Haematological Disease Flashcards
What is the increase in the requirement for iron in pregnancy?
2-3x
What is the increase in requirement for folate in pregnancy?
10-20x
What is B12 deficiency caused by?
Dietary deficiency
IBD
Pernicious anaemia
- intrinsic factor antibodies, leading to B12 malabsorption
What blood test provides an accurate assessment of iron stores?
Serum ferritin
What obestetric outcomes is iron deficiency associated with?
LBW
PTB
Increased risk PPH
What does Sickle Cell Disease lead to?
- Anaemia, chronic haemolytic
- Painful vaso-occlusive crises
- Infections, partly due to loss of splenic function from auto-infarction
- Acute chest syndrome
Describe Sickle Cell Haemoglobin (HbS)
Variant of the beta-chain of haemoglobin
HbA usually made up 2 alpha and 2 beta chains - in sickle cell consists of 2 alpha and 2 HbS chains
Glutamate is replaced by valine
In low oxygen tension, the deoxygenated HbS polymerises forming fibrous precipitates causing the erythrocytes to assume a sickle shape which is inflexible and blocks small vessels leading to an occlusive crisis
What are the three main types of sickle crisis
- Vaso-occlusive symptoms and tissue infarction with severe pain
- Sequestration: splenic sequestration occurs mainly during childhood
- Aplastic: often associated with parvovirus infection
How is Sickle Cell Disease diagnosed?
Haemoglobin electrophoresis
What are the obstetric outcomes associated with Sickle Cell Disease?
Perinatal mortality 4-6x
Miscarriage
SGA
PT
PET
Placental abruption
Fetal distress
CS
What are the maternal risks in Sickle Cell Disease
VTE
Bone marrow embolism
Maternal mortality 2.5%
Infection
What is essential thrombocythaemia
Isolated thrombocytosis
Myeloproliferative disorder
May be associated with Haemorrhagic and thromboembolic manifestations
What is the DDx for Thrombocythaemia
Infection and inflammation
Post-surgical acute phase response
Reactive, following blood loss
What are the obstetric outcomes for essential thrombocythaemia
FGR
Possibly related to placental thrombosis
What is the treatment for platelet > 600, in pregnancy?
Low dose aspirin
Inhibits platelet aggregation and thrombosis
Inteferon-alpha is also used for myelosuppresion
LMWH is used in addition if there is a previous history of thrombosis
What are the causes of thrombocytopenia in pregnancy?
Spurious result
Gestational thrombocytopenia
Immune thrombocytopenic purpura
PET / HELLP
DIC
HUS / TTP
HIV
Drugs
Infections
SLE and APS
Bone marrow suppression
What is the pathogenesis of ITP?
Autoantibodies against platelet surface antigens
Peripheral platelet destruction by the reticuloendothelial system, particularly the spleen
How does ITP affect the fetus?
Antiplatelet IgG can cross the placenta
And cause fetal thrombocytopenia
The level of risk fo the fetus is small, the risks of fetal Plt count <50 is 5-10%
Accurate prediction of the fetal platelet count from the maternal platelet count / antibody level is not possible
0-1.5% risk of antenatal / neonatal intracranial haemorrhage
How often should platelets be monitored in ITP?
Monthly
More frequently in the third trimester
When is treatment required in ITP in the 1st / 2nd trimesters?
Symptomatic with bleeding
Plt < 20
The count needs to be increased prior to a procedure such as CVS
When does ITP need to be treated in the 3rd trimester?
Plt < 50
Plt 50-80 may warrant treatment to facilitate regional anaesthesia
What is the treatment for ITP?
Corticosteroids
Prednisolone
If resistant to above, IVIG
- delayed clearance of IgG coated platelets from the maternal circulation
In Rh positive women - Anti-D IgG
- creates a decoy to competitively inhibit the destruction of antibody -coated platelets
Azathioprine, Ciclosporin
Splenectomy in extreme cases (should be avoided in pregnancy if possible)
Platelet transfusion for bleeding or prior to surgery
What are obstetric causes of DIC?
Haemorrhage, particularly abruption
PET / HELLP
AFE
Infection
Retention of dead fetus
What is the pathogenesis of DIC?
