Pregnancy – induced hypertension, pre-

eclampsia and eclampsia

Introduction

The term ʻpregnancy – induced hypertensionʼ (PIH) suggests a disorder of blood pressure

that arises because of the presence of pregnancy. Such a simple view detracts from the

fundamental pathological process that underlies this condition: PIH, pre-eclampsia and its

variants are part of a multisystem disorder that can affect every organ system in the body and

collectively are the second highest cause of direct maternal deaths in the UK.

Although pre-eclampsia is associated with abnormal trophoblast invasion in the first half

of pregnancy, it is not until later in the pregnancy that the clinical syndrome of pre-eclampsia is

seen. The mechanisms by which the abnormal placentation and subsequent impaired placental

perfusion cause the widespread vascular endothelial dysfunction that characterizes pre-eclampsia

are not fully understood.

Pre-eclampsia is defined as hypertension with proteinurial. It is, however, a very

heterogeneous condition such that the timing of onset and the clinical course are unpredictable.

In some, hypertension and proteinuria are the only manifestation, while others may present with

severe renal or liver impairment, and in yet others the most prominent feature might be

intrauterine fetal growth restriction secondary to placental disease.

Eclampsia is a generalized seizure that occurs during pregnancy in association with the

features of pre-eclampsia. In a proportion of women with with eclampsia, however, the features

of pre-eclampsia are notevident at the time of the first seizure. The only cure for these conditions

is delivery.

Definitions

Hypertension in pregnancy is common and affects up to 15% of pregnant women. Hypertension

in pregnancy is calssified into three groups, depending on the timing of onset and the associated

clinical features:

Pre-existing (essential) hypertension (identifies <20 weeksʼ gestations

Pregnancy-induced hypertension (hypertension only, no proteinuria)

Pre-eclampsia (hypertension an proteinuria ± multisystem involvement).

Hypertension

In normal pregnancy the maternal blood pressure falls slightly during the first trimester,

predominantly as a consequence of reduced system vascular resistance. Maternal blood pressure

continues to fall during the second trimester and reaches a nadir at approximately 22-24 weeks’

gestation. Thereafter, maternal blood pressure steadily aincreases during the third trimester to

reach pre-pregnancy levels. Maternal blood pressure falls immediately after delivery of the baby,

but then rises and peaks on the 4th postnatal day.

Maternal blood pressure should be measured in the siting position with an appropriate-

sized cuff that is palced on the upper arm at the level of the heart (fig.34.1). Phase V Korotkoff

sounds (i.e. ‘disappearance’ rather than ‘muffling’) should be used when measuring the diastolic

blood pressure.

Hypertension in pregnancy is defined as a blood pressure of ≥ 140/90 mmHg on two

occasions more than 4 hours apart.

A diastolic blood pressure of ≥ 100 mmHg on any one occasion or a systolic blood

pressure of ≥ 160 mmHg on any one occasion is also significant hypertension.

A systolic blood pressure of 30 mmHg above the booking systolic blood pressure or a

diastolic blood pressure of 15-25 mmHg above the booking diastolic blood pressure are

alternative and widely used criteria for the diagnosis of hypertension in pregnancy.

Hypertension in pregnancy may be pre-existing or related to pregnancy (PIH or pre-eclampsia).

An increased maternal blood pressure in early pregnancy (before 20 weeks’ gestation) is usually

due to pre-existing hypertension, most commonly essential hypertension. In a young woman with

pre-existing hypertension, consideration should be given to identify the rare secondary causes of

hypertension such as renal disease, cardiac disease, phaeochromocytoma and endocrine disorders

such as Cushing’s syndrome. The diagnosis of essential hypertension may be made

retrospectively if the materbal bllodpressure has not returned to normal within 3 months of

delivery of the baby.

PIH and pre-eclampsia rarely occur before 20 weeks’ gestation unless associated with

trophoblastic disease or fetal triploidy. The hypertension associated with preeclampsia usually

resolves within 6 weeks of delivery.

Proteiunuria

Proteinuria is defined as a urinary protein concentration of more than 300 mg/I, or a urinary

protein excretion of morethan 300 mg in 24 hours. These approximate to ‘1+’ or more on urine

dipstick testing.

Fig.34.1 early detection of pre-eclampsia is important.

(A) Measurement of blood pressure (reproduced with permission).

