scholarly journals Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 5972-5979 ◽  
Author(s):  
James H. Morrissey ◽  
Sharon H. Choi ◽  
Stephanie A. Smith
Keyword(s):  
Blood Clotting ◽  
Molecular Mechanisms ◽  
Fibrin Clot ◽  
Human Platelets ◽  
Factor V ◽  
Inorganic Polyphosphate ◽  
Contact Pathway ◽  
Anticoagulant Function ◽  
Clot Structure

AbstractInorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated.

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

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4353-4359 ◽  
Author(s):  
Stephanie A. Smith ◽  
Sharon H. Choi ◽  
Rebecca Davis-Harrison ◽  
Jillian Huyck ◽  
John Boettcher ◽  
...  
Keyword(s):  
Blood Clotting ◽  
Fibrin Clot ◽  
Host Responses ◽  
Coagulation Cascade ◽  
Factor V ◽  
Differential Effects ◽  
Activated Platelets ◽  
Contact Pathway ◽  
Anticoagulant Function ◽  
Clot Structure

AbstractPolyphosphate, 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 (∼ 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.

Size Matters: Differential Effects of RNA and Polyphosphate on Blood Clotting

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3074-3074
Author(s):  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
Metal Ion ◽  
Blood Clotting ◽  
Factor Xa ◽  
Fibrin Clot ◽  
Factor V ◽  
Clotting Time ◽  
Yeast Trna ◽  
Clotting Cascade ◽  
Contact Pathway ◽  
Clot Structure

Abstract Introduction: Recently, both inorganic polyphosphate (Smith et al., PNAS103:903-8, 2006) and RNA (Kannemeier et al., PNAS104:6388–93, 2007) have been proposed as (patho)physiologic activators of the contact pathway in blood clotting. We also recently showed that polyphosphate of the size secreted by human platelets (approximately 75-mer) acts at two other points in the blood clotting cascade: it accelerates factor V activation and it enhances fibrin clot structure (Smith & Morrissey, Blood, in press). We now compare the ability of RNA and polyphosphate of varying chain lengths to modulate the blood clotting cascade at these three critical points: initiation, factor V activation, and fibrin polymerization. Methods: Polyphosphate was size-fractionated and its procoagulant activities were compared to those of polyinosinic acid, a synthetic singlestranded RNA (ssRNA); polyinosinic acid:polycytidylic acid, a synthetic double-stranded RNA (dsRNA); yeast tRNA or kaolin. Clotting assays were performed using purified fibrinogen, pooled normal plasma, or factor V-deficient plasma to which factor Va was added. Clotting was initiated by CaCl2 (contact pathway), factor Xa, or thrombin. Results: Long-chain polyphosphate (100-mer to 800-mer) triggered the contact pathway with a potency similar to kaolin and was about 30-fold more potent than ssRNA and some 3000- fold more potent than dsRNA or tRNA. Medium-chain polyphosphate (20-mer to 100-mer) and ssRNA both shortened factor Xa clotting times with similar potency, but dsRNA and yeast tRNA were without effect. Replacing plasma factor V with Va blocked the ability of either polyphosphate or ssRNA to shorten factor Xa clotting times, suggesting that both polymers accelerate factor V activation. And finally, when purified fibrinogen was clotted with thrombin, adding either ssRNA or polyphosphate yielded fibrin clots that were about threefold more turbid, indicating that both polymers enhance fibrin clot formation, while dsRNA and yeast tRNA were without effect. (We previously documented that polyphosphate enhances fibrin turbidity by dramatically increasing fibril diameter.) Interestingly, ssRNA significantly shortened the thrombin clotting time of purified fibrinogen, while polyphosphate had no effect on thrombin clotting times. Furthermore, the ability of polyphosphate to enhance fibrin clot structure was calcium-dependent, while ssRNA enhancement of fibrin clotting by thrombin was metal ion-independent. Conclusions: This study shows that RNA modulates critical downstream clotting functions in addition to its previously identified role in triggering the contact pathway. Long-chain polyphosphate (i.e., the size that accumulate in microorganisms, but not the size secreted by platelets) is substantially more potent than RNA in triggering the contact pathway of blood clotting. We therefore propose that polyphosphate may play an important role in host responses to pathogens by triggering the contact pathway. Polyphosphate of the size secreted by platelets had similar potency to ssRNA in accelerating factor V activation. And finally, polyphosphate of the size secreted by platelets had similar potency to RNA in enhancing fibrin clot structure, although the metal ion-dependencies of the two differed, as did their effects on thrombin clotting time. In general, ssRNA was far more potent than dsRNA or tRNA in modulating the blood clotting system.

