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Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review

European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 166, Issue 2, February 2013, Pages 117 - 123

Abstract

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is serious for the mother and the offspring. HELLP occurs in 0.2–0.8% of pregnancies and in 70–80% of cases it coexists with preeclampsia (PE). This review concerns the pathogenetic mechanisms of HELLP syndrome with an emphasis on differences between HELLP and early onset PE. The syndromes show a familial tendency. A previous HELLP pregnancy is associated with an increased risk of HELLP as well as PE in subsequent pregnancies, indicating related etiologies. No single world-wide genetic cause for excessive risk of HELLP or PE has been identified. Combinations of multiple gene variants, each with a moderate risk, with contributing effects of maternal and environmental factors, are probable etiological mechanisms. Immunological maladaptation is the most probable trigger of the insult to the invading trophoblast. This insult occurs early in the first trimester, as indicated by marker molecules in maternal blood. The levels of fetal messenger RNAs in maternal blood at gestational weeks 15–20 are significantly more abnormal in HELLP than in PE, suggesting that the insult is more extensive in HELLP. High levels of HLA-DR in maternal blood in women with HELLP may suggest a similarity to the rejection reaction. In third trimester placentas, gene derangement is more extensive in HELLP. Anti-angiogenic factors released into maternal blood induce the maternal syndromes. Maternal blood levels of anti-angiogenic sFlt1 are similar, but endoglin and Fas Ligand levels are possibly higher in HELLP than in PE. These factors trigger the vascular endothelium, resulting in an enhanced inflammatory response which is stronger in HELLP. Activated coagulation and complement, with high levels of activated leucocytes, inflammatory cytokines, TNF-α, and active von Willebrand factor, induce thrombotic microangiopathy with platelet–fibrin thrombi in microvessels. The angiopathy results in consumption of circulating platelets, causes hemolysis in affected microvessels and reduces portal blood flow in the liver. Placental Fas Ligand damages hepatocytes, resulting in periportal necrosis. In about one half of women with HELLP, activation of coagulation factors and platelets precipitates disseminated intravascular coagulation, which in a minority becomes uncompensated and contributes to life-threatening multiorgan failure.

Keywords: HELLP, Preeclampsia, Pathogenesis, Microangiopathy, Genetic, Biomarkers, Review.

1. Introduction

In 1982 Weinstein described a unique group of obstetric patients with hemolysis (H), elevated liver enzymes (EL) and a low platelet count (LP), and termed this entity the HELLP syndrome [1]. The majority of the patients had mild hypertension and Weinstein regarded the syndrome as a special form of severe preeclampsia. He mentioned three reports each describing 3–5 severely affected patients who probably had suffered from HELLP syndrome. The patients had often been given a non-obstetric diagnosis and treatment had been withheld or modified [1].

The HELLP syndrome occurs in about 0.2–0.8% of pregnancies. It is associated with increased risks of adverse complications for both mother and fetus [1] and [2]. Hypertension is present in most cases, but signs of preeclampsia (PE) may be subtle or missing [1] and [2]. Early detection and accurate diagnosis are essential for correct management. The maternal symptoms may be vague and easily mistaken for a variety of medical or obstetric complications which should be excluded [2] and [3]. There are two main diagnostic definitions of the HELLP syndrome. The widely used Tennessee classification requires the presence of (1) microangiopathic hemolytic anemia with abnormal blood smear, low serum haptoglobin and elevated LDH levels, (2) elevation of ASAT above 70 IU/L and LD above 600 IU/L (both enzyme levels more than twice the upper limit of normal values) or bilirubin more than 1.2 mg/dL, and (3) a platelet count below 100 × 109 L−1[2]. The incomplete syndrome with only two criteria (“ELLP”) may be clinically less severe. The Mississippi Triple-class classification syndrome further classifies the disorder according to the nadir of the platelet count [4].

HELLP is usually associated with PE, which is defined as de novo hypertension in pregnancy (≥140/90 mmHg after 20 weeks’ gestation), returning to normal postpartum, and properly documented proteinuria (≥300 mg/day or a spot urine:creatinine ratio ≥30 mg/mmol) [5]. PE is about ten times more frequent than HELLP. Onset of PE and HELLP prior to 28 weeks’ gestation accounts for about 20–30% of the cases and these early onset types are more often associated with severe disease [6] and [7]. The clinical onset of HELLP may be rapid and associated with severe disease [8].

