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Screening for consumptive coagulopathy in preeclampsia
International Journal of Gynecology & Obstetrics 46 (1994) 3-9
Article
Screening for consumptive coagulopathy
in preeclampsia
J. Metz*a, R. Cincottab, M. Francisa, L. DeRosaa, A. Ballocha “Department of Hematology/immunology. bDepartment of Perinatal Medicine. The Royal Women’s Hospital, Melbourne. Australia
Received 6 October 1993; revision received IS April 1994; accepted I5 April 1994
Abstract Objective: To identify a practical and cost-effective profile of tests to screen for consumptive coagulopathy in preeclampsia (PE). Merhods: Retrospective analysis of the results of measurements of platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen and D-dimers in 100 patients presenting with PE uncomplicated by other disease or antepartum hemorrhage. Twenty-four patients had pregnancy-induced hypertension only, and 76 hypertension with proteinuria. Results: The incidence of abnormal tests on presentation was raised D-dimers 34’S, thrombocytopenia 140/o,prolonged APTT 12X, prolonged PT 3’S, and low fibrinogen 2%. Prolonged APTT without thrombocytopenia occurred in 8% of patients. In 19 patients with elevation of D-dimers alone, only one showed evidence of consumption of coagulation factors on subsequent testing. Conclusions: A combination of platelet count and APTT is probably a practical and cost-effective combination to screen for consumptive coagulopathy in PE. Keywords:
Consumptive
coagulopathy;
Preeclampsia;
Pregnancy-induced
1. Introduction Disseminated intravascular coagulation (DIC) with consumption of coagulation factors is a potentially serious event in preeclampsia (PE). Thus, PE patients are generally screened for evidence of DIC with a battery of tests which usually includes measurement of platelet count, activated partial thromboplastin time (APTT), prothrombin time * Corresponding author, Fax: (03) 3476346 0020-7292/94/$07.00 0 1994 International SSDl 0020-7292(94)02128-L
Federation of Gynecology
hypertension
(PT) and fibrinogen to establish consumption of coagulation factors, and fibrinogen/fibrin degradation products (FDP) to detect increased fibrinolysis. There are doubts, however, as to the cost-effectiveness of performing all these tests on all patients, particularly with regard to tests for FDP, which are labor-intensive and expensive. The results of a recent study of patients with severe PE indicate that measurement of serial platelet counts only was adequate as a screening test in detecting intrapartum coagulation, without recourse to the other tests [ 11. and Obstetrics
4
J. Metz et al. /ht.
J. Gynecol. Obstet. 46 (1994) 3-9
It is uncertain whether the same approach can be applied to patients with less severe degrees of PE. For this reason we have evaluated screening tests for DIC in consecutive patients with PE, irrespective of severity, to identify either a single test or combination of tests, of acceptable sensitivity and predicability for consumptive coagulopathy. 2. Materials and methods
elevated levels in plasma indicate increased Iibrinolysis. The Dimertest is a semiquantitative assay using serial doubling dilutions, and results are expressed as co.25 mg/l, 0.25-0.5 mg/l, 0.5-1.0 mg/l, 1.0-2.0 mg/l, 2.0-4.0 mg/l or >4.0 mg/l. The reference range is O-O.25 mg/l. 3. Results
2.1. Patients
3.1. Clinical findings
A retrospective study was undertaken of the results used to detect DIC in 100 consecutive patients diagnosed as having PE or pregnancy-induced hypertension (PIH) over the period May 1992 to January 1993. Patients with complications of pregnancy such as lupus, diabetes, chronic renal disease or hemoglobinopathy were excluded, as were patients who presented with abruption or antepartum hemorrhage. PIH was defined as an after-rest blood pressure > 140/90 mmHg in patients post 20 weeks’ gestation; for PE, the additional criterion was the presence of proteinuria > 300 mg in a 24-h collection or its equivalent in a random specimen. No selection was made according to the severity of PE. The criteria for HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome were microangiopathic hemolysis with hyperbilirubinemia (serum bilirubin >20 PM/~), platelets < 100 x 109/1 and elevated liver enzymes (aspirate aminotransferase > 72 II-J/l) [2].
The clinical findings at presentation are summarized in Table 1. There were 24 patients with PIH and 76 with PE. Within the PE group were four patients with HELLP syndrome. The average age of the patients did not differ in the two clinical groups. The average gestation at delivery decreased with the severity of the condition, i.e. PIH 38.1 weeks and PE 34.5 weeks. Birthweight also followed this pattern. The cesarean section rate was 46% in PE, compared with the hospital average of 18% for 1991. Perinatal mortality was significantly increased with the severity of the disease and was also related to gestation.
