Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 703-704
CORRESPONDENCE
The Role of Factor XII in Contact System Activation
 |
LETTER |
To the Editor:
Although the excellent review on the contact system by Colman and
Schmaier1 that appeared recently in Blood examines
the subject in great detail, there are some points that deserve further discussion.
A major item in that review is the novel observation, described
recently in Blood,2 that prekallikrein (PK)
becomes activated when it is bound to high molecular weight kininogen
(HK) on endothelial cells, independently of factor XII. This activation
is mediated by an ill-defined cell-associated thiol-protease and is
said to be regulated by HK, because increasing concentrations of HK
upregulate this unknown protease. The investigators speculate that this
novel mechanism may be the predominant activation pathway for the
contact system in vivo, because it does not require an artificial
surface. However, some considerations need to be made. First, the
stimulus for this novel activation mechanism of PK is unclear. The
investigators mention that increasing HK concentrations trigger the
activation of PK by upregulating the thiol-protease. In the original
study describing this novel pathway, activation of PK was observed at
concentrations of HK of 20 nmol/L,2 which is more than
30-fold lower than the plasma concentration of HK.1 So,
this factor XII-independent activation of PK should be turned on under
physiological conditions and may explain why normal persons have higher
levels of kallikrein-C1-inhibitor than of factor
XIIa-C1-inhibitor.3 However, as it is now, this pathway does not provide an explanation for enhanced contact activation under
pathophysiological conditions, because under these conditions HK levels
do not increase markedly. For example, we have observed activation of
PK (and factor XII) in patients with insect sting-induced angioedema
and shock, which was accompanied by decreasing rather then increasing
concentrations of HK.4 Second, there is in vivo evidence
for a factor XII-dependent activation of PK. We have observed
activation of PK in healthy persons upon intravenous injection of
desamino D-arginine vasopressin (DDAVP).5 This activation
was not observed in factor XII-deficient persons,5 indicating the existence of a factor XII-dependent activation of PK in
vivo (and, notably, not triggered by an artificial surface). In our
experience, activation of PK in clinical situations is often, if not
always, accompanied by activation of factor XII, which is not expected
in case of a factor XII-independent activation of PK. Therefore, factor
XII-dependent activation of PK likely predominates contact activation
under pathophysiological conditions.
A second comment concerns the fibrinolytic activities of the contact
system. In their review, Colman and Schmaier1 propose that
factor XII-independent activation of prekallikrein on endothelial cells
is involved in two pathways for fibrinolysis, one involving the release
of tissue-type plasminogen activator induced by bradykinin and another
involving the activation of pro-urokinase by kallikrein. They do not
mention the existence of another fibrinolytic pathway involving the
contact system, ie, factor XII-dependent activation of plasminogen.
There is in vivo evidence for the existence of this pathway, which is
independent of kallikrein and urokinase.5 Direct activation
of plasminogen by factor XIIa is often considered to be an unlikely
scenario for this pathway, because plasminogen is a too poor substrate
for this contact enzyme. For example, 
-factor XIIa is about 300,000 times less active then urokinase in activating plasminogen. However, we
have recently observed that the interaction of factor XII with
plasminogen can be considerably potentiated by the presence of dextran
sulphate, yielding conditions that urokinase is 10,000 and 1,500 times
more active then factor XII in activating Glu- and Lys-plasminogen,
respectively (Ravon et al, unpublished observations).
Thus, considering the relative plasma concentrations of factor XII and
urokinase (that of factor XII is 4 orders of magnitude higher), factor
XII may be equally potent as urokinase in activating plasminogen, as
indeed has been found in vivo.5 Notably, the theme of a
plasminogen-like molecule being activated by a factor XII-like molecule
has been used more often by nature, as is illustrated by hepatocyte
growth factor (scatter factor), which is homologous to plasminogen, and
its activating protease, which is homologous to factor
XII.6 The observation that genetic deficiencies of factor
XII, rather than those of PK or HK, are associated with thromboembolic
disorders underscores the importance of factor XII-dependent activation of plasminogen for in vivo fibrinolysis.
C. Erik
Hack
Central Laboratory of The Netherlands Red Cross Blood
Transfusion Service
Department of Internal Medicine
Free University
Hospital
Amsterdam, The Netherlands
| |
REFERENCES |
1.
Colman RW,
Schmaier AH:
Contact system: A vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes.
Blood
90:3819,
1998[Free Full Text]
2.
Motta G,
Rojkjaer R,
Hasan AAK,
Cines DB,
Schmaier AH:
High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: A novel mechanism for contact activation.
Blood
91:516,
1998[Abstract/Free Full Text]
3.
Nuijens JH,
Huijbregts CCM,
Eerenberg AJM,
Abbink JJ,
Strack van Schijndel RJM,
Felt-Bersma RJF,
Thijs LG,
Hack CE:
Quantification of plasma factor XIIa-C1-Inhibitor and kallikrein-C1-Inhibitor complexes in sepsis.