HELLP and PE are preceded by abnormal placentation in the first trimester. The maternal signs occur in the second half of the pregnancy and are thought to represent the response to emitted products from a stressed placenta [9]. The placental lesion is probably similar in early onset PE and HELLP and is assumed to be the major causative factor. In late onset PE, maternal factors may dominate [6]. Early onset PE and HELLP often coexist with fetal growth restriction (FGR).

Delivery is at present the only efficient treatment of HELLP syndrome and PE. The use of corticosteroids, beyond a single course for fetal lung maturing, in early onset HELLP is of uncertain clinical value [3]. Following the delivery of the placenta, the maternal symptoms and signs often disappear but a protracted course of severe HELLP syndrome is not unusual.

Better knowledge of the pathogenesis of the HELLP syndrome could lead to improved treatment and prevention. The initial molecular etiologies of HELLP syndrome and PE are unknown. A review article from 2008 described the contribution of placenta-derived inflammatory cytokines to the pathogenesis of HELLP [10]. Recent reviews on the pathogenesis of PE have focused on the pathogenic role of immune maladaptation, and the predictive role of fetal markers for PE [6], [9], and [11]. These two latter mechanisms are probably as important for the pathogenesis of HELLP. The aim of the present review is to describe and discuss pathogenetic mechanisms demonstrated in HELLP syndrome, focusing on differences between HELLP syndrome and early onset PE.

2. Inheritance

Sisters and children of a woman who has sustained HELLP have increased risks of HELLP [12]. A woman who has sustained HELLP has a high risk of developing HELLP (14–24%) and PE (22–28%) in subsequent pregnancies [7] and [13], suggesting related pathogenetic mechanisms. A population study indicated that 35% of the variance in susceptibility to PE was attributed to maternal inheritance, and 20% to fetal genetic effects with similar contribution of maternal and paternal inheritance [14].

3. Genetic studies

No world-wide genetic cause for excessive risk of PE or HELLP has been identified. Results from the Dutch genome-wide scan were interpreted as indicating that the genetic background for HELLP was different from that of PE [12] but the findings have neither been confirmed nor refuted.

The combined effect of multiple gene variants, each with moderate risks for HELLP and PE, with additional effects of maternal and environmental factors, is a probable etiological mechanism. Gene variants in the FAS gene, the VEGF gene and the coagulation factor V Leiden (FVL) mutation are associated with increased risk of HELLP compared to healthy women (Table 1) [15], [16], and [17]. Variants in the glucocorticoid receptor gene [18] and the Toll-like receptor gene [19] increased the risk of HELLP significantly more than the risk of PE (Table 1). Risk ratios for HELLP were in the range of 2.3–4.7 (Table 1), which are risk ratios commonly found in studies of multifactorial conditions. Women with a previous HELLP pregnancy have a markedly increased risk of developing chronic hypertension [7], suggesting a common genetic predisposition or a long-term effect of HELLP.

Table 1 Genetic variants associated with an increased risk of HELLP syndrome.

Gene variant HELLP compared to HELLP (n) OR (95% CI), p Effect Reference
Glucocorticoid receptor gene (GCCR),
Bell SNP polymorphisms
Healthy pregnant
Severe PE
17 2.89 (1.45–5.74) p = 0.004
2.56 (1.26–5.23) p = 0.013
Altered immune sensitivity and glucocorticoid sensitivity [18]
Toll-like receptor 4 gene (TLR4),
D299G
T3991
polymorphisms
Healthy pregnant
PE
177 4.7 (2.0–1.9)
2.3 (1.3–4.3)
Uncontrolled or harmful inflammation,
Ineffective immunity
[19]
VEGF gene (VEGFA),
C-460T
G+405C
polymorphisms
Healthy pregnant
Healthy pregnant
16 3.03 (1.51–6.08)
3.67 (1.05–6.08)
Angiogenesis and vasculogenesis, arterial muscular relaxation [16]
FAS (TNFRSF6) gene, homozygous polymorphism in A-670G Healthy pregnant 81 2.7 (1.2–5.9) Immune regulation, apoptosis. Liver disease [15]
FV Leiden Healthy pregnant 71 4.5 (1.31–15.31) Thrombophilia [17]

Several gene variants are probably associated with a moderately increased risk of PE. The association between gene variants and PE was significant for only a minority of the variants studied [20] and [21]. Genome-wide association studies (GWAS) have disclosed susceptibility genes for PE. The results seem compatible with the assumptions that unfavorable genetic variants and interactions between genes regulating maternal–fetal interactions are involved in the development of PE [20] and [21]. The genetic contributions are likely complex, involving numerous genetic variants and fetal–maternal gene–gene interactions. PE in different women might have different triggers [20]. These assumptions also seem to be relevant for HELLP.

