Pete Lollar, MD
Dr. Lollar indicated no relevant
conflicts of interest.
Müller F, Mutch NJ, Schenk WA, et al. Platelet
polyphosphates are proinflammatory and procoagulant mediators in vivo.
For the hematologist
lecturing on hemostasis, it has never been a pleasant task to march students
through the intrinsic pathway and then tell them that the initiating reactions
in the pathway apparently are not necessary in vivo. The intrinsic
pathway starts when blood comes into contact with a variety of negatively
charged surfaces, including non-physiological materials such as glass, kaolin,
and ellagic acid. Binding to these surfaces induces a conformational change in
factor XII (FXII) that allows it to proteolytically activate prekallikrein
(PK). PK proteolytically activates FXII, producing a positive feedback loop
that amplifies the system and leads to activation of FXI and cleavage of
high-molecular-weight kininogen (HK) by kallikrein. Cleavage of HK in turn
produces the inflammatory mediator bradykinin.
|Click image to enlarge
These contact activation reactions
represent the “activated” part of the activated partial thromboplastin time. However,
severe deficiencies of FXII, PK, or HK do not produce a bleeding diathesis, leading
to the teaching that the contact system is somewhat of an orphan in search of a
function. In fact, the first patient who was diagnosed with FXII deficiency,
John Hageman, died of pulmonary embolism. However, recent work in several laboratories
has indicated that the contact system may contribute to the formation of
pathologic intravascular thrombi.1
Now Müller et al. in the laboratory of
Thomas Renné, in collaboration with the laboratory of James Morrissey, provide
evidence that platelet or E. coli-derived polyphosphate (PolyP) provides
a surface for activation of FXII and the contact system and promotes a
prothrombotic/proinflammatory diathesis in mice. PolyP is linear polymer of ~60
to 100 orthophosphate units that is found widely in prokaryotes and eukaryotes.
Recently, PolyP was identified in platelet dense granules2 and found to have
procoagulant properties and antifibrinolytic properties.3
Müller et al. found that
plateletderived PolyP-dependent FXII activation resulted in proteolysis of HK
and release of bradykinin, leading to increased vascular permeability. FXII-deficient
and bradykinin receptor-deficient mice were resistant to PolyP-induced vascular
permeability. Intravenous infusion of platelet-derived PolyP produced lethal
pulmonary embolism in normal mice, which was significantly reduced in
FXII-deficient and/or FXI-deficient mice. A specific inhibitor of FXII also
protected against PolyP-induced pulmonary embolism. A thrombin receptor agonist,
TRAP6, also produced lethal pulmonary embolism in normal mice, which was
significantly decreased in FXII-deficient mice. Degradation of PolyP with
phosphatases inhibited contact activation in vivo and in vitro and
decreased platelet PolyP-induced thrombosis in mice. Additionally, E. coli-derived
PolyP initiated the activation of FXII, KK, and FXI and the production of
bradykinin. Finally, addition of PolyP restored the plasma clotting defect of
Hermansky–Pudlak syndrome platelets, which lack PolyP.
This study indicates that PolyP is a
potentially important mediator of platelet-driven proinflammatory and
procoagulant disorders. PolyP, thus, is a logical target for the development of
a new class of antithrombotic agents.
- Gailani D, Renné T. The
intrinsic pathway of coagulation: a target for treating thromboembolic disease?
J Thromb Haemost. 2007;5:1106-12.
- Ruiz FA, Lea CR, Oldfield E, et al.
platelet dense granules contain polyphosphate and are similar to
acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem.
- Smith SA, Mutch NJ, Baskar D, et al. Polyphosphate
modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA.
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