Distribution of PNH Clone Sizes within High Risk Diagnostic Categories Among 481 PNH Positive Patients Identified by High Sensitivity Flow Cytometry

Abstract Abstract 1271 Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder associated with patients (pts) with aplastic anemia (AA), myelodysplastic syndrome (MDS), unexplained cytopenias, unexplained thrombosis, and hemolysis. High sensitivity flow cytometry (HSFC) is recommended by The International Clinical Cytometry Society (ICCS) as the method of choice for diagnosing PNH. The incidence of PNH clones in these patient groups has been previously reported, but the distribution of clinically significant PNH clones not been previously explored. The purpose of this study is to analyze the distribution of PNH clone sizes using HSFC with sensitivity up to 0.01% among 7,699 pts who were screened for PNH clones utilizing CD235a/CD59 for RBCs, FLAER/CD24/CD15/CD45 for neutrophils and FLAER/CD14/CD64/CD45 for monocytes. We evaluated the distribution of PNH clones sizes against the provided ICD-9 diagnostic (DX) codes and evaluated the significance of hemolysis on PNH clone size. Based on a sensitivity of at least 0.01%, 6.2% of all pts (481/7,699) were found to be PNH positive. Of those pts, 3.8% (293/7,699) were found to have a PNH clone size of >1%, while 2.4% (188/7,699) were found to have a PNH clone size of <1%. Of the 481 PNH positive patients, the distribution of PNH clone sizes among high risk diagnostic categories is shown in Table 1. Aplastic anemia (AA) and hemolysis were more commonly associated with PNH clone sizes >20%. In 32 patients reported to have both aplastic anemia and hemolysis, 20 pts (63%) had PNH clone sizes >20%, while 30 pts (94%) had PNH clone sizes >1%. Pts with MDS, cytopenias and thrombosis more frequently showed PNH clones sizes of <1%. However, in 18 pts reported to have either MDS or cytopenias and hemolysis, 4 pts (22%) showed PNH clone sizes >20%, while 10 pts (56%) showed PNH clone sizes >1%. In this single-laboratory experience, we evaluated the distribution of PNH clone sizes among high risk patient groups based on ICD-9 diagnostic code. Pts with large PNH clone sizes are more likely to have clinical symptoms, particularly those associated with hemolysis, and thus most likely to benefit from therapy. In this study, pts with hemolysis showed a higher incidence of PNH clone sizes >20%, underscoring the need to test for hemolysis in these high risk patient groups. In addition, this study confirmed the need to continue actively testing high risk patient populations, including aplastic anemia, myelodysplastic syndrome, unexplained cytopenias, unexplained thrombosis and hemolysis for PNH based on the ICCS recommendations to ensure accurate diagnosis and appropriate therapy. Table 1. Distribution of PNH Clone Sizes within high risk diagnostic categories among 481 PNH+ Patients at Dahl-Chase Diagnostic Services PNH Clone Sizes Total <1% 1–20% >20% Aplastic Anemia 32 39 40 25.8% (111) MDS 20 9 7 8.4% (36) Cytopenias (including pancytopenia, leukopenia and non-hemolytic anemia) 78 27 10 26.7% (115) Hemolysis (including hemolytic anemia and hemoglobinuria) 24 29 129 42.3% (182) Thrombosis 12 4 5 4.9% (21) Miscellaneous 15 2 5 5.1% (22) Not provided 17 6 28 11.9% (51) Note: Table reflects patients who had more than one associated ICD-9 code. Disclosures: Illingworth: Alexion: Consultancy, Honoraria.

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Observational Study Of PNH Clone Size By High Sensitivity Flow Cytometry In High-Risk Patients InA Large Russian Population

Blood ◽

10.1182/blood.v122.21.4867.4867 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4867-4867

Author(s):

Elena Babenko ◽

Alexandra Sipol ◽

Vyacheslav Borisov ◽

Elena Naumova ◽

Elena Boyakova ◽

...

Keyword(s):

