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Effects of growth hormone on the factor VIII complex in patients with growth hormone deficiency
Metabolism Clinical and Experimental -. __._ DECEMBER 1984
VOL. XxX111, NO. 12
Effects
of Growth Hormone on the Factor VIII Complex in Patients With Growth Hormone Deficiency M. Borkenstein
and W. Muntean
Factor VIII activity (VIII CL factor VIII coagulant antigen (VIII C:Ag), factor VIII-related antigen (VIII RAgI, Ristocetin cofactor (R:Cof), and growth hormone were studied in eight children with growth hormone deficiency prior to, and 60,120, and 180 minutes after administration of human growth hormone (Crescormone, Kabi), 4 U/m’. Growth hormone has been administered for 1 .O to 6.8 years but was stopped one week prior to this investigation. Basal levels of VIII C, VIII C:Ag, VIII R:Ag, and R:Cof were within the normal limits. After administration of human growth hormone, VIII C, VIII C:Ag, VIII R:Ag, and R:Cof showed a significant rise. Our study shows that growth hormone is not necessary to maintain the basal levels of the factor VIII complex within the normal limits. However, our data suggest that growth hormone has some influences on the levels of the factor VIII complex. The mechanisms for the rise of the factor VIII complex-whether this is a direct effect of growth hormone or not-are not clear at this point.
F
ACTOR VIII procoagulant activity (VIII C) is exerted by a low-molecular-weight (LMW) moiety of the factor VIII molecule that can be separated from a high-molecular-weight (HMW) moiety by high-ionic-strength buffers.‘%* The two moieties of the factor VIII molecular complex also have different antigenic sites. The HMW moiety precipitates with heterologous antisera and can be measured by means of such antisera, then termed factor VIII-related antigen (VIII R:Ag).3 This part of the factor VIII molecule or molecule complex supports Ristocetin-induced platelet aggregation and platelet adhesion.4 The HMW factor VIII moiety is synthesized in the vascular endothelium.5 The synthesis site of the LMW factor VIII moiety that exerts coagulant activity is not known. Methods to measure the procoagulant moiety immunologically have been described recently.6 This can be done by means of inhibitors against the procoagulant moiety occurring in polytransfused hemophiliacs. There is some evidence suggesting hormonal and/or metabolic control of the regulation of both the LMW and the HMW moiety-related activities of the factor VIII complex. Human growth hormone, epinephrine, and estrogen have been shown to have some influence on the regulation of the HMW moietyrelated activities of the factor VIII complex.7m9 DDAVP (I -Deamino-S-D-arginine vasopressin) has Metabolism,
Vol 33. No 12 (DecemberI, 1984
been shown to infuence the HMW and LMW moieties of the factor VIII complex.‘&‘* Recently, new work was published showing an effect of Danazol (17 alpha-pregna-2,4 dien-2o-yno 2,3-d isoxazol- 17-ol), mainly on the LMW moiety.13 The duration and quality of control of diabetes mellitus has some influence on the factor VIII complex. Long duration of diabetes is associated with an increase of the HMW moiety whereas poor control is associated with elevation of only the factor VIII procoagulant activity (VIII C).‘” The purpose of our study was to investigate the influence of growth hormone administration to growth hormone deficient children on the regulation of both the LMW and HMW moiety-related activities of the factor VIII complex.