2.2. Laboratory methods The hematological methods were standard. Platelet counts (reference range 140-400 x 109/1)were carried out using a Coulter Max M instrument. PT (reference range 1 l- 14 s) was measured with human placental thromboplastin (Thromborel@ S, Behringwerke AG, Marburg, Germany) APTT (reference range 28-40 s) with a lipid extract from human placenta (Pathromtin, Behringwerke AG, Marburg, Germany), and plasma fibrinogen (reference range 3.0-8.0 fl) by a modification of the method of Ellis and Stransky [3]. When the APTT and PT were prolonged, correction tests were carried out using a 50% mix with normal plasma. FDP were assayed as the D-dimer with the Dimertest II Latex kit (Agen Biomedical, Australia). Only the degradation products from crosslinked fibrin contain D-dimer, and
3.2. Coagulation tests A blood sample for coagulation testing was taken within 24 h of the clinical presentation. The results of the DIC tests (platelet count, PT, APTT, fibrinogen and D-dimers) are summarized in Table 2. The associated abnormalities in the other coagulation tests in patients with thrombocytopenia, prolonged PT, prolonged APTT, low fibrinogen or elevated D-dimers are shown in Table 3. 3.3. Platelet count The initial platelet count was less than 140 x 109/1(range 25-137) in 14 patients, three with PIH and 11 with PE. Of the three PIH patients, the degree of thrombocytopenia was mild in two (platelets 137 and 127 x 109/1) and less than 100 x 109/1(99) in the third. A subnormal platelet count was the only abnormality in these three and no additional abnormalities in the coagulation profile developed subsequently. Thrombocytopenia was more severe in the PE patients, with platelets less than 100 x 109/1in live (range 25-97), four of whom had HELLP syn-
J. Merz et al. /Int. J. Gynecol. Obster. 46 (1994) 3-9
5
Table 1 Clinical characteristics and results of tests of renal and liver function at presentation in patients with PIH and PE. Unless otherwise stated, results are expressed as mean f SD.
No.
Age (years) Primigravidae (Y/u) Twins (n) Gestation at delivery (weeks) Birthweight (g) Cesareans (XI) Systolic BP (mmHg) Diastolic BP (mmHg) Uric acid (mmol/l) Creatinine (mmolll) Urea (mmohl) Abnormal liver function test (“/u) Perinatal deaths (a)
PIH
PE
24 29.1 zt 5.9 71 3 38.1 zt 1.8 2968 f 509 21 148 *9 91 zt6 0.33 f 0.07 0.07 f 0.02 3.2 zt I.1 4 0
76 27.5 zt 5.6 19 I2 34.5 f 4.3 2079 + 847 46 165 f I8 106 f II 0.41 f 0.12 0.08 f 0.06 4.1 f 3.7 29 5
drome. The subnormal platelet count was the only test abnormality in three of the 11 patients. Of the other eight patients, thrombocytopenia was accompanied by raised D-dimers alone in five, and by abnormalities in two or more of the other tests in three. In the three patients with isolated thrombocyto-
penia, raised D-dimers and prolonged APTT developed subsequently in one, and raised D-dimers only in another. 3.4. Prothrombin time The initial PT was prolonged (range 14.8-17.8
Table 2 Mean values, SD. and range for coagulation tests at presentation in patients with PIH and PE
No. PT (s) Mean Range No. prolonged APTT (s) Mean Range No. prolonged Platelet count ( X 109/1) Mean Range No. reduced Fibrinogen Mean Range No. reduced D-Dimer Mean Range No. elevated
PIH
PE
24
16
II.87 f 0.76 10.2-13.6 0
II.80 f 1.22 10.2-17.8 3(3.9X)
33.4 zt 2.5 30-39 0
37.2 zt 5.1 29-62 12(15.8%/u)
241.7 f 105.8 99-537 3( 12.5”Q
212.4 zt 80.8 18-460 I l(l4.5%)
5.38 f 0.88 3.6-8.0 0
5.16 + 1.32 1.7-8.4 2(2.6X)
0.06 f 0.13 < 0.25-0.5 5(20.8X)
0.26 f 0.59 <0.25->4.0 29(38.2X)
6
J. h4et.z et al. /ht.
Table 3 The associated abnormalities in the other coagulation AP’IT, low fibrinogen
or elevated
J. Gynecol. Obstet. 46 (1994) 3-9
tests in patients
Coagulation abnormality
No. of patients
No other abnormality
Thrombocytopenia Prolonged PT Prolonged APTT Low fibrinogen Elevated Ddimer
I4 3 I2 2 34
6 0 I 0 I9
Thrombocytopenia
3.5. Activated partial thromboplastin time The initial APTT was prolonged (range 41-59 s) in 12 patients, all with PE, four of whom had HELLP syndrome. The prolonged APTT was corrected by normal plasma in all patients. In one patient this was the only abnormality but thrombocytopenia developed by the following day. In the other 11 patients with prolonged APTT at onset, D-dimers were elevated in all, thrombocytopenia was present in four, prolonged PT in two, and low fibrinogen in two. 3.6. Fibrinogen The initial plasma fibrinogen level was subnormal in two patients, both with HELLP syndrome, in whom the low fibrinogen was associated with prolonged PT and APTT, and raised D-dimers.
Table 4 Subsequent abnormalities in coagulation tests that developed patients with a normal screening profile on presentation No.
‘%I
59 30 25 IO 5 0 0
100 50.8 42.3 16.9 8.5 0 0
Prolonged PT
3
all with HELLP syndrome. The prolonged PT was associated with prolongation of the APTT, and raised D-dimers in all three, and with additional hypofibrinogenemia in two.