Blood
72:1841,
1988[Abstract/Free Full Text]
4.
van der Linden PWG,
Hack CE,
Eerenberg AJM,
Struyvenberg A,
van der Zwan JK:
Activation of the contact system in insect-sting anaphylaxis: Association with the development of angioedema and shock.
Blood
82:1732,
1993[Abstract/Free Full Text]
5.
Levi M,
Hack CE,
De Boer JP,
Brandjes DPM,
Büller HR,
ten Cate WJ:
Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo.
J Clin Invest
88:1155,
1991
6.
Miyazawa K,
Shimomura T,
Kitamura A,
Kondo J,
Morimoto Y,
Kitamura N:
Molecular cloning and sequence analysis of the cDNA for a human serine protease responsible for activation of hepatocyte growth factor. Structural similarity of the protease precursor to blood coagulation factor XII.
J Biol Chem
268:10024,
1993[Abstract/Free Full Text]
| |
RESPONSE |
We appreciate the opportunity to respond to Dr Hack's comments because
it provides a forum to discuss the implications of our
work.1,2 Dr Hack's questions focus on the novel mechanism for prekallikrein (PK) activation presented in recent
publications.2,3 We agree that we do not know yet what
regulates the membrane-associated PK activating cysteine protease.
However, we propose that this PK activation mechanism is the first
physiologic pathway by which the kallikrein/kinin system can be
activated in vivo. We do not believe that this PK activation system is
constitutively active in vivo. The amount of high molecular weight
kininogen (HK) necessary for maximal PK activation is limited by the
number of kininogen receptors on cells and not the ambient plasma
concentration. How HK modulates the activity of this enzyme needs to be
examined further. Furthermore, HK is not the single regulator of
activation of this pathway. In a study now in press, we
show that activation of this pathway also is dependent on an optimal
free zinc ion concentration.4 In the absence of an optimal
free zinc ion concentration, the system is quiescent. These data
suggest that the local liberation of zinc ion may be the immediate
regulator of activation of this system. Furthermore, we show that on
endothelial cells, factor XII (FXII) does not autoactivate in any
reasonable period of time (<1 hour) and that FXII activation is
dependent on PK activation and not vice versa.4 Activated
FXII is then able to reciprocally activate more plasma PK.
We agree that our proposed pathway for contact system activation is not
a substitute for the role of anionic surfaces (dirt, cardiopulmonary
bypass tubing, bacteria, etc) in FXII activation in nonphysiologic
states. Furthermore, we agree that Dr Hack's DDAVP infusion
experiments suggest that, in response to endothelial cell agonists,
FXII activation can initiate PK activation.5 It was an
unintended oversight not to refer to the FXII-dependent pathway of
plasminogen activation described by Levi et al.5 As
described by Dr Hack, the presence of an artificial surface potentiates
FXIIa's activation of plasminogen. This pathway, which may become
operative in nonphysiologic states, can be conjoined with the proposed
physiologic contact system pathways for fibrinolysis mediated by
bradykinin-induced tPA liberation and kallikrein activation of
single-chain urokinase.2,3,6 Last, it is not rigorously proven that FXII-deficient patients are at increased risk for thrombosis. Furthermore, because PK and HK deficiencies are so rare,
there have not been sufficient number of individuals described with
these defects to determine if they have less of a risk for thrombosis
than FXII-deficient patients.
Alvin H. Schmaier
Rasmus Røjkjaer
Department of Internal Medicine
Division of
Hematology and Oncology
The University of Michigan Medical
Center
Ann Arbor, MI
| |
REFERENCES |
1.
Colman RW,
Schmaier AH:
Contact system: A vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes.
Blood
90:3819,
1998
2.
Motta G,
Rojkjaer R,
Hasan AAK,
Cines DB,
Schmaier AH:
High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: A novel mechanism for contact activation.
Blood
91:516,
1998
3.
Lin Y,
Harris RB,
Yan W,
McCrae KR,
Zhang H,
Colman RW:
High molecular weight kininogen peptides inhibit the formation of kallikrein on endothelial cell surfaces and subsequent urokinase-dependent plasmin formation.
Blood
90:690,
1997[Abstract/Free Full Text]
4. Rojkjaer R, Hasan AAK, Motta G, Schousboe I, Schmaier
AH:Factor XII is not required to initiate prekallikrein activation on
endothelial cells. Thromb Haemost (in press)
5.
Levi M,
Hack CE,
Do Boer JP,
Brandjes DPM,
Buller HR,
ten Cate WJ:
Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo.
J Clin Invest
88:1155,
1991
6.
Brown NJ,
Nadeau JH,
Vaughan DE:
Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin.
Thromb Haemost
77:522,
1997[Medline]
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