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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 179-185
By
From the CLB, Sanquin Blood Supply
Foundation; the Department of Medical Physiology and Sports Medicine,
University of Utrecht, Utrecht; University of Amsterdam, Emma
Children's Hospital Academic Medical Center, the
Departments of Pediatrics and Experimental Internal Medicine,
Amsterdam; the Department of Hematology, University Hospital Dijkzigt,
Rotterdam; and the Department of Hematology, University Hospital
Utrecht, Utrecht, The Netherlands.
Before de novo synthesized von Willebrand factor (vWF) leaves the
endothelial cell, it undergoes endoproteolytic cleavage of its
propeptide (vW antigen II). The processed vWF and propeptide are either
released constitutively or, following activation of the endothelium,
released through the regulated pathway. In a recent study (Borchiellini
et al, Blood 88:2951, 1996), we showed that the half-life of
mature vWF and of its propeptide differ fourfold to fivefold. We
postulated that the molar ratio of the propeptide to mature vWF could
serve as a tool to assess the extent of endothelial cell activation
under physiologic and clinical conditions. To test this hypothesis, we
measured mature vWF and propeptide in patients with documented acute
and chronic vascular disease, including patients with thrombotic
thrombocytopenic purpura (TTP), acute septicemia, and diabetes
mellitus. These data were compared with experimental conditions in
healthy subjects in which perturbation of the endothelium was simulated
by physical exercise or by administration of
1-deamino-8-D-arginine vasopressin (DDAVP) or endotoxin. In
all individuals of the latter study group, both vWF and propeptide
levels were elevated during the acute phase of the experimentally
induced vascular perturbation; at later time points after stimulation,
only vWF levels remained elevated. In patients with sepsis and TTP,
both vWF and propeptide were elevated several-fold. Thus, this pattern
can readily be explained in terms of acute perturbation of the
endothelium. In contrast, in patients with diabetes mellitus propeptide
levels were only slightly elevated, whereas vWF levels were elevated
twofold to threefold. This pattern is a typical feature of chronic,
low-grade activation of the endothelium. These observations support our hypothesis that measurement of both propeptide and vWF levels allows to
discriminate between chronic and acute phases of endothelial cell
activation in vivo. Measurement of only vWF is less indicative in this respect.
VON WILLEBRAND FACTOR (vWF) is a large
adhesive glycoprotein that mediates the adhesion of platelets at sites
of vascular damage and also functions as a stabilizing carrier protein
of coagulation factor VIII. It is one of the circulating blood proteins that is produced and released by vascular endothelial
cells1 and is frequently used as an indicator of
endothelial cell dysfunction in vascular disorders.2-6
Before de novo synthesized vWF leaves the endothelial cell, it
undergoes endoproteolytic cleavage of its propeptide (also known as vW
antigen II7) and, together with the propeptide, is released
through both the constitutive pathway and by stimulus-induced
exocytosis of specialized secretory vesicles (Weibel-Palade bodies).
Both in cultured, resting endothelial cells and in stimulated
endothelial cells, the stoichiometry of the released propeptide to the
released mature vWF is essentially equimolar.8 However, in
normal plasma the molar concentration of the propeptide is about one
tenth of the concentration of mature vWF.9,10 Because the
propeptide disappears four to five times faster from the circulation
than mature vWF, it seems reasonable to assume that the observed
differences in steady-state concentration are due to differences in
half-life of the respective polypeptides. Upon perturbation of the
endothelium, for instance elicited by experimental disseminated
intravascular coagulation (DIC) or administration of
1-deamino-8-D-arginine vasopressin (desmopressin, DDAVP), both mature vWF and propeptide concentrations rapidly increase. Because of
its rapid turnover, the propeptide concentration returns to its
baseline value much faster after termination of the vascular challenge
than the vWF levels.9,10 On the basis of these
observations, it was postulated that measurement of both propeptide and
mature vWF levels could provide a means to assess the extent and time course of endothelial cell activation under clinical
conditions.9,10 For instance, if both vWF and propeptide
levels are elevated, this would be indicative of acute vascular
perturbation, whereas conditions in which only vWF is elevated, this
would rather reflect chronic endothelial cell activation. In the
present cross-sectional study, we have tested this hypothesis. We
measured mature vWF and propeptide in patients with thrombotic
thrombocytopenic purpura (TTP), sepsis, and diabetes mellitus. Healthy
individuals, in whom an acute increase of vWF and propeptide levels
were provoked by a standardized exercise test or injection of a low
dose of endotoxin or DDAVP, served as a control in this study.