Prolonged APTT Thrombocytopenia Prolonged PT Low fibrinogen
with thrombocytopenia,
2 2 2
3 4 2 8
s) in three patients,
Total no. of patients No subsequent abnormality Elevated D-dimers
presenting
prolonged
PT, prolonged
Low fibrinogen
Elevated D-dimer
0 2 2
8 3 II 2
D-dimers
in
Prolonged APIT 4 3 2 II
2
3.7. Fibrinogen/fibrin degradation products Raised D-dimer levels were detected in 34 of the 100 patients at onset, five with PIH and 29 with PE. In the five patients with PIH, the elevation of Ddimers was minimal (0.25 mg/l) in four, and 0.5 mg/l in the fifth. In the PE patients, the level (mg/l) was 0.25-0.5 in 16, 0.5-1.0 in seven, 1.0-2.0 in four, 2.0-4.0 in one, and > 4.0 in one patient. Of the 34 patients with raised D-dimers, 15 showed an abnormality in one or more of the other tests: decreased platelet count alone in five, prolonged APTT alone in six and abnormalities in two or more tests in four. Of the 19 patients with isolated elevation of Ddimers, only one developed a subsequent abnormality. In the other 15 patients, the D-dimers either remained at the same level on subsequent tests, or fell; in one patient the level increased, and this was not associated with any abnormality in the other tests. The results of coagulation tests carried out subsequently in 59 patients with a normal initial screening profile are shown in Table 4. The commonest abnormality to develop was elevation of D-dimers. This generally reflected an increase in a single dilution only, i.e. from co.25 mg/l to 0.25 mg/l. The results of the coagulation tests in all 100 patients with PE, together with the number of abnormal tests at presentation and developing subsequently during the course of the illness, are summarized in Table 5. 4. Discussion The results of the present study provide information on the sensitivity and predictive value of a number of screening tests for intravascular coagulation
7
J. Metz et al. /ht. J. Gynecol. Obstet. 46 (1994) 3-9
Table 5 Summary of the results of coagulation tests in 100 patients with PE, with the number of abnormal tests at presentation and developing subsequently during the course of the illness At presentation (all patients)
Abnormal tests At presentation
PT (s) No. Mean * SD. Range APT-T (s) No. Mean * SD. Range Platelet count x 109/1 No. Mean f SD. Range Fibrinogen (gl) No. Mean f SD. Range D-Dimer (mg/l) No. Mean ?? S.D. Range
Developing during illness
I
Total
100 11.82 f 1.13 10.2-17.8
3 16.8 ?? 1.7 14.8-17.8
15.2
4 16.4 f 1.63 14.8-17.8
100 36.3 f 4.9 29-59
12 46.4 f 5.4 41-59
IO 46.3 f 4.3 42-53
22 46.4 f 4.8 41-59
100 219.5 f 87.8 IS-537
14 91.2 f 36.0 18-129
8 106 f 38.6 28-139
22 96.6 f 36.8 IS-139
100 5.21
1.7-8.4
2 1.95 ?? 0.35 1.7-2.2
2 2.20 f 0.28 2.0-2.4
4 2.08 f 0.30 1.7-2.2
100 0.21 zt 0.52 <0.25- >4.0
34 0.61 f 0.75 0.25- >4.0
27 0.51 f 0.40 0.25-2.0
61 0.57 f 0.62 0.25- >4.0
?? 1.22
in patients presenting with PE. As single tests, PT and plasma fibrinogen have little value. In the series of 100 patients, prolongation of the PT was noted in only three, all with HELLP syndrome, and the prolonged PT was associated with prolongation of the APTT in all, and hypofibrinogenemia in two; these were the only patients in the series with hypofibrinogenemia. Similar results have been reported in patients with severe PE, where prolonged PT occurred in only 2% [l]. The low incidence of hypofibrinogenemia in our patients is in agreement with the results of Trofatter et al. [4] who found no patient with a low fibrinogen level in 204 consecutive PE patients on first examination. However, in patients with PE severe enough to warrant admission to intensive care, subnormal plasma fibrinogen levels were reported in 13%)[ 11.In these patients, the hypotibrinogenemia was accompanied by thrombocytopenia. Thus on the basis of the results of the present study and those of others, the use of PT and plas-
ma fibrinogen level as screening tests for intravascular coagulation in PE does not appear warranted due to their lack of sensitivity. When abnormal results do occur in these tests, they are usually accompanied by a prolonged APTT or a reduced platelet count. Raised D-dimers were noted in 34% of our patients when first seen, an incidence similar to the 38.7% reported by Trofatter et al. [4]. In 15 of our patients, raised D-dimers were accompanied by either thrombocytopenia or a prolonged APTT, and detection of a coagulation abnormality would have been provided by these tests in the absence of a Ddimer result. In the 19 patients with isolated elevation of D-dimers, in only one was an additional abnormality detected on subsequent testing. Similar results were reported by Trofatter et al. [4], who noted that 82% of patients with raised D-dimers had a platelet count in excess of 100 x 109/1. These authors concluded that raised D-dimers were highly sensitive for the detection of increased fibrinolysis