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3942-3951 ◽  
Author(s):  
Joke Konings ◽  
José W. P. Govers-Riemslag ◽  
Helen Philippou ◽  
Nicola J. Mutch ◽  
Julian I. Borissoff ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Direct Interaction ◽  
Fibrin Clot ◽  
Fiber Density ◽  
Contact Pathway ◽  
Clot Structure ◽  
Fibrin Structure

Abstract Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombin-deficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and α-FXIIa, but not β-FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that FXIIa modulates fibrin clot structure independently of thrombin generation through direct binding of the N-terminus of FXIIa to fibrin(ogen). Modification of fibrin structure by FXIIa represents a novel physiologic role for the contact pathway that may contribute to the pathophysiology of thrombosis.

The Various Procoagulant Effects of PolyP Require Different Minimal Polymer Lengths.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1761-1761
Author(s):  
Stephanie A. Smith ◽  
Jillian Huyck ◽  
Sharon H. Choi ◽  
James H. Morrissey
Keyword(s):  
Tissue Factor ◽  
Inflammatory Responses ◽  
Maximal Activity ◽  
Human Platelets ◽  
Minimum Length ◽  
Factor V ◽  
Pathway Activation ◽  
Clotting Cascade ◽  
Contact Pathway ◽  
Anticoagulant Function

Abstract Introduction: Polyphosphates (polyP) are negatively charged, linear phosphate polymers found throughout biology. PolyP in prokaryotes and unicellular eukaryotes is typically hundreds of phosphate units long, while polyP in dense granules of human platelets is ∼75 phosphates long. PolyP is secreted upon platelet activation, and we recently reported that it is a potent hemostatic regulator, acting at multiple points in the clotting cascade: PolyP triggers the contact pathway, accelerates factor V activation, and abrogates the anticoagulant function of tissue factor pathway inhibitor (TFPI). Our previous experiments utilized relatively heterodisperse polyP preparations. We have now isolated polyP fractions of defined polymer lengths and here report the size dependence of the various procoagulant effects of polyP. Methods: PolyP preparations were carefully size-fractionated by gel electrophoresis (Clark and Wood, Anal. Biochem. 1987, 161:280–290). Clotting assays were performed using pooled normal plasma with or without added recombinant TFPI or 40–50 μM polyP. Clotting was initiated by tissue factor (TF), factor Xa (FXa), or CaCl2 alone (contact pathway). Results: Of the polyP procoagulant activities tested, triggering the contact pathway required the longest polymers: We observed weak triggering of the contact pathway with ∼75mers and increasing procoagulant activity as polymer lengths increased, with maximal contact pathway activation requiring 450mers or longer. On the other hand, the downstream procoagulant effects of polyP required significantly shorter polyP polymers. (When clotting is triggered by either TF or FXa, further shortening of clotting times by polyP is attributed to accelerated factor V activation.) Minimum polymer lengths required to shorten TF or FXa clot times were ∼37mers, with maximal activity requiring 75mers or longer. Finally, the ability of polyP to abrogate TFPI anticoagulant function required the shortest minimum polymer lengths: Detectable anti-TFPI activity was observed with 11mers, with maximal activity requiring 49mers or longer. Conclusions: PolyP exhibited different minimum length requirements for its various procoagulant effects, consistent with the idea that polyP interacts with different proteins at various points in the clotting cascade. Contact pathway activation required very long polymers that were similar in size to those in infectious microorganisms. Therefore, triggering of the contact pathway by polyP may contribute to procoagulant/inflammatory responses to infection. In contrast, acceleration of factor V activation by polyP was maximal with polymers of the size released from human platelets. Even shorter polyP polymers abrogated TFPI function, suggesting that at least some of polyP’s anti-TFPI effect may be mediated by mechanisms other than (or in addition to) its ability to accelerate factor V activation.