4. Maternal risk factors

High body mass index (BMI) and metabolic syndrome 6 months postpartum were associated with PE but hardly for HELLP [22]. The antiphospholipid-antibody syndrome (APLS) may be associated with early onset of HELLP [23]. A first pregnancy is probably not associated with a greater risk of HELLP [24] but is associated with a considerably higher risk of PE [11]. Infertility treatment increases the risk of PE whereas pre-conceptual exposure to seminal fluid reduces the risk, supporting a pathogenetic role of immune maladaptation [9]. It is probable, but unknown if these conditions influence the risk of HELLP.

5. Placental pathogenesis of HELLP and PE

A placental stage in HELLP, similar to the placental pathology of PE, has long been recognized [25]. A central issue is whether maternal immune responses to the invading trophoblasts generate normal or abnormal placentation [26]. The early development of the dysfunctional placenta in PE has recently been reviewed [6] and [9]. Only aspects particularly relevant to HELLP will be mentioned below.

5.1. Factors that may predict HELLP and PE and may induce the maternal syndromes

The syncytiotrophoblast membrane which separates maternal and fetal blood has an abnormal morphology of its brush border in PE [27] and [28] and in HELLP [28]. The incorporation of placental protein 13 (PP 13) in the membrane was abnormal in both syndromes [28]. High PP 13 concentrations in maternal blood in the third trimester reflect shedding of PP 13 from the aponecrotic brush border of the membrane [28].

Abnormal concentrations in maternal blood of PP 13 and angiogenic factors emitted from the placenta have been demonstrated in HELLP and PE in the first trimester and onwards [28], [29], [30], [31], [32], [33], [34], [35], and [36]. Alterations in the levels of these “early biomarkers” are shown in Table 2. Although changes were similar in HELLP and PE, some deviations were significantly greater in HELLP (Table 2). Significantly reduced PP 13 concentrations in PE already at gestation weeks 8–14 in PE and in HELLP [29] indicate that the two placental syndromes progress early in the first trimester [37].

Table 2 Biomarkers in maternal blood predicting early onset HELLP or PE.

Biomarker Gestation weeks HELLP PE Ref. no. Function of marker
PP 13 8–14 [29] Development of fetal/maternal interface, immune regulation
24–37 [28]
 
PlGF 8–14 [29] and [32] Angiogenic, prevents hypertension
Term ↓↓ [33]
 
VEGF 14–21 n.e. [30] Angiogenic, prevents hypertension
32 ↑↑ [31]
 
sFlt1 10–17 n.e. [32] Inhibits VEGF and PlGF. Anti-angiogenic
25–40 ↑↑ [33] and [35]
 
sEndoglin 10–17 n.e. [32] Inhibits TNF-β, inhibits vasodilation. Anti-angiogenic
Preterm ↑↑ [34] and [35]
Term [36]

PP 13, placental protein 13; PlGF, placental growth factor; sFlt1, sVEGFR-1; n.e., not examined; ↑, higher than in pregnant controls (p < 0.05); ↑↑, higher than ↑ (p < 0.05); a, Levels in two women with HELLP higher than in 32 women with PE; b, Semiquantitative data.

In human amnion fluid, PP 13 levels were similarly elevated in PE and HELLP [38]. In cord blood PP 13 levels were low in controls and in PE, but several-fold higher in HELLP [38]. PP 13 is exclusively synthesized by syncytiotrophoblast cells [28]. The high PP 13 levels in cord blood might result from an abnormal syncytiotrophoblast passage of PP 13 to fetal blood in HELLP, different from PE and healthy pregnancy. The finding supports the hypothesis of more profound damage to the syncytiotrophoblast membrane in HELLP.

Increased anti-angiogenic factor levels induce maternal vascular endothelial dysfunction which causes arterial hypertension and glomerular endotheliosis in preeclampsia, as recently reviewed [6], [9], and [11]. The placental emissions enhance the inflammatory response in PE [39] and even more in HELLP [10].