Patient Selection
TTP.
Thirteen patients with TTP were studied (mean age, 36 years; range, 23 to 45). Four patients had TTP after allogeneic or autologous bone
marrow transplantation (BMT). All patients had microangiopathic hemolytic anemia, thrombocytopenia (mean platelet count, 28 × 109/L; range, 12 to 48), and impaired renal function. Mean
hemoglobin level was 5.1 mmol/L (range, 2.9 to 6.4); mean lactate
dehydrogenase (LDH) level was 2,311 U/L (range, 658 to 3,841; normal
value, <640 U/L). The mean values of these parameters were not
different in patients with classic TTP and post-BMT TTP. Samples were
obtained before treatment was started.
Sepsis.
Fourteen consecutive patients were recruited into the study from a
primary medical-surgical intensive care unit. The entry criteria for
patients with suspected sepsis syndrome were (American College of Chest
Physicians/Society of Critical Care Medicine consensus
conference11) the presence of a temperature (>38.3°C or <35°C) and low blood pressure. The sepsis syndrome was
verified by positive blood cultures. Seven patients had a pulmonary and seven an abdominal focus for the sepsis. All patients had signs of DIC:
all had a prolonged activated partial thromboplastin time (aPTT; 66 ± 8 seconds; range, 53 to 74 seconds; normal value, <36 seconds)
and prolonged prothrombin time (PT; 24.6 ± 6.1 seconds; range, 18 to 38 seconds; normal value, <15.4 seconds). Fibrin degradation
products (FnDPs) were elevated in 11 patients (4.9 ± 4.1 µg/mL;
normal value, <1.0 µg/mL) and antithrombin levels were decreased in
13 patients (50.6% ± 21.3%; range, 22% to 97%). Platelet count
was decreased in 11 patients (mean, 130 × 109/L;
range, 18 to 372).
Diabetes mellitus.
Twenty-two patients with type 1 (n = 7) and type 2 (n = 15) diabetes
mellitus were studied. The mean age was 60 years (range, 19 to 83). Ten
patients suffered from retinopathy, 10 from nephropathy, and eight from
neuropathy. The mean HbA1c was 7.3% ± 1.8%. There was
no difference in HbA1C levels between type 1 and type 2 diabetes. Six patients were insulin-dependent; all other patients used
oral antidiabetic drugs. Samples were taken when patients were
relatively stable and no acute metabolic complications or infections occurred.
Propeptide and vWF Levels and Platelet Count
Bone marrow aplasia.
Five patients with thrombocytopenia due to chemotherapy for acute
leukemia, two patients with primary aplastic anemia, and two patients
with congenital thrombocythemia were studied. Their mean age was 40 years (range, 19 to 59). Mean platelet count was 23 × 109/L (range, 6 to 45). Patients with signs of infection or
thromboembolic complications were excluded.
Essential thrombocythemia.
Seven patients with high platelet count due to essential
thrombocythemia (ET) were studied (mean age, 53 years; range, 28 to
76). Mean platelet count was 910 × 109/L (range, 494 to 1,800). All other causes for thrombocytosis were excluded by
clinical features and laboratory investigations. Bone marrow
examination by cytogenetic analysis was performed to exclude chronic
myeloid leukemia. All ET patients were studied during treatment with aspirin.
Controls.
Controls were subjects referred to the hospital, but who upon serial
clinical and laboratory investigations were shown to have no vascular
disease, infections, malignancies, diabetes, or other diseases that
could affect vWF and propeptide levels. Eighteen individuals were
recruited as a control for this study (mean age, 48 years; range, 19 to 77).
Healthy Subjects
Experimental endotoxemia.
