Haematology Flashcards
Pathophysiology of alloimmune disorders of pregnancy
RBC carry many antigens on surface
- different types
Sensitising event (e.g. blood transfusion, materno-feto haemorrhage) –> formation of antibodies against foreign antigen
Next pregnancy, maternal antibodies pre-formed, therefore can attack fetal RBCs if they have the relevant antigen.
This causes haemolytic anaemia, hypoxia , high output cardiac failure and hydrops
In the neonate, hyperbilirubinaemia from breakdown of RBCs –> jaundice –> kernicterus (deposition of bilirubin in basal ganglia)
Main antibodies implicated in HDFN
- titres for referral to MFM
D - titre 16 or more
c - titre of 16 or more (anti-c and anti-E combination increases risk of fetal anaemia, therefore at lower titres)
K (part of Kell group) - once detected
All others 32
Antenatal management of positive antibodies
Antibody identification and titre
Paternity screening - If the father is antigen negative and paternity guaranteed, then no further evaluation is required
Fetal genotyping - cfDNA
- from 16/40, 20/40 for Kell
Monitoring - titres every 4 weeks until 28/40, then every 2 weeks until delivery
Fetal monitoring - MCA PSV every 1-2 weeks if critical titre
Anti-Kell antibodies
Most antigenic of the Kell group is K
- Present in ~9% of Caucasian blood donors
Blood transfusion = most common mechanism of K sensitisation
Additional (and thought to be predominant) mechanism for fetal anaemia with anti-KEL: erythrocyte production is suppressed at the level of the progenitor cell
Women with anti-K can be difficult to manage, as levels of the antibody do not correlate as well with the severity of the disease as with anti-D
Refer once detected, as severe fetal anaemia can occur even with low titres
Hyperbilirubinaemia is not a prominent feature
Signs of fetal anaemia and treatment
Overall perinatal survival in pregnancies complicated by red cell antibodies causing fetal anaemia is 84% - (non-hydropic fetuses better survival than hydropic fetuses (94% vs. 74%))
Signs:
- MCA PSV >1.5 MoM
- Hydrops - ascites, pleural effusion, pericardial effusion, polyhydramnios, cardiomegaly
Fetal blood sampling by cordocentesis
- Risk of miscarriage of 1-3%
- Therefore do at same time as intrauterine blood transfusion
IUT - give if <35/40, otherwise deliver
- Irradiated for CMV, K negative, negative for antigens corresponding to maternal red cell antibodies, <5 days old
- transfuse every 14 days until 35/40, then deliver
- Complication rate 3% - PPROM, infection, em CS, fetal death (1.5%)
Deliver at 37-38 weeks if not required transfusion
Tests and management of newborn with HDFN
- If mother has a clinically significant blood group antibody, send cord blood samples for FBC, bilirubin, ABO, D and any other relevant blood group tests and DAT
- DAT = direct antiglobulin test - Detects antibodies on red cells
- Cross-match red cells for neonatal transfusion
Bilirubin cleared by placenta in utero, not harmful. After birth the neonatal liver cannot cope with the excess production of bilirubin –> jaundice
- Regular assessment of its neurobehavioral state and observe for the development of jaundice and/or anaemia
- Regular assessment of bilirubin and Hb
- Advise against early discharge
- Encourage feeding regularly (dehydration can increase the severity of jaundice)
- If bilirubin levels rise rapidly or above the interventional threshold, phototherapy and/or exchange transfusion may be required
Management in future pregnancies after HDFN
If a patient has had a previous pregnancy affected by the antibody, subsequent pregnancies are likely to be affected at a much earlier gestation
Begin monitoring ~10 weeks earlier that the gestation at which the previous fetus was affected
If severely affected pregnancy, refer straight to MFM in future pregnancies
What is the evidence of anti D?
