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REGULAR ARTICLE

Time Course of Recovery and Complications of HELLP

Syndrome with Two Different Treatments: Heparinor DexamethasoneFederico Mecacci1, Lucia Carignani1, Riccardo Cioni1, Elena Parretti1, Marcella Mignosa1, Anna Piccioli2,Gianfranco Scarselli1 and Giorgio Mello11Department 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)

Abstract

HELLP syndrome is a severe complication ofpregnancy characterized by microangiopathichemolytic anemia, hepatic dysfunction andthrombocytopenia. Though delivery is the ulti-mate therapeutic option, medical treatments,including the use of heparin or corticosteroids,have been employed in the attempt to improvematernal prognosis. The aim of this retrospective

study was to compare the time course ofrecovery and the incidence of complications inwomen with HELLP syndrome receiving eitherheparin or dexamethasone. Between January1990 and December 1998, 32 patients withHELLP syndrome were cared for at the Instituteof Obstetrics and Gynecology of the University ofFlorence: 20 patients were treated with heparin,administered subcutaneously at a dose of 5000 IUevery 12 h, whereas 12 women received dex-amethasone, administered intravenously at adose of 10 mg every 12 h. Categorical data were

evaluated with chi-square and Fisher's exact test;continuous data were analyzed with MannWhitney U test; P < .05 was considered signifi-cant. In the subgroup treated with heparin the

incidence of disseminated intravascular coagula-tion (DIC) ( P < .02), the number of patientsrequiring blood transfusion ( P < .05) and thelength of stay at the Intensive Care Unit (ICU)( P < .04) were significantly increased as com-pared with the subgroup receiving dexametha-sone; in this latter subgroup, significantly higherplatelet count and hematocrit values, and sig-nificantly lower levels of lactate dehydrogenase(LDH) could be documented starting from day 2

after delivery. The results of our investigationsuggest that the use of dexamethasone in patientswith HELLP syndrome is associated with fasterregression and lower incidence of complicationsin comparison to heparin. D 2001 ElsevierScience Ltd. All rights reserved.

Key Words: HELLP syndrome; Heparin; Dexamethasone

H

ELLP syndrome is a severe form ofp r e e c l a m p s i a / e c l a m p s i a , w h i c hassumed its own identity as a disease

in 1982 [1]. The syndrome, which is characterizedby microangiopathic hemolytic anemia, hepaticdysfunction and thrombocytopenia, may occur ingestation, as well as in the post partum period[2]. Microangiopathy, particularly at the level ofliver circulation, seems to play a crucial role inthe pathophysiology of the disease; the progres-sion 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

Corresponding author: Prof. Giorgio Mello, Via Masaccio, 92, I-50100 Florence, Italy. Tel: +39 (55) 240255; Fax: +39 (55) 240255;E-mail: .

Thrombosis Research 102 (2001) 99105

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lead to acute renal failure, respiratory distresssyndrome (ARDS) and multiorgan failure [2]. Asa consequence of microangiopathy, there is a``low-grade'' activation of the coagulation cas-cade, referred to as compensated disseminatedintravascular coagulation (DIC) by some authors[3], which evolves in overt DIC in 2155% of thecases [4,5].

Delivery is considered the ultimate therapeu-tic option for HELLP syndrome, however, aconservative medical management has been sug-gested at particularly low gestational ages inorder to reach fetal lung maturity [6]. Bothsteroid and heparin therapies have beenemployed to improve maternal prognosis atany gestational age. The use of heparin in

patients with preeclampsia and HELLP syn-drome is still a controversial matter; accordingto some authors, heparin does not exert anyeffect [7,8], whereas others believe that it can

be beneficial [913].In 1994, Magann et al. [14] proposed a

therapeutic protocol based on the administra-tion of high doses of dexamethasone aimed atinducing fetal lung maturity, reducing maternalcomplications and promoting the regression ofthe syndrome.

At the Institute of Obstetrics and Gynecologyof the University of Florence, the administra-

tion of heparin has been employed since 1990as part of the protocol for the treatment ofHELLP syndrome. Since 1996, a new protocolwas developed: With this protocol, heparinwas no longer administered, whereas dexa-methasone at high doses was given beforeand after delivery.

