-line and the only one anticoagulant used in the treatment of HIT. Methods We prospectively enrolled 5 patients with the diagnosis of HIT who were hospitalized in our intensive cardiac care unit in 2017–2021. Heparin was stopped immediately on the suspicion of HIT and off-label dabigatran therapy was initiated the same day. There were no conversion to another non-heparin anticoagulant – dabigatran was used continuously from suspicion of HIT for at least 3 months. In all patients we used latex immunoassay to confirm the diagnosis of HIT. Lower-extremity compression ultrasonography was performed to exclude thrombosis. We distinguished HIT with thrombosis (HITT) and isolated HIT (HIT without thrombosis). The minimal follow-up period on dabigatran treatment was 3 months and the maximal 4 years. Results All the patients were male with the median age of 73 years (interquartile range, 52–78 years) and all were exposed to both, UFH and LMWH. The median platelet (PLT) count before exposition to heparin was 182000/μl (interquartile range, 171000/μl–321000/μl). Platelet count fall &amp;gt;50% was observed after a median time of 9 days (interquartile range, 7–11 days) after exposition to heparin and a median PLT count nadir was 87000 μl/l (interquartile range, 25000/μl–103000/μl). Two patients had intermediate and three high probability of HIT. HITT was diagnosed in one patient. The manifestation of HITT was upper-extremity arterial thrombosis and pulmonary embolism. Four patients were diagnosed with isolated HIT. PLT count recovery &amp;gt;15ehab724.2982/μl was observed after a median time of 3 days on dabigatran treatment (interquartile range, 2–7 days). In the patient with HITT, a complete resolution of upper-limb arterial thrombosis was observed. At the minimal observation period end point (3 months) all the patients survived without bleeding or new thrombotic event. Moreover, neither bleeding nor recurrence of HIT occurred during the total follow-up period. Conclusion Dabigatran is safe and efficient as first-line treatment for HIT and can be used as the only one anticoagulant in this challenging, clinical scenario. Funding Acknowledgement Type of funding sources: None.

Oseltamivir Improved Thrombocytopenia During Veno-Arterial Extracorporeal Membrane Oxygenation in Adults With Refractory Cardiac Failure: A Single-Center Retrospective Real-World Study.

Background: Severe thrombocytopenia is a common complication of extracorporeal membrane oxygenation (ECMO). Oseltamivir can be used to treat infection-associated thrombocytopenia.Objective: To evaluate the effect of oseltamivir on attenuating severe thrombocytopenia during ECMO.Methods: This was a single-center real-world study in critically ill patients supported with venous-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients suspected or confirmed with influenza received oseltamivir according to the Chinese guidelines. Thrombocytopenia and survival were compared between the oseltamivir-treated and untreated group. The factors associated with survival were analyzed by multivariable Cox analysis.Results: A total of 82 patients were included. All patients developed thrombocytopenia after initiating VA-ECMO. Twenty-three patients received oseltamivir (O+ group), and 59 did not use oseltamivir (O− group). During the first 8 days after VA-ECMO initiation, the platelet count in the O+ group was higher than that in the O− group (all P < 0.05). The patients in the O+ group had a higher median nadir platelet count (77,000/μl, 6,000–169,000/μl) compared with the O− group (49,000/μl, 2,000–168,000/μl; P = 0.04). A nadir platelet count of <50,000/μl was seen in 26% of the patients in the O+ group, compared with 53% in the O− group (P = 0.031). No significant difference in survival from cardiac failure was seen between the O+ and O− group (48 vs. 56%, P = 0.508). The Sequential Organ Failure Assessment (SOFA) score on initiation of VA-ECMO were independently associated with survival (OR = 1.12, 95% confidence interval (95% CI): 1.02–1.22, P = 0.015).Conclusions: Oseltamivir could ameliorate VA-ECMO-related thrombocytopenia. These findings suggested the prophylactic potential of oseltamivir on severe thrombocytopenia associated with the initiation of VA-ECMO.

