Haematology - Pre-eclampsia and HELLP

Pre-eclampsia is relatively common but can become life-threatening, says Professor David Roberts.

HELLP: severe haemolysis with irregular, damaged red blood cells (Photograph: D Roberts and J Burthem)
HELLP: severe haemolysis with irregular, damaged red blood cells (Photograph: D Roberts and J Burthem)

Thrombocytopenia accompanies several medical syndromes that can complicate pregnancy. These include pre-eclampsia and severe pre-eclampsia including haemolysis with elevated liver enzymes and low platelets (HELLP syndrome).

This review will focus on the haematological aspects of pre-eclampsia and HELLP, and the diagnosis and management of HELLP.

Although these serious conditions are the focus of this article, most isolated cases of thrombocytopenia in pregnancy are due to gestational thrombocytopenia, where the platelet count falls to 7-150 x 109/L, often late in the second or in the third trimester.

This condition is common, affecting 15% of women, and benign, with no adverse outcomes for mother or baby. Immune thrombocytopenic purpura accounts for approximately 5% of cases of thrombocytopenia in pregnancy and may present for the first time or recur in pregnancy and may require specific treatment if the platelet count is 50x109/L and the fetus or neonate may have thrombocytopenia.

Pre-eclampsia
Pre-eclampsia is a relatively common condition but may become life-threatening for the mother and the fetus. It is characterised by maternal hypertension, proteinuria, oedema, fetal intrauterine growth retardation and premature birth.

The classification and description of more severe forms of pre-eclampsia are complicated by poor understanding of the underlying mechanisms of disease, but it is known that patients with pre-eclampsia can develop haemolysis and HELLP (3% of cases), disseminated intravascular coagulation (3%), renal failure (4%) and adult respiratory distress syndrome (3 per cent).

Pre-eclampsia can progress to eclampsia with epileptic fits and sometimes other neurological symptoms, including focal motor deficits, cortical blindness and occasionally cerebral haemorrhage.

In severe pre-eclampsia, the fetus and/or newborn may have neurological damage induced by hypoxia. Prompt recognition of pre-eclampsia and signs of clinical deterioration, including a decline in platelet count, allied with swift and precise management, are therefore essential to avoid the serious clinical consequences of these conditions.


Pre-eclampsia affects 15% of women and is more commonly seen in those who have a history of chronic hypertension (Photograph: SPL)

Pathogenesis
The central mechanism that causes pre-eclampsia is not understood, but the pathological pathways leading to severe disease can be explained.

Pre-eclampsia is marked by placental insufficiency and low levels of vascular growth factor ligands, including vascular endothelial growth factor (VEGF), placental growth factor and VEGF receptor-1, are found in patients with HELLP.

Abnormal development of placental blood vessels leads to the release of microparticles, cytokines and signalling molecules including endothelin, prostaglandins (thromboxane A2) and serotonin, which appear to promote hypertension and activate the clotting cascade.

The haematological abnormalities include reduced platelet production and lifespan, and reduced antithrombin, leading to activation of the clotting cascade and the fibrinolytic system, which leads to low platelet counts, fibrin deposition and increased fibrin degradation products. As the disease progresses, small fibrin strands cause microangiopathic haemolytic anaemia.

Presentation
Pre-eclampsia occurs in approximately 5% of primigravidae and less commonly recurs in a subsequent pregnancy or appears in multigravidae with no previous history of the disease.

The condition is more common with a family history of pre-eclampsia, chronic hypertension, obesity or twin pregnancy. HELLP is a serious form of pre-eclampsia and patients may present at any time in the last half of pregnancy. One-third of women with HELLP present shortly after delivery.

Initially, women may report non-specific symptoms including malaise, fatigue, right upper quadrant or epigastric pain, nausea, vomiting, or flu-like symptoms. On examination, oedema, hypertension and proteinuria are found and sometimes, tenderness over the liver. These symptoms of HELLP are relatively non-specific and a high index of clinical suspicion, prompting further investigation, may avoid diagnostic delay.

Features of severe pre-eclampsia
  • New hypertension
  • New and/or significant proteinuria
  • Other clinical features of severe pre-eclampsia include:
  • Severe headache, usually frontal
  • Liver tenderness
  • Visual disturbance
  • Platelet count falling to below 100x109/L
  • Epigastric pain and/or vomiting
  • Abnormal liver enzymes (ALT or AST rising to >70IU/L)
  • Clonus
  • HELLP syndrome: haemolysis, elevated liver enzymes, low platelets
  • Papilloedema
  • Fetal distress - reduced fetal movements
  • Small for gestational age infant

Diagnosis
Pre-eclampsia is diagnosed by hypertension and protein-uria, but a falling platelet count predicts severe disease and demands urgent referral and further investigation.

In severe pre-eclampsia, the platelet count falls to less than 100x109/L and may, at this level, be associated with abnormal clotting results. Lower platelets are associated with poorer outcomes and may themselves pose a risk to the mother.

Diagnosis of HELLP relies on recognising haemolysis with fragmented red cells on the blood film and a raised LDH >600IU/L with a raised bilirubin. Liver enzymes are raised with an AST or ALT level of >70IU/L; levels of >150IU/L are associated with increased maternal morbidity and mortality.

Management
Discussion with the patient about management should take into account the stage of pregnancy, and maternal and fetal health.

Guidelines for monitoring disease progression and the welfare of the mother and the fetus are well defined in pre-eclampsia, and a platelet count falling to <100 x 109/L is a consideration for delivery.

Definitive treatment of severe pre-eclampsia and HELLP requires delivery of the fetus and is advised after 34 weeks' gestation if multisystem disease is present.

Patients can be managed conservatively if they are less than 34 weeks, haemodynamically stable, without coagulation abnormalities and in the absence of HELLP.

Here, dexamethasone can reduce the risk of respiratory distress in the newborn and reduce liver enzymes and possibly the risk of adult respiratory distress syndrome in the mother.

Treatment for severe pre-eclampsia includes magnesium sulphate to prevent seizures, labetalol or hydralazine to control hypertension and careful monitoring of maternal fluid balance and fetal well-being.

Increased right upper quadrant pain might suggest liver pathology, clinical deterioration and prompt delivery by caesarean section. For other cases of severe pre-eclampsia, vaginal delivery may be attempted if a multigravid woman is clinically stable; otherwise, caesarean section would be the usual choice.

Transfusion of red cells, platelets, fresh frozen plasma and cryoprecipitate or fibrinogen concentrate are required as indicated clinically and by blood and coagulation tests. Postpartum HELLP has been treated with steroids and plasma exchange.

Continuing care
Approximately 30% of cases of HELLP and 45% of cases of eclampsia occur after delivery, most by four days postpartum but exceptionally, up to four weeks later. All patients need careful follow-up and a formal postnatal review to establish chronic hypertension, proteinuria or liver damage.

Severe pre-eclampsia threatens the wellbeing of mother and child. Discussion should also review events that occurred during pregnancy. Preconception counselling should be offered because severe pre-eclampsia can recur and preventive strategies are limited.

  • Professor Roberts is a consultant haematologist at NHS Blood and Transplant, and University of Oxford

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