Increasing the sFlt1 level in pregnant rats may induce PE [40]. Elevation of soluble endoglin (sEng) in the blood of rats primed with sFlt1 induced a syndrome similar to human HELLP [35]. Semiquantitation in blood from women with HELLP showed higher soluble endoglin (sEng) values in HELLP than in PE [35]. A clinical study reported higher sEng preterm levels in 2 women with HELLP than in 34 women with PE [34]. A recent study reported similar values of sEng in PE and HELLP at term [36]. Different sEng levels at preterm [34] and [35] might have a bearing on a possibly specific pathogenetic role of sEng in HELLP, but additional preterm data are needed. The placental emissions may particularly in HELLP induce release of inflammatory cytokines in the maternal circulation [10].

5.2. Differences between mRNA levels in HELLP and PE

In blood from symptomatic women the concentrations of fetal mRNA coding for Flt1 (VEGFR-1) and Eng were several-fold higher in HELLP than in early onset PE, both in plasma and cell fractions [41]. In samples from gestation weeks 15 to 20, the differences between women who later developed HELLP or PE and normal controls were also marked, and distinct in the cell-free fractions [42]. In cell-free fractions, the mRNA levels coding for Flt1 and Eng were the best predictors for PE [43]. A score system based on mRNA levels of 7 genes predicted the combined HELLP–PE group with high sensitivity (88.7%) at a specificity of 90%. The HELLP subgroup had the highest mean score of 93.7, severe PE 79.3, and mild PE 56.3, as compared to a score of 9.4 in pregnant controls. Values in severe PE and HELLP overlapped [42]. The statistically significant difference in mean scores suggests a more profound pathophysiological deviation in HELLP than in PE.

5.3. Increased sHLA-DR in HELLP

Soluble HLA-DR (sHLA-DR) levels in maternal blood increased in the second and third trimester [43]. sHLA-DR levels were markedly increased in HELLP, but decreased in PE compared to controls [43]. Hig sHLA-DR in HELLP syndrome was interpreted as a maternal immune reaction against circulating fetal cells which express paternal antigens, but could also represent fetal-derived sHLA-DR molecules. The biological significance is unclear. Steinborn interpreted the findings as maternal rejection of the fetus [43].

5.4. Gene expression and histopathology in placenta

A microarray profiling study on placenta samples at delivery revealed 54 genes differentially expressed in early onset HELLP and 350 genes in early onset PE [44]. The transcriptomes in the two syndromes largely overlapped. The inflammatory response was more pronounced in HELLP. Down-regulation was more frequent in HELLP (239 genes) than in PE (67 genes) [44].

Histopathological comparisons of term placentas have shown a lower frequency of intravillous thrombosis and villous infarcts in HELLP than in PE [45] or no difference [25]. Apoptotic and proliferation marker levels were higher in placenta from HELLP than in PE [46]. Decidual dendritic cells stained differently and reacted differently with decidual natural killer (dNK) cells in HELLP compared to PE [47]. The placental expression of Fas Ligand (FasL) was higher [48], and the expression in villous trophoblast increased in HELLP compared to healthy pregnancy and PE [49].

6. Pathogenetic mechanisms in the mother with HELLP

6.1. The inflammatory response

The inflammatory response of normal pregnancy is more enhanced in HELLP than in PE [10]. Fulminant disseminated intravascular coagulation (DIC) in HELLP may develop superacutely [50], apparently matching the time course of the Shwartzman reaction [10]. The inflammatory response with activation of coagulation and complement is caused by syncytiotrophoblast particles (STBM) and other placental products which interact with maternal immune cells and vascular endothelial cells (EC) [51] and [52].

The concentrations in maternal blood of CRP, interleukin 6 [53] and TNF-α [54] are more increased in HELLP than in PE. In 91 patients with HELLP and 86 patients with severe PE, white cells counts were higher in HELLP and correlated with the severity of the syndrome [55]. Complement is activated in HELLP [56]. Defective regulation of complement may contribute to the development of thrombotic microangiopathy and HELLP [57].

Strongly activated vascular ECs release active multimeric von Willebrand factor (VWF) which promotes platelet aggregation and may cause adherence of platelets to vessel intima. Active VWF levels were higher in HELLP than in PE [58].