From the Department of Pediatrics. University of Gra;. Graz Austria. This work was supported in part by ijsterreichischer Fonds zur Fiirderung der wissenschaftlichen Forschung, grant No. P 45 96. Presented in part at the XIVth Acta Endocrinologica Congress, Stockholm, June 27-30. 1983. Address reprint requests to Univ. Doz. Dr M. Borkenstein, UniversitSts-Kinderklinik Graz. Auenbruggerplatz. .4-8036, Gra:, Austria. ~11984 bv Grune & Stratton, Inc. 0026-04~5/84/3312~0001$3.00/0 1065
1066
BORKENSTEIN
MATERIALS AND METHODS Eight patients, seven boys and one girl, aged 6.8 to 18.4 years (mean II .7 years), regularly attending the endocrine unit of the Department of Pediatrics, were investigated. Informed consent was obtained from the parents of each patient. Isolated growth hormone deficiency was diagnosed in five children, multiple hormone deficiency was diagnosed in three. Growth bormone deficiency was idiopathic in five children, due to septoopticdysplasia (De Morsier syndrome) in two, and to craniopharyngeoma in 1. Growth hormone had been administered for I .O to 6.8 years (mean 3.5 years), but was stopped one week prior to this investigation. The children were free of any medication at the time of the study except for thyroxine replacement therapy in one, and thyroxine and cortisol replacement therapy in two of the children. Blood samples were taken in the fasting condition through a short indwelling plastic catheter (Abbocath, Abbot Ltd., Szigo, Ireland) prior to, and 60, 120, and 180 minutes after administration of human growth hormone intramuscularly (IM) (Crescormone Kabi), 4 U/m*. Without venicompression, blood was collected by a twosyringe technique using 0.1 molar sodium citrate for anticoagulation. After collection of the samples the catheter was flushed with 3 to 5 mL of isotonic saline. Factor VIII coagulant activity (VIII C) was assayed by a onestage method using a commercially available test kit from Behring Company (Marburg, West Germany). Factor VIII coagulant antigen (VIII C:Ag) was measured by means of an immunoradiometric assay (IRIA).6 The antibody used was purified from a polytransfused hemophiliac with an inhibitor against the LMW moiety. Factor VIII-related antigen (VIII R:Ag) was assayed by quantitative immunoelectrophoresis’ using a specific rabbit antibody commercially available from Behring Company. Ristocetin cofactor (R:Cof) was determined by means of an agglutination methodI commercially available from Behring Company.‘6 Calibration curves for all measurements were done with pooled plasma from 20 healthy adults. Growth hormone determinations were done by means of a radioimmunoassay (RIA) kit commercially available from Behring Company. Statistical analyses were done by means of the Student’s I test for paired data.
RESULTS
Growth hormone was X 1.lO ng/mL * 0.22 SEM; VIII C was X 1.256 U/mL + 0.093 SEM; VIII C:Ag Table 1. Values After Administration 60 Minutes
0 Minutes
c U/n-IL
VIII VIII
C:Ag
VIII
A:Ag
R:Cof
HGH
VIII
1.563*
1.589*
1.396
0.207
0.198
0.197
1.200
1.53El*
1.586’
1.321
0.100
0.196
0.203
0.188
1.100
1.127
1.162
1.230*
0.112
0.115
0.144
0.151
U/mL
values
coagulant
0.925
1.050t
1.075t
0.036
0.049
0.052
21.2$ 5.4
antigen
cofactor
120,
180
and
1.1 0.2 k SEM
Ristocetin
(VIII
minutes Kabil,
‘,t,$,S,l]
Statistically
lP
of factor
(R:Cofl,
(Crescormone,
paired
180 Minutes
1.256
ng/mL
Mean
120 Minutes
Hormone
0.093 U/mL
U/mL
of Human Growth
C:Ag),
VIII
58.1$
after
84.95
16.0 procoagulant
factor
and growth
4 U/m’
1.16211 0.070
22.3 activity
VIII-related hormone
administration
(VIII
antigen (HGH)
of human
C), factor (VIII
growth
hormone
IM.
different
by means
of the
Student’s
t test
data prior to and after HGH administration. < 0.05:
tP < 0.025;
R:Ag),
prior to, and 60.
