Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces

Bäck, Jennie; Lang, Markus; Elgue, Graciela; Kalbitz, Miriam; Sánchez, Javier; Ekdahl, Kristina Nilsson; Nilsson, Bo

doi:10.1016/j.biomaterials.2009.07.052

Cited by 34 publications

(53 citation statements)

References 22 publications

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“…This may explain a recent report that polyP type 65 (from the same commercial source as in this study) was very effective at promoting FXII autoactivation in plasma, but much less effective at promoting FXI or prekallikrein activation. 22 Enzymes of the contact pathway participate in a variety of (patho)physiologic processes other than triggering blood clotting, including blood-pressure regulation as well as modulating fibrinolysis, angiogenesis, and apoptosis; in fact, this system has been described as the plasma kallikrein-kinin system, because prekallikrein can be activated on cell surfaces independently of FXII. 23 It is possible that shorter polyP polymers may promote the activation of some of the enzymes of the contact pathway, even when this does not lead to actual clot formation, an idea that we are investigating further.…”

Section: Discussionmentioning

confidence: 99%

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Smith¹,

Choi²,

Davis-Harrison³

et al. 2010

Blood

264

423

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Polyphosphate, a linear polymer of inorganic phosphate, is secreted by activated platelets and accumulates in many infectious microorganisms. We recently showed that polyphosphate modulates the blood coagulation cascade at 3 steps: it triggers the contact pathway, it accelerates factor V activation, and it enhances fibrin polymerization. We now report that polyphosphate exerts differential effects on blood clotting, depending on polymer length. Very long polymers (> 500mers, such as those present in microorganisms) were required for optimal activation of the contact pathway, while shorter polymers (ϳ 100mers, similar to the polymer lengths released by platelets) were sufficient to accelerate factor V activation and abrogate the anticoagulant function of the tissue factor pathway inhibitor. Optimal enhancement of fibrin clot turbidity by polyphosphate required > 250mers. Pyrophosphate, which is also secreted by activated platelets, potently blocked polyphosphate-mediated enhancement of fibrin clot structure, suggesting that pyrophosphate is a novel regulator of fibrin function. In conclusion, polyphosphate of the size secreted by platelets is very efficient at accelerating blood clotting reactions but is less efficient at initiating them or at modulating clot structure. Microbial polyphosphate, which is highly procoagulant, may function in host responses to pathogens. IntroductionPolyphosphate (polyP)-a linear polymer of inorganic phosphateaccumulates in a variety of microorganisms 1 and is secreted by activated human platelets. 2,3 We recently showed that polyP is a potent modulator of the human blood-clotting system. [3][4][5][6] The polymer lengths of polyP are known to vary substantially among different organisms and cell types, with relatively short polymers being secreted by human platelets (ϳ 60-100 phosphate units long) 2,3 and very long polymers accumulating in microorganisms (many hundreds to more than 1000 phosphate units long). 1 In this study, we demonstrate that shorter versus longer polymers of polyP have differential effects on the blood clotting system, with important physiologic/pathophysiologic implications. PolyP has been widely described in unicellular organisms such as bacteria, fungi, algae, and protozoa, where it plays diverse physiologic roles, including regulating growth, stress responses, and virulence. 1,7 Comparatively less is known about the metabolism or physiologic roles of polyP in mammalian cells, 8 although polyP is reported to induce apoptosis in plasma cells, 9 promote calcification in osteoblasts, 10 block metastasis of melanoma cells in a mouse model, 11 and possibly serve as a regulatory factor in proliferative signaling pathways. 12 PolyP is present at high concentrations in dense granules of human platelets and is secreted upon platelet activation. 2,3 PolyP has a half-life in plasma of approximately 90 minutes, because of degradation by phosphatases. 4,13 We recently showed that polyP is a potent hemostatic regulator, acting at 3 points in the blood clotting cascade: it...

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Section: Discussionmentioning

confidence: 99%

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Smith¹,

Choi²,

Davis-Harrison³

et al. 2010

Blood

264

423

View full text Add to dashboard Cite

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“…24 The use of CTI in our assay prevents FXII activated during plasma preparation from influencing thrombin generation, but at the same time allows the intrinsic pathway to function when platelets are present because CTI is much less effective at inhibiting FXIIa generated by activated platelets than that formed in solution. 25 In CTI-inhibited PRP, no thrombin was detected in the control sample during the course of the experiment, whereas a clear dose-dependent enhancement of thrombin generation was still induced by histones ( Figure 1B), with an obvious shortening of the lag time and time-to-peak (about 4-fold reduction between the highest and the lowest concentrations), a striking increase of the peak (7-fold augmentation), and a more modest rise of the ETP (1.5-fold increase; Figure 1C). Similar results were obtained in whole blood based on the measurement of prothrombin fragment 1 and 2 (data not shown).…”

Section: Histones Promote Thrombin Generation In Prp Through Plateletmentioning

confidence: 99%

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Semeraro

Ammollo

Morrissey

et al. 2011

Blood

722

684

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The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process. (Blood. 2011;118(7):1952-1961) IntroductionHistones are cationic proteins that associate with DNA in nucleosomes and are involved in chromatin remodeling and regulation of gene transcription. Despite their physiologic nuclear localization, nucleosomes have been found in the circulation of both healthy subjects and patients, where they can be released from dying cells 1 or actively secreted by activated inflammatory cells (neutrophils, basophils, and mast cells) in the form of "extracellular traps," complex structures of DNA strands, histones, and cell-specific granule proteins. 2,3 High blood levels of nucleosomes have been detected in several inflammatory, ischemic, autoimmune, and neoplastic diseases 4 ; in some cases, a correlation with disease severity has been found. 5 Whether extracellular nucleosomes are merely bystanders or active mediators in disease and which role histones play are important emerging questions. Histones are known to possess cytotoxic properties against both microorganisms 6 and eukaryotic cells. 7 Xu et al 8 reported that extracellular histones behave as late mediators of cell damage and organ dysfunction during the hyperinflammatory reaction that characterizes sepsis, as shown by the efficacy of a neutralizing antibody against histone H4 in reducing mortality in several experimental models of murine sepsis. Moreover, direct injection of histones into mice resulted in death with pathologic lesions suggestive of a massive prothrombotic response similar to that found in sepsis, including diffuse microvascular thrombosis, fibrin and platelet deposition in the lung alveoli, and intra-alveolar hemorrhage. Fuchs et al 9 rec...

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“…FXIIa and FXIa, which are activated on platelet surfaces, are preferentially regulated by antithrombin (AT) rather than by C1 inhibitor (C1INH), the favored regulator when these enzymes are activated on arti fi cial surfaces (Bäck et al 2009 . The mechanism by which activated platelets affect complement involves the release of chondroitin sulfate A (CS-A), a potent activator of complement, leading to generation of the anaphylatoxins C3a and C5a and subsequent leukocyte activation, as revealed by the upregulation of CD11b and formation of leukocyte-platelet complexes (Hamad et al 2008(Hamad et al , 2010a .…”

Section: Examples Of Cross Talk Between Blood Cascade Systems and Cellsmentioning

confidence: 99%

Evaluation of the Blood Compatibility of Materials, Cells, and Tissues: Basic Concepts, Test Models, and Practical Guidelines

Ekdahl

Hong

Hamad

et al. 2012

Complement Therapeutics

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Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation. Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation. Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.

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Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces

Cited by 34 publications

References 22 publications

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Evaluation of the Blood Compatibility of Materials, Cells, and Tissues: Basic Concepts, Test Models, and Practical Guidelines

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