Hyperfibrinogenemia and polycythemia intrauterine growth retardation in fetal lambs LOREN
R.
ROBERT M.
PICKART, K.
MICHAEL
San Francisco,
with
PH.D
CREASY, THALER,
M.D. M.D.
California
Plasma concentrations of albumin and$brinogrn and arterial hematocrits were determined during the last third of gestation in growth-retarded and control fetal lambs. The mean fetal plasma albumin concentration increased slightly a~ term approached and was not significantly dzfferent in the two groups. The mean plasmajbrinogen concentration did not change in the control fetuses, but was significantly elevated in the growth-retarded fetuses, as was the mean arterial hematocrit. The theoretical implications of these findings relative to capillary bloodjow are discussed.
ALTHOUGH intrauterine growth retardation is a relatively common clinical problem, very little is known about the influences that growth retardation may have on the biochemical and physiologic functions of the fetus or neonate. We have produced fetal growth retardation in the fetal lamb by a gradual embolization of the uteroplacental vascular bed.’ Changes in the plasma concentrations of fibrinogen and albumin and in the arterial hematocrit were measured. Hyperfibrinogenemia and polycythemia characterized the terminal portion of the gestation in these growth-retarded fetuses. The theoretical implications of these findings in relation to peripheral capillary blood flow are discussed.
experiments. In brief, catheters were inserted in fetal and maternal vessels at approximately 110 days of gestation. The catheters were exteriorized, and the pregnancies allowed to proceed normally. Alfalfa and water were provided ad libidum for the remainder of the experiment. Growth retardation in the developing fetus was produced by daily injection of nonradioactive microspheres (15~ diameter) into a catheter placed in the main uterine artery supplying the pregnant horn. Control animals were prepared in a similar manner but did not receive the embolization with microspheres. With this procedure, approximately 30 to 40 per cent of the total number of cotyledons are grossly abnormal, being reduced in thickness. Microscopic examination reveals extensive fibrosis and hyalinization. Samples of fetal femoral arterial blood were obtained for biochemical and hematocrit determinations at intervals during the subsequent course of the gestation. Blood samples used for the biochemical assays were placed in titrated tubes and centrifuged, and the plasma was immediately pipetted and frozen at - 20” C. The fetal plasma fibrinogen concentration was determined by the Saifer-Newhouse’ method, the fetal plasma albumin was assayed by paper electrophoresis,3 and the fetal arterial hematocrit was determined with a microcentrifuge. The studies in both groups of animals were terminated at approximately 140 days of gestation and the fetal weight and organ weights determined for confirmation of intrauterine growth retardation.
Methods Embolization of the maternal placental implantation site in pregnant sheep was performed as previously described.’ Dated pregnant sheep were used in all From the Department of Obstetrics and Gynecology, Department of Pediatrics, and the Cardiovascular Research Institute, University of California-San Francisco. The iiivestigation W(IJ supported by United States Public Health Seruice Grants HD-06619 and HD-0?148. Received for publication Acceptid
March
18, 1975.
May 28, 1975.
Reprint requests: Dr. Robert K. Greasy, Department of Obstetis and Gynecology,University of Cal~omiaSan Francisco, San Francisco, Califonzia 94143.
268
Volume Number
Hyperfibrinogenemia
124 3
Table I. Fetal plasma fibrinogen concentration* control and growth-retarded fetal lambs Gestutional Cdvl
age
114-122 123-129 130-140
Control fetuses
131 -t 24 (8)t 143 4 17 (5) 118 2 30 (11)
Growth-retarded fetuses
160? 71 (6) 247 k 89 (3) 236 k 127 (10)
in
and polycythemia
269
ALBUMIN
P values
0.05 0.025 0.0005
FIBRINOGEN
.,b-.-.-
._I_._._
b
*Values are mean concentration in milligrams per 100 ml + 1 S.D. tNumbers in parentheses indicate number of fetuses. Table II. Arterial hematocrit (means k 1 SD.) in control and growth-retarded fetal lambs at the onset and termination of the chronic study Controls
Onset Termination
0.34 t 0.02 0.35 2 0.04
Growth-retarded
0.35 t 0.04 0.44 ?I 0.03*
*Significant difference at p < 0.05.