Effect of Pregnancy on the Clinical Course of ITP Pregnant Women and Their Newborns. Resuts of a Spanish Case Series of 297 Primary ITP Pregnancies

Introduction:Given that there is no large case-series, effect of pregnancy on the course of pre-existing primary immune thrombocytopenia (ITP) patients is unclear1,2. Furthermore, outcome predictors evidence of neonates born to mothers with ITP is very scarce1. Due to obvious ethical reasons, no clinical trial regarding ITP and pregnancy has been reported until recent days3. Nevertheless, the relationship between ITP and pregnancy is considered a “trending topic” nowadays. As it is the, until now, unknown safety and efficacy of new drugs as TPO mimetics in this setting3-6.Aims:To evaluate outcome and global management of pregnancy and delivery on ITP women an on their offspring.Methods:Primary ITP was defined as a platelet count < 100 x 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia.All women diagnosed of primary ITP from 2011 to 2016 in 24 Spanish Hematology Departments who had at least one pregnancy after ITP onset were included in this registry.Results:We included 297 primary ITP pregnancies from 204 women. At pregnancy diagnosis, we observed a majority of chronic ITP cases (71.9 %). At ITP diagnosis, median age of our case-series was 23 years (IQR, 18-31) and median platelet count was 18 x 109/l (IQR, 6-36). Median time from ITP diagnosis to pregnancy was 162 months (IQR, 0-364). Median number of pregnancies prior to ITP diagnosis was 1 (IQR, 0-2) with 1 pregnancy (IQR, 1-2) after ITP diagnosis as a median.51.6% of women received corticosteroids, immunoglobulins (IVIG) (16.6%), rituximab (7.1%) and/or splenectomy (8.7%) as ITP treatments between or before new pregnancies. On the other hand, 26.5% of women needed treatment for ITP during pregnancy, mainly steroids (13.9%) and IVIG (10.2%).The median platelet-count nadir during pregnancy was 73 x 109/l (IQR, 31-174). 135 (45.4%) pregnancies had less than 50 x 109 platelets/l with 77 (25.9%) with less than 30 x 109 platelets/l. 57 women (19.2%) exhibited hemorrhagic symptoms, being 30 (10.1%) of them severe bleedings.Regarding type of delivery, this was vaginal in 187 (62.9%) of pregnancies. Median platelet count at delivery was 111 x 109/l (IQR, 70-187). 47 patients (15.8 %) experienced 60 bleeding episodes. We only observed 52 cases (19.5%) of neonatal thrombocytopenia among 266 living newborns.Conclusions:Our results are comparable to previously reported1,2. No severe bleeding complications during pregnancy and/or delivery were observed in our study. Rate of neonatal thrombocytopenia, and therefore, newborn bleeding is low. DisclosuresNo relevant conflicts of interest to declare.

Incidence and Outcome of Severe Thrombocytopenia Associated with Zika Virus Infection - Puerto Rico, 2016