(B) Testing for urinary protein.

Essential hypertension

Essential hypertension is more common in older women and the prognosis for pregnancy is

generally good; the main risk is from superimposed pre-eclampsia. Women with essential

hypertension are also at increased risk of placental abruption and intrauterine fetal growth

restriction. Some women taking antihypertensive drugs may be able to discontinue their

medication during pregnancy, particularly during the first and second trimesters. Drugs that are

commonly used for the treatment of essential hypertension during pregnancy include

methyldopa, labetalol and nifedipine. Diuretics and angiotension-converting enzyme (ACE)

inhibitors are contraindicated in pregnancy but may be used for the management of hypertension

during the puerperium.

Pregnancy-induced hypertension (PIH), pre-eclampsia and eclampsia

Pathophysiology

Recognized risk factors for PIH and pre-eclampsia are shown in Box 34.1

The precise aetiology and pathophysiology of PIH and pre-eclampsia remain unclear. It is

established, however, that women who develop pre-eclampsia have a genetic or phenotypic

susceptibility and that there are two distinct phases to the condition’s development: first there is

inadequate trophoblast invasion during early pregnancy, and secondly, in later pregnancy, there

is reduced placental perfusion and uteroplacental ischemia, which in turn gives rise to the clinical

syndrome.

Box 34.1

Predisposing factors for developing PIH/pre-eclampsia

First pregnancy

Family history – mother/sister

Extremes of maternal age

Obesity

Medical factors :

o Pre-exixting hypertension

o Renal disease

o Acquired thrombophilia – antiphospolipid antibodies

o Inherited thrombophilia

o Connective tissue diseases (e.g. systemic lupus erythematosus)

o Diabetes mellitus

Obstetric factors :

o Multiple pregnancy

o Previous pre-eclampsia

o Hydatidiform mole

o Triploidy

o Hydrops fetalis (immune and non0immune)

o Inter-pregnancy interval of >10 years

The precise mechanism by which this abnormal placentation causes the multisystem disorder that

characterizes pre-eclampsia is not known. It has been suggested that there is a trigger which

promotes widespread vascular endothelial dysfunction in response to the reduced placental

perfusion. This endothelial dysfunction subsequently causes metabolic changes, an exaggerated

maternal inflammatory response and reduced organ perfusion.

Maternal susceptibility

The evidence for genotypic susceptibility to developing pre-eclampsia is strong. Large

epidemiological studies demonstrate a three-to fivefold increased risk of pre-eclampsia in the

first-degree relatives of affected women. While it is possible that a single maternal gene in some

families may be important, no single gene has been identified. It may be that multiple genes

(maternal, paternal and fetal) interact, and that environmental factors may effect their expression.

Certain phenotypes are also more susceptible. Women with insulin resistance and central

obesity are at increased risk of developing pre-eclampsia, possibly on account of an exaggerated

metabolic response. Those with connective tissue disease, such as systemic lupus erythematosus,

are also at increased risk, possibly because of an exaggerated immune response. In addition,

those with an inherited thrombophilia are more likely to develop pre-eclampsia. These

associations suggest that the pathophysiology of pre-eclampsia involves a significant interaction

between metabolic, immunological and coagulation processes, possibly mediated through

vascular endothelial dysfunction and damage.

Phase 1 – abnormal placentation

In normal pregnancy, placentation occurs between 6 and 18 weeks gestation. During

normal placentation development, major structural alterations of the spiral arteries occur,

allowing an increase in blood supply to the placentation. Trophoblast invasion of the maternal

spiral arteries cause the diameter of these arteries to increase approximately five-fold, converting

a high-resistence, low-flow system to one with a low resistance and high flow. In women who

develop pre-eclampsia, adequate trophoblast invasion does not seem to occur, or the

trophoblastinvation is limited to the decidual portions of the vessels. The result is inadequate

placental perfution. This type of abnormal placentation is also associated with intrauterine fetal

growth restriction that occurs independently of pre-eclampsia.

During early pregnancy, trophoblast invasion is regulated ed at the maternal decidual

barrier by the action of the factors expressed wuthin the decidua and on the trophoblast cells.

These regulatory factors include cell adhesion molecules (CAMs) and the extracellular mattix

(ECM), proteinases and their inhibitors, growth factors and cytokines. Abnormalities in any one

of these factors may lead to invasion and subsequent pre-eclamsia.

