Jose Perdomo

The University of Sydney · Charles Perkins Centre

Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend non-heparin anticoagulants and intravenous immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to case studies involving small patient numbers, confounding factors (e.g. concurrent treatments), and a lack of animal...

Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend non-heparin anticoagulants and intravenous immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to a lack of comparative clinical trials or animal studies. A recent study proposed danaparoid and heparin as potential...

Glycoprotein (GP) Ibα is expressed on the surface of platelets and megakaryocytes and is anchored to the membrane skeleton by Filamin A (FlnA). Whilst GPIb and FlnA have fundamental roles in platelet biogenesis, the nature of this interaction in megakaryocyte biology remains ill-defined. We generated a mouse model expressing either human wild-type...

Simple Summary While neutrophil extracellular traps (NETs) are released by neutrophils as part of immune processes, there is extensive evidence of the involvement of NETs in pathological developments such as thrombosis. Immune complexes, formed by antibodies against diverse antigens, can trigger NETs formation, which induces a generation of neutrop...

Platelets play an important role in hemostasis by forming clots and stopping bleeding. In immune thrombotic conditions, platelets and leukocytes are aberrantly activated by pathogenic antibodies resulting in platelet aggregates and NETosis, leading to thrombosis and thrombocytopenia. A simple assay that assesses platelet function and antibody activ...

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen) against COVID-19. The mechanisms involved in clot formation and thrombocytopenia in VITT are yet to be fully determined. Here we show neutrophils undergoing NETosis...

Immune thrombocytopenia (ITP) is a bleeding disorder caused by dysregulated B and T cell functions, which lead to platelet destruction. A well-recognised mechanism of ITP pathogenesis involves anti-platelet and anti-megakaryocyte antibodies recognising membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa. In addition to the current v...

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and NADPH oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutr...

Cardiovascular disease, including myocardial infarction (MI), is the leading cause of death globally. Current antithrombotic medications used during MI treatment are predominantly directed towards platelet inhibition and, to a lesser extent, anticoagulation. Bleeding is a major risk of such treatment and could be circumvented by targeting other cau...

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of adenoviral vector vaccines (AstraZeneca and Johnson & Johnson) against COVID-19 ¹ . Anti-platelet factor 4 (PF4) antibodies are present in VITT patients 2,3 . Although the current view suggests that platelet activation by anti-PF4 antibodies is the cau...

Background: Novel therapies that can limit or reverse damage caused by myocardial infarction (MI) could ease the increasing burden of heart failure. In this regard Platelet Derived Growth Factor (PDGF) has been previously shown to contribute to cardiac repair after MI. Here, we use a rodent model of MI and recombinant adeno-associated virus 9 (rAAV...

Despite recent advances in the understanding and treatment of immune thrombocytopenia (ITP), its diagnosis remains clinical due to the lack of sensitive laboratory tests. The detection of anti-platelet antibodies (APA) in plasma, although highly specific, is notoriously insensitive. Specialised clinical platelet laboratories routinely perform a scr...

Background: The notable discrepancy between platelet count and bleeding manifestations in immune thrombocytopenia (ITP) patients with acquired Glanzmann thrombasthenia (GT) has been described. Objectives: We aimed to examine the mechanisms responsible for thrombocytopenia and the bleeding phenotype in a patient with acquired GT. Patient, method...

Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocyto...

Heparin and heparin-derived drugs may induce an immune reaction, termed heparin-induced thrombocytopenia (HIT) which is mediated by autoantibodies the recognize heparin/platelet factor 4 complexes. This leads to reduced platelet counts and to severe thrombosis. It's thought that this occurs due to platelet activation by the complex. In this presen...

Introduction The pathogenesis of heparin-induced thrombocytopenia (HIT) primarily involves anti-platelet factor(PF)4/heparin antibodies engaging FcγRIIa receptors on platelets to trigger a deleterious cascade of activation, thrombosis, and thrombocytopenia. Recent work with murine monoclonal antibodies has shed light on epitopic determinants that p...