Introduction: There are many etiologies for thrombocytopenia, such as viral suppression, disseminated intravascular hemolysis, and immune thrombocytopenic purpura (ITP). Zika virus (ZIKV) recently emerged in the Americas and was first detected in Puerto Rico in late 2015. ZIKV disease is generally mild; however, it has been infrequently associated with life-threatening outcomes including severe thrombocytopenia. We sought to define incidence and outcomes of ZIKV disease patients with thrombocytopenia.Methods: We reviewed the medical records of patients with reported thrombocytopenia (platelet count ≤ 100,000 cells/µL) among patients with ZIKV disease (defined by detection of ZIKV nucleic acid by RT-PCR or anti-ZIKV IgM antibody by ELISA and the presence of symptoms) that had been reported via passive surveillance. Among patients with confirmed thrombocytopenia, we collected data on medical history, interventions, and patient outcomes. Cases of severe thrombocytopenia were defined by: a) platelet count <20,000 cells/µL; or b) platelet count <50,000 cells/µL with a clinical diagnosis of and treatment for ITP. Cases in which another likely cause of thrombocytopenia was identified (e.g., sepsis, immunosuppression) were excluded from analysis. Data were collected in REDCap®.Results: Of 37,878 patients with ZIKV disease reported during 2016, a total of 436 had reported thrombocytopenia. Among patients with medical records available for review, 48 (0.1%) had confirmed thrombocytopenia in the absence of an identified etiology. Twelve of these 48 patients (25%) had severe thrombocytopenia (Table 1), and 36 (75%) had non-severe thrombocytopenia.Median age of patients with severe and non-severe thrombocytopenia was 39.5 years (range: 2-88) and 49 years (range: 1-88 years), respectively; 7 (58%) and 19 (53%) were male. Two (17%) patients with severe and 3 (8%) with non-severe thrombocytopenia had a history of ITP. All patients reported recent illness, which most frequently included rash (73%) and/or fever (77%). Median nadir platelet count of patients with severe and non-severe thrombocytopenia was 12,500 cells/µL (range: 1,000-30,250) and 70,000 cells/µL (range: 24,000-100,000), respectively, which occurred a median of 5.7 days (range: 1.4-15.6) and 4.5 days (range: 0.4-34.1) after symptom onset. Blood smears were performed in 9 (75%) patients with severe and 18 (50%) with non-severe thrombocytopenia. No patients with severe thrombocytopenia and 1 (2.8%) patient with non-severe thrombocytopenia had fragmented red blood cells; visualization of platelets on smear was consistent with low platelet counts. Whereas 11 (30.6%) patients with non-severe thrombocytopenia had petechiae, hematuria, or gingival bleeding, all (100%) patients with severe thrombocytopenia had hemorrhagic manifestations including petechiae (66.7%), hematuria (33.3%), ecchymoses (50%), gastrointestinal bleeding (25%), or intracranial hemorrhage (8.3%). Only patients with severe thrombocytopenia were diagnosed with ITP. Only patients with severe thrombocytopenia received platelet transfusion (n = 4; 33.3%) and/or intravenous immunoglobulin (IVIG) (n = 5; 41.7%). The patients with severe thrombocytopenia that received IVIG all had an up-trending platelet count after IVIG administration. Eight (66.6%) patients with severe thrombocytopenia and 9 (25.0%) with non-severe thrombocytopenia received steroids. Among those who received platelet transfusions, the median platelet count increase following transfusion was 6,000 cells/µL; 25% had a decreased platelet count following transfusion. Outcomes among patients with severe or non-severe thrombocytopenia included hospitalization (100% vs. 53%), admission to the intensive care unit (33% vs. 0%), and death (8.3% vs. 0%).Conclusions: Thrombocytopenia appears to be an uncommon occurrence in patients with ZIKV infection. Though rare, severe thrombocytopenia associated with ZIKV disease can be fatal; treatment is necessary. Platelet transfusions alone may not be effective, whereas administration of corticosteroids and IVIG may be of benefit in some cases. Further study is needed to characterize the pathogenesis of ZIKV-associated severe thrombocytopenia and interventions associated with survival. Appropriate diagnosis of the underlying etiology of thrombocytopenia is time-sensitive and crucial to improving patient outcome. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PS1488 ATYPICAL HAEMOLYTIC URAEMIC SYNDROME IN THE ECULIZUMAB ERA: PRESENTATION, RESPONSE TO TREATMENT AND EVALUATION OF AN ECULIZUMAB WITHDRAWAL STRATEGY

