Complement in hemolytic anemia

Brodsky, Robert A.

doi:10.1182/blood-2015-06-640995

Cited by 91 publications

(81 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We recently developed a sensitive and specific serum-based assay to detect heightened activity of the alternative pathway of complement (“modified Ham test”) that readily distinguishes aHUS from other thrombotic microangiopathies such as thrombotic thrombocytopenic purpura [25] The principle of the modified Ham test is similar to the acidified serum (Ham) test that was developed by Dr. Thomas Ham in the 1930s to diagnose PNH [26, 27]. In PNH there is a genetic mutation, PIGA that causes deficiency or absence of glycosylphosphatidylinositol (GPI).…”

Section: Introductionmentioning

confidence: 99%

Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome

Vaught

Gavriilaki

Hueppchen

et al. 2016

Experimental Hematology

Self Cite

View full text Add to dashboard Cite

HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is a severe variant of preeclampsia whose pathogenesis remains unclear. Recent evidence and clinical similarities suggest a link to atypical hemolytic uremic syndrome (aHUS), a disease of excessive activation of the alternative complement pathway effectively treated with a complement inhibitor, eculizumab. Therefore, we utilized a functional complement assay, the modified Ham test, to test sera of women with classic or atypical HELLP syndrome, preeclampsia with severe features, normal pregnancies and healthy non-pregnant women. Sera were also evaluated using levels of the terminal product of complement activation (C5b-9). We tested the in vitro ability of eculizumab to inhibit complement activation in HELLP serum. Increased complement activation was found in participants with classic or atypical HELLP compared to normal pregnancy and non-pregnant controls. Mixing HELLP serum with eculizumab containing serum resulted in a significant decrease in cell killing compared to HELLP serum alone. In conclusion, HELLP syndrome is associated with increased complement activation demonstrated by the modified Ham test. This assay may aid in the diagnosis of HELLP syndrome and confirm its pathophysiology relates to aHUS.

show abstract

Section: Introductionmentioning

confidence: 99%

Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome

Vaught

Gavriilaki

Hueppchen

et al. 2016

Experimental Hematology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Upstream steps in the complement cascade, which include both C1q binding and C3b deposition, also require threshold levels for cytotoxic efficacy (23,24); normal and malignant cells can use a variety of defensive measures to inhibit or neutralize these upstream steps (25)(26)(27). Moreover, nucleated cells can extrude or internalize the MAC, and therefore, a sufficient number of copies of the cell-bound MAC must be generated to overwhelm these defenses (13)(14)(15)(28)(29)(30)(31)(32).…”

mentioning

confidence: 99%

Antibodies That Efficiently Form Hexamers upon Antigen Binding Can Induce Complement-Dependent Cytotoxicity under Complement-Limiting Conditions

Cook

Lindorfer

Horst

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Recently, we demonstrated that IgG Abs can organize into ordered hexamers after binding their cognate Ags expressed on cell surfaces. This process is dependent on Fc:Fc interactions, which promote C1q binding, the first step in classical pathway complement activation. We went on to engineer point mutations that stimulated IgG hexamer formation and complement-dependent cytotoxicity (CDC). The hexamer formation–enhanced (HexaBody) CD20 and CD38 mAbs support faster, more robust CDC than their wild-type counterparts. To further investigate the CDC potential of these mAbs, we used flow cytometry, high-resolution digital imaging, and four-color confocal microscopy to examine their activity against B cell lines and primary chronic lymphocytic leukemia cells in sera depleted of single complement components. We also examined the CDC activity of alemtuzumab (anti-CD52) and mAb W6/32 (anti-HLA), which bind at high density to cells and promote substantial complement activation. Although we observed little CDC for mAb-opsonized cells reacted with sera depleted of early complement components, we were surprised to discover that the Hexabody mAbs, as well as ALM and W6/32, were all quite effective at promoting CDC in sera depleted of individual complement components C6 to C9. However, neutralization studies conducted with an anti-C9 mAb verified that C9 is required for CDC activity against cell lines. These highly effective complement-activating mAbs efficiently focus activated complement components on the cell, including C3b and C9, and promote CDC with a very low threshold of MAC binding, thus providing additional insight into their enhanced efficacy in promoting CDC.

show abstract

“…The bone marrow is usually markedly erythroid, with decreased or absent iron stores, depending on how long the patient has been losing iron in the urine. 9 Our case was interesting because of unusual presentation with thrombocytopenia. In the literatüre the frequency of PNH patients presenting with thrombocytopenia is relatively low.…”

Section: Discussionmentioning

confidence: 84%

Paroxysmal Nocturnal Hemoglobinuria in the Differential Diagnosis of Thrombocytopenia

et al. 2017

View full text Add to dashboard Cite

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease which diagnosis may be delayed due to variable clinical findings. We describe herein a case of PNH in a 21 year old woman who admitted with complaints of chronic weakness, intermittent spontaneous ecchymoses, and an intermittent abdominal pain. On laboratory tests thrombocytopenia and iron deficiency anemia without any clinical findings were found. Flow cytometric evaluations showed a PNH clone of 15% for erythrocytes, 64% for monocytes, and 60% for granulocytes. The patient was diagnosed with PNH and an eculizumab therapy was initiated. Following initiation of eculizumab therapy, the frequency of abdominal pain attacks decreased, hemoglobin level normalized, and platelet values increased slightly. In patients submitting with a triad of symptoms such as thrombocytopenia, iron deficiency anemia, and abdominal pain attacks of unknown etiology we suggest considering PNH. We also encourage physicians to share their similar observations in order to raise the knowledge on infrequent presentations of PNH.

show abstract

Complement in hemolytic anemia

Cited by 91 publications

References 41 publications

Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome

Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome

Antibodies That Efficiently Form Hexamers upon Antigen Binding Can Induce Complement-Dependent Cytotoxicity under Complement-Limiting Conditions

Paroxysmal Nocturnal Hemoglobinuria in the Differential Diagnosis of Thrombocytopenia

Contact Info

Product

Resources

About