6.2. Thrombotic microangiopathy

Biopsies and autopsies in patients with HELLP have shown thrombotic microangiopathy [23] and [59], which is an important pathogenetic mechanism in HELLP. Infusion of TNFα in mice caused microvascular thrombosis [60]. Damage to the vascular EC by anti-angiogenic substances and exposure to TNFα combined with high levels of active VWF in HELLP may interact and cause thrombotic microangiopathy. Active VWF, the newly released, multimeric form of VWF, is depolymerized in the circulation by the metalloproteinase ADAMT13 which is decreased in HELLP [61] probably contributing to the high levels of active VWF. Hulstein et al. concluded that active vWF appears to contribute to thrombocytopenia and thrombotic microangiopathy typical for HELLP [58]. In a woman with anti-phospholipid syndrome (APLS) and HELLP, extensive microangiopathy and multiorgan failure developed, and the condition was termed catastrophic APLS [23].

6.3. Microangiopathic hemolytic anemia

Red blood cells are fragmented as they pass through vessels with damaged endothelium and fibrin strands, resulting in microangiopathic hemolytic anemia (MAHA). An abnormal blood smear with schizocytes and/or burr cells may be a transient sign [2]. The hemolysis may cause anemia and increase lactate dehydrogenase (LDH) [2]. Free hemoglobin binds to unconjugated bilirubin in the spleen, or to haptoglobin in blood plasma. Low serum haptoglobin is characteristic in HELLP [3]. Products of the intravascular hemolysis may activate coagulation and increase the risk of DIC.

6.4. Liver and kidney dysfunctions

The hepatocyte injury is caused by placenta-derived FasL (CD95L) which is toxic to human hepatocytes [48]. The content of FasL in villous trophoblast is higher in HELLP than in PE [49], and FasL concentration in maternal blood is elevated in HELLP [48]. FasL triggers the production of TNFα which may induce hepatocyte apoptosis and necrosis. Staining with TNFα and elastase antibodies in the liver was intense in HELLP [62]. Autopsies have shown hepatocyte necrosis without fatty cell transformation, surrounded by fibrin strands and hemorrhages, more rarely subcapsular bleeding and infarcts [63]. Fibrin and leukostasis were seen in sinusoids [23] probably as manifestations of thrombotic microangiopathy. Hepatocyte damage in HELLP is enhanced by the microangiopathy which impedes portal blood flow. Doppler sonography in severe PE showed significant reduction of portal blood flow and total hepatic blood flow in 9 women with severe preeclampsia who developed HELLP syndrome, but in none of the 49 women with severe PE alone [64].

Kidney dysfunction is usually moderate in HELLP and probably caused by the glomerular endotheliosis of PE [8]. In a woman with HELLP and post partum renal failure, renal biopsy revealed thrombotic microangiopathy and acute tubular necrosis [59].

6.5. Disseminated intravascular coagulation

Tissue factor (TF) is the main activator of coagulation. Fetal microparticles exert TF activity [52]. Injured vascular EC may expose TF on the surface. Activated platelets and high levels of coagulation factors enhance activation which is promoted by the thrombotic microangiopathy. Activated factors are inactivated by the coagulation inhibitors. In a group of patients with severe HELLP and MOF treated in an intensive care ward the concentrations of thrombin-inhibitor complexes were high, indicating intense activation of coagulation [65]. In patients with continued activation the inhibitors may be exhausted. Fibrin and platelet aggregates appear in the microcirculation, platelets and inhibitors are consumed, and overt or uncompensated DIC is present [66]. HELLP may coexist with placental abruption, in which blood clots and thrombin enter the maternal circulation and cause systemic defibrination.

In compensated DIC consumption is moderate, overt bleeding is rare and the condition hardly affects the prognosis [66]. Increased activation may be only partly compensated and may be associated with thrombotic microangiopathy. The clinical condition may rapidly progress to overt DIC, with bleeding from the skin and mucous membranes and often intractable multiorgan failure (MOF).

The informative laboratory tests regarding the diagnosis of DIC in general are the platelet count, D-dimer, antithrombin and protein C, thrombin–antithrombin complex (TAT) and prothrombin time [66]. Criteria for overt (uncompensated) DIC require several abnormal findings in these parameters [66]. In 128 consecutively admitted patients with HELLP and PE and 128 patients with PE only, overt DIC was rare and diagnosed in only 3 patients with HELLP and PE, and in 1 patient with PE [8]. In the group of HELLP patients with DIC and MOF treated in an intensive care ward the median antithrombin level was 60%, range 20–72%. Median TAT level was 50 μg/L, range 11–931, compared to median 2.6 and range (1.7–14.8) in healthy controls [65].