It has been suggested that the primery factor in the aetiology of pre-eclampsia is

immunological in origin. Abnormal placentation may be the resulst of material immune rejection

of paternal antigens expressed by the fetus. HLA-G is a class 1B major histocompatibility

antigen that is expressed by extra-villous trophoblast and may protect cells from natural killer

cell lysis. Women who develop pre-eclampsia in first pregnancies and the protective effect of

pairty further support an immunological mechanism for the condition.

Phase 2 – endothelial dysfunction

The second phase of pre-eclampsia is characterized by widespread endothelial damage

and dysfunction. Women with pre-eclampsia have increased circulating levels of markers of

endothelial dysfunction. Endothelial damage promotes platelet adhesion and thrombosis, and

disturbs the normal physiological modulation of vascular tone, further amplifying the respons.

The underlying pathophysiology of this second phase of pre-eclampsia is characterized

by an exaggerated maternal systemic inflammatory response, with associated activation of

leucocytes, platelets and coagulation system. Pre-eclampsia is also associated with other markers

of inflammation. Features of oxidative stress and dyslipidemia are also evident and the overall

effect is reduced organ perfusion.

Normal pregnancy is a state of systemic inflammation. In normal pregnancy there is

leuccocytosis and an increase in leucocyte activation. Women with pre-eclampsia appear to have

an excessive inflammatory response to pregnancy. Animal models have demonstrated that the

administration of endotoxin during pregnancy can cause hypertension and proteinuria.

It has been suggested that the exaggerated maternal inflammatory response that is seen in

pre-eclampsia may lead to endothelial dysfunction and damage. Other systemic metabolic

changes that are associated with pre-eclampsia include hypertriglyceridaemia and a significant

increase in free fatty acids. This atherogenic lipid profile may also be a contributor to endothelial

dysfunction in women with pre-eclampsia.

Many of the features of the second phase pre-eclampsia are the result of reduced organ

perfusion caused by vasoconstriction, activation of the coagulation system and reduction of

plasma volume. The resulting organ damage caused by hypoperfusion gives rise to the clinical

features of pre-eclampsia, eclampsia and HELP syndrome (see later) (table 34.1).

Normal pregnancy is associated with an increase in angiotensin II levels. Angiotensin II

is a potent vasoconstrictor. However, during normal pregnancy, despite increased angiotensin II

levels, peripheral vascular resistance falls. This appears to be because normal pregnant women

are resistant to the effects of angiotensin II, a phenomen that seems to be lost in women who

develop PIH and pre-eclampsia. This suggests that abnormalities in the renin-angiotensin-

aldosterone system may play a role in the pathogenesis of the condition. Women pre-eclampsia

are also more responsive to other vasoconstrictors such as vasopressin and noradrenaline and

appear to be less responsive to vasodilators such as nitric oxide and prostacyclin (PGI2).

In pre-eclampsia, organ perfusion is further compromised by activation of the coagulation

cascade. Altered platelet function is seen in most women with pre-eclampsia. In normal

pregnancy there is increase biosynthesis of eicosanoids, particularry prostacyclin and

thromboxane A2. Prostacyclin is a vasodilator with platelet-inhibitory properties and

thromboxane A2 is a vasoconstrictor with a tendency to promote platelet aggregation.

Prostacyclin and thromboxane A2 usually increase in proportion to one another and consequently

there is a net neutralization, and homeostasis is disrupted due to a relative deficiency of

prostacyclin. This occurs either because of a reduction in prostacyclin synthesis or because of an

increased production of thromboxane A2. This imbalance leads to plateletstimulstion and also

vasoconstriction and hypertension.

In pre-eclampsia, plasma volume is reduced as a consequence of increased capillary

permeability. This further reduces organ perfusion.

Table 34.1

Potential secondary effects of the metabolic, inflammatory endothelial alterations in pre-

eclampsia

CVS Increased peripheral resistance leading to

hypertension

Increased vascular permeability and reduced

maternal plasma volume

Lungs Laryngeal and pulmonary oedema

Renal Glomerular damage leading to proteinuria,

hypoproteinaemia and reduced oncotic

pressure which futher exacerbates the

hypovolaemia.