The unpaired t test (two-tailed) was used to check for significant differences between the control and embolization groups.
I
115
120
I
I
I
I
125
130
135
140
GESTATIONAL
AGE (DAYS)
Fig. 1. Changes in plasma albumin (squares) and fibrinogen (circles) concentrations during gestation in fetal sheep. Growth-retarded fetuses are denoted by interrupted lines. Differences between normal and growth-retarded fetuses at the ages tested were not significant for albumin and highly significant for fibrinogen (see Table I.).
was 0.35 f 0.04, retarded fetuses-a
and 0.44 ? 0.03 in the significant difference.
growth-
Comment Results The results of the embolization procedure in regard to detailed anatomic and physiologic data have been previously reported. ia 4 In brief, this procedure results in fetuses which are significantly smaller in weight and length. Most fetal organs are reduced in size, particularly the liver and thymus. Fetal PO, is reduced 15 to 25s.‘. 4 The fetuses in the present embolization group showed similar evidence of fetal growth retardation. The mean fetal plasma fibrinogen concentration in the control group remained relatively constant between 114 and 140 days of gestation, as shown in Table I. The mean fetal plasma fibrinogen in the growth retarded fetuses was significantly increased over the control group. Small but statistically significant differences in plasma fibrinogen concentrations were noted in the earlier sampling period (114 to 122 days). The differences in fibrinogen concentration between control and growth-retarded fetuses became more pronounced as gestation progressed, as shown in Fig. 1. The plasma albumin concentrations in the control group increased in a linear manner as gestation advanced and were not significantly different from those of the growth-retarded fetuses. At the onset of the study the mean fetal hematocrits were similar, as shown in Table II. At the end of the study the mean fetal hematocrit in the control group
The results indicate that embolization of the maternal uteroplacental vascular bed is associated with an increase in the concentration of plasma fibrinogen and the arterial hematocrit of the fetal lamb. The increase in fibrinogen is not derived from maternal sources, as it is not transferred across the mammalian placenta,5 and it is most unlikely that the increase in hematocrit is due to transfer of maternal red cells. The polycythemia in the growth-retarded fetuses may be explained as a response to arterial hypoxemia found in these fetuses. The hyperfibrinogenemia may be explained as a result of fetal stress, as the concentration of the plasma clotting protein fibrinogen is an excellent indicator of stress in adult mammals. Various types of traumatic or toxic injuries, such as burns, crushing of extremities, and treatment with endotoxin, talcum powder, and turpentine, rapidly stimulate production of fibrinogen in the liver and increase the plasma fibrinogen concentration.6 Even psychological stresses, such as electroshock’ or crowding,* will produce a rise in circulating fibrinogen within 24 hours. A number of studies on hyperfibrinogenemic states have indicated that the increased concentration of the protein is due to an accelerated hepatic synthesis rather than a decreased catabolism of fibrinogen63 ’ In these experimental growth-retarded fetuses an etiologic factor could have been the embolization process itself,
270
Pickart,
Creasy,
and Thaler
as intravascular clotting and formation of thrombin are known to increase the rate of hepatic fibrinogen synthesis. lo Small peptides produced by the clotting mechanism have also been proposed as being able to stimulate synthesis of fibrinogen.” Although fibrinogen does not cross the placental barrier, it is conceivable that the small peptides could cross the placenta and affect the fetal liver. It is also interesting that the increase in fetal fibrinogen concentrations occurred despite an approximately one-third reduction in fetal liver weight. In contrast with fibrinogen, the albumin concentrations in stressed fetuses in our experiments were either unaffected or depressed, but the decreases in albumin were not statistically significant. Similarly, Neuhaus and associates” have shown that in traumatized adult animals hepatic production of fibrinogen, seromucoid, and acute-phase globulin are increased, whereas albumin synthesis either is reduced slightly or remains unaltered. Thus the response of fetal sheep to placental embolization appears to be similar to that seen in stressed adult animals. Sarcione13 demonstrated that plasma proteins which are elevated during stress (e.g., acute phase protein, fetal alpha protein, fibrinogen) are characteristic of “fetal synthetic patterns.” Sarcione suggested that de-repression of “fetal genes” in adult liver may be responsible for this effect. The possibility that the increased fibrinogen concentration seen in the growth-retarded lamb fetuses could conceivably reflect a retarded progression to adult plasma protein patterns deserves further investigation. The in vivo flow of blood through the microcirculation has been shown to be of an intermittent and pulsative nature. 