This study was designed as described previously.9 In the
present, more extended study, eight healthy male volunteers were treated with endotoxin, administered as a 4-ng/kg injection
intravenously in 1 minute. At different time points after the injection
of endotoxin, blood samples were collected from the antecubital vein.
DDAVP.
This study group consisted of nine healthy volunteers (five males and
four females; mean age, 31 years) previously studied to assess the
half-life of vWF after administration of DDAVP.12 They
received 0.4 µg DDAVP/kg body weight.
Exercise.
Five healthy males (mean age, 40 years; range, 35 to 45) were subjected
to a standardized exercise test (cycle ergometer) as described
previously.13 Blood samples were collected immediately before the exercise test and at 15 minutes after maximal performance.
Collection of Blood and Assays
Statistical Analysis All data are presented as the mean ± SEM. The means in vWF and propeptide levels were compared by Student's t-test with vWF and propeptide levels found in the respective control samples. The Pearson correlation coefficient was used as a measure of linear association between two variables.
Effect of Experimental Endotoxemia, Administration of DDAVP, and Exercise on vWF and Propeptide Levels in Healthy Subjects As previously shown,9 combined elevations of vWF and propeptide levels is a typical feature of experimental endotoxemia and DDAVP-induced vascular perturbation. To document this picture in more detail, eight subjects received endotoxin and nine received DDAVP. Subsequently, vWF and propeptide levels were measured at different time points after injection. In all subjects studied, administration of low-dose endotoxin led to a distinct increase of both vWF and propeptide levels after a lag phase of 1 to 2 hours (Fig 1A). The rise of vWF and propeptide concentration was followed by a decline of propeptide levels, whereas the vWF concentration remained elevated for at least 20 hours. The half-life of vWF and propeptide after administration of endotoxin, calculated from the disappearance curves, was approximately 12 and 3 hours, respectively. This observation clearly documents that under conditions in which acute perturbation of the endothelium is induced, the clearance of circulating propeptide is much faster than that of vWF. Similarly, administration of DDAVP resulted in a prompt increase of both propeptide and vWF levels (Fig 1B). The propeptide level returned close to baseline values after about 6 hours, whereas at this time point the vWF level was still twice as high as the vWF concentration before injection of DDAVP. The estimated half-lives of propeptide and vWF differed about threefold to fourfold. To facilitate comparison with clinical data (see later), data of peak levels of vWF and propeptide and vWF and propeptide concentration measured at later time points after endothelial stimulation are summarized (Table 1). We also tested the effect of physical exercise on the plasma concentrations of propeptide and vWF in healthy volunteers. Similar to DDAVP and endotoxin, exercise enhances vWF release twofold to threefold and the propeptide level fivefold to eightfold (Table 1).
Propeptide and vWF Levels in Patients With Chronic and Acute Vascular Disease A total of 49 patients was studied with different signs of vascular pathology. Patients with diabetes mellitus suffered from chronic vascular dysfunction, whereas patients with TTP and sepsis were admitted to the hospital with acute symptoms of vascular pathophysiology. Eighteen patients, referred to the hospital for underlying disorders other than vascular disease, served as a control group in this study. In the latter study group, the mean vWF and propeptide level was 54.2 ± 6.0 and 7.1 ± 0.7 nmol/L, respectively. The mean level of mature vWF was significantly increased in all patient groups studied (P < .001, Table 2). These values were about twice as high as the mean plasma levels of patients without vascular pathology. In patients with diabetes mellitus, the mean propeptide level was normal (8.0 ± 0.4 nmol/L). However, there was a significant correlation between propeptide and vWF levels (r = .61, P < .01). There was no difference in glycosylated hemoglobin levels and vWF or propeptide levels between type 1 and type 2 diabetes. The individual data for each of the patients and the control group are shown in Fig 2. In patients with TTP, both the mean vWF level (112.7 ± 16.6 nmol/L) and the mean propeptide level (17.3 ± 3.3 nmol/L) were substantially elevated (P < .001 and P < .01, respectively). Similarly, in septic patients, both vWF and propeptide concentrations were significantly elevated (127.8 ± 14.7 and 17.8 ± 2.3 nmol/L, respectively; P < .001). The data, on an individual basis, are shown in Fig 2. In the majority of these patients, both vWF and propeptide were elevated. In patients with TTP, a significant correlation between the LDH and propeptide levels was observed (r = .82, P < .001). The correlation between LDH and vWF levels was not significant (r = .51, P = .09). In patients with sepsis, a significant correlation between FnDPs and propeptide was found (r = .58, P < .03). The correlation between vWF levels and FnDPs was not significant (r = .47, P = .07).