May develop acute renal failure ± cortical

necrosis

Clotting Hypercoagulability, with increased fibrin

formation and increased fibrinolysis, i.e.

disseminated intravascular coagulation

Liver HELLP syndrome

Hepatic rupture

CNS Thrombosis and fibrinoid necrosis of the

cerebral arterioles

Eclampsia (convulsions), cerebral haemorrhage

and cerebral oedema

Fetus Impaired uteroplacental circulation, potentially

leading to FGR, hypoxaemia and intrauterine

death

CVS, cardiovascular system; CNS, central nervous system; FGR, fetal growth restriction.

Linking phase 1 and phase 2

It has been suggested that reduced placental perfusion that is a feature of the first phase of

pre-eclampsia is associated with oxidative stress. Women who develop pre-eclampsia have

reduced levels of the antioxidant ascorbic acid, as well as increased levels of markers of

oxidative stress. Furthermore, women who develop pre-eclampsia have increased cytrophoblast

levels of xanthine oxidase, a superoxide-generating enzyme. The oxidative stress that is

associated with placental hypoperfussion may lead to leucocyte activation and/or cytokinr

production and subsequently the production of free radicals. Oxidative stress may also cause

placental apoptosis and result in the shedding of placental debris into the maternal circulation.

This debris, along with the free radicals produced by osidative stress, may then lead to vascular

endothelial damage that characterizes the maternal syndrome of the second phase of pre-

eclampsia.

Fig.34.2 Uterine artery Doppler notching at 24 weeks is predictive of pre-eclampsia and

intrauterine growth restriction in high-risk mothers.

Screening and detection

Pre-eclampsia is an unpredictable condition and extremely variable in its manner of

presentation. The aim of antenatal screening is to detect pre eclampsia early enough to prevent

disease progression, and hence both maternal and fetal complications, by timely delivery of the

baby.

An important component of routine antenatal care for all pregnant women is directed

towards screening for hypertension and proteinuria. Risk factor for preeclamsia can be identified

at the booking visit. A number of additional screening tests for predicting pre eclampsia have

been proposed, but most are of limited clinical use. Abnormalities of the maternal uterine artery

Doppler waveform between 18 and 24 weeks gestation may identify a group of women at

increased risk of developing severe pre eclampsia that requires preterm delivery (<34 weeks

gestation).

Abnormalities of the maternal uterine artery Doppler waveform appear to be more significant if

they are bilateral and if they are bilateral and if they persist into the third trimester of pregnancy.

In PIH and pre eclampsia there are many non specific symptoms and signs that are

important indicators of

Box 34.2

Symptoms and signs of impending eclampsia

1. Unusual headaches, typically frontal

2. Visual disturbances (blurring of vision, diplopia, scotomas or flashes of light)

3. Restlessness or agitation

4. Epigastric pain, nausea and vomiting

5. Sudden severe hypertension and proteinuria

6. Fluid retention with reduced urine output

7. Hyperreflexia or ankle clonus

8. Retinal oedema, haemorrhages or papilloedema

Table 34.2

Investigations is PIH and pre eclampsia

Investigation Finding in pre eclampsia

FBC - Reduced platelets, reduced haemoglobin, haemolysis on blood film

Renal function -Reduced urine output

-increased urate, increased urea, increased cretinine

Coagulation system -Prolonged coagulation indices

Hepatic system -elevated alanine transaminase (ALT)

and aspartate transaminase (AST)

FBC,Full Blood Count

Widespread multisystem involvement and these symptomps may herald the onset of severe pre

eclampsia.

Clinical management of hypertension in pregnancy without proteinuria

If the maternal blood pressure is found to be elevated, measurement should be repeated after 10-

20 minutes if it settles, no further actionis needed; if still elevated, further assessment is required,

ideally at an antenatal day care unit. The woman should be asked about the symptoms of

preeclampsia (headaches, visual disturbance, epigastric pain, oedema), and the fetal size and well

being should be assessed clinically. Ultrasound can be used to assess fetal size, amniotic fluid

volume and fetal umbilical artery Doppler waveform. Serum urate (whice rises with pre

eclampsia), urea and electrolytes (U&Es), liver enzymes and platelets (which fall with pre

eclampsia) should also be checked.