Release of procoagulant substances into circulation
- thromboplastin, phospholipid
- cause stimulation of coagulation activity with increased production and breakdown of coagulation factors
Consumption of clotting factors and platelets
Stimulation of fibrinolysis. Fibrinogen degradation products interfere with the production of firm fibrin clots, exacerbating bleeding
How is DIC diagnosed?
Thrombocytopenia
Fibrinogen <2 (highly significant)
Prolongation of clotting times
Increased FDPs
Increased soluble fibrin complexes
How is DIC managed?
Treatment of underlying cause: delivery of the fetus
FFP
Red cells
Platelets
Cryoprecipitate
Recombinant fibrinogen
Recombinant factors VIIa
What is the most common inherited bleeding disorder?
Von Willebrand’s disease
Usually autosomal dominant inheritance
Incidence 1%
What is the pathogenesis of von Willebrand’s disease?
Large multivalent adhesive protein
Important roles in platelet function and stability of factor VIII
Required for the binding of platelets to the USB-endothelium after vessel injury
How is von Willebrand’s diagnosed?
Prolonged bleeding time, APTT
Reduced wWf and factor VIII
What are the obstetric risks in vWD?
Primary and secondary postpartum haemorrhage
Due to the rapid fall in vWf and factor VIII levels postnatally
Having risen in pregnancy to 3-4x their baseline
What is the management of vWD?
Desmopression (DDAVP) - some respond,some don’t
Avoidance of Aspirin and NSAIDs
FFP
Plasma-derived factors
What type of inheritance do Haemophilia A and B have?
What factors are involved in the diseases
X-linked recessive disorders
A - factor VIII deficiency
B - factor IX deficiency
What is the classic Pentad of TTP?
Microangiopathic haemolytic anaemia
Thrombocytopenia
Fever
Neurological manifestations
AKI
What is the effect of TTP/HUS on pregnancy?
The fetus is not affected
Prognosis is related to the gestational age at delivery
No evidence that delivery affects the course
This is why differentiation from HELLP is important
What is the management of TTP /HUS?
TTP requires URGENT Plasmaphoresis
FFP
Corticosteroids may be of benefit
Antiplatelet therapy, controversial
Supportive therapy for AKI (dialysis) and cerebral involvement
Platelet transfusions are contraindicated
What is the pathogenesis of TTP / HUS?
Thrombotic microangiopathy
Aggregates of platelets reversible obstruct the arterioles and capillaries
Diffuse vascular endothelial insult
Endothelial cells secrete unusually large forms of vWf. These large multiverses agglutinate platelets
What is the pathogenesis of sickle cell disease and associated complications?
• Sickle cell haemoglobin (HbS) is a variant of the beta-chain on Hb where glutamic acid is replaced by valine at the sixth position from the N-terminus.
○ In deoxygenated state, HbS has low solubility and aggregates to form liquid crystals and erythrocyte assumes sickle shape.
○ Sickling of red cells occurs in response to hypoxia, cold, acidosis and dehydration.
- Sickle cells are cleared more quickly by the reticulo-endothelial system.
- Vaso-occlusion: HbS red cells are less deformable and more fragile.
○ Increased adhesions of red cells to vascular endothelium due to increased expression of adhesion molecule expression, upregulation of thrombotic pathway and endothelial activation.
What are some clinical features associated with sickle cell disease?
- Chronic haemolytic anaemia
- Painful vaso-occlusive crises
- Acute chest syndrome: fever, tachypnoea, SOB, cough, pleuritic chest pain, pulmonary infiltrates on CXR, worsening anaemia.
- Acute stroke
- Acute anaemia (secondary to Parvovirus B19)
- Gallstones
- Retinopathy
- Avascular necrosis of bones
- Leg ulcers
- Splenic sequestration
- Pulmonary HTN
- Renal papillary necrosis
What are the maternal effects of sickle cell disease in pregnancy?
• Increased acute painful crises (27-50%)
• Increased antenatal hospitalisation
• Acute chest syndrome (7-20%)
• Spontaneous miscarriage
• Increased maternal mortality
• Delivery by Caesarean section
• Infection
• VTE
• APH
• PET
• Alloimmunisation (18-36%) from transfusions and delayed transfusions.
