Sei sulla pagina 1di 7

Thrombosis Research 102 (2001) 99 105

REGULAR ARTICLE

Federico Mecacci1, Lucia Carignani1, Riccardo Cioni1, Elena Parretti1, Marcella Mignosa1, Anna Piccioli2, Gianfranco Scarselli1 and Giorgio Mello1 1 Department of Gynecology, Perinatology and Human Reproduction, University of Florence, Viale Morgagni, 85, I-50134 Florence, Italy; 2Intensive Care Unit, University of Florence, Viale Morgagni, 85, I-50134 Florence, Italy (Received 25 October 2000 by Editor D. Prisco; revised/accepted 27 December 2000)

Time Course of Recovery and Complications of HELLP Syndrome with Two Different Treatments: Heparin or Dexamethasone

Abstract
HELLP syndrome is a severe complication of pregnancy characterized by microangiopathic hemolytic anemia, hepatic dysfunction and thrombocytopenia. Though delivery is the ultimate therapeutic option, medical treatments, including the use of heparin or corticosteroids, have been employed in the attempt to improve maternal prognosis. The aim of this retrospective study was to compare the time course of recovery and the incidence of complications in women with HELLP syndrome receiving either heparin or dexamethasone. Between January 1990 and December 1998, 32 patients with HELLP syndrome were cared for at the Institute of Obstetrics and Gynecology of the University of Florence: 20 patients were treated with heparin, administered subcutaneously at a dose of 5000 IU every 12 h, whereas 12 women received dexamethasone, administered intravenously at a dose of 10 mg every 12 h. Categorical data were evaluated with chi-square and Fisher's exact test; continuous data were analyzed with Mann Whitney U test; P < .05 was considered significant. In the subgroup treated with heparin the
Corresponding author: Prof. Giorgio Mello, Via Masaccio, 92, I50100 Florence, Italy. Tel: +39 (55) 240255; Fax: +39 (55) 240255; E-mail: <mellog@unifi.it>.

incidence of disseminated intravascular coagulation (DIC) ( P < .02), the number of patients requiring blood transfusion ( P < .05) and the length of stay at the Intensive Care Unit (ICU) ( P < .04) were significantly increased as compared with the subgroup receiving dexamethasone; in this latter subgroup, significantly higher platelet count and hematocrit values, and significantly lower levels of lactate dehydrogenase (LDH) could be documented starting from day 2 after delivery. The results of our investigation suggest that the use of dexamethasone in patients with HELLP syndrome is associated with faster regression and lower incidence of complications in comparison to heparin. D 2001 Elsevier Science Ltd. All rights reserved.
Key Words: HELLP syndrome; Heparin; Dexamethasone

ELLP syndrome is a severe form of preeclampsia/eclampsia, which assumed its own identity as a disease in 1982 [1]. The syndrome, which is characterized by microangiopathic hemolytic anemia, hepatic dysfunction and thrombocytopenia, may occur in gestation, as well as in the post partum period [2]. Microangiopathy, particularly at the level of liver circulation, seems to play a crucial role in the pathophysiology of the disease; the progression of the disease may involve other organs and

0049-3848/01/$ see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII S0049-3848(01)00234-1

100

F. Mecacci et al./Thrombosis Research 102 (2001) 99105

lead to acute renal failure, respiratory distress syndrome (ARDS) and multiorgan failure [2]. As a consequence of microangiopathy, there is a ``low-grade'' activation of the coagulation cascade, referred to as compensated disseminated intravascular coagulation (DIC) by some authors [3], which evolves in overt DIC in 2155% of the cases [4,5]. Delivery is considered the ultimate therapeutic option for HELLP syndrome, however, a conservative medical management has been suggested at particularly low gestational ages in order to reach fetal lung maturity [6]. Both steroid and heparin therapies have been employed to improve maternal prognosis at any gestational age. The use of heparin in patients with preeclampsia and HELLP syndrome is still a controversial matter; according to some authors, heparin does not exert any effect [7,8], whereas others believe that it can be beneficial [913]. In 1994, Magann et al. [14] proposed a therapeutic protocol based on the administration of high doses of dexamethasone aimed at inducing fetal lung maturity, reducing maternal complications and promoting the regression of the syndrome. At the Institute of Obstetrics and Gynecology of the University of Florence, the administraTable 1. Demographic and clinical characteristcs of patients Dexamethasone (N = 12) Maternal age (years, median, range) Parity (n, %) 0 !1 Gestational age at delivery (weeks, median, range) Interval between diagnosis and delivery (days, median, range) Systolic blood pressure (mm Hg, median, range) D iastolic blood pressure (mm Hg, median, range) DIC (n, %) Term pregnancy (n, %) Vaginal delivery (n, %) Cesarean section (n, %) Antithrombin III (%, range)
* P < .03.

