British Journal of Obstetrics and GynaecoIogy August 1976. VOI 83. pp 636-639
A SERIAL STUDY OF COAGULATION FACTORS XII, XI AND X IN PLASMA IN NORMAL PREGNANCY AND IN PREGNANCY COMPLICATED BY PRE-ECLAMPSIA BY
R. G. CONDIE Departments of Obstetrics and Gynaecology and Medicine University of Aberdeen Foresterhill, Aberdeen Summary A serial study of coagulation factors XII, XI and X in plasma has been carried out on 60 primigravidae, prospectively comparing those who remained normal with those who developed pre-eclampsia. In the normal group of 48 patients, the levels of all factors rose as pregnancy advanced, a secondary increase in factors XI and X occurring in the puerperium. Cord levels of all three factors were depressed. In the pre-eclampsia group of 12 patients, factor XI1 was significantly higher than in the normal group throughout the study, while factors XI and X were slightly lower. Observed changes failed to support the idea of a strong primary role for the coagulation mechanism in the pathogenesis of pre-eclampsia.
secondary rise of certain factors occurs, especially factor VIII. Regarding cord blood, factor X has been reported as low (Bonnar et al, 1970); factor XI has been found to be depressed in the newborn (Nossel et al, 1966; Hathaway, 1970), as has factor XI1 (Bleyer and Breckenridge, 1970: Biland and Duckert, 1973). Changes in the haemostatic mechanism have been mooted in the pathogenesis of preeclampsia (Schneider, 1950; Stalker et al, 1968; Page, 1972); and numerous differences from normal pregnancy have been reported in the circulating blood of patients with pre-eclampsia suggesting a tendency to intravascular coagulation (McKay and Corey, 1964; Wardle and Menon, 1969; Henderson et al, 1970; Bonnar et al, 1971a and 1971b; Howie et al, 1971). Since few truly serial studies of the coagulation system have been performed in normal pregnancy or pre-eclampsia, it was decided to carry out such a study, prospectively comparing a group remaining normal with a group developing pre-eclampsia.
CONTACT with a surface such as glass or damaged vascular endothelium appears to be the trigger for the intrinsic coagulation system, the probable sequence of reactions being likened to a ‘cascade’ (Macfarlane, 1964). The contact phase involves the activation of factor XI1 (Hageman factor) which combines with factor XI (Plasma Thromboplastin Antecedent or PTA) as a ‘contact reaction product’ (Nossel, 1964). This activates factor IX which, in conjunction with factor VIII, causes activation of factor X. Activated factor X (Stuart-Prower factor) participates in the prothrombin converting principle which is responsible for the further sequence of events culminating in fibrin deposition. Coagulation factors IT, VII, VIII and X are known to increase in pregnancy (Pechet and Alexander, 1961; Todd et al, 1965; Markarian et al, 1967). Factor XI has been reported to decrease (Hilgartner and Smith, 1965; Phillips et al, 1973),while factor XI1 has been found to be elevated in maternal blood at delivery (Biland and Duckert, 1973). In the puerperium, a 636
COAGULATION FACTORS IN PREGNANCY PATIENTS AND METHODS A group of 60 primigravidae were followed from 12 weeks of gestation through to the puerperium. The age range of the patients was 18 to 25 years, their heights were over 152 cm, and their weightlheight ratios were in the interquartile range (Kemsley et al, 1962); in none was there a history of abortion, hypertension, or renal disease. A total of 48 women remained normal throughout the study, and 12 developed preeclampsia at or after 38 weeks of gestation. A diagnosis of pre-eclampsia was made if a previously normotensive patient had a sustained rise in blood pressure to 140/90 mm Hg or more after the 26th week of pregnancy. Four patients had at least 0.5 g/l of proteinuria. All patients had sterile urine on booking and all were aproteinuric and normotensive at the postnatal visit. An additional ten non-pregnant women were studied as controls. Citrated peripheral venous blood samples were collected without torniquet at 12, 20, 30 and 38 weeks of gestation; at 30 minutes after placental delivery; and at 24, 48, 96 and 144 hours and also six weeks after delivery. Cord venous blood was collected before placental expulsion. On each occasion glass contact was totally avoided in order to prevent premature activation of factor XII, and plasma was separated and stored in aliquots for assay at -20” C within 20 minutes of collection. Assays of factors XI1 and XI were carried out using the method of Nossel (1964), factor deficient plasma being obtained from Warner Lambert Co, New Jersey. Factor X was assayed by the method of Denson (1961), deficient plasma being provided by ‘Diagen’ Diagnostic Reagents Ltd, Oxon. All assays were done in duplicate, and expressed as per cent normal activity from a ‘normal’ graph constructed for each assay batch. ‘Normal’ pooled plasma was obtained for all assays from 20 normal male blood donors aged between 20 and 30 years. Statistical analysis was by Student’s‘t’ test and significance was recorded if less than 0.05.