In the absence of severe hypertension (160/110 or above), significant proteinuria or

symptoms of pre-eclampsia, and if the biochemistry and haematology results are normal, then

the woman can usually be managed as an outpatient. She should be seen at least twice weekly,

for blood pressure and urinalysis checks. Serum biochemistry and haematology should also be

repeated at least once a week. The women should be advised to return to hospital if she feels

unwell, or if there is any headache, visual disturbance or epigastric pain.

Treatment of the mother with antihypertensive drugs controls the hypertension but does

not alter the course of pre-eclampsia. Treatment of hypertension may allow prolongation of the

pregnancy and thereby may indirectly improve fetak outcome. Antilhypertensive treatment is

appropriate with consistent recordings of 150/100 or greater.

The only true ‘cure’ for pre-eclampsia is delivery of the fetus and placenta, but the timing

of this will significantly influence the outcome for both the mother and the baby.

Clinical management of pre-eclampsia

In a womwn with pre-eclampsia, it is important to consider the overall picture rather than make

decisions on the basis of a single parameter. Progression of the diseases is not consistent and

further management should be tailored to the individual women.

Indications for admission to hospital include :

Blood pressure >170/110 mmhg or >140/90 with 2+ proteinuria

Significant symptoms (headaches, visual distrurbance, epigastric pain, oedema)

Abnormal biochemistery or heamatology results

Significant proteinuria

The need for antihypertensive treatment

Signs of fetal compromise.

The aim should be to prolong the pregnancy in order to reduce the risk to the baby, but this must

be balanced against the risks to the mother. The decision to deliver and the method of delivery

are dependent on many factors. There are usually fetal advantages to conservative management

before 34 weeks if the blood pressure, laboratory values and fetal condition are stable.

The principles of management of pre-eclampsia are :

To control the maternal blood pressure. Reduce the diastolic blood pressure to <100

mmHg using labetalol, nifedipine, hydralazine or methyldopa (table 34.3)

To assess maternal fluid balance. Pre-eclampsia isassociated with an increased vascular

permeability and a reduced intravascular compartment. In women with pre-eclampsia,

administering too little fluid risks maternal renal failure and giving too much fluid

maycause pulmonary oedema. Fluid input and urine aoutput should therefore be

monitored. In severe pre-eclampsia the maternal oxygen saturation (SaO2) should also be

monitored, along with serum U&Es, urate, LFTs, haemoglobin, haematocrit, platelets and

coagulation. If there is marked oliguria, central venous pressure monitoring may be

helpful to differentiate intravascular volume depletion from renal impairment.

To prevent seizures (eclampsia). The use of magnesium sulphate in severe pre-eclampsia

halves the risk of subsequent aclampsia, and may reduce the risk of maternal death.

Magnesium sulphate, given to those who have had an eclamptic seizure, also prevents

further seizures.

To consider delivery. The timing of this depends on the maternal condition, the fetal

condition and the gestational age. If preterm delivery is being considered, corticosteroids

should be administered to the mother toreduce the risks associated with prematurity (fig.

34.3).

Management of eclampsia

Eclampsia occurs when there is a tonic-clonic convulsionin association with the features of pre-

eclampsia (the word ‘eclampsia’ means ‘lightning’). In the UK, the incidence of eclampsia is

4.9/10,000 maternities, with 38% of eclamptic seizures occurring anterpartum, 18 % intrapartum

and 44% postpartum. Over a third of eclamptic seizures occur before proteinuria and

hypertension have been documented. In the UK, the maternal mortality associated with

eclampsia is 1.8%. with a neonatal death rate of 34/1000. In lessdeveloped countries, incidences

of up to 80/10,000 maternities have been reported, with maternal death occurring in

approximately 10% of cases.

The treatment of eclampsia is outlined in Box 34,3.

Fig.34.3 This baby, born at weeks to a mother with severe pre-eclampsia, weighed 1.6 kg.

(Usual weight at 36 weeks: 2.2-3.3 kg.)