14. ” At the velocities of blood flow, or shear rates. found in the capillaries, blood exhibits non-Newtonian flow characteristics, acting as a solid during a no-flow period and as a liquid during flow periods. These properties of capillary flow are due to the intermittent formation and dissolution of red blood cell-fibrinogen aggregates at low blood velocities (0.1 to 0.5 cm. per second) found in the microcirculation. The propensity of human blood to form these aggregates appears to be a synergistic function of the plasma fibrinogen concentration and the hematocrit. While there is only a weak interaction of fibrinogen and red blood cells in sheep and goats, most mammals studied demonstrate a strong interaction of the two factors, which markedly increases erythrocyte aggregation in the capillaries. In a human fetus, an increase in hematocrit and fibrinogen similar to that in the growth-retarded sheep fetus would theoretically be expected to greatly increase the clumping and sludging
of blood in the capillary beds, with the potential of reducing oxygen tension and tissue perfusion.i6-‘” In an attempt to quantify the above interactions, Merrill’” and co-workers have defined the force required to cause static blood to flow as the +rld shear Stress of blood. Yield shear stress alternately may be considered to represent the force necessary to disrupt the fibrinogen-erythrocyte aggregates formed in nonflowing blood. When the theoretical yield shear stress is calculated by the equations obtained by Merrill with the data from these studies, we find that a tenfold increase in yield shear stress would be expected to exist in blood of human fetuses if a similar situation in hematocrit and fibrinogen existed (see Appendix). This synergistic interaction between polycythemic and hyperfibrinogenemic states could, in human subjects, exacerbate a number of factors which contribute to fetal distress. Clinically, sludging of blood has been associated with anoxic lesions of tissues, low blood flow rates, reduced carcliac output, increased vascular resistance, and congestive heart failure.“. *’ These studies on fetal sheep suggest that an elevated blood fibrinogen may play a role in the frequent occurrence of life-threatening situations in growth-retarded human fetuses and newborn infants. Appendix Merrill” and co-workers measured the yield shear stress (Ty) of blood at the shear strain rates found in the microcirculation. The yield shear stress of human blood when the hematocrit ranges between 30 and 50 per cent is closely approximated by the equation: Ty
= A(H
- 0.06)”
(1)
where the hematocrit is H, and A is a strong function of the fibrinogen concentration. The effect of plasma fibrinogen concentrations of 100 to 400 mg. per 100 ml. on Ty correlates with the equation: Ty
= BCf2
(2)
where Cf is the plasma fibrinogen concentration in mg. per 100 ml., and B is a constant which is a weak function of other plasma proteins. These equations were used to estimate the increase in yield shear stress in the blood of growth-retarded fetuses over control fetuses in our experiments. If A = BCf’, then substitution in Eq. (1) yields: Ty
= BCf2(H
- 0.06)3.
(3)
In the last sampling interval (130 to 140 days) the mean hematocrit and fibrinogen levels were 33.7 per cent and 118 mg. per 100 ml. for the control fetuses, and 43.7 per cent and 236 mg. per 100 ml. for the
Volume Number
Hyperfibrinogenemia
124 3
growth-retarded these
values
fetuses, give
Ty (retarded) Ty (control)
the =
respectively.
From
Eq.
(3),
ratio:
Thus,
the
growth-retarded 3 = 10.06,
be approximately
increase
in fetuses
yield
shear
compared
and polycythemia
stress with
of
controls
271
blood
in
would
tenfold.
REFERENCES 1. Creasy, R. K., Barrett, C. T., de Swiet, M., Kahanpaa, K. V., and Rudolph, A. M.: AM. J. OBSTET. GYNECOL. 112: 566, 1972. 2. Saifer, A., and Newhouse, A.: J. Biol. Chem. 208: 159, 1954. 3. Gelman Procedures: Techniques and Apparatus for Electrophoresis, Ann Arbor, Mich., 1968, Gelman Instrument Company. K. V., Young, W. 4. Creasy, R. K., de Swiet, M., Kahanpaa, P., and Rudolph, A. M.: Pathophysiological changes in the fetal lamb with growth retardation, in Foetal and Neonatal Physiology: Proceedings of the Sir Joseph Barcroft Centenary Symposium, Cambridge, England, 1973, Cambridge University Press. 5. Schultze, H. E., and Heremans, J. F.: Molecular Biology of Human Proteins, New York, 1966, Elsevier Publishing Company, chap. 3. 6. Regoeczi, E.: In Rothschild, M. A., and Waldmann, T., editors: Plasma Protein Metabolism, New York, 1970, Academic Press, Inc., p. 459. 7. McKenzie, J., Celander, D., and Guest, M.: Am. J. Physiol. 208: 1009, 1965.