SP < 0.01; $P < 0.005;
llP < 0.0025
for
AND
MUNTEAN
was X 1.20 U/mL + 0.10 SEM; VIII R:Ag was X 1.10 U/mL + 0.112 SEM; R:Cof was 0.925 U/mL tr 0.037 SEM. Growth hormone, VIII C, VIII C:Ag, VIII R:Ag, and R:Cof values showed a rise 60 to 180 minutes after the administration of growth hormone in each of the patients. Concentrations of VIII C, and of VIII C:Ag at 60, and 120 minutes were significantly higher than baseline concentrations prior to growth hormone administration, but were not different at 180 minutes (Table 1). Concentrations of VIII R:Ag at 180 minutes, and concentrations of R:Cof at 60, 120, and 180 minutes were significantly higher than baseline concentrations prior to growth hormone administration (Table 1). No rise of VIII C, VIII C:Ag, VIII R:Ag, and R:Cof values was observed in three healthy normal adult volunteers after administration of 5 mL isotonic saline IM; the blood was collected in the same way as in the patients. DISCUSSION
Basal levels of both parts of the factor VIII complex were within the normal limits in all our patients with growth hormone deficiency. This fact seems to indicate that growth hormone is not necessary for the synthesis of the factor VIII complex and is not necessary to maintain the basal levels within the normal limits. Obviously, other regulatory mechanisms for factor VIII complex exist. Some regulatory influences on the factor VIII complex have been already shown for glucose, insulin, epinephrine, and for estrogen.8.9,‘7 The duration and quality of control of diabetes mellitus also were shown to have some influences on the factor VIII complex.‘4 Administration of human growth hormone to growth hormone-deficient children induced a rapid rise of the factor VIII complex in all children studied. A rise of the HMW moiety measured as VIII R:Cof has been described previously.7 In addition, in this paper we describe a raise of the LMW moiety (VIII C, VIII C:Ag) after administration of human growth hormone. Therefore, our results suggest that growth hormone has some influence on the circulating levels of both the moieties of the factor VIII complex. The mechanisms for this increase-whether this is a direct effect of growth hormone or not-are not clear at this point. The rise of the HMW moiety after growth hormone administration appears so rapidly that increased synthesis is unlikely to account for it. Release of the HMW moiety from its storage sites in the vascular endothelium into the plasma appears more likely. Similar mechanisms were discussed for DDAVPinduced changes in circulating levels of the factor VIII complex.‘O,” All synthesis sites of the LMW moiety are not known; its rise after growth hormone administration
1067
FACTOR VIII IN HGH DEFICIENCY
again may be a direct effect of human growth hormone or not. Furthermore, it might be secondary to the increase of the HMW moiety because administration of only the HMW moiety to patients suffering from severe von Willebrand’s disease-missing both moieties of the factor VIII complex-results in a rise of VIII C in these patients. Growth hormone has been implicated as a causal factor in the development of diabetic vascular disease because of its direct effects on blood vessels.‘* It has been shown that growth hormone-deficient dwarfs do not develop diabetic vascular disease.” Abnormalities in the factor VIII complex can be demonstrated in diabetic vascular disease.‘4,20 Those abnormalities might be secondary to the vascular disease but also might play a role in the pathogenesis and/or the propagation of the vascular disease. However, Porta and co-workers found no correlations between growth hormone levels and levels of the HM W moiety of the factor VIII complex in nine patients with Type-l diabetes.*’ Therefore, further studies will be necessary to elucidate any relations
between circulating growth hormone levels and circulating levels of both the moieties of the factor VIII complex that might be significant in the pathogenesis of diabetic vascular disease. Furthermore, human growth hormone might be useful to rise the factor VIII complex in patients congenitally deficient in one or both moieties of the factor VIII complex. Preliminary studies show that a raise of both the moieties of the factor VIII complex can be achieved with human growth hormone in hemophiliacs or von Willebrand’s disease patients, but this rise seems not to be as predictable as, for example, with the use of DDAVP.” However, because administration of human growth hormone for a short period seems not to have many side effects and biosynthetic human growth hormone might be available in great amounts, further investigation of the therapeutic use of human growth hormone in factor VIII complex-deficient patients might be worthwhile. ACKNOWLEDGMENT Crescormone
was kindly provided by Kabi-Vitrum,
Austria.
