scholarly journals Activated platelets kill Staphylococcus aureus , but not Streptococcus pneumoniae —The role of FcγRIIa and platelet factor 4/heparinantibodies

2020 ◽  
Vol 18 (6) ◽  
pp. 1459-1468 ◽  
Author(s):  
Martina Wolff ◽  
Stefan Handtke ◽  
Raghavendra Palankar ◽  
Jan Wesche ◽  
Thomas P. Kohler ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Activated Platelets

Heparin Neutralizing Activity in the Diagnosis of Acute Myocardial Infarction

1975 ◽  
Author(s):  
J. R. O’Brien ◽  
M. D. Etherington ◽  
S. Jamieson ◽  
J. Sussex
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Chest Pain ◽  
Acute Chest Pain ◽  
Platelet Factor 4 ◽  
Clotting Time ◽  
Platelet Factor ◽  
Neutralizing Activity ◽  
Platelet Poor Plasma ◽  
Activated Platelets

We have previously demonstrated that, relative to controls, patients long after myocardial infarction and patients with atherosclerosis have highly significantly shorter heparin thrombin clotting times (HTCT) using platelet poor plasma; but there was considerable overlap between the two groups.We have now studied 89 patients admitted with acute chest pain. In 54 of these a firm diagnosis of acute myocardial infarction (ac-MI) was made and the HTCT was very short (mean 12.8 sees) and in 48 it was less than 16 sees. In 34 patients, ac-MI was excluded and the diagnosis was usually “angina”; the HTCT was much longer (mean 25.1 sees) and in 32 it was over 16 sees. Thus there was almost no overlap between these two groups. It is suggested that this test should be adopted as a quick and reliable further test to establish a diagnosis of ac-MI (providing other reasons for very short HTCTs can be excluded, e.g. D. I. C., and provinding the patient’s thrombin clotting time is normal).This HTCT measures non-specific heparin neutralizing activity; nevertheless the evidence suggests that it is measuring platelet factor 4 liberated from damaged or “activated” platelets into the plasma. These findings underline the probable important contribution of platelets in ac-MI.

Molten globule monomer to condensed dimer: role of disulfide bonds in platelet factor-4 folding and subunit association

Biochemistry ◽  
1992 ◽  
Vol 31 (48) ◽  
pp. 12255-12265 ◽  
Author(s):  
Kevin H. Mayo ◽  
Sharon Barker ◽  
Michael J. Kuranda ◽  
Anthony J. Hunt ◽  
Jill A. Myers ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Molten Globule ◽  
Platelet Factor 4 ◽  
Platelet Factor

scholarly journals The Role of Platelet Factor 4 in Local and Remote Tissue Damage in a Mouse Model of Mesenteric Ischemia/Reperfusion Injury

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e39934 ◽  
Author(s):  
Peter H. Lapchak ◽  
Antonis Ioannou ◽  
Poonam Rani ◽  
Linda A. Lieberman ◽  
Kazuhisa Yoshiya ◽  
...  
Keyword(s):  
Mouse Model ◽  
Reperfusion Injury ◽  
Tissue Damage ◽  
Mesenteric Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Platelet Factor 4 ◽  
Platelet Factor

The role of platelet factor 4 in platelet aggregation induced by the antibodies implicated in heparin-induced thrombocytopenia

2001 ◽  
Vol 12 (7) ◽  
pp. 511-520 ◽  
Author(s):  
G. T. Gerotziafas ◽  
I. Elalamy ◽  
C. Lecrubier ◽  
J. Lebrazi ◽  
M. Mirshahi ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia

scholarly journals Conditional Knockout of LRP1 in Murine Megakaryocytes and Its Affects on Platelet Factor 4 Biology in Megakaryocytes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4150-4150
Author(s):  
Michele P Lambert ◽  
Liqing Xiao ◽  
Mortimer Poncz
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Steady State ◽  
Platelet Factor 4 ◽  
Conditional Knockout ◽  
Platelet Factor ◽  
Paracrine Effects ◽  
Animal Survival ◽  
Count Recovery