8. McKenzie, 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19. 20.
J., Celander, D., and Guest, M.: Am. J. Physiol. 204: 42, 1963. Kropatkin, N. L., and Izak, G.: Thromb. Diath. Haemorrh. 19: 547, 1968. Pickart, L. R., and Pilgeram, L. 0.: Thromb. Diath. Haemorrh. 17: 358, 1967. Bocci, V., Conti, T., Muscettola, M., Pacini, A., and Pessina, G. P.: Thromb. Diath. Haemorrh. 31: 395, 1974. Neuhaus, 0. W., Balegno, H. F., and Changler, A. M.: Am. I. Phvsiol. 211: 151. 1966. Sarc&ne, K. J.: Biochemistry 9: 3059, 1970. F&on, G. P., and Lutz, B. R.: Boston Med. Q. 8: 1, 1957. Palmer, A. A.: Q. J. Exp. Physiol. 44: 149, 1959. Merrill, E. W.: Physiol. Rev. 49: 863, 1969. Replogle. R. L., Meiselman, H. J., and Merrill, E. W.: Circulation 36: 148, 1967. Bicher, H. I., Reneau, D. D., Bruley, D. F., Kolmodin, G., and Kniselv. M. H.: In Sixth Euronean Conference on Microcirculation, Base], 1971, S. K&ger AG, p. 298. Groth, C. G., Lofstrom, B., Rybeck, B., and Thorsen, G.: Biol. Anat. 4: 174, 1964. Dintenfass, L.: Arch. Intern. Med. 118: 427, 1966.
R.
ROBERT M.
PICKART, K.
MICHAEL
San Francisco,
with
PH.D
CREASY, THALER,
M.D. M.D.
California
Plasma concentrations of albumin and$brinogrn and arterial hematocrits were determined during the last third of gestation in growth-retarded and control fetal lambs. The mean fetal plasma albumin concentration increased slightly a~ term approached and was not significantly dzfferent in the two groups. The mean plasmajbrinogen concentration did not change in the control fetuses, but was significantly elevated in the growth-retarded fetuses, as was the mean arterial hematocrit. The theoretical implications of these findings relative to capillary bloodjow are discussed.
ALTHOUGH intrauterine growth retardation is a relatively common clinical problem, very little is known about the influences that growth retardation may have on the biochemical and physiologic functions of the fetus or neonate. We have produced fetal growth retardation in the fetal lamb by a gradual embolization of the uteroplacental vascular bed.’ Changes in the plasma concentrations of fibrinogen and albumin and in the arterial hematocrit were measured. Hyperfibrinogenemia and polycythemia characterized the terminal portion of the gestation in these growth-retarded fetuses. The theoretical implications of these findings in relation to peripheral capillary blood flow are discussed.
experiments. In brief, catheters were inserted in fetal and maternal vessels at approximately 110 days of gestation. The catheters were exteriorized, and the pregnancies allowed to proceed normally. Alfalfa and water were provided ad libidum for the remainder of the experiment. Growth retardation in the developing fetus was produced by daily injection of nonradioactive microspheres (15~ diameter) into a catheter placed in the main uterine artery supplying the pregnant horn. Control animals were prepared in a similar manner but did not receive the embolization with microspheres. With this procedure, approximately 30 to 40 per cent of the total number of cotyledons are grossly abnormal, being reduced in thickness. Microscopic examination reveals extensive fibrosis and hyalinization. Samples of fetal femoral arterial blood were obtained for biochemical and hematocrit determinations at intervals during the subsequent course of the gestation. Blood samples used for the biochemical assays were placed in titrated tubes and centrifuged, and the plasma was immediately pipetted and frozen at - 20” C. The fetal plasma fibrinogen concentration was determined by the Saifer-Newhouse’ method, the fetal plasma albumin was assayed by paper electrophoresis,3 and the fetal arterial hematocrit was determined with a microcentrifuge. The studies in both groups of animals were terminated at approximately 140 days of gestation and the fetal weight and organ weights determined for confirmation of intrauterine growth retardation.
