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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2522-2529
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Biphasic transmittance waveform in the APTT
coagulation assay is due to the formation of a
Ca++-dependent complex of C-reactive protein with
very-low-density lipoprotein and is a novel marker of impending
disseminated intravascular coagulation
Cheng Hock Toh,
John Samis,
Colin Downey,
John Walker,
Lev Becker,
Nicole Brufatto,
Liliana Tejidor,
Greg Jones,
Wim Houdijk,
Alan Giles,
Marlys Koschinsky,
Larry O. Ticknor,
Ray Paton,
Richard Wenstone, and
Michael Nesheim
From the Departments of Biochemistry and Pathology,
Queen's University, Kingston, ON, Canada; Organon Teknika, Durham, NC;
Decision Applications Division, Statistical Sciences Group, Los Alamos
National Laboratory, NM; and Departments of Hematology, Intensive Care,
and Computer Science, University of Liverpool, United Kingdom.
A decrease in light transmittance before clot formation,
manifesting as a biphasic waveform (BPW) pattern in coagulation assays, was previously correlated with the onset of disseminated intravascular coagulation (DIC). In this study of 1187 consecutive admissions to the
intensive care unit, the degree of this change on admission predicts
DIC better than D-dimer measurements. Additionally, the BPW preceded
the time of DIC diagnosis by 18 hours, on average, in 56% (203 of 362)
of DIC patients. The BPW is due to the rapid formation of a precipitate
and coincident turbidity change on recalcification of plasma. The
isolated precipitate contains very-low-density lipoprotein (VLDL) and
C-reactive protein (CRP). The addition of CRP and Ca++ to
normal plasma also causes the precipitation of VLDL and IDL, but not
LDL or HDL. The Kd of the CRP/VLDL interaction
is 340 nM, and the IC50 for Ca++ is 5.0 mM. In
15 plasmas with the BPW, CRP was highly elevated (77-398 µg/mL), and
the concentration of isolated VLDL ranged from 0.082 to 1.32 mM
(cholesterol). The turbidity change on recalcification correlates well
with the calculated level of the CRP-VLDL complex. Clinically, the BPW
better predicts for DIC than either CRP or triglyceride alone. The
complex may have pathophysiological implications because CRP can be
detected in the VLDL fraction from sera of patients with the BPW, and
the VLDL fraction has enhanced prothrombinase surface activity. The
complex has been designated lipoprotein complexed C-reactive protein.
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