Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor

AbstractRefractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS) who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD) and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA) therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E) in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS

Antiplatelet factor 4/heparin antibodies in patients with gram negative bacteremia

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome of thrombocytopenia and prothrombotic state that follows exposure to heparin. However, spontaneous HIT has been described in the setting of infection, without evidence of previous heparin administration. Since PF4 binds to lipid A portion of lipopolysaccharide, we tested for the presence of antiPF4/heparin antibodies in patients with gram-negative bacteremia. Patients with bacteremia had higher titers of antiPF4/heparin antibodies compared to normal controls 26.3 +/- SD 34 units, N = 32 versus 6.3 +/- SD 2.38 units, N = 10, P = 0.001. FITC-labeled PF4 interacted with lipopolysaccharide in a concentration-dependent manner as determined by quenching of the emission spectrum following excitation at lambda 488. In addition, immunoaffinity purified antiPF4/Heparin antibodies from 3 patients with HIT cross-reacted with PF4/heparin complex. These results show that PF4/LPS complex is immunogenic and can elicit cross-reacting antibodies against PF4/Heparin, providing an explanation for the presence of these antibodies in individuals, who were never been exposed to heparin before. These antibodies may also be at least partly responsible for the thrombocytopenia associated with infection. Published by Elsevier Ltd

Ticagrelor induces paraoxonase-1 (PON1) and better protects hypercholesterolemic mice against atherosclerosis compared to clopidogrel.

Ticagrelor (TIC), a P2Y purinoceptor 12 (P2Y12)-receptor antagonist, has been widely used to treat patients with acute coronary syndrome. Although animal studies suggest that TIC protects against atherosclerosis, it remains unknown whether it does so through its potent platelet inhibition or through other pathways. Here, we placed hypercholesterolemic Ldlr-/-Apobec1-/- mice on a high-fat diet and treated them with either 25 mg/kg/day of clopidogrel (CLO) or 180 mg/kg/day of TIC for 16 weeks and evaluated the extent of atherosclerosis. Both treatments equally inhibited platelets as determined by ex vivo platelet aggregation assays. The extent of atherosclerosis, however, was significantly less in the TIC group than in the CLO group. Immunohistochemical staining and ELISA showed that TIC treatment was associated with less macrophage infiltration to the atherosclerotic intima and lower serum levels of CCL4, CXCL10, and TNFα, respectively, than CLO treatment. Treatment with TIC, but not CLO, was associated with higher serum activity and tissue level of paraoxonase-1 (PON1), an anti-atherosclerotic molecule, suggesting that TIC might exert greater anti-atherosclerotic activity, compared with CLO, through its unique ability to induce PON1. Although further studies are needed, TIC may prove to be a viable strategy in the prevention and treatment of chronic stable human atherosclerosis

A monoclonal antibody to human platelet glycoprotein Ilia detects a related protein in cultured human endothelial cells

We have previously described a series of monoclonal antibodies against platelet membrane glycoproteins. Two of the antibodies, B59.2 and B2.12, recognize the glycoprotein UIb-II1a complex. These two antibodies react specifically with glycoprotein (GP) IIla, as shown by immiunoblotting of sodium dodecyl sulfatepolyacrylamide gels of solubilized platelet membranes. Monoclonal B2.12, but not B59.2, binds to cultured human endothelial cells obtained from umbilical vein, internal iliac artery, and inferior vena cava. At saturation '100,000 binding sites were detected per human umbilical vein endothelial cell. When solubilized radioiodinated cells were chromatographed on a column of agarose-bound 82.12, a single radiolabeled protein was obtained whose apparent molecular weight is slightly larger than that of platelet GP IIIa. This protein incorporated I35Slmethionine when endothelial cells were labeled metabolically. These results demonstrate that human endothelial cell membranes synthesize a protein immunologically related to platelet GP IIIa