Methods Embolization of the maternal placental implantation site in pregnant sheep was performed as previously described.’ Dated pregnant sheep were used in all From the Department of Obstetrics and Gynecology, Department of Pediatrics, and the Cardiovascular Research Institute, University of California-San Francisco. The iiivestigation W(IJ supported by United States Public Health Seruice Grants HD-06619 and HD-0?148. Received for publication Acceptid
March
18, 1975.
May 28, 1975.
Reprint requests: Dr. Robert K. Greasy, Department of Obstetis and Gynecology,University of Cal~omiaSan Francisco, San Francisco, Califonzia 94143.
268
Volume Number
Hyperfibrinogenemia
124 3
Table I. Fetal plasma fibrinogen concentration* control and growth-retarded fetal lambs Gestutional Cdvl
age
114-122 123-129 130-140
Control fetuses
131 -t 24 (8)t 143 4 17 (5) 118 2 30 (11)
Growth-retarded fetuses
160? 71 (6) 247 k 89 (3) 236 k 127 (10)
in
and polycythemia
269
ALBUMIN
P values
0.05 0.025 0.0005
FIBRINOGEN
.,b-.-.-
._I_._._
b
*Values are mean concentration in milligrams per 100 ml + 1 S.D. tNumbers in parentheses indicate number of fetuses. Table II. Arterial hematocrit (means k 1 SD.) in control and growth-retarded fetal lambs at the onset and termination of the chronic study Controls
Onset Termination
0.34 t 0.02 0.35 2 0.04
Growth-retarded
0.35 t 0.04 0.44 ?I 0.03*
*Significant difference at p < 0.05.
The unpaired t test (two-tailed) was used to check for significant differences between the control and embolization groups.
I
115
120
I
I
I
I
125
130
135
140
GESTATIONAL
AGE (DAYS)
Fig. 1. Changes in plasma albumin (squares) and fibrinogen (circles) concentrations during gestation in fetal sheep. Growth-retarded fetuses are denoted by interrupted lines. Differences between normal and growth-retarded fetuses at the ages tested were not significant for albumin and highly significant for fibrinogen (see Table I.).
was 0.35 f 0.04, retarded fetuses-a
and 0.44 ? 0.03 in the significant difference.
growth-
Comment Results The results of the embolization procedure in regard to detailed anatomic and physiologic data have been previously reported. ia 4 In brief, this procedure results in fetuses which are significantly smaller in weight and length. Most fetal organs are reduced in size, particularly the liver and thymus. Fetal PO, is reduced 15 to 25s.‘. 4 The fetuses in the present embolization group showed similar evidence of fetal growth retardation. The mean fetal plasma fibrinogen concentration in the control group remained relatively constant between 114 and 140 days of gestation, as shown in Table I. The mean fetal plasma fibrinogen in the growth retarded fetuses was significantly increased over the control group. Small but statistically significant differences in plasma fibrinogen concentrations were noted in the earlier sampling period (114 to 122 days). The differences in fibrinogen concentration between control and growth-retarded fetuses became more pronounced as gestation progressed, as shown in Fig. 1. The plasma albumin concentrations in the control group increased in a linear manner as gestation advanced and were not significantly different from those of the growth-retarded fetuses. At the onset of the study the mean fetal hematocrits were similar, as shown in Table II. At the end of the study the mean fetal hematocrit in the control group
The results indicate that embolization of the maternal uteroplacental vascular bed is associated with an increase in the concentration of plasma fibrinogen and the arterial hematocrit of the fetal lamb. The increase in fibrinogen is not derived from maternal sources, as it is not transferred across the mammalian placenta,5 and it is most unlikely that the increase in hematocrit is due to transfer of maternal red cells. The polycythemia in the growth-retarded fetuses may be explained as a response to arterial hypoxemia found in these fetuses. The hyperfibrinogenemia may be explained as a result of fetal stress, as the concentration of the plasma clotting protein fibrinogen is an excellent indicator of stress in adult mammals. Various types of traumatic or toxic injuries, such as burns, crushing of extremities, and treatment with endotoxin, talcum powder, and turpentine, rapidly stimulate production of fibrinogen in the liver and increase the plasma fibrinogen concentration.6 Even psychological stresses, such as electroshock’ or crowding,* will produce a rise in circulating fibrinogen within 24 hours. A number of studies on hyperfibrinogenemic states have indicated that the increased concentration of the protein is due to an accelerated hepatic synthesis rather than a decreased catabolism of fibrinogen63 ’ In these experimental growth-retarded fetuses an etiologic factor could have been the embolization process itself,
270
Pickart,
Creasy,
and Thaler
