BMJ 2016;353:i3035 doi: 10.1136/bmj.i3035 (Published 3 June 2016)
Page 1 of 4
Endgames
ENDGAMES
CASE REVIEW
A pregnant woman with anaemia and thrombocytopenia
12
Muhajir Mohamed consultant haematologist and associate professor in medicine , Arsalan Mahmud
3
basic trainee medical registrar
Department of Medicine, Launceston General Hospital, Launceston, Tasmania 7250, Australia; 2University of Tasmania, Launceston Clinical School,
Launceston, Australia; 3Department of Medicine, Launceston General Hospital
1
A 28 year old woman who was 31 weeks pregnant attended the
emergency department of our hospital with acute onset of
abdominal pain in her right upper quadrant. She had undergone
regular antenatal check-ups in the midwifery clinic, with no
problems reported. She had no medical history of note and was
not taking any drugs. She was a non-smoker and before she was
pregnant she rarely drank alcohol. Her cardiovascular,
respiratory, and neurological examinations were unremarkable
and she had no peripheral oedema. The fetal heart sounds were
normal. Her blood pressure was high (136/104 mm Hg) and her
pulse was 88 beats/min. The urine protein to creatinine ratio
showed no evidence of proteinuria.
A full blood screen showed a low platelet count (25×109/L;
reference range 150-400), high neutrophil count (14×109/L;
2.0-8.0), low haemoglobin (94 g/L; 130-170), and raised
absolute reticulocyte count (204×109/L; 50-100). Red blood
cells with morphological abnormalities were seen on the blood
film (fig 1). Liver function tests showed moderately raised
alanine transferase (356 U/L; 0-33) and aspartate transferase
(304 U/L; 0-32), mildly deranged alkaline phosphatase and
γ-glutamyl transferase values, and normal bilirubin levels. Serum
lactate dehydrogenase (LDH) was high (951 U/L; 125-243) and
serum haptoglobin was undetectable. A direct antiglobulin test
was negative. Coagulation parameters—prothrombin time,
activated partial thromboplastin time, and fibrinogen
concentration—were within normal limits and D-dimer was
raised. Blood glucose, serum creatinine, iron studies, vitamin
B12, and folate values were within the normal ranges.
Questions
1.What does the blood film show?
2.What is the most likely diagnosis?
3.What are the differential diagnoses in this patient?
4.How do you diagnose this condition?
5.How should the patient be managed and what is the
prognosis?
Answers
1.
What does the blood film show?
Short answer
Polychromasia, fragmented red blood cells (schistocytes), and
thrombocytopenia. These features are suggestive of
microangiopathic haemolytic anaemia.
Correspondence to: M Mohamed [email protected]
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BMJ 2016;353:i3035 doi: 10.1136/bmj.i3035 (Published 3 June 2016)
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ENDGAMES
Discussion
Light microscopic examination of a peripheral blood film stained
by standard procedures shows polychromasia and fragmented
red blood cells or schistocytes. Polychromasia in the blood film
appearing as bluish grey shades in the red blood cells is an
indicator of reticulocytosis, which occurs in active haemolysis
or infiltration of the bone marrow.
Red cell fragmentation is caused by extrinsic mechanical damage
to red blood cells within the circulation. Schistocytes are smaller
than normal red blood cells and assume different shapes, such
as crescents, helmets, or fragments with sharp angles and straight
borders. Microangiopathic haemolytic anaemia can be diagnosed
when schistocytes make up more than 1% of the red blood cells
in the blood film.1
Microangiopathic haemolytic anaemia is characterised by
endothelial injury and activation of the clotting mechanism
within the microvasculature, which leads to haemolysis,
thrombocytopenia, and end organ injury.
2.
What is the most likely diagnosis?
Short answer
HELLP (Haemolysis, Elevated Liver enzymes, and Low Platelet
count) syndrome.