Flow Cytometry ◽

High Risk ◽

Research Funding ◽

Surface Membrane ◽

High Risk Patient ◽

High Sensitivity ◽

Clone Size ◽

Hematopoietic Stem ◽

Pnh Clone

Abstract Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematopoietic stem cell disease caused by a partial or absolute deficiency of proteins linked to the cell surface membrane via a glycosylphosphatidyl-inositol anchor, which leads to complement-induced intravascular hemolysis mediated via the membrane attack complex. Multiparameter high-sensitivity flow cytometric measurement of PNH clones is the method of choice for the diagnosis of PNH, as recommended by the International Clinical Cytometry Society (ICCS). After publication of the ICCS guidelines, screening of patients considered at high risk of PNH was commenced in Russia. Data are presented on PNH clone size distribution across patients with relevant ICD-10 diagnostic codes (based on patients′ initial assumed diagnoses). Methods Patients were tested for the presence and size of PNH clones using high-sensitivity flow cytometry across nine laboratories. PNH clone evaluations were performed as described in the ICCS guidelines: CD59/CD235a monoclonal antibodies for RBC; CD45/CD15/CD24/FLAER for granulocytes and; CD45/CD64/CD14/FLAER or CD45/CD33/CD14/FLAER for monocytes. The sensitivity for PNH clone detection was 0.01%. Changes in PNH clone size were evaluated among patients who had follow-up studies after initial measurements. Results 1889 patients were assessed between October 2011 and June 2013 (Table 1). Suspected PNH and bone-marrow disorders (AA, MDS, cytopenia) were the most common reasons for PNH testing. The greatest proportions of patients with PNH clones were among those with of an initial assumed diagnosis of AA or PNH. Notably, around 40% of patients with an initial assumed diagnosis of PNH actually had no detectable PNH clones. Most patients with small clone sizes (< 1%) were in the AA, MDS and hemolytic anemia groups. Overall, mean clone sizes were slightly higher in monocytes (31.5%) than in granulocytes (30.1%) across the diagnostic categories. While there was generally a good correlation between clone size measurements in granulocytes and monocytes (linear regression r2 = 0.9851), 10% of PNH-positive patients had detectable clones only in one of these leucocyte populations (i.e. either in monocytes or in granulocytes, but not both). PNH clones in RBCs were generally lower than in granulocytes. Repeat clone size measurements were performed in 316 patients over a mean follow-up period of 7.8 months. In patients with initial clone sizes <50% the PNH clones tended to decrease over time, whereas in patients with initial clone sizes >50%, clones tended to increase. PNH clones were not changed at all in 98 patients at follow-up, among whom 48% were patients with AA. Conclusion These screening data confirm the utility of high-sensitivity flow cytometry testing in high-risk patient groups to ensure early and accurate diagnosis and to aid in the effective clinical management of patients. Disclosures: Babenko: Alexion: Research Funding. Sipol:Alexion: Research Funding. Borisov:Alexion: Employment. Naumova:Alexion: Research Funding. Boyakova:Alexion: Research Funding. Glazanova:Alexion: Research Funding. Chubukina:Alexion: Research Funding. Pronkina:Alexion: Research Funding. Popov:Alexion: Research Funding. Mustafin:Alexion: Research Funding. Fidarova:Alexion: Honoraria. Lisukov:Alexion: Honoraria. Kulagin:Alexion: Honoraria.

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Minimally invasive aortic valve replacement in high risk patient groups

Journal of Thoracic Disease ◽

10.21037/jtd.2017.05.21 ◽

2017 ◽

Vol 9 (6) ◽

pp. 1672-1696 ◽

Cited By ~ 8

Author(s):

Daniel Fudulu ◽

Harriet Lewis ◽

Umberto Benedetto ◽

Massimo Caputo ◽

Gianni Angelini ◽

...

Keyword(s):

High Risk ◽

Aortic Valve ◽

Aortic Valve Replacement ◽

Minimally Invasive ◽

Valve Replacement ◽

High Risk Patient ◽

Risk Patient ◽

Patient Groups

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Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets

The American Journal of Gastroenterology ◽

10.1111/j.1572-0241.2000.02196.x ◽

2000 ◽

Vol 95 (7) ◽

pp. 1669-1676 ◽

Cited By ~ 26

Author(s):

Brian J. Reid ◽

Douglas S. Levine ◽

Gary Longton ◽

Patricia L. Blount ◽

Peter S. Rabinovitch

Keyword(s):

Flow Cytometry ◽

High Risk ◽

Barrett’S Esophagus ◽

Barrett's Esophagus ◽

High Risk Patient ◽

Risk Patient

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A theory on SARS-CoV-2 susceptibility:  low sensitivity of tlr7-signalling as a mechanistic explanation for the increased risk of obese and elderly COVID-19 patients

10.31219/osf.io/2r5fc ◽

2020 ◽

Author(s):

Ludwig Englmeier

Keyword(s):

High Risk ◽

Virus Infection ◽

High Risk Patient ◽

Mechanistic Explanation ◽

Risk Patient ◽

Increased Risk ◽

Patient Groups ◽

Innate Antiviral Response ◽

Low Sensitivity ◽

Lower Expression

I hypothesize that high-risk patient groups for developing severe Covid-19 have in common that there is a chronic, low-level activation of tlr7 by intrinsic substrates prior to virus infection. This leads to acquired desensitization of tlr7-signalling and, more generally, to a state of tlr-tolerance. Upon SARS-CoV-2 infection the induced activation of tlr7-signalling in high-risk patient groups can be expected to be weaker and delayed and consequently these patients will show a weaker or delayed initial innate antiviral response immediately after infection. In men, this is then exacerbated further by the naturally lower expression level of tlr7. The implications for therapy and prophylaxis are discussed.

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