Abstract We have previously shown that platelet factor 4 (PF4, CXCL4), which is synthesized almost exclusively by megakaryocytes undergoes release intramedullary after which it can undergo reuptake into alpha-granules, but also can be an important negative paracrine regulator of megakaryopoiesis, effecting platelet recovery post-radiation or chemotherapy. Animals that express high levels of human (h) PF4 in addition to their normal levels of murine (m) PF4 (hPF4+) have increased sensitivity to radiation- and chemotherapy-induced thrombocytopenia when compared to wild type (WT) mice or to mice that lack endogenous PF4 (mPF4-/-). Both PF4 reuptake and the negative paracrine effects are at least partially dependent upon the presence of low-density lipoprotein receptor related protein-1 (LRP1) on the surface of megakaryocytes as shown using shRNA suppression of megakaryocyte LRP1 levels. To further understand the role of LRP1 in megakaryopoiesis, we studied LRP1 expressed on primary megakaryocytes in murine models. Homozygous knockout for LRP1 constitutively is embryonically lethal and heterozygous deficiency of LRP1 is insufficient to have an observed effect on PF4 biology. We now established a megakaryocyte-specific knockout of LRP1 using a floxed LRP1 mouse previously described by Rohlman et al, mated to the Cre- PF4 promotor-driven Cre recombinase (Cre+) mice previously described by Tiedt et al. Megakaryocytes from mice that were LRP1fl/fl/Cre+ had no detectable LRP1 mRNA or LRP1 surface protein expression by flow cytometry, while LRP1fl/fl/Cre- mice were essentially identical to WT mice. Baseline platelet counts in LRP1fl/fl/Cre+ and LRP1fl/fl/Cre- mice did not different from each other, and there was no difference in bone marrow derived megakaryocyte ploidy. PF4 available in platelet releasate of LRP1fl/fl/Cre+ platelets was also significantly less than in LRP1fl/fl/Cre- platelets (208 ± 42 vs. 362 ± 47 IU/106 platelets, p=0.002) consistent with a role of LRP1 in PF4 reuptake into megakaryocytes in the steady-state and demonstrating that >42% of PF4 may be released during PF4 megakaryopoiesis and requires megakaryocyte LRP1 expression. In siru cultured LRP1fl/fl/Cre+ megakaryocytes exposed to exogenous hPF4 has a lower level of total PF4 levels than LRP1fl/fl/Cre- megakaryocytes (191 ± 7 vs. 236 ± 17 IU/106 cells, respectively (p=0.03)). A similar effect was seen in liquid bone marrow culture assays. Finally, while LRP1fl/fl/Cre+/hPF4+ mice had similar platelet count recovery after irradiation compared to LRP1fl/fl/Cre+/WT mice, treatment of these mice with a heparin-derivative (ODSH) shown to significantly improve platelet count recovery and animal survival in both WT and hPF4+ mice had no effect on either platelet count recovery or animal survival in animals that were also LRP1fl/fl/Cre+. These data demonstrate that nearly half of the total PF4 in megakaryocytes undergoes recycling in vivo and that LRP1 is important for this phenomenon in the steady-state. LRP1 is also important in the negative paracrine effect of PF4 in stress megakaryopoiesis though LRP1 may affect megakaryocyte biology by non-PF4-dependent pathways as well. Whether the two observations – PF4 uptake and negative paracrine effects – are mechanistically related or are distinct LRP1-dependent pathways now needs to be elucidated. Disclosures Xiao: ECRI Institute: Employment.

scholarly journals Role of kidney in the catabolic clearance of human platelet antiheparin proteins from rat circulation