Discussion
HELLP is the acronym for a syndrome associated with severe
pre-eclampsia characterised by microangiopathic Haemolytic
anaemia, Elevated Liver enzymes, and Low Platelets. It occurs
in about 1% of pregnancies2 and in 10-20% of women with
severe pre-eclampsia or eclampsia.3 The causes of pre-eclampsia
and HELLP syndrome are not clear. Increased resistance to
placental blood flow and systemic hypertension caused by
abnormal placental function have been suggested.4
HELLP syndrome typically develops in the third trimester and
sometimes in the second trimester or during the postpartum
period. A prospective cohort study on 442 pregnancies with
HELLP syndrome found that 70% of women developed HELLP
before delivery and 30% developed it after birth. Common
symptoms include pain and tenderness in the upper abdomen,
nausea, and vomiting. Headache, visual changes, jaundice, and
ascites are less common manifestations. Hypertension, with
blood pressure more than 140/90 mm Hg, and proteinuria occur
in about 85% of cases.5 Hypertension and proteinuria are signs
of pre-eclampsia that can be detected early by midwives or
general practitioners during antenatal examinations, and patients
should be referred to obstetrics for further management.
3.
What are the differential diagnoses in this
patient?
Short answer
Other conditions that cause thrombocytopenia, microangiopathic
haemolysis, and acute liver impairment during pregnancy.
Discussion
The causes of thrombocytopenia during pregnancy include
gestational thrombocytopenia, immune thrombocytopenia
purpura, thrombotic microangiopathies, disseminated
intravascular coagulation, connective tissue disorders, drugs,
and infections.
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Gestational thrombocytopenia is the most common cause
(70-80%). It is characterised by thrombocytopenia in the second
to third trimester, with platelet counts generally >70×109/L;
haemodilution and accelerated clearance are possible
mechanisms. No intervention is needed and the condition
typically resolves within six weeks of delivery.6
Immune thrombocytopenia purpura (ITP) occurs in one to two
of 1000 pregnant women, and onset can occur during any
trimester.7 Most patients have a history of ITP, although in a
small proportion the first episode occurs during pregnancy. The
condition is typically associated with petechiae, ecchymoses,
or other bleeding manifestations.6
Disseminated intravascular coagulation (DIC) has been
associated with complications of pregnancy such as placental
abruption, severe pre-eclampsia or eclampsia, retained stillbirth,
septic abortion, uterine rupture, and amniotic fluid embolism.
Severe DIC is characterised by coagulopathy and microthrombi
in small blood vessels, which lead to diffuse multiorgan bleeding
and haemorrhagic necrosis.8
Thrombotic microangiopathies such as thrombotic
thrombocytopenia purpura (TTP) and atypical haemolytic
uraemic syndrome (HUS) are associated with microangiopathic
haemolytic anaemia and thrombocytopenia. Pregnancy is a
precipitating factor for TTP in 5-25% of patients with TTP.9
TTP is caused by deficiency of ADAMTS13, a metalloprotease
enzyme that cleaves von Willebrand factor, as a result of
autoantibodies or congenital deficiency. Onset can occur during
any trimester but is most common during the third trimester or
post partum. Atypical haemolytic uraemic syndrome is caused
by complement dysregulation and rarely occurs during
pregnancy. The presenting features of TTP and atypical HUS
are generally similar to those seen with HELLP, although liver
function tests and blood pressure are usually normal.
Acute liver impairment during pregnancy can also occur in
women with acute fatty liver of pregnancy (AFLP), hepatitis,
gallbladder disease, and non-alcoholic fatty liver disease. AFLP
occurs usually in the third trimester and is seen in <1/20 000
pregnancies; it is characterised by raised liver enzymes, with
thrombocytopenia occurring in less than half of cases. AFLP is
differentiated from HELLP by the presence of severe
hypoglycaemia and coagulopathy.10
4.
How do you diagnose this condition?
Short answer
By the presence of microangiopathic haemolytic anaemia,
abnormal liver enzymes, and thrombocytopenia in a pregnant
woman with severe pre-eclampsia.
Discussion
HELLP syndrome is associated with severe pre-eclampsia and
is diagnosed by the presence of microangiopathic haemolytic
anaemia, abnormal liver enzymes, and thrombocytopenia.
Laboratory tests should include a complete blood count,
peripheral blood smear, and reticulocyte count; liver function
tests; LDH, haptoglobin, and serum creatinine concentrations;
and urine protein to creatinine ratio.
