Heparin Cofactor II in Adult Glomerulopathy and. Nephrotic Syndrome. Marie-Agnès Pech^, Guy Rostokerà , Claudine Soriaa, fhilippe Langî, Bertrand Weila, ...
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Heparin Cofactor II in Adult Glomerulopathy and Nephrotic Syndrome Marie-Agnès Pech^, Guy Rostokerà, Claudine Soriaa, fhilippe Langî, Bertrand Weila, Jacques Caenb,
Gilbert Lagrue^ aService de Néphrologie, AURA, INSERM b
U 139, Association Claude-Bernard, Hôpital Henri-Mondor, Créteil, France; Laboratoire d'Hématologie, Hôpital Lariboisière, Paris, France
Dear Editor, Nephrotic patients run a higher risk of developing thrombotic complications [1], but the reason for this hypercoagulability remains unclear despite multiple investigations. Various abnormalities in the clotting factors, platelet aggregation and fibrinolysis have been reported without a clear relationship with thrombotic events. Two natural anticoagulant systems are implicated in the coagulation regulation: (a) the thrombin inhibitors, the activity of which is dramatically enhanced by heparin [2], antithrombin III (AT III) and heparin cofactor II (HC II) [2]; (b) the protein C-protein S system [3].
Several reports have described severe thrombotic complications in patients with congenital deficiencies in AT III and protein C/S; other studies have led to the hypothesis that the thrombotic tendency of nephrotic syndrome (NS) could be related to an acquired defrciency in natural anticoagulant proteins: AT III [4], protein C or free protein S [5, 6]. Since congenital deficiencies in HC II have been described in patients with recurrent thromboembolic events [7, 8], this factor, which is a heparin-dependent thrombin .inhibitor active only against thrombin and distinct from AT III [2], was evaluated in adult patients with various primary glomerular diseases. The study included a total of28 patients. They were subdivided into two groups based on the following criteria: group I : proteinuric patients without NS (pro-
: 18; 9 : women, 9 men; mean age 43.60 years, range = 20-68 years); group 2 : proteinuric patients with NS (proteinteinuria 30g/l; n
) 3 E/24 h, serum albumin < 30 g/l; n: l0; 2 women, 8 men; mean age = 4l years, range = 17-73 years). Group 3 consisted of 32 healthy matched adults; no difference could be established between HC II levels in men uria
and women controls. The histological diagnoses (idiopathic nephrotic syndrome and membranous nephropathy) are summarized in table 1. Venous blood was collected into evacuated tubes containing trisodium citrate 0.129 M. Plasma was obtained after centrifugation at 3,000rpm for 15min at 4"C. Samples were collected and stored at -80 oC until assay. HC II was assayed as dermatan sulfate cofactor at 37 o C, p}l7.4, as end point reaction: HC II inhibits the human
thrombin activity in the presence of dermatan sulfate which enhances the antithrombin activity of HC II but not of AT III [9]. Proteinuria, albuminemia, creatinine, cholesterol, triglycerides, protein C, total protein S, free protein S, AT III, C4BP and proteinuria selectivity index were assayed by routine techniques. Since the values did not conform to gaussian distribution, they wer€ cornl pared with the nonparametric, nonpaired Wilcoxon test, and the correlations were studied either with the nonparametric Spearman test or with the Yates corrected y2. HC II activities in the different groups are summarized in table 1: HC II was not statistically different between control group and proteinuric patients without NS (median: group 3: 1110/o; group I : 1060/o) but differed significantly between control group and NS patients who had a lower HC II activity (group 2:76.50/o; p < 0.05 by the Wilcoxon test). Two and 3 patients, respectively, in groups I and 2 exhibited a mild decrease in HC II activ-
Heparin Cofactor II in Nephrotic Syndrome
75
ity