RESULTS The results are summarized in Table I.
637
Factor X I I Normal pregnancy. By 20 weeks of gestation, the level was above the non-pregnant and continued to rise to 135 per cent at 38 weeks. It remained elevated in the puerperium and had returned to the non-pregnant level at six weeks post partum. The cord level of 84 per cent of ‘normal’ was less than maternal or non-pregnant levels. Pregnancy complicated by pre-eclampsiu. Preeclampsia levels were significantly higher than in normal pregnancy from 20 weeks of gestation onwards, a peak of 190 per cent being achieved at 30 weeks; levels remaining higher post partum. The mean cord level of 74 per cent was slightly lower than in normal pregnancy. Factor X I Normal pregnancy. The level was above the non-pregnant at 12 weeks of gestation, and rose to 139 per cent at 38 weeks. A small fall occurred at 30 minutes after delivery followed by a sharp secondary rise over the first week of the puerperium, the non-pregnant level being approached at 6 weeks post partum. The mean cord level was 65 per cent of ‘normal’. Pregnancy complicated by pre-eclampsia. Levels were lower than in normal pregnancy until 38 weeks of gestation, a nadir of 95 per cent occurring at 20 weeks. In the puerperium, an earlier fall towards the non-pregnant level occurred in the pre-eclampsia group. The cord level was similar to that in normal pregnancy. Factor A’ Normalpregnancy. A rise was observed at 12 weeks of gestation and the trend continued to a peak of 163 per cent at 30 weeks. A secondary rise to 173 per cent occurred at 144 hours post partum, the level again approaching the nonpregnant at 6 weeks after delivery. The mean cord level was 65 per cent of ‘normal’. Pregnancy complicated by pre-eclampsia. Unlike the normal pregnancy series, a rise did not commence until 20 weeks of gestation, a similar peak of 165 per cent being reached at 38 weeks. Levels slightly lower than in normal pregnancy occurred in the puerperium, while the cord level was close to that in normal pregnancy.
TABLEI Plasma levels of factors XII, X I and X during and after pregnancy, in umbilical cord blood and in non-pregnant women. Statistical comparisons are shown -__ .. Coagulation factors (per cent of normal activity in pooled male plasma) Mean SD ~~~~
+
_ _ ~ _ _ _ _
I. Normalpregnancy (48 patients)
XI1
-.
XI
x
124+33
127&42
~- - . __
~
_____
a.
12 weeks
b.
20
,,
c.
30
,,
131t 4 5
d.
38
,,
e.
30 minutes post partum
f.
24 hours
g.
48 hours
144141
151i-50
168142
h.
96 hours
,,
,,
128151
166&49
154+37
,,
,,
136126
178*71
173161
,, .___
96 & 30
125131
116*36
84h37
65 1 2 7
65 i37
120132
115120
102h39
104128
-
__
,,
,, ~
i.
144 hours
j.
6 weeks
k.
Cord blood
~-
11. Pregnancy with pre-eclampsia A.
,, -
,,
-
,,
,,
C. 30
,,
D. 38
,,
__ ~
E. -
-
.
30 minutes post partum
_
145f 56 163154
135127
139148
152137
1411 4 2
116136
123136
146&53
~~
141J-50
-
145146
~~~
.-
~~
B. 20
_
131 $50 ___ 129+42
-
12 weeks
(12 patients)
_
128*38
158k31
95122
109124
121 1 3 8
1411-44
~.
~
190188
~ _ _ _ _ _
145140
149160
112126
165*52
_ .
151 1 6 4
_ _
~~
~
,,
_ -
~~~~
I80178
,, ,,
_
161*42
140+37
G. 48 hours
,,
175&41
158130
155&44
H. 96 hours
,,
,,
161k 2 7
130127
141 1 3 0
I.
,,
,,
137113
126528
145125
107128
101 t 2 0
116137
74 *27
69121
F. 24 hours -
~
_
144 hours
_
-~ -
134133
-
- -
_-
~
J.