The laboratory diagnostic criteria for HELLP syndrome
proposed by Sibai5 and used in clinical practice comprise:
• Intravascular haemolysis with features of microangiopathic
haemolytic anaemia in the peripheral blood smear
• Increased serum bilirubin (≥20.5 μmol/L or ≥1.2 mg/dL)
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BMJ 2016;353:i3035 doi: 10.1136/bmj.i3035 (Published 3 June 2016)
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ENDGAMES
• Aspartate aminotransferase ≥70 U/L
• Raised LDH (>600 U/L).
A blood film should be examined in pregnant women with
thrombocytopenia. This will help to detect morphological
abnormalities, such as red cell fragments or blasts, and exclude
platelet clumps, which are a cause for spurious
thrombocytopenia.
Because HELLP syndrome is associated with severe
pre-eclampsia,11 GPs and midwives should be aware that the
following abnormalities in pregnancy are red flags for HELLP
syndrome:
• Blood pressure ≥160/110 mm Hg
• Platelet count <100×109/L
• Impaired liver function or severe abdominal pain in the
right upper quadrant
• Creatinine >97.24 μmol/L or >1.1 mg/dL
• Pulmonary oedema
• Cerebral or visual disturbances.
It is also important to exclude other causes of thrombocytopenia
associated with pregnancy, so tests for DIC, TTP, HUS,
connective tissue disorders, and infections should be performed.
These include coagulation assays (prothrombin time, activated
partial thromboplastin time, fibrinogen) and D-dimer
concentrations; autoimmune screen (antinuclear antibodies,
rheumatoid factor, antiphospholipid antibodies, complement
assays); direct antiglobulin test; and serological tests for HIV,
hepatitis C, and hepatitis B infections. In patients with diarrhoea,
stools should be tested for Escherichia coli that produce the
shiga toxin.12 ADAMTS13 assays may be needed to exclude
TTP. ADAMTS13 activity of less than 10% (reference range
≥50%), with or without the presence of IgG anti-ADAMTS13
autoantibodies, supports the diagnosis of TTP.13
5.
How should the patient be managed and what
is the prognosis?
Short answer
Delivery usually cures HELLP syndrome. Management includes
stabilising the mother, assessing fetal wellbeing, and deciding
the timing of delivery.
Discussion
Because delivery of the baby generally cures HELLP syndrome,
initial management involves systematically assessing the patient
and the fetus and deciding on the timing of delivery. On the
basis of guidelines from American College of Obstetricians and
Gynecologists’ task force on hypertension in pregnancy, for
pregnancies more than 34 weeks’ gestation the potential risks
of premature birth are outweighed by the risks associated with
HELLP syndrome so immediate delivery is recommended.
However, for pregnancies less than 34 weeks’ gestation, the
risks of premature delivery should be weighed against the
complications of HELLP syndrome in the mother and baby.
Hence, watchful waiting and conservative management are
recommended for pregnancies of less than 34 weeks’ gestation.
In such situations the patient should be admitted to a tertiary
care facility with a neonatal intensive care unit. If the maternal
or fetal condition worsens, immediate delivery should be
planned and corticosteroids administered before delivery to
promote fetal lung maturity. If the patient’s condition remains
stable, clinical observation and close monitoring of blood
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parameters should be performed in the tertiary care unit until
34 weeks’ gestation when delivery should be planned.11
Intensive clinical monitoring and laboratory testing should be
performed for 48-72 hours post partum because platelet counts
and other parameters may worsen soon after delivery.3
Platelet transfusion is indicated in patients with
thrombocytopenia and active bleeding to prevent excessive
bleeding during caesarean delivery if the platelet count is
<50×109/L.14
The outcome for mothers with HELLP is generally good.12 The
average time for the platelets to increase to >100×109/L is 72
hours after delivery, but LDH values are slower to recover than
platelet counts.15 A prospective cohort study found that maternal
mortality was 1% and the serious complications were DIC
(21%), placental abruption (16%), acute renal failure (8%),
pulmonary oedema (6%), and subcapsular liver haematoma
(1%).5 Fetal and neonatal prognosis is mainly related to
gestational age at delivery and birth weight. Prematurity and
intrauterine growth retardation are the most common
complications (70%) and perinatal mortality is about 20%.14
Patient outcome
After she was reviewed by the obstetric team in the emergency
department, our patient was started on antihypertensive drugs
and magnesium sulphate. Because of the imminent risk of
maternal and fetal complications secondary to HELLP
syndrome, emergency caesarean section was performed. After
delivery her blood pressure normalised within six hours and her
platelet count recovered after three days; however, LDH and
liver enzymes did not return to normal until 12 days later. Soon
after delivery her preterm baby was managed in the nursery for
feeding difficulty and was discharged home after three weeks.