below the 90th percentile lower limit of controls but a severe decrease in HC II was only observed patients in 2 from group 2 (No. 6: 630/o; No. 7: 450lo). No correlation could be demonstrated either between HC II levels and albuminemia, proteinuria, cholesterol, triglycerides, total S protein, free S protein, AT III, protein C, C4BP and proteinuria selectivity index (p > 0.05 by the Spearman test) or between HC II levels and the type of primary glomerulonephritis (p > 0.05 by the Yates corrected I2). With the method used, we recorded mean values and normal ranges for HC II in the control group in fair agreement \vith previous published reports: Tran and Duckert [10] first reported the normal range of HC II between 0.7 and 1.5 U/ml (70/150o/o activity) as compared to a standard plasma pool containing I U/ml (1000/o activity). In proteinuric patients without NS (group l), HC II levels were within the normal range but in NS patients (group 2),HC II levels were significantly decreased contrary to Sié et al. [11], who did not find any decrease in HC II levels in nephrotic children as did Hannedouche et al. [2] in 15 adult proteinuric patients. Moreover, 2 patients in gioup 2 exhibited a frank decrease in HC II. Nevertheless, this study does not demonstrate any relation between thrombosis and HC II deficiency since no patient had any thrombotic event. Thus, other investigations are needed to possibly link HC II defrciency and thrombosis in NS. The high risk of thrombosis in NS may be due to the combination of various defrciencies: AT III [8], free protein S or protein C
Table 1. Histological diagnoses
(800/o),
HC
SA > 30gn n=18(INSn:l0,MNn=8) Group2 P>3gl24h SA < 30e/l n: 10 (INS n - 8, MN n: 2)
Group
3
Controls,
n:
32
Llach F: Hypercoagulability, renal vein thrombosis and other thrombotic complications of nephrotic syndrome. Kidney Int 1985;28:429-439.
2 Briginshaw GF, Shanberge JN: Identifrcation of two distinct heparin cofactors in human plasma. Arch Biochem Biophys
L: Acquired AT III deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978;65:607-613. 5 Vigano D'Angelo S, D'Angelo A, Kaufman C, Sholer C, Esmon C, Comp P: Protein S deficiency occurs in the nephrotic syndrome. Ann Int Méd 1987;107:42-47.
76.5* lll
45-121
73-r60
M, Levent M, Intrator L, Branellec A, Lagrue G: Natural anticoagulant proteins in the adult nephrotic syndrome. Clin Nephrol 1988;'29:214-215.
7 Tran TH, Marbet GA, Duckert F: Association of hereditary heparin cofactor II defrciency with thrombosis. Lancet I 985;ii:4 I 3414.
8 Sié P, Dupouy D, Pichon J, Boneu B: Constitutional heparin cofactor II deficiency associated with recurrent thrombosis. Lancet 1985;ii:414-416.
9 Tollefsen DM, Pestka CA, Monafo WJ: Activation of heparin cofactor by dermatan sulfate. J Biol Chem 1983;258:67136716.
l0
Tran TH, Duckert F: Heparin cofactor II: Determination levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation. Thromb
Haemost 1984;52:l l2-l 16. Sié P, Meguira B, Bouissou F, Boneu B, Barthe Ph: Plasma levels of heparin cofactor II in nephrotic syndrome of children. Nephron 1988;48:175-176. 12 Hannedouche T, Fischer AM, Blanche P, Tapon-Bretaudière J, Ganneval D: Plasma heparin cofactor II and antithrombin III concentrations in adult nephrotic syndrome. Clin Nephrol 1987; 28:305-306. 13 SiéP:Thesecondheparincofactor.AnnBiolClin 1987;45:18l183.
3 Comp P, Miletich J, Marlar R: The protein C pathway and Es
80-1 33
6 Rostoker G, Gadela-Parente T, Pech MA, Gouault-Heilmann
974;l 6l:683-690.
thrombosis. Blood 1985;66(suppl l):45-47.
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References
4 Kau{ftnann R, Veltkamp J, Van Tilburg R, Van
range
Values are expressed in percentages of a normal pooled plasma, < 0.05 by Wilcoxon's test. P: Proteinuria; SA: serum albumin; INS idiopathic nephrotic syndrome (minimal-change disease + IgM nephropathy + segmental glomerulosclerosis); MN: membranous nephropathy.
*p
factor for thrombosis [13].
I
median
Groupl P