Short Polyphosphates Inhibit the Procoagulant Activities of Long-Chain Polyphosphate: A Novel Role for Platelet-Derived Pyrophosphate?.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1140-1140
Author(s):  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
Factor Xa ◽  
Fibrin Clot ◽  
Short Chain ◽  
Factor V ◽  
Fibrin Polymerization ◽  
Dense Granules ◽  
Contact Pathway ◽  
Clot Structure ◽  
Long Chain ◽  
Potent Inhibitory Activity

Abstract Abstract 1140 Introduction: Inorganic polyphosphates are negatively charged, linear phosphate polymers that influence hemostasis via accelerating factor V activation, triggering the contact pathway, and enhancing fibrin polymerization. The latter two effects require long-chain polyphosphates for optimal activity (>1000mers for activating the contact pathway and >250mers for enhancing fibrin polymerization). We explored whether short polyphosphates could inhibit the procoagulant effects of long polyphosphate polymers. Methods: Polyphosphate was size-fractionated by gel electrophoresis. “Long-chain polyphosphate” (LCP) was a heterogeneous polyphosphate preparation containing polymers ranging from 400 to several thousand phosphates long. Short-chain polyphosphate preparations were narrow fractions of homogeneous size. We also tested additional phosphate-containing molecules including ADP, ATP, monophosphate, pyrophosphate (PPi), and triphosphate. Clotting assays were performed using pooled normal plasma spiked with 0–20 μM LCP and 0–500 μM small (poly)phosphate; clotting was initiated by factor Xa plus CaCl2, or by CaCl2 alone (contact pathway). Fibrin was formed by clotting 2.6 mg/ml fibrinogen with 10 nM thrombin in the presence of 0–500 μM small (poly)phosphate plus 150 μM LCP and CaCl2. Results: Small polyphosphates (size range 23–83mer) reduced the ability of LCP to trigger the contact pathway of blood clotting, while monophosphate, PPi, triphosphate, ADP, and ATP all failed to influence the procoagulant activity of LCP. None of the small (poly)phosphates antagonized the ability of LCP to enhance factor V activation. Interestingly, monophosphate, PPi and triphosphate all inhibited the ability of LCP to enhance fibrin clot structure, with PPi being the most potent. Although ADP and ATP contain di- and tri-phosphates, they did not recapitulate the potent inhibitory activity of PPi. On the other hand, PPi had no measurable effect on the turbidity of fibrin clots formed in the absence of LCP. Conclusions: Short-chain polyphosphates inhibit the ability of LCP to initiate the contact pathway of coagulation. Platelet dense granules contain abundant PPi which is secreted in response to platelet agonists, although biological roles for platelet-secreted PPi are unclear. We propose that PPi is a novel modulator of fibrin clot structure, acting to regulate the effects of longer-chain polyphosphates on fibrin fibril formation. Disclosures: Smith: University of Illinois: Patents & Royalties. Morrissey:University of Illinois: Patents & Royalties.

scholarly journals Polyphosphate enhances fibrin clot structure

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2810-2816 ◽  
Author(s):  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
Fibrin Clot ◽  
Factor Xiiia ◽  
Clot Lysis ◽  
Factor V ◽  
Scanning Electron Micrographs ◽  
Dependent Manner ◽  
Dense Granules ◽  
Contact Pathway ◽  
Clot Structure ◽  
Fibrin Clots

Abstract Polyphosphate, a linear polymer of inorganic phosphate, is present in platelet dense granules and is secreted on platelet activation. We recently reported that polyphosphate is a potent hemostatic regulator, serving to activate the contact pathway of blood clotting and accelerate factor V activation. Because polyphosphate did not alter thrombin clotting times, it appeared to exert all its procoagulant actions upstream of thrombin. We now report that polyphosphate enhances fibrin clot structure in a calcium-dependent manner. Fibrin clots formed in the presence of polyphosphate had up to 3-fold higher turbidity, had higher mass-length ratios, and exhibited thicker fibers in scanning electron micrographs. The ability of polyphosphate to enhance fibrin clot turbidity was independent of factor XIIIa activity. When plasmin or a combination of plasminogen and tissue plasminogen activators were included in clotting reactions, fibrin clots formed in the presence of polyphosphate exhibited prolonged clot lysis times. Release of polyphosphate from activated platelets or infectious microorganisms may play an important role in modulating fibrin clot structure and increasing its resistance to fibrinolysis. Polyphosphate may also be useful in enhancing the structure of surgical fibrin sealants.

Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4486-4493 ◽  
Author(s):  
Gregor Theilmeier ◽  
Carine Michiels ◽  
Erik Spaepen ◽  
Ingrid Vreys ◽  
Désiré Collen ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Human Platelets ◽  
Platelet Glycoprotein ◽  
Perfusion Studies ◽  
Von Willebrand ◽  
Willebrand Factor

Platelets are thought to play a causal role during atherogenesis. Platelet-endothelial interactions in vivo and their molecular mechanisms under shear are, however, incompletely characterized. Here, an in vivo platelet homing assay was used in hypercholesterolemic rabbits to track platelet adhesion to plaque predilection sites. The role of platelet versus aortic endothelial cell (EC) activation was studied in an ex vivo flow chamber. Pathways of human platelet immobilization were detailed during in vitro perfusion studies. In rabbits, a 0.125% cholesterol diet induced no lesions within 3 months, but fatty streaks were found after 12 months. ECs at segmental arteries of 3- month rabbits expressed more von Willebrand factor (VWF) and recruited 5-fold more platelets than controls (P < .05, n = 5 and 4, respectively). The 3-month ostia had an increased likelihood to recruit platelets compared to control ostia (56% versus 18%, P < .0001, n = 89 and 63, respectively). Ex vivo, the adhesion of 3-month platelets to 3-month aortas was 8.4-fold increased compared to control studies (P < .01, n = 7 and 5, respectively). In vitro, endothelial VWF–platelet glycoprotein (GP) Ib and platelet P-selectin– endothelial P-selectin glycoprotein ligand 1 interactions accounted in combination for 83% of translocation and 90% of adhesion (P < .01, n = 4) of activated human platelets to activated human ECs. Platelet tethering was mainly mediated by platelet GPIbα, whereas platelet GPIIb/IIIa contributed 20% to arrest (P < .05). In conclusion, hypercholesterolemia primes platelets for recruitment via VWF, GPIbα, and P-selectin to lesion-prone sites, before lesions are detectable.

Polyphosphate Enhances Fibrin Clot Structure.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 403-403
Author(s):  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
High Energy ◽  
Fibrin Clot ◽  
Clot Formation ◽  
Length Ratio ◽  
Factor Xiiia ◽  
Clot Lysis ◽  
Cross Linking ◽  
Inorganic Polyphosphate ◽  
Calcium Dependent ◽  
Clot Structure

Abstract Introduction: Inorganic polyphosphate (polyP) is a negatively charged polymer of phosphate units linked by high energy phosphoanhydride bonds. Dense granules of human platelets contain polyP which is released in response to thrombin stimulation. We recently reported that polyphosphate is a potent hemostatic regulator, accelerating blood clotting by activating the contact pathway and promoting the activation of factor V. Our previous studies found that polyP did not affect the time to clot formation when plasma was clotted with thrombin, however, suggesting that polyP exerts its procoagulant actions upstream of thrombin. We now report that polyP enhances fibrin clot structure. Methods: Purified fibrinogen and polyP were preincubated for 15 min in multiwell plates in buffer containing CaCl2, after which clotting was initiated by adding 0.1 to 8 nM thrombin and fibrin clot formation was evaluated by quantifying the change in turbidity (A405). Mass-length ratios were calculated from scans of A400 to A800. The effect of polyP on fibrinolysis was examined by adding 8 nM plasmin to the reaction mixtures immediately prior to thrombin. Scanning electron microscopy (SEM) was employed to visualize clot structure, and time courses of covalent fibrin cross-linking were assessed by SDS-PAGE. Results: PolyP had no effect on time to clot formation, but clots formed in the presence of polyP had markedly (up to threefold) higher turbidity than clots formed in the absence of polyP (see figure), irrespective of thrombin concentration. The increased turbidity in the presence of polyP was calcium-dependent and was enhanced when fibrinogen, CaCl2, and polyP were preincubated for up to 15 min prior to initiation of clotting with thrombin. PolyP increased the mass-length ratio of fibrin, and SEM confirmed that fibers formed with polyP were thicker than those formed without polyP. The ability of polyP to enhance fibrin clot turbidity was independent of factor XIIIa activity, and polyP did not alter the rate or extent of covalent fibrin cross-linking by factor XIIIa. When plasmin was included in clotting reactions containing polyP, mean times to 50% clot lysis were 28.5 ± 0.8 min for clots without polyP but 120.4 ± 5.6 min for clots with polyP. Conclusions: PolyP alters polymerization of fibrin, resulting in fibers of higher mass-length ratio that are lysed more slowly. This effect is calcium-dependent and is enhanced by preincubation of fibrinogen with calcium and polyP. Release of polyP from activated platelets or infectious microorganisms may therefore enhance fibrin clot structure. Figure Figure