Blood ◽  
1981 ◽  
Vol 57 (2) ◽  
pp. 233-238
Author(s):  
CP Bastl ◽  
J Musial ◽  
M Kloczewiak ◽  
J Guzzo ◽  
I Berman ◽  
...  
Keyword(s):  
Renal Excretion ◽  
Kidney Tissue ◽  
Rat Plasma ◽  
Renal Tissue ◽  
Human Platelets ◽  
Platelet Factor 4 ◽  
Metabolic Clearance ◽  
Platelet Factor ◽  
Functioning Kidney

Stimulated platelets release at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4) from which beta-thromboglobulin (beta TG) is derived. We have found previously marked elevation of LA-PF4/beta TG antigen in platelet poor plasma of patients with chronic renal failure, whereas levels of PF4 remained normal. Therefore, we examined the role of the kidneys in the metabolic clearance of LA-PF4/beta TG and PF4. The supernates of aggregates of thrombin-stimulated human platelets were injected into sham operated control rats, nephrectomized rats, and into rats with acute ureteral ligation. The disappearance of human LA-PF4/beta TG antigen and PF4 in rat plasma determined by specific radioimmunoassays followed biphasic exponential curves. The half-lives (t1/2) for the fast and slow components of LA-PF4 in control rats were 6.4 and 68.4 min. Nephrectomy significantly increased these times to 9.7 and 144 min, while ureteral ligation resulted in no significant change. Comparison of the level of LA-PF4/beta TG antigen and of creatinine in aorta and in renal vein showed 25%-30% extraction of these compounds by the kidney. Less than 0.1% of the total LA-PF4 antigen injected was recovered in the urine of control rats. In contrast to these results, the clearance of PF4 was not affected by nephrectomy. In conclusion: (1) functional renal tissue is necessary for normal clearance of LA- PF4/beta TG, but renal excretion does not play a major role in its elimination suggesting that the protein is catabolized by the kidney; and (2) catabolic clearance of PF4 does not depend on functioning kidney tissue.

Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 924-930 ◽  
Author(s):  
Philipp von Hundelshausen ◽  
Rory R. Koenen ◽  
Markus Sack ◽  
Sebastian F. Mause ◽  
Wencke Adriaens ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Cell Types ◽  
Platelet Factor 4 ◽  
Flow Conditions ◽  
Monocytic Cells ◽  
Platelet Factor ◽  
Activated Platelets ◽  
Progenitor Cell Proliferation ◽  
Multiple Cell ◽  
Inhibition Studies

AbstractThe chemokines platelet factor 4 (PF4) and RANTES (regulated on activation normal T cell expressed and secreted) are secreted by activated platelets and influence multiple cell types and biologic processes. For instance, PF4 inhibits progenitor cell proliferation and angiogenesis, while platelet-derived RANTES is involved in vascular recruitment of monocytes. However, little is known about functional interactions of PF4 and RANTES. Here we show that the presence of PF4 enhanced the arrest of RANTES-stimulated monocytes and monocytic cells on activated endothelial cells under flow conditions, while binding of PF4 to the monocyte surface was increased by RANTES. Both RANTES-triggered arrest and PF4 binding involved monocytic chondroitin sulfate. Ligand blots and surface plasmon resonance revealed a robust heterophilic interaction of PF4 with RANTES but not with RANTES variants defective in higher order oligomerization. The tetrameric mutant E26A bound to the monocyte surface without increasing PF4 binding, and monocyte arrest induced by E26A-RANTES was not enhanced by PF4. Stimulation of monocytes with supernatants of activated platelets triggered arrest involving RANTES and PF4, as shown by inhibition studies. Our results suggest that heterophilic interactions with PF4 require structural motifs important in RANTES oligomerization and amplify RANTES-triggered effects on monocyte adhesion. This may have implications for the modulation of inflammatory recruitment by platelet-derived chemokines.