8
J. Merz et al. /ht.
J. Gynecol. Obsref. 46 (1994) 3-9
in PE, but had a low positive predictive value for consumptive coagulopathy. The results of the present study concur with this conclusion, and indicate that raised D-dimers as an isolated abnormality are only occasionally the harbinger of clinically significant coagulopathy. Further evidence of the sensitivity of the D-dimer level, not necessarily of clinical significance, is the finding of raised D-dimer levels in apparently normal pregnancy [5]. The finding of an isolated elevation of D-dimers did not influence the management of any patient in the present study. It seems reasonable to conclude that the D-dimer test, an expensive and labor-intensive procedure, is probably not warranted as part of routine screening for consumptive coagulopathy in PE. The APTT was prolonged in 12% of our patients when first seen. Prolongation of the APTT was accompanied by elevation of D-dimers, but the platelet count was normal in eight of these patients. Although a prolonged APTT is not invariably accompanied by thrombocytopenia in DIC, it is unusual to find such a high proportion of patients with a prolonged APTT and no thrombocytopenia. Leduc et al. [I] reported that all PE patients with a coagulation abnormality had thrombocytopenia as well, but the patient material, being severe PE warranting admission to intensive care, was different from that of the present study. It would seem that monitoring the platelet count only is adequate as a screening test for coagulopathy in severe PE, but not in patients with milder forms of the disease. The incidence of thrombocytopenia (14%) in the present study is comparable to that of other reports on unselected patients with PE [6]. In the six patients with thrombocytopenia only, four did not develop other coagulation abnormalities subsequently, and the thrombocytopenia in these patients presumably reflects either low-grade consumptive coagulopathy, or peripheral sequestration of platelets without consumption of coagulation factorsor these patients are examples of gestational thrombocytopenia. The latter two would seem to be distinct possibilities in view of the absence of accompanying elevation of D-dimers in these patients. The incidence of gestational thrombocytopenia is reported to be about 5% in otherwise normal pregnancy [7]. Thus on statistical grounds alone, some 5% of our patients would be expected to show
thrombocytopenia as an incidental finding unrelated to the PE. PIH, PE and HELLP syndrome probably constitute three stages of increasing severity in the same pathological process. Patients with PIH only, have a low incidence of coagulation abnormalities, and when they occur they are mild. The only significant abnormality in our 24 PIH patients was a platelet count of 99 x 109/1in one, and elevation of D-dimers to 0.5 mg/l in another. The degree of abnormality in coagulation tests was greater in the PE patients. Patients with HELLP syndrome are by definition moderately to markedly thrombocytopenic, and it is not surprising that the most severe coagulopathies are found in this group. Further evidence that PE and HELLP syndrome are a continuum of the same process is the finding that 22% of our patients with PE had elevated liver enzymes without fulfilling the other criteria for HELLP syndrome. We conclude that of the tests currently used to screen for consumptive coagulopathy in PE, PT and plasma fibrinogen can be omitted due to poor sensitivity, and similarly the assay of D-dimers on the basis of poor predictive value. In our patients, the platelet count was not invariably reduced when the APTT was prolonged. A combination of platelet count and APTT is thus recommended as a practical and cost-effective screening procedure. The screening profile provides information on the presence of consumptive coagulopathy at the time the tests are performed. Of the 59 patients who had normal screening tests at presentation, 10 (17%) subsequently developed a prolonged APTT during the course of their illness. Thus a normal screening test profile does not exclude the subsequent development of consumptive coagulopathy. The need for subsequent monitoring depends on both the clinical condition and the presence of abnormalities detected on the initial screen. Regular monitoring with the full DIC profile is indicated in HELLP syndrome, and in patients with PE where a significant abnormality is detected in either the APTT or platelet count. Acknowledgment
We wish to thank Professor R. Pepperell for helpful advice.
J. Metz
et al. /ht.
J. Gynecol.
References III
PI
t31
[41
Leduc L, Wheeler JM, Kirshon B, Mitchell P, Cotton DB: Coagulation profile in severe preeclampsia. Obstet Gynecol 79: 14, 1992. Sibai BM, Taslimi MM, EI-Nazar A, Amon E, Mabie BC, Ryan GM: Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia. Am J Obstet Gynecol 155: 501, 1986. Ellis BC, Stransky A: A quick and accurate method for the determination of fibrinogen in plasma. J Lab Clin Med 58: 477, 1961. Trofatter KF, Howell ML, Greenberg GS, Hage ML:
Obstet.
46 (1994)
3-9
Use of the fibrin D-dimer in screening for coagulation abnormalities in preeclampsia. Obstet Gynecol 73: 435, 1989. VI Ho CH, Yang ZL: The predictive value of the hemostasis parameters in the development of preeclampsia. Thromb Haemostasis 67: 214, 1992. 161 Romero R, Mazor M, Lockwood CJ, Emamian M, Belanger KP, Hobbins JG, Duffy T: Clinical significance, prevalence and natural history of thrombocytopenia in pregnancy-induced hypertension. Am J Perinatol 6: 32, 1989. 171 Burrows RF, Kelton JG: Thrombocytopenia at delivery: a prospective survey of 6715 deliveries. Am J Obstet Gynecol 162: 73 I, 1990.