6 weeks
,,
,, ,,
~ _ _ _ _ ~ _ _ _ _ ~ ~ ~ _
K. Cord blood ,, 111. Non-pregnant women (10) _ _ _
1121341
~
p
A SERIAL STUDY OF COAGULATION FACTORS XII, XI AND X IN PLASMA IN NORMAL PREGNANCY AND IN PREGNANCY COMPLICATED BY PRE-ECLAMPSIA BY
R. G. CONDIE Departments of Obstetrics and Gynaecology and Medicine University of Aberdeen Foresterhill, Aberdeen Summary A serial study of coagulation factors XII, XI and X in plasma has been carried out on 60 primigravidae, prospectively comparing those who remained normal with those who developed pre-eclampsia. In the normal group of 48 patients, the levels of all factors rose as pregnancy advanced, a secondary increase in factors XI and X occurring in the puerperium. Cord levels of all three factors were depressed. In the pre-eclampsia group of 12 patients, factor XI1 was significantly higher than in the normal group throughout the study, while factors XI and X were slightly lower. Observed changes failed to support the idea of a strong primary role for the coagulation mechanism in the pathogenesis of pre-eclampsia.
secondary rise of certain factors occurs, especially factor VIII. Regarding cord blood, factor X has been reported as low (Bonnar et al, 1970); factor XI has been found to be depressed in the newborn (Nossel et al, 1966; Hathaway, 1970), as has factor XI1 (Bleyer and Breckenridge, 1970: Biland and Duckert, 1973). Changes in the haemostatic mechanism have been mooted in the pathogenesis of preeclampsia (Schneider, 1950; Stalker et al, 1968; Page, 1972); and numerous differences from normal pregnancy have been reported in the circulating blood of patients with pre-eclampsia suggesting a tendency to intravascular coagulation (McKay and Corey, 1964; Wardle and Menon, 1969; Henderson et al, 1970; Bonnar et al, 1971a and 1971b; Howie et al, 1971). Since few truly serial studies of the coagulation system have been performed in normal pregnancy or pre-eclampsia, it was decided to carry out such a study, prospectively comparing a group remaining normal with a group developing pre-eclampsia.
CONTACT with a surface such as glass or damaged vascular endothelium appears to be the trigger for the intrinsic coagulation system, the probable sequence of reactions being likened to a ‘cascade’ (Macfarlane, 1964). The contact phase involves the activation of factor XI1 (Hageman factor) which combines with factor XI (Plasma Thromboplastin Antecedent or PTA) as a ‘contact reaction product’ (Nossel, 1964). This activates factor IX which, in conjunction with factor VIII, causes activation of factor X. Activated factor X (Stuart-Prower factor) participates in the prothrombin converting principle which is responsible for the further sequence of events culminating in fibrin deposition. Coagulation factors IT, VII, VIII and X are known to increase in pregnancy (Pechet and Alexander, 1961; Todd et al, 1965; Markarian et al, 1967). Factor XI has been reported to decrease (Hilgartner and Smith, 1965; Phillips et al, 1973),while factor XI1 has been found to be elevated in maternal blood at delivery (Biland and Duckert, 1973). In the puerperium, a 636
COAGULATION FACTORS IN PREGNANCY PATIENTS AND METHODS A group of 60 primigravidae were followed from 12 weeks of gestation through to the puerperium. The age range of the patients was 18 to 25 years, their heights were over 152 cm, and their weightlheight ratios were in the interquartile range (Kemsley et al, 1962); in none was there a history of abortion, hypertension, or renal disease. A total of 48 women remained normal throughout the study, and 12 developed preeclampsia at or after 38 weeks of gestation. A diagnosis of pre-eclampsia was made if a previously normotensive patient had a sustained rise in blood pressure to 140/90 mm Hg or more after the 26th week of pregnancy. Four patients had at least 0.5 g/l of proteinuria. All patients had sterile urine on booking and all were aproteinuric and normotensive at the postnatal visit. An additional ten non-pregnant women were studied as controls. Citrated peripheral venous blood samples were collected without torniquet at 12, 20, 30 and 38 weeks of gestation; at 30 minutes after placental delivery; and at 24, 48, 96 and 144 hours and also six weeks after delivery. Cord venous blood was collected before placental expulsion. On each occasion glass contact was totally avoided in order to prevent premature activation of factor XII, and plasma was separated and stored in aliquots for assay at -20” C within 20 minutes of collection. Assays of factors XI1 and XI were carried out using the method of Nossel (1964), factor deficient plasma being obtained from Warner Lambert Co, New Jersey. Factor X was assayed by the method of Denson (1961), deficient plasma being provided by ‘Diagen’ Diagnostic Reagents Ltd, Oxon. All assays were done in duplicate, and expressed as per cent normal activity from a ‘normal’ graph constructed for each assay batch. ‘Normal’ pooled plasma was obtained for all assays from 20 normal male blood donors aged between 20 and 30 years. Statistical analysis was by Student’s‘t’ test and significance was recorded if less than 0.05.