1/7 women is Rh(D) negative blood group
Routine AN administration of Anti-D can result in a reduction of alloimmunisation of 78% (Cochrane)
Anti-D at 28 and 34 weeks during pregnancy to all Rh(D) negative women who have not actively formed their own Anti-D will result in a reduction of alloimmunisation from ~1% to 0.35%
The Anti-D given does not cross the placenta
First trimester indications and dose for anti-D
Dose 250 IU
- CVS - Miscarriage - Abortion (MTOP or STOP) - Ectopic pregnancy - If multiple pregnancy give 625 IU
Insufficient evidence to give Anti-D for threatened miscarriage <12/40
2nd and 3rd trimester indications and dose for anti-D
Dose 625 IU
- Obstetric haemorrhage
- Amniocentesis or other invasive fetal intervention
- ECV (whether successful or not)
- Abdominal trauma or any other suspected intra-uterine bleeding or sensitising event
- Abortion
Following delivery of Rh(D) positive baby, do quantification of fetomaternal haemorrhage to guide appropriate dose of anti-D prophylaxis (if Kleihauer >6ml need more than 625IU)
Dose should be given within 72h
Prophylactic anti-D recommendations
Offer prophylactic dose of 625 IU at approx 28/40 and 34/40
Clinical features of HDN
Pathological jaundice - Can occur within the first 24h - Kernicterus Splenomegaly Hepatomegaly
Lipid soluble unconjugated bilirubin –> water soluble conjugated bilirubin so can excrete in the urine
Lipid soluble UCB can pass through membranes if the membrane is lipid
- Blood brain barrier (BBB) = lipid bilayer membrane
- BBB is immature, therefore UCB can pass through
- Get yellow discolouration of the basal ganglia, cerebral cortex, cerebellum, spinal cord
Pathogenesis of FNAIT
All platelets have natural proteins on their surface = human platelet antigens (HPA)
Fetal platelets can cross into maternal bloodstream
Maternal-paternal platelet type incompatibility –> maternal platelet specific alloantibodies
Antibodies (anti-HPA) cross placenta - destroy fetal platelets –> thrombocytopenia
Anti-HPA-1a implicated in 95% of severe FNAIT
Investigation of ? FNAIT
Maternal platelet specific alloantibodies (anti-HPA)
Platelet typing and compatibility of both parents
Management in pregnancy with risk of FNAIT
Prenatal testing for genotype - If father is heterozygosity for the particular antibody producing antigen
- ? invasive testing ? cfDNA
MFM referral
- USS at 18-20 weeks
- Serial scans every 2-4 weeks, with focus on the fetal brain
IVIG +/- steroids
- Shown to improve platelet count in fetuses at risk of FNAIT
FBS
- Higher risk in FNAIT due to risk of bleeding
- Transfused platelets have a short half life (2-5 days)
- Platelet sampling and transfusion reserved for time of delivery planning
Elective CS at 36/40
If fetus has ICH
- Fetal MRI - MDM review
- Consider TOP
- Other IVIG weekly and elective CS at 34/40
Key differences with NAIT to HDN
- Occurs in first pregnancy
- Don’t need sensitising event
- If partner homozygous will happen in every pregnancy
- Don’t screen for it, only screen if bad outcome
- Limited use of IUT
Diagnosis of APS
- Thrombosis and / or
- Pregnancy morbidity:
- >3 consecutive miscarriages <10/40
- >1 fetal death >10/40 with normal fetal morphology
- >1 preterm birth <34/40 with normal fetal morphology due to PET or placental insufficiency - Combined with presence of aPL on 2 separate occasions >12/52 apart
- Anti-cardiolipin antibody
- Lupus anticoagulant
- Anti-B2-glycoprotein 1 antibody
Lab criteria for diagnosis of APS
Anti-cardiolipin
- IgG and/or IgM aCL in moderate or high titre (>99th centile) used standardised enzyme-linked immunosorbant assay (ELISA)
Anti-B2-glycoprotein-1
- same
Lupus anticoagulant
- Requires >2 phospholipid-dependent coagulation tests
- Prolonged activated partial thromboplastin time (APTT) and dilute Russel viper venom time (dRVVT)
Pathophysiology for APS
Antibodies bind with phospholipids which interfere with coagulation cascade –> procoagulant state