9
Article
Screening for consumptive coagulopathy
in preeclampsia
J. Metz*a, R. Cincottab, M. Francisa, L. DeRosaa, A. Ballocha “Department of Hematology/immunology. bDepartment of Perinatal Medicine. The Royal Women’s Hospital, Melbourne. Australia
Received 6 October 1993; revision received IS April 1994; accepted I5 April 1994
Abstract Objective: To identify a practical and cost-effective profile of tests to screen for consumptive coagulopathy in preeclampsia (PE). Merhods: Retrospective analysis of the results of measurements of platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen and D-dimers in 100 patients presenting with PE uncomplicated by other disease or antepartum hemorrhage. Twenty-four patients had pregnancy-induced hypertension only, and 76 hypertension with proteinuria. Results: The incidence of abnormal tests on presentation was raised D-dimers 34’S, thrombocytopenia 140/o,prolonged APTT 12X, prolonged PT 3’S, and low fibrinogen 2%. Prolonged APTT without thrombocytopenia occurred in 8% of patients. In 19 patients with elevation of D-dimers alone, only one showed evidence of consumption of coagulation factors on subsequent testing. Conclusions: A combination of platelet count and APTT is probably a practical and cost-effective combination to screen for consumptive coagulopathy in PE. Keywords:
Consumptive
coagulopathy;
Preeclampsia;
Pregnancy-induced
1. Introduction Disseminated intravascular coagulation (DIC) with consumption of coagulation factors is a potentially serious event in preeclampsia (PE). Thus, PE patients are generally screened for evidence of DIC with a battery of tests which usually includes measurement of platelet count, activated partial thromboplastin time (APTT), prothrombin time * Corresponding author, Fax: (03) 3476346 0020-7292/94/$07.00 0 1994 International SSDl 0020-7292(94)02128-L
Federation of Gynecology
hypertension
(PT) and fibrinogen to establish consumption of coagulation factors, and fibrinogen/fibrin degradation products (FDP) to detect increased fibrinolysis. There are doubts, however, as to the cost-effectiveness of performing all these tests on all patients, particularly with regard to tests for FDP, which are labor-intensive and expensive. The results of a recent study of patients with severe PE indicate that measurement of serial platelet counts only was adequate as a screening test in detecting intrapartum coagulation, without recourse to the other tests [ 11. and Obstetrics
4
J. Metz et al. /ht.
J. Gynecol. Obstet. 46 (1994) 3-9
It is uncertain whether the same approach can be applied to patients with less severe degrees of PE. For this reason we have evaluated screening tests for DIC in consecutive patients with PE, irrespective of severity, to identify either a single test or combination of tests, of acceptable sensitivity and predicability for consumptive coagulopathy. 2. Materials and methods
elevated levels in plasma indicate increased Iibrinolysis. The Dimertest is a semiquantitative assay using serial doubling dilutions, and results are expressed as co.25 mg/l, 0.25-0.5 mg/l, 0.5-1.0 mg/l, 1.0-2.0 mg/l, 2.0-4.0 mg/l or >4.0 mg/l. The reference range is O-O.25 mg/l. 3. Results
2.1. Patients
3.1. Clinical findings
A retrospective study was undertaken of the results used to detect DIC in 100 consecutive patients diagnosed as having PE or pregnancy-induced hypertension (PIH) over the period May 1992 to January 1993. Patients with complications of pregnancy such as lupus, diabetes, chronic renal disease or hemoglobinopathy were excluded, as were patients who presented with abruption or antepartum hemorrhage. PIH was defined as an after-rest blood pressure > 140/90 mmHg in patients post 20 weeks’ gestation; for PE, the additional criterion was the presence of proteinuria > 300 mg in a 24-h collection or its equivalent in a random specimen. No selection was made according to the severity of PE. The criteria for HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome were microangiopathic hemolysis with hyperbilirubinemia (serum bilirubin >20 PM/~), platelets < 100 x 109/1 and elevated liver enzymes (aspirate aminotransferase > 72 II-J/l) [2].
The clinical findings at presentation are summarized in Table 1. There were 24 patients with PIH and 76 with PE. Within the PE group were four patients with HELLP syndrome. The average age of the patients did not differ in the two clinical groups. The average gestation at delivery decreased with the severity of the condition, i.e. PIH 38.1 weeks and PE 34.5 weeks. Birthweight also followed this pattern. The cesarean section rate was 46% in PE, compared with the hospital average of 18% for 1991. Perinatal mortality was significantly increased with the severity of the disease and was also related to gestation.