Regarding the diagnosis of compensated DIC, D-dimer is elevated in nearly all HELLP patients and in the majority of patients with severe PE. Moderately elevated D-dimer is an unspecific indicator of disease activity. In HELLP patients, the angiopathy and the liver affection may result in decreased values of platelet count, antithrombin and protein C. In a clinical study, compensated DIC was diagnosed in all 15 consecutively admitted HELLP patients, with mean values of antithrombin 66% and protein C of 57% [67]. Similar results were found in other studies. Low levels of antithrombin and protein C in such studies may reflect the combined effect of liver dysfunction, extravasation of blood plasma, and irreversible binding to activated coagulation factors in the DIC process. With high D-dimer levels, compensated DIC may well be present.

Better insight into the complex pathophysiology of HELLP patients may lead to improved clinical management [3]. The only one of the conventional laboratory tests that may specifically reflect the DIC process is the TAT assay. A value above 10 μg/L suggests presence of DIC. Regrettably, data on TAT in HELLP and DIC patients are mostly missing. We suggest that the TAT assay may be added to platelet count, D-dimer and antithrombin (or protein C) assays for monitoring HELLP patients.

6.6. Pathogenetic cascades

The pathogenesis of the maternal HELLP and PE syndromes may be perceived as cascades of reactions, as shown in Fig. 1. The suggested mechanisms shown in the figure and briefly described in the text of this review are based on statistically significant data. Some results obtained in single studies may be of limited validity and a need for further studies is evident. Although the relative importance of the substances inducing the thrombotic microangiopathy are not well known, the central role of the angiopathy in the development of the clinical HELLP seems well established. It is not only the main cause of the platelet consumption and the microangiopathic anemia, but also contributes to the liver damage. It is logical to assume that therapeutic inhibition of platelet activation, and of anticoagulation could reduce the extent of thrombotic microangiopathy. Clinical multicenter studies regarding the possible prophylactic effect of anti-platelet or anticoagulation medication in pregnant women with a high risk of HELLP seem warranted. Pregnant women with a previous HELLP pregnancy would constitute an obvious patient group that could be studied. A sufficiently large prophylactic study would need a validated selective test panel for detecting women at high risk of HELLP syndrome.

gr1

Fig. 1 Development of the maternal HELLP and preeclampsia syndromes. Bioactive substances emitted from placenta are shown in the top row of boxes (names of the substances in italics). The substances are emitted from the oxidatively stressed placenta to the maternal blood. Their concentrations gradually increase and they in the second half of pregnancy activate cascades of reactions terminating in the maternal signs and symptoms of HELLP syndrome (right side of panel) or preeclampsia (left side of panel). The scheme is focused on pathways in the HELLP syndrome. For details regarding HELLP see text in Section 6. For details regarding preeclampsia see Ref. [8]. Reactants shown in the HELLP pathways are also present at lower concentrations in preeclampsia. Abbreviations. HELLP, hemolytic anemia, elevated liver enzymes, low platelet count; NKB, neurokinin B; sFlt1, soluble fms-like tyrosine kinase; sEng, soluble endoglin; Fas L, FasLligand, also called CD95 ligand; EC, vascular endothelial cells; VWF, von Willebrand Factor; TNAα, tumor necrosis factor α; MAHA, microangiopathic hemolytic anemia.

7. Conclusion

Inadequate immune tolerance resulting in damage to the invading fetal trophoblast occurring early in the first trimester is probably the essential initial phenomenon in the pathogenesis of HELLP and PE. Messenger RNA levels in maternal blood are significantly more abnormal in HELLP than in PE, suggesting that the early trophoblast lesion is more extensive in HELLP. Gene expression in placenta is more abnormal in HELLP. The concentrations of anti-angiogenic factors in maternal blood are similar, but probably not identical, in HELLP and PE. The inflammatory response is excessive in HELLP. A combination of activated coagulation and complement, with high circulating levels of sEndoglin, sFlt1, TNFα and active von Willebrand factor may cause the thrombotic microangiopathy in HELLP. The liver damage is probably caused by circulating FasL from placenta, enhanced by the angiopathy. Compensated DIC is probably frequent in HELLP, but uncompensated DIC is rare.

Conflict of interest

None reported.

Acknowledgements

We thank Anne Cathrine Staff for constructive criticism and helpful suggestions, Nandor Gabor Than for advice and for disclosing data on PP 13 metabolism prior to their publication, and Kjell Haram who contributed to the literature search and to the text on the maternal syndrome.

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Footnotes

a Department of Haematology, Oslo University Hospital, Oslo, Norway

b Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

Corresponding author. Tel.: +47 22143730.