Acute stroke
What are the fetal effects of sickle cell disease?
• Increased perinatal mortality
• Premature labour
FGR
Outline your preconceptual care plan for a woman with sickl cell disease:
• See sickle specialist to receive information on:
○ How SCD affects pregnancy
○ How pregnancy affects SCD: increased risk of crises, acute chest syndrome (ACS) and infection (especially UTIs) during pregnancy.
○ How to improve outcomes for mother and baby:
§ Avoid dehydration, cold, hypoxia, overexertion and stress to prevent sickle cell crises.
• Assessment for chronic disease complications:
○ Screening for pulmonary HTN: ECHO if not been carried out in last year.
○ Screening for HTN and proteinuria: baseline BP and urinalysis
○ Screening for renal and liver function.
○ Retinal screening: proliferative retinopathy common especially in HbSC patients and can lead to loss of vision.
○ Screening for iron overload:
§ Ferritin level
§ T2 cardiac MRI if high ferritin level to assess body iron loading.
§ Aggressive iron chelation therapy before conception in women who are significantly iron loaded.
○ Screening for red cell antibodies: associated with risk of HDFN.
• Genetic screening of partner for haemoglobinopathies:
○ If determined to be an ‘at risk couple’ should be referred for counselling and offered prenatal diagnosis.
○ If partner status is unknown, fetus should be treated as high risk for haemoglobinopathy.
• Antibiotic prophylaxis and immunisations:
○ Penicillin prophylaxis (or erythromycin if allergic) daily as at increased risk of infection.
○ H influenza type B and conjugated meningococcal C vaccine
○ Hepatitis B immune status and vaccination if non-immune.
○ Influenza and ‘swine flu’ vaccine annually.
• Folate supplementation: 5 mg daily preconceptually and throughout pregnancy.
§ Increased risk of folate deficiency due to haemolytic anaemia.
• Review and stop medications:
○ Hydroxycarbamide (hydroxyurea): decreases incidence of acute painful crises and ACS but is teratogenic in animal studies. Should be stopped at least 3 months before conception.
§ Women who become pregnant while taking this should stop it immediately and have tertiary fetal anatomy ultrasound for structural abnormalities. Termination is not indicated based on exposure alone.
○ ACE inhibitors and ARBs: stop.
• Provide contraceptive advice: progesterone methods preferred, COCP second line.
Outline your antenatal care plan for women with sickle cell disease in addition to usual care:
• Multidisciplinary team: obstetrician and midwife with experience in high-risk antenatal care, haematologist with interest in SCD.
○ MDT reviews every 4 weeks with midwife review every intervening 2 weeks.
• Partner haemoglobinopathy testing: ideally by 10 weeks gestation to allow option of first trimester diagnosis and termination if that is the woman’s choice.
• Medications that should be given in pregnancy:
○ Stop any drugs contraindicated in pregnancy.
○ Antibiotic prophylaxis: penicillin or erythromycin daily.
○ Folic acid 5 mg daily
○ Iron supplementation: only if lab evidence of iron deficiency.
○ Low dose aspirin 75 mg daily from 12 weeks gestation: to reduce risk of PET.
○ Prophylactic clexane: whenever woman is admitted to hospital.
• BP, urine dipstick for protein every antenatal visit to screen for gestational HTN and PET:
○ Women with pre-existing proteinuria or renal impairment may need more frequent monitoring.
• Urine dipstick for infection every antenatal visit and urine M/C/S monthly
• Ultrasounds:
○ Early dating USS
○ NT USS (11-14 weeks)
○ Anatomy scan 20 weeks
○ Serial growth USS from 24 weeks gestation due to increased risk of FGR and PET.
Anaesthetic review in third trimester.
Outline your intrapartum management plan for a women with sickle cell disease:
• IOL between 38+0 to 40+0 weeks recommended if normally grown fetus.
• Mode of delivery: vaginal delivery or VBAC.
○ Caesarean section only for obstetric indications.
• Cross-match if red cell antibodies/risk of delayed transfusion.