The aim of this study was to compare thesetwo different protocols for the treatment ofHELLP syndrome with respect to both inci-dence of maternal complications and timecourse of recovery.

1. Materials and Methods

Thirty-two patients with HELLP syndrome,referred to the Institute of Obstetrics and Gyne-cology of the University of Florence between

January 1990 and December 1998, were retro-spectively studied. Patients with hemorrhagicdiathesis, renal and cardiovascular diseases orsuffering from any other medical disorder werenot included in the study group.

HELLP syndrome was diagnosed in the pre-sence of: thrombocytopenia with peripartumnadir 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)

Table 1. Demographic and clinical characteristcs of patients

Dexamethasone(N=12)

Heparin(N=20)

Total(N=32)

Maternal age(years, median, range)

33.5 (19 37) 29 (23 39) 30 (1939)

Parity (n, %)0 7 (58.3) 16 (80.0) 23 (71.9)! 1 5 (41.7) 4 (20.0) 9 (28.1)

Gestational age at delivery(weeks, median, range)

29.1 (24.1 38)* 34.5 (27.1 42)* 31.95 (24.1 42)

Interval between diagnosis anddelivery (days, median, range)

0 (0 2) 0 (0 3) 0 (03)

Systolic blood pressure(mm Hg, median, range)

160 (130210) 170 (120 200) 166.5 (130210)

D iastolic blood pressure(mm Hg, median, range)

100 (90 140) 100 (80 140) 100 (90140)

DIC (n, %) 1 (8.3) 1 (5.0)Term pregnancy (n, %) 1 (8.3) 1 (3.1)Vaginal delivery (n, %) 1 (8.3) 3 (15.0) 4 (12.5)Cesarean section (n, %) 11 (91.7) 17 (85.0) 28 (87.5)Antithrombin III (%, range) 70 (35 90) 67 (35 89) 67.5 (35 90)

* P < .03.

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(Mississippi triple class system classification[15]); hemolysis [lactate dehydrogenase (LDH)! 600 U/l, bilirubin ! 1.2 mg/dl]; hepatic dys-function [aspartate aminotransferase (AST) ! 72U/l]; clinical and laboratory findings suggestive

of preeclampsia/eclampsia [16].The diagnosis of DIC was made in the pre-sence of three or more parameters of the follow-ing: platelet count 100,000/mm3, prothrombintime (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 pre-sence of oliguria/anuria, with severe reductionof renal function (creatinine clearance 20 ml/min) [18].

Shortly after delivery, all the patients werecared for at the Intensive Care Unit (ICU) ofCareggi University Hospital until laboratoryand clinical evidence of recovery was achieved.LDH, liver enzyme [AST and alanine amino-transferase (ALT)] and bilirubin levels, as wellas CBC, platelet count, parameters of renalfunction, fibrinogen, antithrombin activity, PT,PTT and d-dimers were determined every 6 huntil the stabilisation of the disease and every1224 h thereafter.

Magnesium sulfate was employed in all casesto prevent seizures; all the patients receivedantihypertensive therapy consisting of hydrala-zine, nifedipine, enalapril or a combination ofthese drugs. Patients were transfused with red

blood cells when hemoglobin concentration was50,000/mm3; 100,000/mm3

5 (41.7) 7 (35.0) ns 12 (37.5)

Class III (n, %): platelet count nadir>100,000/mm3; 150,000/mm3

2 (16.6) 3 (15.0) ns 5 (15.6)

Table 3. Post partum complications and outcomeDexamethasone

(N= 12)Heparin(N= 20) P

Eclampsia (n, %) 0 2 (10.0%)Acute renal failure (n, %) 0 5 (25.0%)a nsARDS (n, %) 1 (8.3%) 1 (5.0%) nsDIC (n, %) 1 7 (35.0%) < .02Patients transfused (n, %) 5 (41.7%) 15 (75.0%) < .05Length of stay in ICU

(days, median, range)1.5 (0 9) 3.5 (0 37) < .04

a Two cases of dialysis, one case of plasmapheresis.

ns

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analyzed with Mann Whitney Utest; P < .05 was

considered significant.