A Proposed Role for Platelet Factor 4 in Histone Pathobiology in Sepsis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 98-98
Author(s):  
M. Anna Kowalska ◽  
Guohua Zhao ◽  
Ian Johnston ◽  
Elsa Treffeisen ◽  
Fatoumata Diarra ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Positive Charge ◽  
Conflicts Of Interest ◽  
Peak Effect ◽  
Platelet Factor 4 ◽  
Vascular Damage ◽  
Platelet Factor ◽  
Competitive Binding Assay ◽  
Activated Platelets ◽  
Bell Shaped Curve

Abstract Sepsis is a high-risk clinical setting often resulting in multi-organ failure and death. Release of chromatin NETS (neutrophil extracellular traps) from neutrophils and the toxic role of highly-positively charged histones in late sepsis have been noted previously. Also, for NET formation to occur, peptidylarginine deiminase 4 activity must be present in the neutrophils, leading to citrullinated (cit) histones formation and loss of a portion of the positive charge. The four histones (H2A, H2B, H3 and H4) alone and as octamers of the four units tightly bind DNA. H3 and H4 histones as well as mixed octameric histones can induce a sepsis-like state in mice. One feature previously noted was that histones could inhibit activated protein C (aPC) production in the presence of thrombomodulin (TM). Since aPC generation is felt to protect against vascular damage, it was felt that this might - in part - account for the deleterious effects of histones in sepsis. We have shown that another highly-positive, small molecule, platelet factor 4 (PF4, CXCL4), which exists as a tetramer and which is stored in high concentrations in platelet alpha granules to be released in large amounts post-platelet activation, binds to the chondroitin sulfate (CS) side-chain of TM (TMCS) and enhanced aPC production along a bell-shaped curve with a peak effect around 25 µg/ml. Non-modified mixed histones had a similar bell-shaped effect on aPC generation and [histones + PF4] are additive on affecting aPC generation via TMCS. We wondered, because of this overlapping biology and the fact that significant levels of free PF4 are available in late sepsis, whether PF4 might affect other histone pathobiological pathways in late sepsis focusing on PF4’s interactions with non-modified and cit-histones. We first asked whether released PF4 might affect the binding of histones to DNA within NETS. We found that PF4 binds to DNA with greater affinity than histones in a competitive binding assay and that this effect was more marked for cit-histone consistent with its decreased positive charge. We then studied PF4 biology in three known targets of histone in sepsis. (1) In aPC generation, we examined cit-histones (either mixed, H3 or H4) relative to non-modified histones in stimulating aPC generation and found that they had a more limited effect on aPC generation with TMCS, but that again, PF4 cooperated in inducing aPC generation along a bell-shaped curve. (2) Histones are known to activate platelets (known to involve the toll-like receptor 4), likely contributing to the observed thrombocytopenia in late sepsis. We affirmed this affect with mixed histones and H4. Cit-mixed histones and cit-H4 also activated platelets in a platelet aggregation system, but much more weakly. PF4 had no effect on platelet activation by non-modified histones, but enhanced platelet activation by both cit-mixed histones and cit-H4. This was especially true for platelet activation studies with cit-H4 which on its own had nearly no affect on platelet activation though in the presence of moderate levels of PF4 (25 µg/ml), cit-H4 activated platelets as well as non-modified histones. (3) Finally, both non-modified and cit-histones activate endothelial cells (EC) by binding to their cell surfaces and likely contribute to the vascular damage of late sepsis. Using a microfluidic system involving controlled photochemical injury of the EC lining we found that PF4 enhanced the observed damage after cit-H4 exposure, but not notably after a comparable H4 exposure so that peak damage (as detected by propidium iodide staining) after cit-H4 approached that seen after H4 alone. In conclusion, NET formation involves citrullination of histones, and these modified histones likely contribute significantly to pathobiology in late sepsis. We now propose that in late sepsis, free histones, especially cit-histones, are mobilized out of NETs by PF4 because the PF4 binds DNA with higher affinity. After the histones and cit-histones are released from DNA, PF4 modifies the biology of these histones, especially the cit-histones enhancing their effects on aPC generation, platelet activation and EC injury. These studies provide additional insights of how histones achieve their pathobiological effects in sepsis. Such new insights may be critical for both understanding and monitoring clinical outcome and may lead to new therapeutic targets in sepsis. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document