○ If no antibodies a group and save is sufficient.
• Location of birth: hospital.
○ Obstetric team, anaesthetist and haematologist should be aware of labour admission.
○ CEFM during labour.
• Positioning in labour important for women with hip replacements secondary to avascular necrosis.
• Prevention of acute sickle cell crisis:
○ Keep warm
○ Give adequate fluid during labour
○ Monitor oxygen saturation with pulse oximetry.
• Analgesia:
○ Avoid pethidine due to risk of seizures.
○ Epidural as per normal indications.
What organ systems are affected by Thalassaema major, and how are they affected?
- Cardiac
- Iron overload
- Cardiac failure, primary cause of death in >50%
- need MRI T2 monitoring of cardiac iron overload, and Echo - Hepatic
- Iron overload
- MRI T2 monitoring of liver iron overload - Endocrine
- DM: Serum fructosamine to monitor BSLs
- Anterior pituitary: hypogonadotrophic hypogonadism, might need GnRH OI
- Hypothyroidism: assess TFTs
- Bone: osteoporosis, should have bone density scan and Vit D supplementation
What is the general management of Thalassaemia major?
Regular RBC transfusions
BUT they may cause iron overload resulting in
Cardiac, hepatic and endocrine dysfunction
Iron cheating therapy as well
Historically: splenectomy, but no longer mainstay of treatment
What is the effect of Thalssaemia on pregnancy and vice versa?
Cardiomyopathy
SGA
No chelation for 9 months
- new endocrinopathies, in particular DM, hypothyroidism, hypoparathyroidism
What are the advantages of planning a pregnancy, in a woman with Thalassaemia major?
(As opposed to unplanned)
Can organise a prolonged period of aggressive iron chelation therapy
To control iron overload
Prior to both OI and pregnancy
Reduces end-organ damage
Reverses cardiac iron loading
Can do Hep C as part of booking bloods (transfusion-related infection)
Can check for alloantibodies, risk of HDN
What are the 2 main types of thalassaemia?
Name a risk factor for each.
Alpha thalasemia - 1 to 4 alpha genes are deleted
–> more common in SE Asians
Beta thalassaemia - 1 to 2 beta genes are defective
–> more common in Cypriots and from indian subcontinents
What are the 4 phenotypes of alpha thalassaemia?
Silent carrier
- 1 a gene affected
- asymptomatic
Alpha thalassaemia trait
- 2 a gene affected
- Mild anaemia, low MCV
Haemoglobin H
- 3 alpha gene affected
- Abnormal Hb has high affinity for O2 and poor delivery to tissues
- Microcytic hypochromic anaemia
- target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear
- splenomegaly
- transfusion dependent
Haemoglobin barts
- 4 alpha gene affected
- no functioning haemoglobin, very high affinity for O2
- Hydrops fetalis
- Not compatible with life
What is the structure of haemoglobin?
What are the types of haemoglobin and their make up?
Which is most common on adults and foetuses?
Haemoglobin is made of 4 globin chains each around a central haem molecule.
Adult haemoglobin contains 3 different types:
HbA (96-98% adult Hb) - a2ß2
HbF (commonest in fetus) - a2y2
HbA2 - a2∂2
What are the 3 phenotypes of beta thalassaemia?
How do they present?
ß thalasssemia trait
- 1 defective ß gene
- mild microcytic hypochromic anaemia
ß thalassaemia major
- 2 defective ß thalassaemia genes
- Severe anaemia with multi-system disease
- Transfusion dependent
- At high risk of iron overload
- Detected within first 2 years of life: severe anaemia, poor growth, skeletal abnormalities (e.g. frontal bossing) due to increased erythropoiesis, splenomegaly
ß thalassaemia intermedia
- milder form of thalassaemia major - some functioning ß globin
What are the complications of thalassaemia major?
- hypersplenism
- hormone problems, such as delayed puberty and restricted growth
- Iron overload causing…
- cardiomyopathy – arrhythmias and heart failure, pulmonary hypertension, vascular aging
- hepatitis, fibrosis and cirrhosis
- joint pains and osteoporosis.