tion of heparin has been employed since 1990 as part of the protocol for the treatment of HELLP syndrome. Since 1996, a new protocol was developed: With this protocol, heparin was no longer administered, whereas dexamethasone at high doses was given before and after delivery. The aim of this study was to compare these two different protocols for the treatment of HELLP syndrome with respect to both incidence of maternal complications and time course of recovery.

1. Materials and Methods


Thirty-two patients with HELLP syndrome, referred to the Institute of Obstetrics and Gynecology of the University of Florence between January 1990 and December 1998, were retrospectively studied. Patients with hemorrhagic diathesis, renal and cardiovascular diseases or suffering from any other medical disorder were not included in the study group. HELLP syndrome was diagnosed in the presence of: thrombocytopenia with peripartum nadir 50,000 platelets/mm3 (class 1), > 50,000 and 100,000 platelets/mm 3 (class 2), or >100,000 and 150,000 platelets/mm3 (class 3)
Heparin (N = 20) 29 (23 39) 16 (80.0) 4 (20.0) 34.5 (27.1 42)* 0 (0 3) 170 (120 200) 100 (80 140) 1 (5.0) 3 (15.0) 17 (85.0) 67 (35 89) Total (N = 32) 30 (19 39) 23 (71.9) 9 (28.1) 31.95 (24.1 42) 0 (0 3) 166.5 (130 210) 100 (90 140) 1 (3.1) 4 (12.5) 28 (87.5) 67.5 (35 90)

33.5 (19 37) 7 (58.3) 5 (41.7) 29.1 (24.1 38)* 0 (0 2) 160 (130 210) 100 (90 140) 1 (8.3) 1 (8.3) 1 (8.3) 11 (91.7) 70 (35 90)

F. Mecacci et al./Thrombosis Research 102 (2001) 99105

101

Table 2. Classification according to the ``Mississippi class system'' Dexamethasone (N = 12) Class I (n, %): platelet count nadir 50,000/mm3 Class II (n, %): platelet count nadir >50,000/mm3; 100,000/mm3 Class III (n, %): platelet count nadir >100,000/mm3; 150,000/mm3 5 (41.7) 5 (41.7) 2 (16.6) Heparin (N = 20) 10 (50.0) 7 (35.0) 3 (15.0) P ns ns ns Total (N = 32) 15 (46.9) 12 (37.5) 5 (15.6)

(Mississippi triple class system classification [15]); hemolysis [lactate dehydrogenase (LDH) ! 600 U/l, bilirubin ! 1.2 mg/dl]; hepatic dysfunction [aspartate aminotransferase (AST) ! 72 U/l]; clinical and laboratory findings suggestive of preeclampsia/eclampsia [16]. The diagnosis of DIC was made in the presence of three or more parameters of the following: platelet count 100,000/mm3, prothrombin time (PT) 70%, partial thromboplastin time (PTT) ! 40 s, fibrinogen 300 mg/dl, d-dimer ! 800 ng/ml (latex assay) [17]. Acute renal failure was diagnosed in the presence of oliguria/anuria, with severe reduction of renal function (creatinine clearance 20 ml/ min) [18]. Shortly after delivery, all the patients were cared for at the Intensive Care Unit (ICU) of Careggi University Hospital until laboratory and clinical evidence of recovery was achieved. LDH, liver enzyme [AST and alanine aminotransferase (ALT)] and bilirubin levels, as well as CBC, platelet count, parameters of renal function, fibrinogen, antithrombin activity, PT, PTT and d-dimers were determined every 6 h until the stabilisation of the disease and every 1224 h thereafter.
Table 3. Post partum complications and outcome Dexamethasone (N = 12) Eclampsia (n, %) Acute renal failure (n, %) ARDS (n, %) DIC (n, %) Patients transfused (n, %) Length of stay in ICU (days, median, range)
a