2.2. Laboratory methods The hematological methods were standard. Platelet counts (reference range 140-400 x 109/1)were carried out using a Coulter Max M instrument. PT (reference range 1 l- 14 s) was measured with human placental thromboplastin (Thromborel@ S, Behringwerke AG, Marburg, Germany) APTT (reference range 28-40 s) with a lipid extract from human placenta (Pathromtin, Behringwerke AG, Marburg, Germany), and plasma fibrinogen (reference range 3.0-8.0 fl) by a modification of the method of Ellis and Stransky [3]. When the APTT and PT were prolonged, correction tests were carried out using a 50% mix with normal plasma. FDP were assayed as the D-dimer with the Dimertest II Latex kit (Agen Biomedical, Australia). Only the degradation products from crosslinked fibrin contain D-dimer, and
3.2. Coagulation tests A blood sample for coagulation testing was taken within 24 h of the clinical presentation. The results of the DIC tests (platelet count, PT, APTT, fibrinogen and D-dimers) are summarized in Table 2. The associated abnormalities in the other coagulation tests in patients with thrombocytopenia, prolonged PT, prolonged APTT, low fibrinogen or elevated D-dimers are shown in Table 3. 3.3. Platelet count The initial platelet count was less than 140 x 109/1(range 25-137) in 14 patients, three with PIH and 11 with PE. Of the three PIH patients, the degree of thrombocytopenia was mild in two (platelets 137 and 127 x 109/1) and less than 100 x 109/1(99) in the third. A subnormal platelet count was the only abnormality in these three and no additional abnormalities in the coagulation profile developed subsequently. Thrombocytopenia was more severe in the PE patients, with platelets less than 100 x 109/1in live (range 25-97), four of whom had HELLP syn-
J. Merz et al. /Int. J. Gynecol. Obster. 46 (1994) 3-9
5
Table 1 Clinical characteristics and results of tests of renal and liver function at presentation in patients with PIH and PE. Unless otherwise stated, results are expressed as mean f SD.
No.
Age (years) Primigravidae (Y/u) Twins (n) Gestation at delivery (weeks) Birthweight (g) Cesareans (XI) Systolic BP (mmHg) Diastolic BP (mmHg) Uric acid (mmol/l) Creatinine (mmolll) Urea (mmohl) Abnormal liver function test (“/u) Perinatal deaths (a)
PIH
PE
24 29.1 zt 5.9 71 3 38.1 zt 1.8 2968 f 509 21 148 *9 91 zt6 0.33 f 0.07 0.07 f 0.02 3.2 zt I.1 4 0
76 27.5 zt 5.6 19 I2 34.5 f 4.3 2079 + 847 46 165 f I8 106 f II 0.41 f 0.12 0.08 f 0.06 4.1 f 3.7 29 5
drome. The subnormal platelet count was the only test abnormality in three of the 11 patients. Of the other eight patients, thrombocytopenia was accompanied by raised D-dimers alone in five, and by abnormalities in two or more of the other tests in three. In the three patients with isolated thrombocyto-
penia, raised D-dimers and prolonged APTT developed subsequently in one, and raised D-dimers only in another. 3.4. Prothrombin time The initial PT was prolonged (range 14.8-17.8
Table 2 Mean values, SD. and range for coagulation tests at presentation in patients with PIH and PE
No. PT (s) Mean Range No. prolonged APTT (s) Mean Range No. prolonged Platelet count ( X 109/1) Mean Range No. reduced Fibrinogen Mean Range No. reduced D-Dimer Mean Range No. elevated
PIH
PE
24
16
II.87 f 0.76 10.2-13.6 0
II.80 f 1.22 10.2-17.8 3(3.9X)
33.4 zt 2.5 30-39 0
37.2 zt 5.1 29-62 12(15.8%/u)
241.7 f 105.8 99-537 3( 12.5”Q
212.4 zt 80.8 18-460 I l(l4.5%)
5.38 f 0.88 3.6-8.0 0
5.16 + 1.32 1.7-8.4 2(2.6X)
0.06 f 0.13 < 0.25-0.5 5(20.8X)
0.26 f 0.59 <0.25->4.0 29(38.2X)
6
J. h4et.z et al. /ht.
Table 3 The associated abnormalities in the other coagulation AP’IT, low fibrinogen
or elevated
J. Gynecol. Obstet. 46 (1994) 3-9
tests in patients
Coagulation abnormality
No. of patients
No other abnormality
Thrombocytopenia Prolonged PT Prolonged APTT Low fibrinogen Elevated Ddimer
I4 3 I2 2 34
6 0 I 0 I9
Thrombocytopenia
3.5. Activated partial thromboplastin time The initial APTT was prolonged (range 41-59 s) in 12 patients, all with PE, four of whom had HELLP syndrome. The prolonged APTT was corrected by normal plasma in all patients. In one patient this was the only abnormality but thrombocytopenia developed by the following day. In the other 11 patients with prolonged APTT at onset, D-dimers were elevated in all, thrombocytopenia was present in four, prolonged PT in two, and low fibrinogen in two. 3.6. Fibrinogen The initial plasma fibrinogen level was subnormal in two patients, both with HELLP syndrome, in whom the low fibrinogen was associated with prolonged PT and APTT, and raised D-dimers.
Table 4 Subsequent abnormalities in coagulation tests that developed patients with a normal screening profile on presentation No.
‘%I
59 30 25 IO 5 0 0
100 50.8 42.3 16.9 8.5 0 0
Prolonged PT
3
all with HELLP syndrome. The prolonged PT was associated with prolongation of the APTT, and raised D-dimers in all three, and with additional hypofibrinogenemia in two.