2. Results

Demographic and clinical characteristics of allthe 32 patients of the study group are presentedin Table 1. Overall, parity ! 1 was found in 9 outof 32 cases (28.1%) and a cesarean section wasperformed in 28 out of 32 patients (87.5%). Med-ian gestational age at delivery was 29.1 weeks inthe subset receiving corticosteroids and 34.5weeks in the subgroup treated with heparin,the difference being statistically significant( P < .03). Significant differences between thetwo subgroups could not be documented for

blood pressure values and antithrombin III levelsat first observation and for any of the otherparameters 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 arisenin the post partum period is summarised in Table3. Among the 20 patients receiving heparin,seven developed DIC with hemorrhage, whichwas stopped either medically or surgically, fivedeveloped acute renal failure and two requireddialysis, whereas plasmapheresis was performedin one case, owing to the worsening of both renalfunction and microangiopathic anemia, afterrepeated blood transfusions in the absence ofovert bleeding. Overall, 15 patients received

blood transfusion.In the group of patients treated with corti-

costeroids, one had DIC (with good outcome),one had ARDS and five were transfused.Significant differences in the incidence ofDIC, blood transfusion and duration of admis-

Table 4. Platelet count ( 109/l, median, range) and hematocrit (n, range)

Platelet Count Hematocrit

Dexamethasone(N= 12)

Heparin(N= 20) P


Heparin(N= 20) P

Admission 83.5 37.5 93.8 38.2 ns 33.9 6.9 34.8 6.2 nsDelivery 69.5 28.5 77.3 38.1 ns 32.5 5.9 30.0 6.5 ns

Post partum12 h 61.4 26.0 67.0 34.9 ns 29.3 4.9 26.8 6.5 ns24 h 77.2 42.6 59.4 31.6 ns 29.6 3.4 25.7 5.6 < .0336 h 97.3 41.4 60.7 27.9 < .001 32.1 2.1 24.8 3.6 < .00148 h 112.0 43.5 70.2 28.2 < .001 32.6 2.5 26.1 3.6 < .00160 h 129.2 45.2 87.5 28.5 < .001 32.3 2.9 27.4 3.8 < .00172 h 152.3 77.9 97.8 38.2 < .01 34.1 1.6 28.5 3.4 < .001

Table 5. LDH levels (IU/l, median, range) and AST/ALT ratio (n, median, range)

LDH Levels AST/ALT Ratio


Heparin(N= 20) P


Heparin(N= 20) P

Admission 1168.3 755.1 1332.6 959.1 ns 1.48 1.1 1.95 1.4 nsDelivery 1459.2 583.9 1754.4 1054.2 ns 2.84 2.6 2.45 2.2 ns

Post partum12 h 1471.3 665.2 1733.6 916.3 ns 2.01 1.8 3.02 3.3 ns24 h 1224.9 541.3 1729.9 987.9 ns 1.92 1.1 3.25 2.0 < .0436 h 827.1 389.2 1564.7 919.2 < .01 3.25 5.4 2.86 1.9 ns48 h 632.9 308.8 1309.3 799.8 < .001 1.15 0.6 3.27 2.2 < .00160 h 480.9 201.6 1015.4 570.6 < .001 1.08 0.4 3.03 2.2 < .00172 h 442.3 130.7 827.8 410.3 < .001 1.01 0.4 3.93 2.9 < .001


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sion at ICU could be documented between thetwo groups undergoing two different thera-peutic approaches.

Though significant differences were not pre-sent between the two groups with respect tomedian platelet count at first observation, atdelivery and on Day 1 after delivery, it is possibleto note that platelet count was significantlyhigher in patients receiving dexamethasone start-ing from Day 2 after delivery (Table 4). The sametrend of regression could also be observed forhematocrit (Table 4) AST/ALT ratio and LDHvalues (Table 5).

3. Discussion

So far, the pathophysiological mechanism under-lying HELLP syndrome has not been understoodin full. An endothelial/trophoblastic dysfunctionand a low-grade activation of the coagulation inmicrocirculation are likely to play a major role inthe pathogenesis of the disorder [2,3], which ischaracterized by a localized increase in intravas-cular coagulation in uteroplacental vascular bed,kidney and liver [19]. Our data, in agreementwith the observations of other authors [3], show a

reduced incidence of overt DIC at the time ofdiagnosis, whereas the reduction of antithrombinactivity seems to confirm the presence of a con-dition of compensated consumption (Table 3).