Magnesium sulfate was employed in all cases to prevent seizures; all the patients received antihypertensive therapy consisting of hydralazine, nifedipine, enalapril or a combination of these drugs. Patients were transfused with red blood cells when hemoglobin concentration was < 8 g/dl. Among the 32 patients of the study group, 20 were treated from the time of diagnosis (during pregnancy in 16 cases, in the post partum period in four cases) with heparin, which was administered subcutaneously at a dose of 5000 IU every 12 h until patients' discharge. From 1996, 12 patients with HELLP syndrome were given dexamethasone at high doses. The treatment was started as early as the diagnosis was made, that is during gestation in 10 cases and in the post partum period in two cases. In particular, dexamethasone was administered intravenously at a dose of 10 mg every 12 h until the stabilization of the disorder and of 5 mg every 12 h afterwards until clinical and laboratory signs of recovery were observed. 1.1. Statistical Analysis Categorical data were evaluated with chi-square and Fisher's exact test; continuous data were

Heparin (N = 20) 2 (10.0%) 5 (25.0%)a 1 (5.0%) 7 (35.0%) 15 (75.0%) 3.5 (0 37)

P ns ns ns < .02 < .05 < .04

0 0 1 (8.3%) 1 5 (41.7%) 1.5 (0 9)

Two cases of dialysis, one case of plasmapheresis.

102

F. Mecacci et al./Thrombosis Research 102 (2001) 99105

Table 4. Platelet count ( 109/l, median, range) and hematocrit (n, range) Platelet Count Dexamethasone (N = 12) Admission Delivery Post partum 12 h 24 h 36 h 48 h 60 h 72 h 83.5 37.5 69.5 28.5 61.4 26.0 77.2 42.6 97.3 41.4 112.0 43.5 129.2 45.2 152.3 77.9 Heparin (N = 20) 93.8 38.2 77.3 38.1 67.0 34.9 59.4 31.6 60.7 27.9 70.2 28.2 87.5 28.5 97.8 38.2 ns ns ns ns < .001 < .001 < .001 < .01 P Dexamethasone (N = 12) 33.9 6.9 32.5 5.9 29.3 4.9 29.6 3.4 32.1 2.1 32.6 2.5 32.3 2.9 34.1 1.6 Hematocrit Heparin (N = 20) 34.8 6.2 30.0 6.5 26.8 6.5 25.7 5.6 24.8 3.6 26.1 3.6 27.4 3.8 28.5 3.4 ns ns ns < .03 < .001 < .001 < .001 < .001 P

analyzed with MannWhitney U test; P < .05 was considered significant.

2. Results
Demographic and clinical characteristics of all the 32 patients of the study group are presented in Table 1. Overall, parity ! 1 was found in 9 out of 32 cases (28.1%) and a cesarean section was performed in 28 out of 32 patients (87.5%). Median gestational age at delivery was 29.1 weeks in the subset receiving corticosteroids and 34.5 weeks in the subgroup treated with heparin, the difference being statistically significant ( P < .03). Significant differences between the two subgroups could not be documented for blood pressure values and antithrombin III levels at first observation and for any of the other parameters considered.

The distribution of the patients in classes according to the ``Mississippi triple class system'' was not different in the two subgroups (Table 2). The incidence of maternal complications arisen in the post partum period is summarised in Table 3. Among the 20 patients receiving heparin, seven developed DIC with hemorrhage, which was stopped either medically or surgically, five developed acute renal failure and two required dialysis, whereas plasmapheresis was performed in one case, owing to the worsening of both renal function and microangiopathic anemia, after repeated blood transfusions in the absence of overt bleeding. Overall, 15 patients received blood transfusion. In the group of patients treated with corticosteroids, one had DIC (with good outcome), one had ARDS and five were transfused. Significant differences in the incidence of DIC, blood transfusion and duration of admis-

Table 5. LDH levels (IU/l, median, range) and AST/ALT ratio (n, median, range) LDH Levels Dexamethasone (N = 12) Admission Delivery Post partum 12 h 24 h 36 h 48 h 60 h 72 h 1168.3 755.1 1459.2 583.9 1471.3 665.2 1224.9 541.3 827.1 389.2 632.9 308.8 480.9 201.6 442.3 130.7 Heparin (N = 20) 1332.6 959.1 1754.4 1054.2 1733.6 916.3 1729.9 987.9 1564.7 919.2 1309.3 799.8 1015.4 570.6 827.8 410.3 ns ns ns ns < .01 < .001 < .001 < .001 P AST/ALT Ratio Dexamethasone (N = 12) 1.48 1.1 2.84 2.6 2.01 1.8 1.92 1.1 3.25 5.4 1.15 0.6 1.08 0.4 1.01 0.4 Heparin (N = 20) 1.95 1.4 2.45 2.2 3.02 3.3 3.25 2.0 2.86 1.9 3.27 2.2 3.03 2.2 3.93 2.9 ns ns ns < .04 ns < .001 < .001 < .001 P

F. Mecacci et al./Thrombosis Research 102 (2001) 99105

103

sion at ICU could be documented between the two groups undergoing two different therapeutic approaches. Though significant differences were not present between the two groups with respect to median platelet count at first observation, at delivery and on Day 1 after delivery, it is possible to note that platelet count was significantly higher in patients receiving dexamethasone starting from Day 2 after delivery (Table 4). The same trend of regression could also be observed for hematocrit (Table 4) AST/ALT ratio and LDH values (Table 5).