scholarly journals Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2462-2469 ◽  
Author(s):  
JP Collet ◽  
J Soria ◽  
M Mirshahi ◽  
M Hirsch ◽  
FB Dagonnet ◽  
...  
Keyword(s):  
Blood Clot ◽  
Fibrin Clot ◽  
Important Change ◽  
High Incidence ◽  
Gel Porosity ◽  
Clot Structure ◽  
The Relationship ◽  
Dose Dependent ◽  
Thrombotic Disorder

Fibrinogen Dusart is a congenital dysfibrinogenemia (A-alpha 554 Arginine-->Cysteine) associated with severe thrombotic disorder, high incidence of thrombotic embolism, and abnormal fibrin polymerization. This thrombotic disorder was attributed to an abnormal clot thrombolysis with reduced plasminogen binding to fibrin and defective plasminogen activation by tissue plasminogen activator. The purpose of this work was to assess whether clot architecture could be involved in the thromboresistance of the fibrin Dusart and the high incidence of embolism. An important change in Dusart fibrin clot structure was identified with dramatic decrease of gel porosity (Ks), fiber diameters (d), and fiber mass-length ratios (mu) derived from permeation analysis. In addition, rigidity of the Dusart clot was found to be greatly increased compared with normal fibrin. We provide evidence that both thrombolysis resistance and abnormal rigidity of the fibrin Dusart are related to this abnormal architecture, which impairs the access of fibrinolytic enzymes to the fibrin and which is responsible for a brittle clot that breaks easily, resulting in a high incidence of embolism. Indeed, when restoring a normal clot structure by adding dextran 40 (30 mg/mL) before coagulation, clot thrombolysis and clot rigidity recovered normal values. This effect was found to be dose- dependent. We conclude that clot architecture is crucial for the propensity of blood clot to be degraded and that abnormal clot structure can be highly thrombogenic in vivo. The alpha-C domains of fibrinogen are determinant in fibrin clot structure.

Poly-P as Modulator of Hemostasis, Thrombosis, and Inflammation

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-1-SCI-1
Author(s):  
James H. Morrissey
Keyword(s):  
Mammalian Cells ◽  
Research Funding ◽  
Blood Clotting ◽  
Anticoagulant Activity ◽  
Fibrin Clot ◽  
Factor V ◽  
Linear Polymers ◽  
Clotting System ◽  
Subsequent Work ◽  
Dense Granules

Polyphosphate (polyP), consisting of linear polymers of inorganic phosphates, is ubiquitous in biology. PolyP metabolism has been most extensively explored in microbes, but until very recently, roles for polyP in mammalian cells have been poorly understood. In 2004, polyP was shown to be a major component of dense granules in human platelets, and to be secreted upon platelet activation.1 In 2006, we demonstrated that polyP is a potent modulator of the blood clotting system.2 Subsequent work from our lab and others has shown that polyP accelerates blood clotting and slows fibrinolysis, in a manner that is highly dependent on polymer length.3 Long-chain polyP (present in infectious microorganisms) potently triggers the contact pathway and may participate in innate immunity/host responses to pathogens. PolyP of the size secreted by platelets (60 to 100 phosphates long) accelerates factor V activation, abrogates the anticoagulant activity of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. PolyP also enhances the proinflammatory activity of histones and inhibits complement. PolyP is a potential antithrombotic drug target, with a novel mechanism of action and possibly fewer bleeding side-effects compared to conventional anticoagulant drugs.4 1. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem . 2004;279(43):44250-44257. 2. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A . 2006;103(4):903-908. 3. Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost . 2015;13 Suppl 1:S92-97. 4. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood . 2014;124(22):3183-3190. Disclosures Morrissey: Novo Nordisk: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Paul, Weiss, Rifkind, Wharton & Garrison LLP: Consultancy; Cayuga Pharmaceuticals: Consultancy; PrevThro Pharmaceuticals: Equity Ownership; Kerafast, Inc.: Research Funding.

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