Abstract: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a platelet count of less than 100 x 109 platelets/L. ITP results from two distinct processes: accelerated platelet destruction and reduced platelet production. A distinction of the relative contribution of these pathologies should help guide more targeted tr...

Drug-induced Immune thrombocytopenia (DIT) is a common complication of several medications, including commonly used antibiotics. The most widely studied DIT is caused by quinine. In DIT, antibodies predominantly bind to the platelet membrane glycoprotein (GP) IX in a drug-dependent fashion resulting in increased platelet clearance. Binding of the s...

Platelet production occurs principally in the bone marrow in a process known as thrombopoiesis. During thrombopoiesis, hematopoietic progenitor cells differentiate to form platelet precursors called megakaryocytes, which terminally differentiate to release platelets from long cytoplasmic processes termed proplatelets. Megakaryocytes are rare cells...

Jose Perdomo Hematology Research Unit, St George and Sutherland Clinical School, University of New South Wales, Kogarah, NSW, Australia Abstract: Romiplostim is a thrombopoietin receptor agonist (TPO-RA) used for the treatment of adult primary immune thrombocytopenia (ITP). ITP is an autoimmune condition characterized by low platelet counts due to...

Introduction. Heparin is widely used as an anticoagulant to prevent thrombosis and to treat venous thromboembolism and myocardial infarction. A complication of heparin use is the development of heparin-induced thrombocytopenia (HIT), which is a limb- and life-threatening disorder due to associated thrombotic events. HIT arises through the formation...

Primary immune thrombocytopenia is an autoimmune disease mediated by antiplatelet autoantibodies that cause platelet destruction and suppression of platelet production. In vitro effects of autoantibodies on megakaryocyte production and maturation have been recently reported. However, the impact of these autoantibodies on the crucial megakaryocyte f...

Transcription factors play a crucial role in regulation of cardiac biology. FOG-2 is indispensable in this setting, predominantly functioning through a physical interaction with GATA-4. This study aimed to identify novel co-regulators of FOG-2 to further elaborate on its inhibitory activity on GATA-4. The Art27 transcription factor was identified b...

Thrombocytopenia is caused by immune reactions elicited by diverse drugs in clinical practice. The activity of the drug-dependent antibodies produces a marked decrease in blood platelets and a risk of serious bleeding. Understanding of the cellular mechanisms that drive drug-induced thrombocytopenia has advanced recently but there is still a need f...

Friend of GATA 2 (FOG-2), a co-factor of several GATA transcription factors (GATA-4, -5 and 6), is a critical regulator of coronary vessel formation and heart morphogenesis. Here we demonstrate that FOG-2 is SUMOylated and that this modification modulates its transcriptional activity. FOG-2 SUMOylation occurs at four lysine residues (K312, 471, 915...

E3 ligases or Ubc9 do not increase FOG-2 SUMOylation. (A) COS-7 cells were transfected with a FOG-2 expression vector (left panel) or FOG-2 plus GFP-SUMO-1 (right panel) and the expression vectors indicated in the figure. Cell lysates were obtained in the presence of NEM and the proteins detected by Western blot. The presence of the SUMO E2 ligase...

3346 Introduction and Aim Heparin-Induced Thrombocytopenia and Thrombosis (HIT) is a life threatening disorder that affects 1–5% of patients receiving heparin therapy. A low platelet count is usually recorded (<150,000 per cubic millimetre) with a decrease of 50% or more from the baseline. The occurrence of HIT is due to the presence of an IgG ant...

Primary immune thrombocytopenia (ITP) and drug-induced thrombocytopenia (DITP) are disorders caused primarily by the presence of anti-platelet auto-antibodies (Abs). Hematologists have traditionally seen thrombocytopenia as the result of increased destruction of Ab-coated platelets by the reticuloendothelial system. While accurate, this approach do...

The CACCC-box binding protein erythroid Krüppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Krüppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by exami...