Table 34.3

Drug treatment of hypertension in pregnancy

Drug Action Side-effects comments

Methyldopa (oral) Central acting Initial drowsiness Safe;oral drug of

choice.slow onset of

action.not suitable if

history of depression

Labetalol Alpha- and beta-

antagonist

Postural

hypotension,tiredness

Widely used in

antenatal setting(oral)

and hypertensive

crisis (i.v)

Hydralazine (oral/i.v.) Direct- acting

vasodilator

Parcipitate

hypotension

Widely used in

hypertensive crisis

(i.v)

Nifedipine (orally/s, Calcoium-chanel

antagonist

Flushing, headaches Caution – interacts

with mgSO4. Watch

for precipitous fall in

blood pressure

Prevention

Various preventive stratergie have been employed in women considered to be at risk of

developing pre-eclampsia. The estimated value of these intervention is shown in box 34.4

Box 34.3

Treatment of eclampsia

The patient should be turned onto her left side to avoid aortocaval compression. The

airway should be secured and high-low oxtgen be administered.

Magnesium sulphate (MgSO4) should be administered intravenously to terminate the

seizure and then by intravenous infusion to reduce the chance of further convulsions. The

infusion should be continued for at least 24 hours following delivery or after the last

seizure. MgSO4 can depress neuromuscular transmission and the patient should be

monitored for sign of toxicity. The respiratory rate and patellar reflexes should be

monitored ( reduced patellar reflexes usually precede respiratory depression). If there is

significant respiratory depression, calcium glukonate can be used to reverse the effect of

MgSO4 and consideration given to ventilation.

Urgent delivery is necessary if the seizure has occurred antenatally or intrapartum.

Paralysis and ventilation should be considered if the seizure are prolonged or recurrent.

Box 34.4

Prevention of Pre- eclampsia

Possibly of value

Low-dose aspirin

Calcium supplementation

Not of value

Diet with high protein content

Restriction of salt in diet

Restriction of weight gain

Vitamins C and E

Aspirint inhibits prostaglandin synthesis via cyclooxygenase and the dose of aspirin

required to inhibit thromboxane synthesis is less than that required for prostacyclin inhibition.

Low-dose aspirin should reduce that vasculan and prothrombotic effects of thromboxane A2 in

woman at risk of developing pre-eclampsia. Taking 75% aspirin daily from the firts tremester of

pregnancy leads to a 15% reduction in the incidence of pre-eclamsia. It should be offered to

those woman at high risk of developing pre-eclampsia and should be commenced on or before 12

week gestation.

Calsium supplementation (<1g/day) may olso reduce that risk of hypertension by up to

30% and may reduce the risk of pre-eclampsia by up to 50%. Although calsium supplementation

my reduce the rate of maternal mortality by up to 20%, it has no significant effect on preterm

birth or stillbirth.

The use of antioxidants such as vitamin C and e is not useful for the preventation of pre-

eclampsia. Likewise, restriction of salt intake and limiting weight gain during pregnancy are not

useful in this regard.

HELLP syndrome

Help is the acronym for hemolysis, elevated liver enzymes (particularly transaminases)

and effects up to 12% of those with pre-eclampsia/eclampsia. HELLP syndrome is more

common in multiparous women experiencing pre-eclampsia. Women HELLP syndrome may

present with epigasrtic pain, nausea and vomiting, and right upper quadrant tenderness may be

evident on examination. Aspartate transminase (AST) rises firtst, followed by a rise in lactate

dehydrogenase (LDH). A blood film may show burr cells and polychromasia consistent with

haemolysis, although frank anaemia is uncommon. Platelet tranfusion is only rarely required.

HELLP syndrome is olso associated with acute renal failure and disseminated intravaskular

coagulation (DIC), and there is olso an increased incidence of placental abruption.

The managment of HALLP syndrome is to stabilize the mother, correct any coagulation

disorder, assess fetal well-being and assess the need of delivery. It is generally considered that

delivery is appropriate for moderate or severe cases, but managment my be more concervative

(with close monitoring) if the condition is mild. Vigilance is required for at least 48 hours

postpartum as deterioration in the maternal condition may accur. The risk of recurrence of

HELLP syndrome in subsequent pregnancies is approximately 20%.

Key point

Pre-eclampsia is a multisystem disorder, and is a major cause of maternal and perinatal

morbidity and mortality.

There are two phases; phase 1 is associated with abnormal placentation ang pahe 2 is

characterized by an exaggerated maternal inflammatory response, endothelial dysfuntion

and reduse organ perfusion.

The cure for pre-eclampsia is delivery of the fetus. Antihypertensive therapy does not

fundamentally alter the progress of the condition.

HELLP syndrome is a variant of pre-eclampsia; HELLP is an acronym for haemolysis,

elevated liver enzymes and low platelets.