RESULTS The results are summarized in Table I.
637
Factor X I I Normal pregnancy. By 20 weeks of gestation, the level was above the non-pregnant and continued to rise to 135 per cent at 38 weeks. It remained elevated in the puerperium and had returned to the non-pregnant level at six weeks post partum. The cord level of 84 per cent of ‘normal’ was less than maternal or non-pregnant levels. Pregnancy complicated by pre-eclampsiu. Preeclampsia levels were significantly higher than in normal pregnancy from 20 weeks of gestation onwards, a peak of 190 per cent being achieved at 30 weeks; levels remaining higher post partum. The mean cord level of 74 per cent was slightly lower than in normal pregnancy. Factor X I Normal pregnancy. The level was above the non-pregnant at 12 weeks of gestation, and rose to 139 per cent at 38 weeks. A small fall occurred at 30 minutes after delivery followed by a sharp secondary rise over the first week of the puerperium, the non-pregnant level being approached at 6 weeks post partum. The mean cord level was 65 per cent of ‘normal’. Pregnancy complicated by pre-eclampsia. Levels were lower than in normal pregnancy until 38 weeks of gestation, a nadir of 95 per cent occurring at 20 weeks. In the puerperium, an earlier fall towards the non-pregnant level occurred in the pre-eclampsia group. The cord level was similar to that in normal pregnancy. Factor A’ Normalpregnancy. A rise was observed at 12 weeks of gestation and the trend continued to a peak of 163 per cent at 30 weeks. A secondary rise to 173 per cent occurred at 144 hours post partum, the level again approaching the nonpregnant at 6 weeks after delivery. The mean cord level was 65 per cent of ‘normal’. Pregnancy complicated by pre-eclampsia. Unlike the normal pregnancy series, a rise did not commence until 20 weeks of gestation, a similar peak of 165 per cent being reached at 38 weeks. Levels slightly lower than in normal pregnancy occurred in the puerperium, while the cord level was close to that in normal pregnancy.
TABLEI Plasma levels of factors XII, X I and X during and after pregnancy, in umbilical cord blood and in non-pregnant women. Statistical comparisons are shown -__ .. Coagulation factors (per cent of normal activity in pooled male plasma) Mean SD ~~~~
+
_ _ ~ _ _ _ _
I. Normalpregnancy (48 patients)
XI1
-.
XI
x
124+33
127&42
~- - . __
~
_____
a.
12 weeks
b.
20
,,
c.
30
,,
131t 4 5
d.
38
,,
e.
30 minutes post partum
f.
24 hours
g.
48 hours
144141
151i-50
168142
h.
96 hours
,,
,,
128151
166&49
154+37
,,
,,
136126
178*71
173161
,, .___
96 & 30
125131
116*36
84h37
65 1 2 7
65 i37
120132
115120
102h39
104128
-
__
,,
,, ~
i.
144 hours
j.
6 weeks
k.
Cord blood
~-
11. Pregnancy with pre-eclampsia A.
,, -
,,
-
,,
,,
C. 30
,,
D. 38
,,
__ ~
E. -
-
.
30 minutes post partum
_
145f 56 163154
135127
139148
152137
1411 4 2
116136
123136
146&53
~~
141J-50
-
145146
~~~
.-
~~
B. 20
_
131 $50 ___ 129+42
-
12 weeks
(12 patients)
_
128*38
158k31
95122
109124
121 1 3 8
1411-44
~.
~
190188
~ _ _ _ _ _
145140
149160
112126
165*52
_ .
151 1 6 4
_ _
~~
~
,,
_ -
~~~~
I80178
,, ,,
_
161*42
140+37
G. 48 hours
,,
175&41
158130
155&44
H. 96 hours
,,
,,
161k 2 7
130127
141 1 3 0
I.
,,
,,
137113
126528
145125
107128
101 t 2 0
116137
74 *27
69121
F. 24 hours -
~
_
144 hours
_
-~ -
134133
-
- -
_-
~
J.
6 weeks
,,
,, ,,
~ _ _ _ _ ~ _ _ _ _ ~ ~ ~ _
K. Cord blood ,, 111. Non-pregnant women (10) _ _ _
1121341
~
p