as intravascular clotting and formation of thrombin are known to increase the rate of hepatic fibrinogen synthesis. lo Small peptides produced by the clotting mechanism have also been proposed as being able to stimulate synthesis of fibrinogen.” Although fibrinogen does not cross the placental barrier, it is conceivable that the small peptides could cross the placenta and affect the fetal liver. It is also interesting that the increase in fetal fibrinogen concentrations occurred despite an approximately one-third reduction in fetal liver weight. In contrast with fibrinogen, the albumin concentrations in stressed fetuses in our experiments were either unaffected or depressed, but the decreases in albumin were not statistically significant. Similarly, Neuhaus and associates” have shown that in traumatized adult animals hepatic production of fibrinogen, seromucoid, and acute-phase globulin are increased, whereas albumin synthesis either is reduced slightly or remains unaltered. Thus the response of fetal sheep to placental embolization appears to be similar to that seen in stressed adult animals. Sarcione13 demonstrated that plasma proteins which are elevated during stress (e.g., acute phase protein, fetal alpha protein, fibrinogen) are characteristic of “fetal synthetic patterns.” Sarcione suggested that de-repression of “fetal genes” in adult liver may be responsible for this effect. The possibility that the increased fibrinogen concentration seen in the growth-retarded lamb fetuses could conceivably reflect a retarded progression to adult plasma protein patterns deserves further investigation. The in vivo flow of blood through the microcirculation has been shown to be of an intermittent and pulsative nature. 14. ” At the velocities of blood flow, or shear rates. found in the capillaries, blood exhibits non-Newtonian flow characteristics, acting as a solid during a no-flow period and as a liquid during flow periods. These properties of capillary flow are due to the intermittent formation and dissolution of red blood cell-fibrinogen aggregates at low blood velocities (0.1 to 0.5 cm. per second) found in the microcirculation. The propensity of human blood to form these aggregates appears to be a synergistic function of the plasma fibrinogen concentration and the hematocrit. While there is only a weak interaction of fibrinogen and red blood cells in sheep and goats, most mammals studied demonstrate a strong interaction of the two factors, which markedly increases erythrocyte aggregation in the capillaries. In a human fetus, an increase in hematocrit and fibrinogen similar to that in the growth-retarded sheep fetus would theoretically be expected to greatly increase the clumping and sludging
of blood in the capillary beds, with the potential of reducing oxygen tension and tissue perfusion.i6-‘” In an attempt to quantify the above interactions, Merrill’” and co-workers have defined the force required to cause static blood to flow as the +rld shear Stress of blood. Yield shear stress alternately may be considered to represent the force necessary to disrupt the fibrinogen-erythrocyte aggregates formed in nonflowing blood. When the theoretical yield shear stress is calculated by the equations obtained by Merrill with the data from these studies, we find that a tenfold increase in yield shear stress would be expected to exist in blood of human fetuses if a similar situation in hematocrit and fibrinogen existed (see Appendix). This synergistic interaction between polycythemic and hyperfibrinogenemic states could, in human subjects, exacerbate a number of factors which contribute to fetal distress. Clinically, sludging of blood has been associated with anoxic lesions of tissues, low blood flow rates, reduced carcliac output, increased vascular resistance, and congestive heart failure.“. *’ These studies on fetal sheep suggest that an elevated blood fibrinogen may play a role in the frequent occurrence of life-threatening situations in growth-retarded human fetuses and newborn infants. Appendix Merrill” and co-workers measured the yield shear stress (Ty) of blood at the shear strain rates found in the microcirculation. The yield shear stress of human blood when the hematocrit ranges between 30 and 50 per cent is closely approximated by the equation: Ty
= A(H
- 0.06)”
(1)
where the hematocrit is H, and A is a strong function of the fibrinogen concentration. The effect of plasma fibrinogen concentrations of 100 to 400 mg. per 100 ml. on Ty correlates with the equation: Ty
= BCf2
(2)
where Cf is the plasma fibrinogen concentration in mg. per 100 ml., and B is a constant which is a weak function of other plasma proteins. These equations were used to estimate the increase in yield shear stress in the blood of growth-retarded fetuses over control fetuses in our experiments. If A = BCf’, then substitution in Eq. (1) yields: Ty
= BCf2(H
- 0.06)3.