Prolonged APTT Thrombocytopenia Prolonged PT Low fibrinogen
with thrombocytopenia,
2 2 2
3 4 2 8
s) in three patients,
Total no. of patients No subsequent abnormality Elevated D-dimers
presenting
prolonged
PT, prolonged
Low fibrinogen
Elevated D-dimer
0 2 2
8 3 II 2
D-dimers
in
Prolonged APIT 4 3 2 II
2
3.7. Fibrinogen/fibrin degradation products Raised D-dimer levels were detected in 34 of the 100 patients at onset, five with PIH and 29 with PE. In the five patients with PIH, the elevation of Ddimers was minimal (0.25 mg/l) in four, and 0.5 mg/l in the fifth. In the PE patients, the level (mg/l) was 0.25-0.5 in 16, 0.5-1.0 in seven, 1.0-2.0 in four, 2.0-4.0 in one, and > 4.0 in one patient. Of the 34 patients with raised D-dimers, 15 showed an abnormality in one or more of the other tests: decreased platelet count alone in five, prolonged APTT alone in six and abnormalities in two or more tests in four. Of the 19 patients with isolated elevation of Ddimers, only one developed a subsequent abnormality. In the other 15 patients, the D-dimers either remained at the same level on subsequent tests, or fell; in one patient the level increased, and this was not associated with any abnormality in the other tests. The results of coagulation tests carried out subsequently in 59 patients with a normal initial screening profile are shown in Table 4. The commonest abnormality to develop was elevation of D-dimers. This generally reflected an increase in a single dilution only, i.e. from co.25 mg/l to 0.25 mg/l. The results of the coagulation tests in all 100 patients with PE, together with the number of abnormal tests at presentation and developing subsequently during the course of the illness, are summarized in Table 5. 4. Discussion The results of the present study provide information on the sensitivity and predictive value of a number of screening tests for intravascular coagulation
7
J. Metz et al. /ht. J. Gynecol. Obstet. 46 (1994) 3-9
Table 5 Summary of the results of coagulation tests in 100 patients with PE, with the number of abnormal tests at presentation and developing subsequently during the course of the illness At presentation (all patients)
Abnormal tests At presentation
PT (s) No. Mean * SD. Range APT-T (s) No. Mean * SD. Range Platelet count x 109/1 No. Mean f SD. Range Fibrinogen (gl) No. Mean f SD. Range D-Dimer (mg/l) No. Mean ?? S.D. Range
Developing during illness
I
Total
100 11.82 f 1.13 10.2-17.8
3 16.8 ?? 1.7 14.8-17.8
15.2
4 16.4 f 1.63 14.8-17.8
100 36.3 f 4.9 29-59
12 46.4 f 5.4 41-59
IO 46.3 f 4.3 42-53
22 46.4 f 4.8 41-59
100 219.5 f 87.8 IS-537
14 91.2 f 36.0 18-129
8 106 f 38.6 28-139
22 96.6 f 36.8 IS-139
100 5.21
1.7-8.4
2 1.95 ?? 0.35 1.7-2.2
2 2.20 f 0.28 2.0-2.4
4 2.08 f 0.30 1.7-2.2
100 0.21 zt 0.52 <0.25- >4.0
34 0.61 f 0.75 0.25- >4.0
27 0.51 f 0.40 0.25-2.0
61 0.57 f 0.62 0.25- >4.0
?? 1.22
in patients presenting with PE. As single tests, PT and plasma fibrinogen have little value. In the series of 100 patients, prolongation of the PT was noted in only three, all with HELLP syndrome, and the prolonged PT was associated with prolongation of the APTT in all, and hypofibrinogenemia in two; these were the only patients in the series with hypofibrinogenemia. Similar results have been reported in patients with severe PE, where prolonged PT occurred in only 2% [l]. The low incidence of hypofibrinogenemia in our patients is in agreement with the results of Trofatter et al. [4] who found no patient with a low fibrinogen level in 204 consecutive PE patients on first examination. However, in patients with PE severe enough to warrant admission to intensive care, subnormal plasma fibrinogen levels were reported in 13%)[ 11.In these patients, the hypotibrinogenemia was accompanied by thrombocytopenia. Thus on the basis of the results of the present study and those of others, the use of PT and plas-
ma fibrinogen level as screening tests for intravascular coagulation in PE does not appear warranted due to their lack of sensitivity. When abnormal results do occur in these tests, they are usually accompanied by a prolonged APTT or a reduced platelet count. Raised D-dimers were noted in 34% of our patients when first seen, an incidence similar to the 38.7% reported by Trofatter et al. [4]. In 15 of our patients, raised D-dimers were accompanied by either thrombocytopenia or a prolonged APTT, and detection of a coagulation abnormality would have been provided by these tests in the absence of a Ddimer result. In the 19 patients with isolated elevation of D-dimers, in only one was an additional abnormality detected on subsequent testing. Similar results were reported by Trofatter et al. [4], who noted that 82% of patients with raised D-dimers had a platelet count in excess of 100 x 109/1. These authors concluded that raised D-dimers were highly sensitive for the detection of increased fibrinolysis