3. Discussion
So far, the pathophysiological mechanism underlying HELLP syndrome has not been understood in full. An endothelial/trophoblastic dysfunction and a low-grade activation of the coagulation in microcirculation are likely to play a major role in the pathogenesis of the disorder [2,3], which is characterized by a localized increase in intravascular coagulation in uteroplacental vascular bed, kidney and liver [19]. Our data, in agreement with the observations of other authors [3], show a reduced incidence of overt DIC at the time of diagnosis, whereas the reduction of antithrombin activity seems to confirm the presence of a condition of compensated consumption (Table 3). The administration of heparin had been occasionally employed for the treatment of preclampsia/eclampsia associated with hemolysis and thrombocytopenia [9,10]. In particular, Brain et al. [9] had suggested that heparin could act by preventing the continuing formation of microthrombi, thus, controlling the cause of the intravascular hemolysis and the thrombocytopenia. Despite the theoretical risk of bleeding, these studies failed to demonstrate an increased incidence of hemorrhage. At the end of 1980s and in 1990, especially in European countries, some authors were considering the use of heparin for the treatment of HELLP syndrome [11,12] in the attempt to interrupt the progression of the compensated consumption coagulopathy. In addition, Rathgeber et al. [13], in 1990, suggested that heparin could be a valuable tool to trap the excess coagulation which is present in pree-

clampsia and in HELLP syndrome. On the basis of these findings, in 1990, we began to employ heparin for treatment of patients with HELLP syndrome admitted in our clinic. In our investigation, 20 patients received heparin; the dosage and schedule of administration were similar to those reported in previous studies. Concerns might be raised as to the low dose of heparin used; however, if HELLP syndrome is regarded as a compensated DIC [3], then heparin treatment could be seen as a helpful tool, as reported also by Bick [17] who suggested that the use of subcutaneous low-dose heparin appears to be highly effective in mild and moderate DIC. From the analysis of platelet count, LDH, AST/ALT ratio and hematocrit modifications, it is possible to note that in these patients the time required for the regression of the disorder is increased and the course of the disease is much more complicated. In 35% of the cases, we observed DIC with hemorrhage, complicated by renal failure in 25% of the cases. These findings seem to suggest that the condition of microangiopathy was prolonged and the clinical course not improved by heparin treatment. In patients receiving corticosteroids, the time course of recovery was shorter and maternal morbility was significantly reduced as compared to patients treated with heparin. In addition, hemorrhagic complications were not observed, and the patient presenting with DIC at the time of admission had a significant improvement in the post partum period. No patients suffered from acute renal failure, and the number of patients undergoing blood transfusion as well as the number of days of admission at ICU were significantly lowered. Though the mechanism by which corticosteroids exert a beneficial effect in the regression of HELLP syndrome remains unclear, we believe, in agreement with Martin et al. [16], that they might influence the underlying condition of microangiopathic hemolytic anemia thus reducing the severity of the disease. Our retrospective study involved a small series of patients; there was also quite an important difference in the number of cases in each subgroup. Despite these limiting factors, partially due to the infrequent occurrence of HELLP syn-

104

F. Mecacci et al./Thrombosis Research 102 (2001) 99105

drome, our results suggest that heparin therapy, when administered subcutaneously at low doses, does not stop the consumption coagulopathy associated with endothelial damage and might conversely lead to the onset of overt DIC. Since heparin treatment was used in earlier years and then replaced by dexamethasone, it is possible that our results reflect in part differences attributable to improvements in the general management of the patients; however, this is more likely to explain differences in clinical aspects such as gestational age at the time of diagnosis and the length of stay at ICU, whereas the trend of laboratory parameters is most probably influenced by the effect of the two therapeutic options on the underlying condition. On the other hand, therapy with dexamethasone at high doses is associated with significantly reduced maternal morbility and seems to positively influence the time course of the disorder with a quicker regression. As it is possible that there is a critical time, in the progression of the disease, beyond which steroid therapy can be less effective [16], we strongly believe that this therapy should be administered as early as HELLP syndrome is diagnosed, even before the referral to a tertiary care center. This can be crucially important for the stabilization of those patients at particularly low gestational ages, in the attempt to postpone delivery and achieve better perinatal outcomes.