Propeptide and vWF Levels in Patients With Thrombocytopenia and Thrombocythemia As both vWF and its propeptide may not only originate from endothelial cells but also from platelets, vWF and propeptide levels were measured in plasma from healthy individuals and patients with low or high platelet counts. Figure 3 shows the relationship between propeptide concentration and platelet count in patients with bone-marrow aplasia, essential thrombocythemia and healthy controls. These parameters did not correlate (r = .2, difference not significant [NS]). Similarly, vWF levels did not correlate with platelet number (not shown). In contrast, there was a significant relationship (r = .7, P < .001) between platelet number and the concentration of plasma sP-selectin (Fig 3), a specific marker of platelet activation.16,17 Also in patients with TTP, sepsis, or diabetes, there was no correlation between platelet count and propeptide or vWF concentration (not shown). These observations suggest that in these individuals both propeptide and mature vWF originate from the endothelium, rather than from platelets.
The primary purpose of this study was to determine the potential value of measurement of plasma concentrations of both vWF and its propeptide as a means to discriminate between acute and chronic vascular disease. This concept is illustrated by a number of control experiments in healthy subjects in which perturbation of the endothelium was provoked by administration of endotoxin or DDAVP, both agents known for their ability to elicit increases of plasma vWF and propeptide levels. DDAVP induces immediate release of vWF and propeptide, whereas lipopolysaccharide (LPS)-induced secretion is preceded by the release of one or more second messengers, which most likely mediate vWF and propeptide secretion through the regulated pathway.9,18,19 In all subjects studied, the concomitant rise of vWF and propeptide levels was followed by a rapid decline of propeptide levels, whereas vWF concentrations only slowly normalized (Table 1 and Fig 1). Similarly, physical exercise induced a rapid increase of both vWF and propeptide. Thus, during the acute phase of vascular perturbation, both vWF and propeptide were elevated. However, at later time points (eg, 6 or 24 hours after stimulation), only vWF levels were still elevated. Clearly, the vWF-propeptide is more rapidly cleared from the circulation than mature vWF.9,10 Thus, there is an experimentally based rationale for the hypothesis that elevated propeptide (together with elevated vWF) is a marker of acute but transient endothelial cell activation.
We gratefully thank Drs J. Voorberg, K. Mertens, P.J. Lenting, and W.G. van Aken (CLB, Sanquin Blood Supply Foundation, Amsterdam, The Netherlands) for valuable discussion and comments on the manuscript.
Submitted October 19, 1998; accepted March 3, 1999.
Supported by the Dutch Thrombosis Foundation (Grant No. 96.001).
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to Jan A. van Mourik, PhD, Department of Blood Coagulation, CLB, Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands; e-mail: J_van_Mourik{at}clb.nl.
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TOP
ABSTRACT
INTRODUCTION
70°C until batchwise assessment. Propeptide and mature vWF concentrations were measured by enzyme-linked immunosorbent assay (ELISA) as described previously.
) and propeptide levels (
) in healthy individuals. Endotoxin
(4 ng/kg body weight) or DDAVP (0.4 µg/kg body weight) were
administered at time 0. The endotoxin study group consisted of 8 subjects, the DDAVP study group of 9 subjects. Data points represent
the mean and bars the SEM.
50 and 150 nmol/L, respectively) that were also observed briefly after
exposure of healthy individuals to DDAVP or endotoxin. This suggests
that the provoking event in these patients had occurred just before admission.
-granules of
platelets is probably not sufficient to account for the increased propeptide concentrations.