Zimmerman_subbed_Cardiology_book_temp 10/12/2009 13:46 Page 26
Thrombosis
Table 1: Clinical Conditions in Which Platelet–Leukocyte
lung capillaries.
7
However, in addition to mechanical consequences,
Interactions Have Been Reported or Platelet–Leukocyte
platelet–leukocyte interactions can alter the functional responses of both
Aggregates Have Been Detected in the Circulation
the leukocyte and the platelet.
30
For example, platelet activation resulting
from signals delivered by myeloid leukocytes or leukocyte microparticles
Atherosclerosis Sepsis
may amplify thrombosis by triggering α
Acute coronary syndromes Acute lung injury
IIb
β
3
-dependent adhesive events
Percutaneous coronary interventions Cystic fibrosis
and surface expression of P-selection.
29
P-selectin is reported to act
Cerebrovascular ischemia and stroke Complications of transfusion
synergistically with tissue factor, which is generated in platelet–monocyte
Venous stasis ulceration Hip arthroplasty
interactions and by activated platelets,
46–49
thereby accelerating fibrin
Smoking Ulcerative colitis
deposition.
4
Conversely, it is clear that signals delivered to monocytes or
Diabetes Cirrhosis PMNs by activated platelets can induce functional responses by the
leukocytes that have inflammatory and thrombotic consequences. Some
lesion development.
36
Furthermore, animal studies indicated that of these signaling mechanisms have been characterized relatively recently,
platelet–leukocyte aggregates form and associate with endothelium while others are still in the process of being identified and dissected.
in response to cigarette smoke, a known environmental risk factor
for atherosclerosis.
37
Signals from activated platelets induce expression of nuclear factor kappa
B (NF-κB)-dependent genes by human monocytes. An early report
In models of vessel injury, P-selectin-deficient mice accumulate fewer described synthesis of monocyte chemotactic protein 1 (MCP-1) by
leukocytes, resulting in protection against intimal hyperplasia and reduced human monocytes adherent to thrombin-stimulated platelets in
number and size of atherosclerotic lesions.
38,39
ApoE
-/-
mice transplanted heterotypic clusters.
16
The mechanism involves parallel signaling via
with bone marrow from P-selectin
-/-
mice had 30% smaller atherosclerotic P-selectin–PSGL-1 engagement and the soluble chemokine RANTES,
lesions than ApoE
-/-
mice transplanted with P-selectin
+/+
marrow; this was which is released from activated platelets and is recognized by CC
interpreted as indicating a role for platelet-expressed P-selectin in chemokine receptor 5 (CCR5) on the monocyte (see Figure 1); these
atherosclerosis lesions.
40
Consistent with this possibility, one potential signals are integrated to yield transcription of the messenger RNA (mRNA)
explanation is adhesion of activated platelets to myeloid leukocytes and for MCP-1 and synthesis of the protein.
16
Monocytes also synthesized
recruitment of these cells to the evolving atherosclerotic plaques. In a IL-8 and tumor necrosis factor alpha (TNF-α) under these conditions.
different study, infusion of activated platelets into C57BL/6 mice increased
the number of circulating leukocyte–platelet aggregates. This induced More recently, engagement of PSGL-1 on human monocytes by
monocyte and, to a lesser extent, neutrophil accumulation in the P-selectin and parallel signaling by IL-1β were shown to mediate biphasic
atherosclerotic lesion, indicating that circulating activated platelets and and temporally regulated expression of cyclo-oxygenase 2 (cox-2) in
platelet–leukocyte aggregates promote the evolution of atherosclerotic adhesive interactions of the leukocytes with thrombin-stimulated
lesions.
41
Intercellular signaling between platelets and myeloid leukocytes platelets.
33
Apart from thrombin, additional agonists trigger formation of
in vivo may be required for their local accumulation in experimental human platelet–monocyte aggregates and consequent chemokine
vascular injury.
42
Such adhesion and signaling interactions occur in both synthesis.
37
Early and more recent studies using primary monocytes and
experimental and clinical angioplasty and vascular stent placement.
43,44
myeloid cells transfected with reporter constructs demonstrated that
engagement of PSGL-1 induces nuclear translocation and activation of
Animal models also suggest important roles for platelet interactions with NF-κB; parallel signaling by RANTES or IL-1 can then deliver parallel signals
leukocytes in other inflammatory syndromes besides atherosclerosis and for transcriptionally controlled expression of multiple NF-κB-dependent
its sequelae. For example, several studies indicate that this is a feature of inflammatory gene products.
16,33
Nevertheless, there are additional
murine models of acute lung injury and experimental acute respiratory pathways in the repertoire of mechanisms by which the pattern of genes
distress syndrome.
7
Nevertheless, it should be remembered that there are expressed by monocytes can be altered by intercellular signaling in
differences in circulating platelet and leukocyte numbers and perhaps platelet–leukocyte interactions. There is also evidence that engagement of
function in mice and other species,
7,45
which may influence the clinical PSGL-1 by P-selectin signals to specialized translational control
relevance of outcomes in these experimental systems. checkpoints.
50,51
For example, adhesion of human monocytes to purified,
immobilized P-selectin or to activated platelets in heterotypic aggregates
Functional Consequences of Platelet–Leukocyte induces expression of urokinase plasminogen activator receptor (UPAR),
Interactions in Inflammation and Thrombosis— a surface protease receptor and regulator of cell adhesion and
Intercellular Signaling and Signal Transduction migration.
50
Engagement of PSGL-1 appears to be sufficient for rapid
Platelet–leukocyte interactions appear to be mechanisms for targeting synthesis of UPAR from constitutive, silenced mRNA without a
and local accumulation of leukocytes in physiological inflammation and requirement for new transcription, although transcription also occurs. This
hemostasis, and for local or systemic cell–cell contact in pathological specialized translational mechanism was shown to be mediated by
inflammatory and thrombotic syndromes.
2,7,18
It has also been suggested mammalian target of rapamycin (mTOR), identifying a new role for the
that formation of platelet–leukocyte aggregates contributes to the complex pathway regulated by this kinase in myeloid leukocytes.
50
clearance of activated cells from the circulating blood.
4
In pathological Additional post-transcriptional pathways in monocytes may be triggered
conditions in which platelet–monocyte or platelet–neutrophil aggregates by interactions with activated platelets,
51
and the studies together
form and are retained in the vasculature, these multicell clusters may be indicate that the pattern of inflammatory proteins expressed by the
involved in mechanical occlusion of vessels, such as coronary arteries
4
or leukocytes in response to signals from platelets is regulated by precise
26 US HEMATOLOGY
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