Competing interests: We have read and understood BMJ policy on
declaration of interests and declare the following interests: None.
Provenance and peer review: Not commissioned; externally peer
reviewed.
Patient consent obtained.
1
2
3
4
5
6
7
8
9
10
11
12
Zini G, d’Onofrio G, Briggs C, et al. International Council for Standardization in
Haematology (ICSH). ICSH recommendations for identification, diagnostic value, and
quantitation of schistocytes. Int J Lab Hematol 2012;34:107-16. doi:10.1111/j.1751-553X.
2011.01380.x pmid:22081912.
Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and severe obstetric morbidity
in the United States. Obstet Gynecol 2009;113:1299-306. doi:10.1097/AOG.
0b013e3181a45b25 pmid:19461426.
Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and
management. A review. BMC Pregnancy Childbirth 2009;9:8. doi:10.1186/1471-2393-98 pmid:19245695.
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet
2010;376:631-44. doi:10.1016/S0140-6736(10)60279-6 pmid:20598363.
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;169:1000-6. doi:10.1016/0002-9378(93)
90043-I pmid:8238109.
Gernsheimer T, James AH, Stasi R. How I treat thrombocytopenia in pregnancy. Blood
2013;121:38-47. doi:10.1182/blood-2012-08-448944 pmid:23149846.
Provan D, Newland A. Idiopathic thrombocytopenic purpura in adults. J Pediatr Hematol
Oncol 2003;25(Suppl 1):S34-8. doi:10.1097/00043426-200312001-00008 pmid:14668637.
Erez O, Mastrolia SA, Thachil J. Disseminated intravascular coagulation in pregnancy:
insights in pathophysiology, diagnosis and management. Am J Obstet Gynecol
2015;213:452-63. doi:10.1016/j.ajog.2015.03.054 pmid:25840271.
Vesely SK, Li X, McMinn JR, Terrell DR, George JN. Pregnancy outcomes after recovery
from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Transfusion
2004;44:1149-58. doi:10.1111/j.1537-2995.2004.03422.x pmid:15265118.
Knight M, Nelson-Piercy C, Kurinczuk JJ, Spark P, Brocklehurst P. UK Obstetric
Surveillance System. A prospective national study of acute fatty liver of pregnancy in the
UK. Gut 2008;57:951-6. doi:10.1136/gut.2008.148676 pmid:18332072.
American College of Obstetricians and Gynecologists Task Force on Hypertension in
Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians
and Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol
2013;122:1122-31.pmid:24150027.
George JN, Nester CM, McIntosh JJ. Syndromes of thrombotic microangiopathy associated
with pregnancy. Hematology Am Soc Hematol Educ Program 2015;2015:644-8.pmid:
26637783.
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BMJ 2016;353:i3035 doi: 10.1136/bmj.i3035 (Published 3 June 2016)
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ENDGAMES
13
14
Peyvandi F, Ferrari S, Lavoretano S, Canciani MT, Mannucci PM. von Willebrand factor
cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100
patients with thrombotic thrombocytopenic purpura. Br J Haematol 2004;127:433-9. doi:
10.1111/j.1365-2141.2004.05217.x pmid:15521921.
Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis,
elevated liver enzymes, and low platelet count. Obstet Gynecol 2004;103:981-91. doi:10.
1097/01.AOG.0000126245.35811.2a pmid:15121574.
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15
Martin JN Jr, , Blake PG, Perry KG Jr, , McCaul JF, Hess LW, Martin RW. The natural
history of HELLP syndrome: patterns of disease progression and regression. Am J Obstet
Gynecol 1991;164:1500-9, discussion 1509-13. doi:10.1016/0002-9378(91)91429-Z pmid:
2048596.
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