8
J. Merz et al. /ht.
J. Gynecol. Obsref. 46 (1994) 3-9
in PE, but had a low positive predictive value for consumptive coagulopathy. The results of the present study concur with this conclusion, and indicate that raised D-dimers as an isolated abnormality are only occasionally the harbinger of clinically significant coagulopathy. Further evidence of the sensitivity of the D-dimer level, not necessarily of clinical significance, is the finding of raised D-dimer levels in apparently normal pregnancy [5]. The finding of an isolated elevation of D-dimers did not influence the management of any patient in the present study. It seems reasonable to conclude that the D-dimer test, an expensive and labor-intensive procedure, is probably not warranted as part of routine screening for consumptive coagulopathy in PE. The APTT was prolonged in 12% of our patients when first seen. Prolongation of the APTT was accompanied by elevation of D-dimers, but the platelet count was normal in eight of these patients. Although a prolonged APTT is not invariably accompanied by thrombocytopenia in DIC, it is unusual to find such a high proportion of patients with a prolonged APTT and no thrombocytopenia. Leduc et al. [I] reported that all PE patients with a coagulation abnormality had thrombocytopenia as well, but the patient material, being severe PE warranting admission to intensive care, was different from that of the present study. It would seem that monitoring the platelet count only is adequate as a screening test for coagulopathy in severe PE, but not in patients with milder forms of the disease. The incidence of thrombocytopenia (14%) in the present study is comparable to that of other reports on unselected patients with PE [6]. In the six patients with thrombocytopenia only, four did not develop other coagulation abnormalities subsequently, and the thrombocytopenia in these patients presumably reflects either low-grade consumptive coagulopathy, or peripheral sequestration of platelets without consumption of coagulation factorsor these patients are examples of gestational thrombocytopenia. The latter two would seem to be distinct possibilities in view of the absence of accompanying elevation of D-dimers in these patients. The incidence of gestational thrombocytopenia is reported to be about 5% in otherwise normal pregnancy [7]. Thus on statistical grounds alone, some 5% of our patients would be expected to show
thrombocytopenia as an incidental finding unrelated to the PE. PIH, PE and HELLP syndrome probably constitute three stages of increasing severity in the same pathological process. Patients with PIH only, have a low incidence of coagulation abnormalities, and when they occur they are mild. The only significant abnormality in our 24 PIH patients was a platelet count of 99 x 109/1in one, and elevation of D-dimers to 0.5 mg/l in another. The degree of abnormality in coagulation tests was greater in the PE patients. Patients with HELLP syndrome are by definition moderately to markedly thrombocytopenic, and it is not surprising that the most severe coagulopathies are found in this group. Further evidence that PE and HELLP syndrome are a continuum of the same process is the finding that 22% of our patients with PE had elevated liver enzymes without fulfilling the other criteria for HELLP syndrome. We conclude that of the tests currently used to screen for consumptive coagulopathy in PE, PT and plasma fibrinogen can be omitted due to poor sensitivity, and similarly the assay of D-dimers on the basis of poor predictive value. In our patients, the platelet count was not invariably reduced when the APTT was prolonged. A combination of platelet count and APTT is thus recommended as a practical and cost-effective screening procedure. The screening profile provides information on the presence of consumptive coagulopathy at the time the tests are performed. Of the 59 patients who had normal screening tests at presentation, 10 (17%) subsequently developed a prolonged APTT during the course of their illness. Thus a normal screening test profile does not exclude the subsequent development of consumptive coagulopathy. The need for subsequent monitoring depends on both the clinical condition and the presence of abnormalities detected on the initial screen. Regular monitoring with the full DIC profile is indicated in HELLP syndrome, and in patients with PE where a significant abnormality is detected in either the APTT or platelet count. Acknowledgment
We wish to thank Professor R. Pepperell for helpful advice.
J. Metz
et al. /ht.
J. Gynecol.
References III
PI
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[41
Leduc L, Wheeler JM, Kirshon B, Mitchell P, Cotton DB: Coagulation profile in severe preeclampsia. Obstet Gynecol 79: 14, 1992. Sibai BM, Taslimi MM, EI-Nazar A, Amon E, Mabie BC, Ryan GM: Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia. Am J Obstet Gynecol 155: 501, 1986. Ellis BC, Stransky A: A quick and accurate method for the determination of fibrinogen in plasma. J Lab Clin Med 58: 477, 1961. Trofatter KF, Howell ML, Greenberg GS, Hage ML:
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Use of the fibrin D-dimer in screening for coagulation abnormalities in preeclampsia. Obstet Gynecol 73: 435, 1989. VI Ho CH, Yang ZL: The predictive value of the hemostasis parameters in the development of preeclampsia. Thromb Haemostasis 67: 214, 1992. 161 Romero R, Mazor M, Lockwood CJ, Emamian M, Belanger KP, Hobbins JG, Duffy T: Clinical significance, prevalence and natural history of thrombocytopenia in pregnancy-induced hypertension. Am J Perinatol 6: 32, 1989. 171 Burrows RF, Kelton JG: Thrombocytopenia at delivery: a prospective survey of 6715 deliveries. Am J Obstet Gynecol 162: 73 I, 1990.
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