The administration of heparin had been occa-sionally employed for the treatment of preclamp-sia/eclampsia associated with hemolysis andthrombocytopenia [9,10]. In particular, Brain etal. [9] had suggested that heparin could act bypreventing the continuing formation of micro-thrombi, thus, controlling the cause of the intra-vascular hemolysis and the thrombocytopenia.

Despite the theoretical risk of bleeding, thesestudies failed to demonstrate an increased inci-dence of hemorrhage. At the end of 1980s and in1990, especially in European countries, someauthors were considering the use of heparin forthe treatment of HELLP syndrome [11,12] in theattempt to interrupt the progression of the com-pensated consumption coagulopathy. In addi-tion, Rathgeber et al. [13], in 1990, suggestedthat heparin could be a valuable tool to trap theexcess coagulation which is present in pree-

clampsia and in HELLP syndrome. On the basisof these findings, in 1990, we began to employheparin for treatment of patients with HELLPsyndrome admitted in our clinic.

In our investigation, 20 patients receivedheparin; the dosage and schedule of administra-tion were similar to those reported in previousstudies. Concerns might be raised as to the lowdose of heparin used; however, if HELLP syn-drome is regarded as a compensated DIC [3],then heparin treatment could be seen as a helpfultool, as reported also by Bick [17] who suggestedthat the use of subcutaneous low-dose heparinappears to be highly effective in mild and mod-erate DIC.

From the analysis of platelet count, LDH,

AST/ALT ratio and hematocrit modifications, itis possible to note that in these patients the timerequired for the regression of the disorder isincreased and the course of the disease is muchmore complicated. In 35% of the cases, weobserved DIC with hemorrhage, complicated byrenal failure in 25% of the cases. These findingsseem to suggest that the condition of microangio-pathy was prolonged and the clinical course notimproved by heparin treatment.

In patients receiving corticosteroids, the time

course of recovery was shorter and maternalmorbility was significantly reduced as comparedto patients treated with heparin. In addition,hemorrhagic complications were not observed,and the patient presenting with DIC at the timeof admission had a significant improvement inthe post partum period. No patients sufferedfrom acute renal failure, and the number ofpatients undergoing blood transfusion as wellas the number of days of admission at ICU weresignificantly lowered.

Though the mechanism by which corticoster-

oids exert a beneficial effect in the regression ofHELLP syndrome remains unclear, we believe,in agreement with Martin et al. [16], that theymight influence the underlying condition ofmicroangiopathic hemolytic anemia thus redu-cing the severity of the disease.

Our retrospective study involved a small ser-ies of patients; there was also quite an importantdifference in the number of cases in each sub-group. Despite these limiting factors, partiallydue to the infrequent occurrence of HELLP syn-


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drome, our results suggest that heparin therapy,when administered subcutaneously at low doses,does not stop the consumption coagulopathyassociated with endothelial damage and mightconversely lead to the onset of overt DIC.

Since heparin treatment was used in earlieryears and then replaced by dexamethasone, it ispossible that our results reflect in part differencesattributable to improvements in the general man-agement of the patients; however, this is morelikely to explain differences in clinical aspectssuch as gestational age at the time of diagnosisand the length of stay at ICU, whereas the trendof laboratory parameters is most probably influ-enced by the effect of the two therapeutic optionson the underlying condition.

On the other hand, therapy with dexametha-sone at high doses is associated with significantlyreduced maternal morbility and seems to posi-tively influence the time course of the disorderwith a quicker regression. As it is possible thatthere is a critical time, in the progression of thedisease, beyond which steroid therapy can beless effective [16], we strongly believe that thistherapy should be administered as early asHELLP syndrome is diagnosed, even beforethe referral to a tertiary care center. This can

be crucially important for the stabilization ofthose patients at particularly low gestationalages, in the attempt to postpone delivery andachieve better perinatal outcomes.

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