Visions & Reflections
The search for a unified theory of coagulation
and inflammation
A. Veldman* and D. Fischer
Division Neonatology, NICU, Department of Pediatrics, J. W. Goethe University Hospital, Theodor Stern Kai 7,
60590 Frankfurt (Germany), Fax: +49 69 6301 4757, e-mail: alex.veldman@kgu.de
Received 10 March 2004; received after revision 4 July 2004; accepted 12 July 2004
CMLS, Cell. Mol. Life Sci. 61 (2004) 2744– 2749
1420-682X/04/212744-06
DOI 10.1007/s00018-004-4106-z
© Birkhäuser Verlag, Basel, 2004
CMLS
Cellular and Molecular Life Sciences
Key words. Coagulation; inflammation; model; tissue factor; signaling.
Coagulation is an essential phenomenon in the living
macro-organism. For centuries, theories have been devel-
oped by scientists to describe clotting and fibrinolysis
and to predict the physiology and pathophysiology of this
system. Almost all of these theories, including the so-
called cascade model developed by Davie and Ratnoff [1]
and MacFarlane [2] in 1964, exhibited the properties of
what philosopher Sir Karl Raimund Popper called a good
scientific theory: they made definite predictions which
could be tested by observation and, possibly, rejected.
Unfortunately for the theories, they were rejected along
with many others. To have a theory rejected is hard for
scientists who have worked with or, even worse, devel-
oped the theory to accept. However, rejection of theories
almost always implies significant progress in thinking
and results in a new theory which extends the old theory
in accomodating a wider range of observations in one
model. The result, therefore is both scientific progress
and another theory waiting to be falsified. Refuting basic
beliefs paves the way for advancement.
The cascade theory described blood clotting as two series
(intrinsic and extrinsic) of proteases cleaving and activat-
ing the following factor converging at the activation of
factor X (FX) to FXa with the following activation of pro-
thrombin (FII) into thrombin (FIIa) and subsequent acti-
vation of fibrinogen to fibrin by FIIa. While being useful
tool to describe pathologic results in the in vitro coagula-
tion tests prothrombin time (PT) and activated partial
*
Corresponding author.
thromboplastin time (aPTT), the theory was not consis-
tent with the clinical observations that deficiencies of
some proteins in the cascade remain almost nonsympto-
matic, whereas lack of others causes severe hemophilia.
Additionally, the observation that some proteases not
only activate the following factor in the cascade but also
factors upstream and in the other pathway disturbed our
classical understanding of coagulation as a row of domi-
noes. The initiator of the extrinsic pathway, the tissue fac-
tor/factor VII (TF/FVII) complex, can not only activate
FX but also one of the enzymes of the intrinsic pathway,
factor IX (FIX). These features, in combination with the
observation that factor XI (FXI) can be directly activated
by thrombin on the surface of activated platelets in vivo
explain why factor XII (FXII), as well as high-molecular-
weight kininogen (HMK) and pre-kallikrein (PK) might
not be required for successful hemostasis. Inspired by this
contradiction, almost 40 years after the cascade model, a
cell-based model of coagulation was developed by Hoff-
man and Monroe in 2001 [3].
In this model, the process of hemostasis is described in
three phases: initiation, amplification and propagation.
The mainstay of hemostasis initiation in this model is the
exposure of a TF-bearing cell to the blood flow. Fibro-
blasts in the subendothelial matrix and, in sepsis and en-
dotoxin exposure, endothelial cells and blood mononu-
clear cells rapidly express TF which is an integral mem-
brane protein and does not usually circulate in plasma.
However, one possible source of TF in plasma are mi-
croparticles (MPs) originating from platelets or granulo-