(3)
In the last sampling interval (130 to 140 days) the mean hematocrit and fibrinogen levels were 33.7 per cent and 118 mg. per 100 ml. for the control fetuses, and 43.7 per cent and 236 mg. per 100 ml. for the
Volume Number
Hyperfibrinogenemia
124 3
growth-retarded these
values
fetuses, give
Ty (retarded) Ty (control)
the =
respectively.
From
Eq.
(3),
ratio:
Thus,
the
growth-retarded 3 = 10.06,
be approximately
increase
in fetuses
yield
shear
compared
and polycythemia
stress with
of
controls
271
blood
in
would
tenfold.
REFERENCES 1. Creasy, R. K., Barrett, C. T., de Swiet, M., Kahanpaa, K. V., and Rudolph, A. M.: AM. J. OBSTET. GYNECOL. 112: 566, 1972. 2. Saifer, A., and Newhouse, A.: J. Biol. Chem. 208: 159, 1954. 3. Gelman Procedures: Techniques and Apparatus for Electrophoresis, Ann Arbor, Mich., 1968, Gelman Instrument Company. K. V., Young, W. 4. Creasy, R. K., de Swiet, M., Kahanpaa, P., and Rudolph, A. M.: Pathophysiological changes in the fetal lamb with growth retardation, in Foetal and Neonatal Physiology: Proceedings of the Sir Joseph Barcroft Centenary Symposium, Cambridge, England, 1973, Cambridge University Press. 5. Schultze, H. E., and Heremans, J. F.: Molecular Biology of Human Proteins, New York, 1966, Elsevier Publishing Company, chap. 3. 6. Regoeczi, E.: In Rothschild, M. A., and Waldmann, T., editors: Plasma Protein Metabolism, New York, 1970, Academic Press, Inc., p. 459. 7. McKenzie, J., Celander, D., and Guest, M.: Am. J. Physiol. 208: 1009, 1965.
8. McKenzie, 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19. 20.
J., Celander, D., and Guest, M.: Am. J. Physiol. 204: 42, 1963. Kropatkin, N. L., and Izak, G.: Thromb. Diath. Haemorrh. 19: 547, 1968. Pickart, L. R., and Pilgeram, L. 0.: Thromb. Diath. Haemorrh. 17: 358, 1967. Bocci, V., Conti, T., Muscettola, M., Pacini, A., and Pessina, G. P.: Thromb. Diath. Haemorrh. 31: 395, 1974. Neuhaus, 0. W., Balegno, H. F., and Changler, A. M.: Am. I. Phvsiol. 211: 151. 1966. Sarc&ne, K. J.: Biochemistry 9: 3059, 1970. F&on, G. P., and Lutz, B. R.: Boston Med. Q. 8: 1, 1957. Palmer, A. A.: Q. J. Exp. Physiol. 44: 149, 1959. Merrill, E. W.: Physiol. Rev. 49: 863, 1969. Replogle. R. L., Meiselman, H. J., and Merrill, E. W.: Circulation 36: 148, 1967. Bicher, H. I., Reneau, D. D., Bruley, D. F., Kolmodin, G., and Kniselv. M. H.: In Sixth Euronean Conference on Microcirculation, Base], 1971, S. K&ger AG, p. 298. Groth, C. G., Lofstrom, B., Rybeck, B., and Thorsen, G.: Biol. Anat. 4: 174, 1964. Dintenfass, L.: Arch. Intern. Med. 118: 427, 1966.