Background:Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy with a predilection for the kidneys, and results from dysregulation of the alternative pathway of complement. The prognosis has historically been poor but the humanised monoclonal anti‐C5 antibody eculizumab has revolutionised management in the last decade. Whilst haematological and renal efficacy has been demonstrated, the optimum treatment duration is unknown, and is of key clinical relevance given the high drug costs and potential adverse effects including bacterial meningitis.Aims:‐ To review presenting features and responses to eculizumab therapy in cases of acute aHUS‐ To assess outcomes of eculizumab withdrawal in cases of complete responseMethods:All cases of acute aHUS presenting to a single UK centre between 2012–2018 and managed with eculizumab were retrospectively reviewed, from diagnosis to last follow up in our institution. AHUS was diagnosed according to international consensus criteria. Withdrawal of eculizumab, with subsequent close monitoring, was offered to all patients achieving complete haematological response (platelets &gt;150 x109/L and normal LDH) and complete renal recovery (eGFR back to baseline without significant proteinuria), with discussion of risks/benefits.Results:22 patients (68% female, median age 32 years (range 16–67), all with native kidneys and no known chronic kidney disease (CKD), were identified. 21/22 were de novo presentations. Median nadir platelet count was 23 x109/L (range 7–85), and median nadir eGFR was 11.5 ml/min/1.73m2 (range 3–57), with a high incidence of nephrotic range proteinuria (47%). 14/22 (64%) of patients required renal replacement therapy (RRT). GI (64%) and neurological (41%) symptoms were common. 77% had elevated cardiac troponin T (median 64.5 ng/L, range 17–397, NR 0–14), suggesting subclinical cardiac involvement. 41% had an associated complement genetic abnormality but mutation status did not affect severity of clinical presentation.Eculizumab followed a median of 6 days (range 2–38) of plasma exchange (PEX). After a median duration of therapy of 11 weeks (range 1–227), haematological recovery was seen in 100%, while 81% achieved at least partial renal recovery (median increase in eGFR 49 ml/min/1.73m2 (range 22–80)). At median duration of follow up of 85 weeks (range 4–255), 54.5% had eGFR &gt;60 ml/min/1.73m2, 27% had CKD, 14% were on RRT, and 4.5% had died.Eculizumab was withdrawn in 13/22 (59%) following complete haematological and renal recovery, after a median 10 weeks (range 1–26). 10/13 remained in remission at median 66 weeks (range 14–238) since withdrawal. 3/13 (23%) subsequently relapsed, all within 1 year of withdrawal, with defined triggers in 2/3. All made a full recovery with rapid resumption of eculizumab without need for PEX or RRT. Those who relapsed were more likely to have a complement genetic abnormality, with a trend for a shorter duration of initial therapy (Table 1).Summary/Conclusion:The cohort demonstrates the multisystem nature of aHUS, and reiterates that severe thrombocytopenia and mild renal impairment, although classically associated with TTP, can also be seen in aHUS. Haematological and renal outcomes in the cohort compare favourably with the existing prospective and retrospective literature, demonstrating a positive outlook for aHUS in the eculizumab era. Our withdrawal strategy led to no long term adverse effects, with undeniable benefits (including drug cost savings of over £11 million), and as such adds to the growing body of evidence in favour of such an approach.image

Heparin-induced thrombocytopenia during extracorporeal life support: incidence, management and outcomes.

Heparin-induced thrombocytopenia (HIT) is a severe antibody-mediated reaction leading to transient prothrombosis. However, its incidence in patients on extracorporeal life support (ECLS) is not well described. The aim of this systematic review was to report the incidence of HIT in patients on ECLS, as well as compare the characteristics and outcomes of HIT in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and veno-venous ECMO (VV-ECMO). An electronic search was performed to identify all studies in the English literature examining outcomes of patients with HIT on ECLS. All identified articles were systematically assessed using specific inclusion and exclusion criteria. Random effects meta-analysis as well as univariate analysis was performed. Of 309 patients from six retrospective studies undergoing ECLS, 83% were suspected, and 17% were confirmed to have HIT. Due to the sparsity of relevant retrospective data regarding patients with confirmed HIT on ECLS, patient-based data was subsequently collected on 28 patients from case reports and case series. Out of these 28 patients, 53.6% and 46.4% of them underwent VA-ECMO and VV-ECMO, respectively. Patients on VA-ECMO had a lower median platelet count nadir (VA-ECMO: 26.0 vs. VV-ECMO: 45.0 per µL, P=0.012) and were more likely to experience arterial thromboembolism (VA-ECMO: 53.3% vs. VV-ECMO: 0.0%, P=0.007), though there was a trend towards decreased likelihood of experiencing ECLS circuit oxygenator thromboembolism (VA-ECMO: 0.0% vs. VV-ECMO: 30.8%, P=0.075) and thromboembolism necessitating ECLS device or circuit exchange (VA-ECMO: 13.3% vs. VV-ECMO 53.8%, P=0.060). Kaplan-Meier survival plots including time from ECLS initiation reveal no significant differences in survival in patients supported on VA-ECMO as compared to VV-ECMO (P=0.300). Patients who develop HIT on VA-ECMO are more likely to experience more severe thrombocytopenia and arterial thromboembolism than those on VV-ECMO. Further research in this area and development of standardized protocols for the monitoring, diagnosis and management of HIT in patients on ECLS support are warranted.