REFERENCES I. Peake IR, Bloom AL: The dissociation of factor VIII by reducing agents, high salt concentration and affinity chromatography. Thromb Haemost 35:191~201, 1976 2. Muntean W, Hathaway Wm E. Montgomery RR: Influence of high molecular weight factor VIII on the measurement of low molecular weight factor VIII procoagulant in different assay systems Br J Haematol 5 1:649%658, 1982 3. Zimmerman TS, Hoyer LW. Dickson L, et al: Determination of the von Willebrand’s disease antigen (factor VIII related antigen) in plasma by quantitative immunoelectrophoresis. Lab Clin Med 86:152-159, 1975 4. Weiss HJ, Hoyer LW, Rickles FR. et al: Quantitative assay of plasna factor deficient in von Willebrand’s disease that is necessary for platelet aggregation. J Clin Invest 52:2708--2716, 1973 5. Rand JH. Sussman II, Gordon RE, et al: Localization of factor Vi I I -related antigen in human vascular subendothelium. Blood 55:7:;2-756. 1980 6. Peake IR, Bloom AL, Giddings JC, et al: An immunoradiometric assay for procoagulant factor VIII antigen: results in haemophilia. von Willebrand’s disease and fetal plasma and serum. Br J Haematol42:269 -28 I, 1979 7. Sarji KE, Levine JH, Nair RMG, et al: Relation between growth hormone and von Willebrand factor activity. J Clin Endocrinol Metab 45:853-856, 1977 8. Rickles FR, Hoycr LW, epintphrine infusion in patients Clin Invest 57:1618 1620. 1976
Rick ME, et al: The etTects of with von Willebrand’s disease. J
9. Muntean W. Borkenstein M: Hemostatic alterations in tall girls treated with ethinyloestradiol. Europ J Pediatr 134:245-248, 1980 IO. Mannucci PM, Canciani MT, Rota L, et al: Response of factor VIII van Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Hacmatol 47283-293. 1981
I I. Ruggeri ZM, Mannucci PM, Lombardi R. et al: Multimeric composition of factor VIII von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand’s subtypes. Blood 59: 1272-l 278, 198 I 12. Warrier AI, Lusher JM: DDAVP: A useful alternative to blood components in moderate hemophilia A and von Willebrand disease. J Pediatr 102:228-233. 1983 13. Gralnick HR, Rick ME: Danazol increases factor VIII and factor 1X in classic hemophilia and Christmas disease. N Engl J Med 308:1393%1395, 1983 14. Borkenstein HM, Muntean EW: Elevated factor VIII activity and factor VIII-related antigen in diabetic children without vascular disease. Diabetes 31:1006~1009, 1982 15. Reisner HM, Katz HJ, Graham JB: A rapid qualitative macroscopic assay for Willebrand factor. Fed Proc 35:756. 1976 16. Fuhge P. Braun K, Heimberger N: Neues Reagenz fiir die Bestimmung des Ristocetinfaktors, Faktor VIII R:Cof. In: Van de Loo J, and Asbeck F (eds): HPmostase, Thrombophilie und Arteriosklerose Schattauer, Stuttgart, 1982. pp 700-703 17. Graves JM. Colwell JA, Nair RMG, et al: The effect of oral glucose on van Willebrand factor activity in normal and diabetic subjects. Clin Endocrinol 6~437-442, 1977 18. Lundbaek K: Growth hormone’s role in diabetic microangiopathy. Diabetes 25(Suppl):845-849, 1976 19. Merimee TJ. Fineberg S, Hollander W: Vascular disease in the chronic hGH-deficient state. Diabetes 22:813-819. 1973 20. Gonzalez J, Colwell JA. Sarji KE, et al: Effect of metabolic control with insulin on plasma von Willebrand factor activity (VIII R:WF) in diabetes mellitus. Thromb Res 17:26 I-266, 1980 21. Porta M, Maneschi F, White M, et al: 24 hours variations of von Willebrand factors and factor VIII-related antigen in diabetic retinopathy. Metabolism 30:695-699, I98 I 22. Muntean W, Borkenstein M: Behandlungsversuch der Hlmophilie A mit humanem Wachstumshormon. in Landbcck G (ed): 14. Hlmophilie-Symposion. Schattauer. Stuttgart (in press)
VOL. XxX111, NO. 12
Effects
of Growth Hormone on the Factor VIII Complex in Patients With Growth Hormone Deficiency M. Borkenstein
and W. Muntean
Factor VIII activity (VIII CL factor VIII coagulant antigen (VIII C:Ag), factor VIII-related antigen (VIII RAgI, Ristocetin cofactor (R:Cof), and growth hormone were studied in eight children with growth hormone deficiency prior to, and 60,120, and 180 minutes after administration of human growth hormone (Crescormone, Kabi), 4 U/m’. Growth hormone has been administered for 1 .O to 6.8 years but was stopped one week prior to this investigation. Basal levels of VIII C, VIII C:Ag, VIII R:Ag, and R:Cof were within the normal limits. After administration of human growth hormone, VIII C, VIII C:Ag, VIII R:Ag, and R:Cof showed a significant rise. Our study shows that growth hormone is not necessary to maintain the basal levels of the factor VIII complex within the normal limits. However, our data suggest that growth hormone has some influences on the levels of the factor VIII complex. The mechanisms for the rise of the factor VIII complex-whether this is a direct effect of growth hormone or not-are not clear at this point.