References
1. Weinstein L. Syndrome of hemolysis, elevated liver enzymes and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142: 15967. 2. Sibai BM. The HELLP Syndrome (hemolysis, elevated liver enzymes and low platelets): much ado about nothing? Am J Obstet Gynecol 1990;162:3116. 3. De Boer K, Buller HR, ten Cate JW, Treffers PE. Coagulation studies in the syndrome of haemolysis, elevated liver enzymes and low platelets. Br J Obstet Gynaecol 1991;98: 427.

4. Van Dam PA, Renier M, Baekelandt M, Buytaert P, Uyttenbroeck F. Disseminated intravascular coagulation and the syndrome of hemolysis, elevated liver enzymes and low platelets in severe preeclampsia. Obstet Gynecol 1989;73(1):97102. 5. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169:10006. 6. Van Pampus MG, Wolf H, Westenberg SM, Van der Post JA, Bonsel GJ, Treffers PE. Maternal and perinatal outcome after expectant management of HELLP Syndrome compared with preeclampsia without HELLP syndrome. Eur J Obstet Gynecol Reprod Biol 1998;76:31. 7. Howie PW, Prentice CRM, Forbes CD. Failure of heparin therapy to affect the clinical course of severe preeclampsia. Br J Obstet Gynaecol 1975;82:7117. 8. Beller FK, Dame WR, Ebert C. Pregnancy induced hypertension complicated by thrombocytopenia, haemolysis and elevated liver enzymes (HELLP) syndrome. Renal biopsies and outcome. Aust NZJ Obstet Gynaecol 1985;25:836. 9. Brain MC, Kuah KB, Dixon HG. Heparin treatment of hemolysis and thrombocytopenia in preeclampsia. J Obstet Gynaecol Br Commonw 1967;74:70211. 10. Goldsmith HJ, Menzies DN, De Boer CH, Caplan W, McCandless A. Delivery of healthy infant after five weeks' dialysis treatment for fulminating toxaemia of pregnancy. Lancet 1971;2:73841. 11. Monnier JC, Vaksmann S, Vinatier D, PateySavatier P, Maunoury-Lefebvre C. Is it necessary to specify the HELLP syndrome? J Gynecol Obstet Biol Reprod 1987;16:76571. 12. Ellart D, Guevart E, Forzy G, Houze de L'Aulnoit D, Nabi A, Delcroix M, Brabant G. HELLP syndrome. Apropos of a series of 9 cases without disseminated intravascular coagulation. Rev Fr Gynecol Obstet 1990; 85:2206.

F. Mecacci et al./Thrombosis Research 102 (2001) 99105

105

13. Rathgeber J, Rath W, Wieding JU. Anesthesiologic and intensive care aspects of severe preeclampsia with HELLP syndrome. sth, Intensivther, Notfallmed 1990;25: Ana 20611. 14. Magann EF, Bass D, Chauhan SP, Sullivan DL, Martin RW, Martin JN. Antepartum corticosteroids: disease stabilization in patiens with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol 1994;171: 114853. 15. Martin JN, Blake PG, Lowry SL, Perry JC, Files JC, Morrison JC. Pregnancy complicated by preeclampsia eclampsia with the syndrome of hemolysis, elevated liver enzymes, and low platelet count: how rapid is postpartum recovery? Obstet Gynecol 1990;76:73741. 16. Martin JN, Perry KG, Blake PG, May WA, Moore A, Robinette L. Better maternal out-

comes are achieved with dexamethasone therapy for postpartum HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome. Am J Obstet Gynecol 1997; 177:10117. 17. Bick RL. Disseminated intravascular coagulation. Objective clinical and laboratory diagnosis, treatment, and assessment of therapeutic response. Semin Thromb Hemostasis 1996;22(1):6988. 18. Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome. Am J Obstet Gynecol 1996;175:4604. 19. Dekker GA, Walker JJ. Maternal assessment in pregnancy-induced hypertensive disorders: special investigations and their pathophysiological basis. In: Walker JJ, Gant NF, editors. Hypertension in pregnancy. London: Chapman & Hall, 1997. pp. 10761.