Introduction: Paclitaxel, a cytotoxic agent that destroys cancer cells by stabilizing the microtubule, inhibits tube formation by human umbilical vein endothelial cells (HUVEC) at subtoxic concentrations (≤10nM). The clear separation of the antiangiogenic effect of paclitaxel from its cytotoxicity suggests the possibility of alternative mechanisms...

The development of immune cytopenias is a well-recognized side effect of many drugs. Quinine- and quinidine-dependent antibodies are classic examples of drug-induced effects that cause severe, life-threatening thrombocytopenia. Whereas the effects of drug-dependent antibodies on platelets have been well documented, their effects on megakaryocyte (M...

384 The development of immune cytopenias is a well recognized side-effect of many drugs. Of a number of causative agents quinine- and quinidine-induced antibodies are classical examples of drugs that cause severe, life threatening thrombocytopenia and their mechanisms of action could be applicable to other drug-induced factors. The antibodies respo...

p45 NF-E2 is a bZIP transcription factor crucial for thrombopoiesis, as indicated by the fact that loss of p45 NF-E2 function results in dramatic embryonic lethal thrombopoietic defects and its overexpression boosts platelet release. In the present study, we set out to identify the sequences responsible for p45 NF-E2 nuclear import, evaluate its tr...

The C-terminal binding proteins (CtBPs) are ubiquitous corepressors that recruit histone-modifying enzymes to a variety of sequence specific DNA-binding proteins and other transcriptional regulators. CtBPs appear to play an important role in mediating repression and transforming activities of a variety of hematopoietic transcription factors such as...

The Ets transcription factor PU.1 is an essential regulator of normal hematopoiesis, especially within the myeloid lineage. As such, endogenous PU.1 predominantly localizes to the nucleus of mammalian cells to facilitate gene regulation. However, to date, little is known regarding the mechanisms of PU.1 nuclear transport. We found, using HeLa and R...

C-terminal binding proteins (CtBPs) are multifunctional proteins that can mediate gene repression. CtBPs contain a cleft that binds Pro-X-Asp-Leu-Ser (PXDLS) motifs. PXDLS motifs occur in numerous transcription factors and in effectors of gene repression, such as certain histone deacetylases. CtBPs have been depicted as bridging proteins that self-...

Small ubiquitin-like modifier (SUMO) is a protein moiety that is ligated to lysine residues on a variety of target proteins. Many known SUMO substrates are transcription factors or coregulators of transcription, and in most cases, modification with SUMO leads to the attenuation of transcriptional activation. We have examined basic Krüppel-like fact...

The oligomerization domain that is present at the C terminus of Ikaros-family proteins and the protein Trps-1 is important for the proper regulation of developmental processes such as hematopoiesis. Remarkably, this domain is predicted to contain two classical zinc fingers (ZnFs), domains normally associated with the recognition of nucleic acids. T...

Ikaros family transcription factors play important roles in the control of hematopoiesis. Family members are predicted to contain up to six classic zinc fingers that are arranged into N- and C-terminal domains. The N-terminal domain is responsible for site-specific DNA binding, whereas the C-terminal domain primarily mediates the homo- and hetero-o...

Small ubiquitin-related modifier (SUMO) is a protein moiety that is ligated to lysine residues in a variety of target proteins. The addition of SUMO can modulate the ability of proteins to interact with their partners, alter their patterns of subcellular localization and control their stability. It is clear that SUMO influences many different biolo...

Eos is a zinc finger transcription factor of the Ikaros family. It binds typical GGGAA Ikaros recognition sites in DNA and functions as a transcriptional repressor. Here we show that Eos associates with the corepressor C-terminal-binding protein (CtBP). CtBP has previously been shown to bind Pro-X-Asp-Leu-Ser (PXDLS) motifs in several DNA-binding p...

Members of the Ikaros family of transcription factors, Ikaros, Aiolos, and Helios, are expressed in lymphocytes and have been implicated in controlling lymphoid development. These proteins contain two characteristic clusters of zinc fingers, an N-terminal domain important for DNA recognition, and a C-terminal domain that mediates homo- and heteroty...

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