F
ACTOR VIII procoagulant activity (VIII C) is exerted by a low-molecular-weight (LMW) moiety of the factor VIII molecule that can be separated from a high-molecular-weight (HMW) moiety by high-ionic-strength buffers.‘%* The two moieties of the factor VIII molecular complex also have different antigenic sites. The HMW moiety precipitates with heterologous antisera and can be measured by means of such antisera, then termed factor VIII-related antigen (VIII R:Ag).3 This part of the factor VIII molecule or molecule complex supports Ristocetin-induced platelet aggregation and platelet adhesion.4 The HMW factor VIII moiety is synthesized in the vascular endothelium.5 The synthesis site of the LMW factor VIII moiety that exerts coagulant activity is not known. Methods to measure the procoagulant moiety immunologically have been described recently.6 This can be done by means of inhibitors against the procoagulant moiety occurring in polytransfused hemophiliacs. There is some evidence suggesting hormonal and/or metabolic control of the regulation of both the LMW and the HMW moiety-related activities of the factor VIII complex. Human growth hormone, epinephrine, and estrogen have been shown to have some influence on the regulation of the HMW moietyrelated activities of the factor VIII complex.7m9 DDAVP (I -Deamino-S-D-arginine vasopressin) has Metabolism,
Vol 33. No 12 (DecemberI, 1984
been shown to infuence the HMW and LMW moieties of the factor VIII complex.‘&‘* Recently, new work was published showing an effect of Danazol (17 alpha-pregna-2,4 dien-2o-yno 2,3-d isoxazol- 17-ol), mainly on the LMW moiety.13 The duration and quality of control of diabetes mellitus has some influence on the factor VIII complex. Long duration of diabetes is associated with an increase of the HMW moiety whereas poor control is associated with elevation of only the factor VIII procoagulant activity (VIII C).‘” The purpose of our study was to investigate the influence of growth hormone administration to growth hormone deficient children on the regulation of both the LMW and HMW moiety-related activities of the factor VIII complex.
From the Department of Pediatrics. University of Gra;. Graz Austria. This work was supported in part by ijsterreichischer Fonds zur Fiirderung der wissenschaftlichen Forschung, grant No. P 45 96. Presented in part at the XIVth Acta Endocrinologica Congress, Stockholm, June 27-30. 1983. Address reprint requests to Univ. Doz. Dr M. Borkenstein, UniversitSts-Kinderklinik Graz. Auenbruggerplatz. .4-8036, Gra:, Austria. ~11984 bv Grune & Stratton, Inc. 0026-04~5/84/3312~0001$3.00/0 1065
1066
BORKENSTEIN
MATERIALS AND METHODS Eight patients, seven boys and one girl, aged 6.8 to 18.4 years (mean II .7 years), regularly attending the endocrine unit of the Department of Pediatrics, were investigated. Informed consent was obtained from the parents of each patient. Isolated growth hormone deficiency was diagnosed in five children, multiple hormone deficiency was diagnosed in three. Growth bormone deficiency was idiopathic in five children, due to septoopticdysplasia (De Morsier syndrome) in two, and to craniopharyngeoma in 1. Growth hormone had been administered for I .O to 6.8 years (mean 3.5 years), but was stopped one week prior to this investigation. The children were free of any medication at the time of the study except for thyroxine replacement therapy in one, and thyroxine and cortisol replacement therapy in two of the children. Blood samples were taken in the fasting condition through a short indwelling plastic catheter (Abbocath, Abbot Ltd., Szigo, Ireland) prior to, and 60, 120, and 180 minutes after administration of human growth hormone intramuscularly (IM) (Crescormone Kabi), 4 U/m*. Without venicompression, blood was collected by a twosyringe technique using 0.1 molar sodium citrate for anticoagulation. After collection of the samples the catheter was flushed with 3 to 5 mL of isotonic saline. Factor VIII coagulant activity (VIII C) was assayed by a onestage method using a commercially available test kit from Behring Company (Marburg, West Germany). Factor VIII coagulant antigen (VIII C:Ag) was measured by means of an immunoradiometric assay (IRIA).6 The antibody used was purified from a polytransfused hemophiliac with an inhibitor against the LMW moiety. Factor VIII-related antigen (VIII R:Ag) was assayed by quantitative immunoelectrophoresis’ using a specific rabbit antibody commercially available from Behring Company. Ristocetin cofactor (R:Cof) was determined by means of an agglutination methodI commercially available from Behring Company.‘6 Calibration curves for all measurements were done with pooled plasma from 20 healthy adults. Growth hormone determinations were done by means of a radioimmunoassay (RIA) kit commercially available from Behring Company. Statistical analyses were done by means of the Student’s I test for paired data.
