Review Article
The role of the red cell membrane in thrombin generation

https://doi.org/10.1016/j.thromres.2013.01.023Get rights and content

Abstract

Red blood cells have historically been viewed as innocent bystanders in the process of blood coagulation and thrombin generation; however a century of clinical evidence linking red blood cells to thrombosis suggests the contrary. In this brief review, the biochemical evidence for red blood cell involvement in thrombin generation is evaluated. It is concluded that in addition to platelets, red blood cells actively participate in thrombin generation. A sub-fraction of red blood cells express phosphatidylserine on their surface and unlike platelets, red blood cells produce thrombin through the meizothrombin pathway, which has interesting consequences in the context of clot formation and stabilization.

Section snippets

Background

Red blood cells (RBCs) are the most abundant cellular component of blood and have been extensively characterized since their initial observation in the late 1600s [1]. They make up the majority of the cellular fraction of blood, comprising 35–45% of the blood volume. The unique discoid shape (Fig. 1) of the RBC plasma membrane provides the biological and mechanical properties necessary to perform its primary role in hemoglobin-mediated oxygen transport throughout the body. In general, RBCs have

Red Blood Cells and Thrombin Generation

The first study directly examining the contribution of RBCs to thrombin generation was reported by Peyrou et al. in 1999 [27]. This group took advantage of the growing field of tissue factor-activated thrombin generation assays (TGA) [28] in platelet poor (PPP) and platelet rich plasma (PRP) to gain insight into the cellular contributions to thrombin generation. Owing to the complexity of the assay, the authors simplified it to directly measure the hemostatic properties of “normal” RBCs in

Conclusions

Thrombin generation occurs via an integrated enzymatic cascade that involves plasma, tissue, blood and cell components. Platelets have been traditionally viewed as the primary cellular component playing an active role in thrombin generation. Upon activation by thrombin and other activators, platelets support binding of the coagulation complexes (intrinsic factor Xase and prothrombinase) on their membranes which serves to localize thrombin generation near the site of vascular injury [10], [23],

Conflict of Interest Statement

Matt Whelihan has no conflicts of interest to declare. Ken Mann is consultant to Daiichi-Sankyo, Merck, Baxter, GTI, Alnylam, T2 Biosystems and chairman of the board of Haematologic Technologies, Inc.

Acknowledgments

KGM received funding from the National Institutes of Health P01HL046703.

References (77)

  • R.R. Hantgan et al.

    Assembly of fibrin. A light scattering study

    J Biol Chem

    (Nov 25 1979)
  • F.A. Kuypers et al.

    Detection of altered membrane phospholipid asymmetry in subpopulations of human red blood cells using fluorescently labeled annexin V

    Blood

    (Feb 1 1996)
  • B.L. Wood et al.

    Increased erythrocyte phosphatidylserine exposure in sickle cell disease: flow-cytometric measurement and clinical associations

    Blood

    (Sep 1 1996)
  • K.G. Mann et al.

    Citrate anticoagulation and the dynamics of thrombin generation

    J Thromb Haemost

    (Oct 2007)
  • S. Butenas et al.

    "Normal" thrombin generation

    Blood

    (Oct 1 1999)
  • C.M. Heldebrant et al.

    The activation of prothrombin. I. Isolation and preliminary characterization of intermediates

    J Biol Chem

    (May 25 1973)
  • C.M. Heldebrant et al.

    The activation of prothrombin. II. Partial reactions, physical and chemical characterization of the intermediates of activation

    J Biol Chem

    (Oct 25 1973)
  • S. Krishnaswamy et al.

    Activation of human prothrombin by human prothrombinase. Influence of factor Va on the reaction mechanism

    J Biol Chem

    (Mar 5 1987)
  • J.P. Wood et al.

    Prothrombin activation on the activated platelet surface optimizes expression of procoagulant activity

    Blood

    (Feb 3 2011)
  • L.M. Haynes et al.

    Prothrombin activation by platelet-associated prothrombinase proceeds through the prethrombin-2 pathway via a concerted mechanism

    J Biol Chem

    (Nov 9 2012)
  • P.Y. Kim et al.

    Further evidence for two functional forms of prothrombinase each specific for either of the two prothrombin activation cleavages

    J Biol Chem

    (Nov 9 2007)
  • H.C. Cote et al.

    Functional characterization of recombinant human meizothrombin and Meizothrombin(desF1). Thrombomodulin-dependent activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI), platelet aggregation, antithrombin-III inhibition

    J Biol Chem

    (Mar 7 1997)
  • P.B. Tracy et al.

    Human prothrombinase complex assembly and function on isolated peripheral blood cell populations

    J Biol Chem

    (Feb 25 1985)
  • P.B. Tracy et al.

    Functional prothrombinase complex assembly on isolated monocytes and lymphocytes

    J Biol Chem

    (Jun 25 1983)
  • M.F. Whelihan et al.

    Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation

    Blood

    (Nov 1 2012)
  • A. Szczeklik et al.

    Antiplatelet drugs and generation of thrombin in clotting blood

    Blood

    (Oct 15 1992)
  • M.D. Rand et al.

    Blood clotting in minimally altered whole blood

    Blood

    (Nov 1 1996)
  • P.A. Aarts et al.

    Red blood cell deformability influences platelets–vessel wall interaction in flowing blood

    Blood

    (Dec 1984)
  • P. Hermand et al.

    Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3 integrin

    J Biol Chem

    (Feb 14 2003)
  • M.R. van Schravendijk et al.

    Normal human erythrocytes express CD36, an adhesion molecule of monocytes, platelets, and endothelial cells

    Blood

    (Oct 15 1992)
  • H.C. Cote et al.

    Characterization of a stable form of human meizothrombin derived from recombinant prothrombin (R155A, R271A, and R284A)

    J Biol Chem

    (Apr 15 1994)
  • M. Kalafatis et al.

    The mechanism of inactivation of human factor V and human factor Va by activated protein C

    J Biol Chem

    (Dec 16 1994)
  • A. Tefferi

    Polycythemia vera: a comprehensive review and clinical recommendations

    Mayo Clin Proc

    (Feb 2003)
  • B.N. Setty et al.

    Thrombophilia in sickle cell disease: the red cell connection

    Blood

    (Dec 1 2001)
  • A. Eldor et al.

    The hypercoagulable state in thalassemia

    Blood

    (Jan 1 2002)
  • M. Bessis et al.

    Discovery of the red blood cell with notes on priorities and credits of discoveries, past, present and future

    Blood Cells

    (1981)
  • K.G. Mann

    The coagulation explosion

    Ann N Y Acad Sci

    (Apr 18 1994)
  • Y. Komiyama et al.

    Proteolytic activation of human factors IX and X by recombinant human factor VIIa: effects of calcium, phospholipids, and tissue factor

    Biochemistry

    (Oct 9 1990)
  • Cited by (70)

    View all citing articles on Scopus
    View full text