Thrombocytopenia Is a Biomarker for Response in Patients Treated with Anti PD-1/Pdl-1 Therapy

Background: Immunotherapy directed against the PD-1/PDL-1 (programmed cell death protein [ligand] 1) pathway has shown activity across a range of malignancies. Immune-related adverse events have been shown to be associated with the efficacy of PD-1/PDL-1 inhibitors in patients with melanoma and non-small cell lung cancer. Thrombocytopenia has been reported in up to 33% of patients receiving anti PD-1/PDL-1 therapy. Our hypothesis is that immune-mediated thrombocytopenia may be a biomarker for response to anti PD-1/PDL-1 therapy.Methods: We collected data on 250 patients aged 18 years and older who were treated with anti PD-1/PDL-1 therapy at the University of Oklahoma Health Sciences Center between January 2014 and January 2016. Initial platelet count at baseline as well as nadir platelet count during treatment were examined. Patient's clinicopathologic characteristics were analyzed using simple descriptive statistics [median (range) for continuous covariates and n (%) for categorical variables]. Kaplan Meier Analysis was performed to assess how thrombocytopenia was associated with overall survival (OS) and progression free survival (PFS). Patients were grouped according to their nadir platelet count: normal platelets (≥150k), grade 1 (75k-150k), and combined grades 2, 3, 4 (<75k). Cox proportional hazard regression models were used to assess the association of thrombocytopenia with OS and PFS adjusted for various covariates. The objective of the study is to assess whether the degree of thrombocytopenia correlates with the PFS and OS in patients receiving anti PD-1/PDL-1 therapy.Results: A total of 250 patients were reviewed in this study. After excluding 27 patients with baseline platelet count <100k and 14 patients with missing platelet count data, 209 patients were included in the analysis. Fifty-five percent were females. Median age at diagnosis was 62 (23-91) years. The most common cancer diagnoses were lung cancer (21.1%), melanoma (17%), and ovarian cancer (9%). Nivolumab was the most commonly used agent (40.9%), followed by Pembrolizumab (38.4%). Median number of treatments received was 5. Median platelet count at baseline was 227 (102-535). Median nadir platelet count was 180 (4-552). Thrombocytopenia of any grade was observed in 70 (33%) patients .The number of patients with grade 1, 2, and 3/4 were 56 (26.8%), 1 (0.5%) and 13 (6.2%), respectively. Median follow-up time was 226 days. Univariate analysis showed that patients with grade I thrombocytopenia had higher PFS and OS when compared to patients who did not develop thrombocytopenia [HR 0.48 (95% CI, 0.29-0.81), P = 0.0053 and HR 0.49 (95% CI, 0.27-0.9), P = 0.0209, respectively]. When adjusted for age, cancer type, performance status, and line of treatment, grade 1 thrombocytopenia remained positively associated with survival outcome [HR 0.50 (95% CI, 0.29-0.87), P = 0.0146 for PFS and HR 0.40 (95% CI, 0.21-0.77), P = 0.0061 for OS]. Only 14 patients had grade 2-4 thrombocytopenia, and there was no statistically significant difference in survival compared to patients with no thrombocytopenia [adjusted HR 0.52 (95% CI, 0.2-1.38), P = 0.189 for OS].Conclusion: Our study shows that in patients treated with anti PD-1/PDL-1 therapy, grade 1 thrombocytopenia appears to be positively correlated with survival outcomes. This survival advantage was not seen with higher grades of thrombocytopenia. PD-L1 was recently shown to be expressed on human platelets; thus, thrombocytopenia is likely immune-mediated. Thrombocytopenia may be a biomarker for efficacy of immune checkpoint therapy. The predictive significance of thrombocytopenia in patients receiving PD-1/PDL-1 therapy warrants further investigations. DisclosuresNo relevant conflicts of interest to declare.