RESULTS
Growth hormone was X 1.lO ng/mL * 0.22 SEM; VIII C was X 1.256 U/mL + 0.093 SEM; VIII C:Ag Table 1. Values After Administration 60 Minutes
0 Minutes
c U/n-IL
VIII VIII
C:Ag
VIII
A:Ag
R:Cof
HGH
VIII
1.563*
1.589*
1.396
0.207
0.198
0.197
1.200
1.53El*
1.586’
1.321
0.100
0.196
0.203
0.188
1.100
1.127
1.162
1.230*
0.112
0.115
0.144
0.151
U/mL
values
coagulant
0.925
1.050t
1.075t
0.036
0.049
0.052
21.2$ 5.4
antigen
cofactor
120,
180
and
1.1 0.2 k SEM
Ristocetin
(VIII
minutes Kabil,
‘,t,$,S,l]
Statistically
lP
of factor
(R:Cofl,
(Crescormone,
paired
180 Minutes
1.256
ng/mL
Mean
120 Minutes
Hormone
0.093 U/mL
U/mL
of Human Growth
C:Ag),
VIII
58.1$
after
84.95
16.0 procoagulant
factor
and growth
4 U/m’
1.16211 0.070
22.3 activity
VIII-related hormone
administration
(VIII
antigen (HGH)
of human
C), factor (VIII
growth
hormone
IM.
different
by means
of the
Student’s
t test
data prior to and after HGH administration. < 0.05:
tP < 0.025;
R:Ag),
prior to, and 60.
SP < 0.01; $P < 0.005;
llP < 0.0025
for
AND
MUNTEAN
was X 1.20 U/mL + 0.10 SEM; VIII R:Ag was X 1.10 U/mL + 0.112 SEM; R:Cof was 0.925 U/mL tr 0.037 SEM. Growth hormone, VIII C, VIII C:Ag, VIII R:Ag, and R:Cof values showed a rise 60 to 180 minutes after the administration of growth hormone in each of the patients. Concentrations of VIII C, and of VIII C:Ag at 60, and 120 minutes were significantly higher than baseline concentrations prior to growth hormone administration, but were not different at 180 minutes (Table 1). Concentrations of VIII R:Ag at 180 minutes, and concentrations of R:Cof at 60, 120, and 180 minutes were significantly higher than baseline concentrations prior to growth hormone administration (Table 1). No rise of VIII C, VIII C:Ag, VIII R:Ag, and R:Cof values was observed in three healthy normal adult volunteers after administration of 5 mL isotonic saline IM; the blood was collected in the same way as in the patients. DISCUSSION
Basal levels of both parts of the factor VIII complex were within the normal limits in all our patients with growth hormone deficiency. This fact seems to indicate that growth hormone is not necessary for the synthesis of the factor VIII complex and is not necessary to maintain the basal levels within the normal limits. Obviously, other regulatory mechanisms for factor VIII complex exist. Some regulatory influences on the factor VIII complex have been already shown for glucose, insulin, epinephrine, and for estrogen.8.9,‘7 The duration and quality of control of diabetes mellitus also were shown to have some influences on the factor VIII complex.‘4 Administration of human growth hormone to growth hormone-deficient children induced a rapid rise of the factor VIII complex in all children studied. A rise of the HMW moiety measured as VIII R:Cof has been described previously.7 In addition, in this paper we describe a raise of the LMW moiety (VIII C, VIII C:Ag) after administration of human growth hormone. Therefore, our results suggest that growth hormone has some influence on the circulating levels of both the moieties of the factor VIII complex. The mechanisms for this increase-whether this is a direct effect of growth hormone or not-are not clear at this point. The rise of the HMW moiety after growth hormone administration appears so rapidly that increased synthesis is unlikely to account for it. Release of the HMW moiety from its storage sites in the vascular endothelium into the plasma appears more likely. Similar mechanisms were discussed for DDAVPinduced changes in circulating levels of the factor VIII complex.‘O,” All synthesis sites of the LMW moiety are not known; its rise after growth hormone administration
1067
FACTOR VIII IN HGH DEFICIENCY