- With regular transfusions and iron chelation therapy - many will live into their thirties
Management of different types of a-thalassemia carrier?
- All require partner carrier screening and genetic counselling if partner is also carrier
- silent carrier
- nil
- a Thalassaemia trait
- 5mg folic acid; iron only if proven iron deficiency
- blood transfusion for anaemia if required
- HbH
- 5mg folic acid; iron only if proven iron deficiency
- blood transfusion for anaemia if required
- HbBarts
- If fetus has it, mother is at high risk of early and severe PET and PPH
Management of ß thalassaemia trait and major in pregnancy.
Trait:
- partner carrier screening and genetic counselling if pos
- 5mg folic acid
- Oral iron only if iron deficiency - avoid IV iron
- Blood transfusion if severe anaemia
Major:
- assisted conception and aggressive pre-pregnancy iron chelation programmes.
- chelating agents are contraindicated in pregnancy, thus aggressive chelation is required before pregnancy
- pregnancy often requires extra transfusions and, without chelation, the transfusions increase the chances of iron overload
- folic acid supplementation of 5 mg/day is required
- a cardiology assessment is required to look for evidence of myocardial dysfunction secondary to iron deposition
- an obstetrician and a haematologist with experience of haemoglobin disorders should manage the woman
- partners should be tested and, if relevant, there should be a discussion regarding prenatal diagnosis
- avoid iron supplementation in pregnancy and treat anaemia with transfusions
- monitor fetal growth.
- As a result of multiple transfusions, may have multiple red cell alloantibodies, thus putting the fetus at risk of HDFN (monitor in utero with middle cerebral artery Dopplers).
What is sickle cell disease?
A group of conditions including sickle cell anaemia (HbSS) and other heterozygote with sickle and another abnormal haemoglobin (HbSC (commonest), HbS/ßthalassemia, HbSD, HbSE, HbS/O-Arab).
Phenotypically similar and managed as singular entity.
What are the complications of SSD?
- painful crises including acute chest crisis
- stroke,
- pulmonary hypertension,
- renal dysfunction,
- retinal disease,
- leg ulcers,
- cholelithiasis
- avascular necrosis (which commonly affects the femoral head and may necessitate hip replacement)
Preconception counselling for SSD.
● the role of dehydration, cold, hypoxia, overexertion and stress in the frequency of sickle cell crises
● how nausea and vomiting in pregnancy can result in dehydration and the precipitation of crises
● the risk of worsening anaemia, the increased risk of crises and acute chest syndrome (ACS) and the risk of increased infection (especially urinary tract infection) during pregnancy
● the increased risk of having a growth-restricted baby, which increases the likelihood of fetal distress, induction of labour and caesarean section
● the chance of their baby being affected by SCD
Ensure taking penicillin prophylaxis as susceptible to encapsulated bacteria due to hyposplenism
check up to date with meningococcal C, HIB and pneumococcal vaccines; given flu/whooping cough vaccine in pregnancy
Take 5mg folic acid
Consider LDA from 1st trimester to reduce risk of PET
Stop hydroxycarbamide prior to conception
● an up-to-date assessment for chronic disease complications:
Screening for pulmonary hypertension with echocardiography.
● Blood pressure and urinalysis should be performed to identify women with hypertension and/or proteinuria.
● Retinal screening. Proliferative retinopathy is common in patients with SCD, especially patients
● Screening for iron overload - cardiac magnetic resonance imaging may be helpful to assess body iron loading.
Aggressive iron chelation before conception is advisable in women who are significantly iron loaded.
● Screening for red cell antibodies. Red cell antibodies may indicate an increased risk of haemolytic disease of the newborn.
What is the management of acute painful sickle cell crises in pregnancy?
- LMWH at any admission
- IV pain relief (avoid pethidine as can precipitate seizure in SCD)
- IV fluid hydration
- Keep warm
- Ensure good oxygenation (monitor O2 sats +/- ABG)
- CXR for acute chest syndrome - if suspected start Abs, blood transfusion and respiratory or O2 support)
- Consider CTPA if concern re. PE
- Exchange transfusion may be required if acute stroke or chest crisis and pt is volume replete.