Venous thromboembolism in patients with hematologic malignancy and thrombocytopenia

The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty-seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000-45,000/µL) versus 165,000/µL (50,000-429,000/µL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic-dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21-1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. © 2016 Wiley Periodicals, Inc.

Use of Low Molecular Weight Heparin (LMWH) in Thrombocytopenic Patients with Hematologic Malignancy-Associated Venous Thromboembolism (VTE)

Introduction:The management of hematologic malignancy-associated VTEin patients with moderate to severe thrombocytopenia is unclear. Clinical trials of anticoagulants in VTE exclude such patients, hence do not inform the risk of bleeding or clot progression. Consensus-based guidelines recommend case-by-case consideration for either platelet transfusion to maintain platelet count >50,000/µL and therapeutic anticoagulation, or 50% dose reduction in LMWH (J Thromb Haemost. 2013 Jan;11(1):56-70.; Curr Oncol. 2015 Apr;22(2):144-55). At our institution, our approach is to use prophylactic dose LMWH for patients with platelet count ≤50,000/µL.Method:This is a single-center retrospective study of 128 adult patients with hematologic malignancies, who were diagnosed with VTE. Patients were identified from hospital research database. The diagnoses were verified after the review of medical records. The platelet count was assessed during the period of anticoagulation for VTE. The outcomes of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Bleeding and clot recurrence was assessed until the last follow-up (median of >1 month). Fisher's Exact test was used to test the association between two categorical variables, and Analysis of Variance (ANOVA) was used to test the association between a continuous variable and a categorical variable.Results:Characteristics of the study population were as follows: 51% male, 47% non-Hodgkin lymphoma, 20% acute leukemia/myelodysplastic syndrome, 40% status-post hematopoietic stem cell transplant, 9% with creatinine >2 mg/dl, 36% with pulmonary embolism and 28% with catheter-related VTE. Forty six patients (36%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 9000/µL( range 2000-45,000/µL) versus 166,000/µL (range 50,000-389,000/µL) in those without (p<0.001). The median duration of significant thrombocytopenia in the first group was 10 days (range 1-68 days). Therapy during the period of significant thrombocytopenia included prophylactic dosing of LMWH (46%), therapeutic dose of LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%) and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At last follow-up, the risk of bleeding (p=0.65) and clot progression (p=0.81) were similar in the two groups (Table 1).Conclusion:Within the limits of this retrospective study, cautious use of dose-adjusted LMWH in thrombocytopenic patients with hematologic malignancy-associated VTE may be safe. A prospective trial of prophylactic dose LMWH in patients with VTE during thrombocytopenia is required to confirm the safety and, to some extent, efficacy of such an approach.Table 1Outcome of patients with VTEOutcomeThrombocytopenic cohort (Platelet count ≤50,000/µL)Patients without significant thrombocytopenia (Platelet count >50,000/µL)p-valueBleeding after VTE treatment0.65No38 (82.6%)75 (91.5%)Minor (without significant clinical implications)1 (2.2%)1 (1.2%)Clinically significant (causing drop in hemoglobin; requiring transfusion or other interventions)4 (8.7%)5 (6.1%)Missing3 (6.5%)1 (1.2%)Clot progression or recurrence at last follow-up0.81No35 (76.1%)67 (81.7%)Yes9 (19.6%)15 (18.3%)Missing2 (4.3%)0 DisclosuresVose:Allos Therapeutics/Spectrum: Research Funding; US Biotest, Inc: Research Funding; Janssen Biotech: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corp: Research Funding; Acerta Pharma: Research Funding; GlaxoSmithKline: Research Funding. Armitage:Celgene: Consultancy; Ziopharm: Consultancy; Spectrum: Consultancy; Roche: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Spectrum: Consultancy; Genentech: Consultancy; BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.