again may be a direct effect of human growth hormone or not. Furthermore, it might be secondary to the increase of the HMW moiety because administration of only the HMW moiety to patients suffering from severe von Willebrand’s disease-missing both moieties of the factor VIII complex-results in a rise of VIII C in these patients. Growth hormone has been implicated as a causal factor in the development of diabetic vascular disease because of its direct effects on blood vessels.‘* It has been shown that growth hormone-deficient dwarfs do not develop diabetic vascular disease.” Abnormalities in the factor VIII complex can be demonstrated in diabetic vascular disease.‘4,20 Those abnormalities might be secondary to the vascular disease but also might play a role in the pathogenesis and/or the propagation of the vascular disease. However, Porta and co-workers found no correlations between growth hormone levels and levels of the HM W moiety of the factor VIII complex in nine patients with Type-l diabetes.*’ Therefore, further studies will be necessary to elucidate any relations
between circulating growth hormone levels and circulating levels of both the moieties of the factor VIII complex that might be significant in the pathogenesis of diabetic vascular disease. Furthermore, human growth hormone might be useful to rise the factor VIII complex in patients congenitally deficient in one or both moieties of the factor VIII complex. Preliminary studies show that a raise of both the moieties of the factor VIII complex can be achieved with human growth hormone in hemophiliacs or von Willebrand’s disease patients, but this rise seems not to be as predictable as, for example, with the use of DDAVP.” However, because administration of human growth hormone for a short period seems not to have many side effects and biosynthetic human growth hormone might be available in great amounts, further investigation of the therapeutic use of human growth hormone in factor VIII complex-deficient patients might be worthwhile. ACKNOWLEDGMENT Crescormone
was kindly provided by Kabi-Vitrum,
Austria.
REFERENCES I. Peake IR, Bloom AL: The dissociation of factor VIII by reducing agents, high salt concentration and affinity chromatography. Thromb Haemost 35:191~201, 1976 2. Muntean W, Hathaway Wm E. Montgomery RR: Influence of high molecular weight factor VIII on the measurement of low molecular weight factor VIII procoagulant in different assay systems Br J Haematol 5 1:649%658, 1982 3. Zimmerman TS, Hoyer LW. Dickson L, et al: Determination of the von Willebrand’s disease antigen (factor VIII related antigen) in plasma by quantitative immunoelectrophoresis. Lab Clin Med 86:152-159, 1975 4. Weiss HJ, Hoyer LW, Rickles FR. et al: Quantitative assay of plasna factor deficient in von Willebrand’s disease that is necessary for platelet aggregation. J Clin Invest 52:2708--2716, 1973 5. Rand JH. Sussman II, Gordon RE, et al: Localization of factor Vi I I -related antigen in human vascular subendothelium. Blood 55:7:;2-756. 1980 6. Peake IR, Bloom AL, Giddings JC, et al: An immunoradiometric assay for procoagulant factor VIII antigen: results in haemophilia. von Willebrand’s disease and fetal plasma and serum. Br J Haematol42:269 -28 I, 1979 7. Sarji KE, Levine JH, Nair RMG, et al: Relation between growth hormone and von Willebrand factor activity. J Clin Endocrinol Metab 45:853-856, 1977 8. Rickles FR, Hoycr LW, epintphrine infusion in patients Clin Invest 57:1618 1620. 1976
Rick ME, et al: The etTects of with von Willebrand’s disease. J
9. Muntean W. Borkenstein M: Hemostatic alterations in tall girls treated with ethinyloestradiol. Europ J Pediatr 134:245-248, 1980 IO. Mannucci PM, Canciani MT, Rota L, et al: Response of factor VIII van Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Hacmatol 47283-293. 1981
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