Activation of complement pathways at the maternal-fetal interface –> local inflammatory response and in later pregnancy thrombosis of the uteroplacental vasculature
APS and pregnancy implications
Effect of pregnancy on APS
- Risk of thrombosis is exacerbated by the hypercoagulable pregnant state
- Pre-existing thrombocytopenia may worsen in pregnancy
Effect of APS on pregnancy
- Miscarriage
- HTN/PET
- FGR
- IUFD
- PTB
- Abruption
Past obstetric history is the best predictor of outcome
Women with aPL antibodies but no clinical features - pregnancy outcomes similar to general population
Pre-pregnancy counselling APS
Screen women for aCL or LA if history of: - Recurrent miscarriages - Thrombosis - Severe early-onset PET or FGR - Fetal death Detailed medical and obstetric history, exclude other causes of recurrent misc (e.g. cervical incompetence) Counsel on outcomes Check for concurrent SLE - Anti-Ro, anti-LA antibodies Screen for other risk factors - HTN, renal failure, thrombocytopenia Lifestyle advice / optimisation
Defer pregnancy until 6/12 after thrombotic event
- COCP avoided
LDA prior to conception
Antenatal management of APS
MDT
Aspirin until 36/40
Review VTE prophylaxis
- If on warfarin change at 6/40
- If prev VTE, minimal high dose 40mg bd clexane or therapeutic dose
- if no prev VTE, prophylactic LMWH from pregnancy confirmed
Screen for anti-Ro and anti-La antibodies Baseline PET screen - regular BP and urinalysis Uterine artery dopplers with anatomy Serial growth scans
Post-partum
Resume anticoagulation Recommence warfarin day 2-3 PP Encourage breastfeeding Avoid COCP Women without prev VTE, clexane 10 days to 6 weeks depending on Hx
Why increased risk of VTE in pregnancy?
Pregnancy –> hypercoagulable state
- Assumed in preparation for controlling bleeding at time of delivery
- Increased clotting factors VIII, IX, X
- Increased fibrinogen
- Decreased fibrinolytic activity - decreased endogenous fibrinolytics, e.g. protein S, antithrombin
Further increased risk post-delivery
- Vessel wall injury
- Period of immobility
- Blood loss
Venous stasis in lower limbs –> increased risk
- Left > right - compression of left iliac vein by iliac and ovarian arteries
Risk factors for VTE - pre-existing
Thrombophilia Medical co-morbidities (e.g. cancer, heart failure, SLE, diabetes) >35y Obesity Parity >3 Smoker Paraplegia Varicose veins
Risk factors for VTE - obstetric
Multiple pregnancy PET CS Prolonged labour Stillbirth PTB PPH Placental abruption ART
Risk factors for VTE - transient
Hyperemesis OHSS Immobility Sepsis Long distance travel
Indications for VTE prophylaxis
Recommendations based on consensus /expert opinion rather than good evidence
50% of antenatal VTE occurs in 1st and 2nd trimester
Lower threshold for commencement of prophylaxis post-partum
Antenatal - assess for VTE risk
- If >/= 3 of the risk factors, prophylaxis from first trimester
- If >2 risk factors, prophylaxis if inpatient
Risk factors for anaemia
Low SES
Short interpregnancy interval
Previous anaemia or PPH
<18y
Iron deficiency anaemia pathogenesis
Most common cause of anaemia
Increased iron requirements in pregnancy due to expanding red cell mass and increasing fetal requirements
Increased demands for iron –> increased intestinal absorption + iron mobilised from Hb of circulating red cells
Many women enter pregnancy with deplete iron stores
More common in multiple pregnancy
In women from developing countries, consider intestinal infestations (e.g. Hookworm, Giardia, Tapeworm, Schistosomiasis)
Effect of iron deficiency on pregnancy:
- LBW - PTB - Increased blood loss at delivery
Folate deficiency
- pathogenesis
Macrocytic anaemia with megaloblastic change in bone marrow
- Normal dietary folate is inadequate to prevent changes in ~25%
Requirements increase in pregnancy due to:
- Increased red cell mass
- Expanding feto-placental unit
- Increase in cell replication taking place in the fetus, uterus and bone marrow
Incidence variable depending on the SES and nutrition
More common if taking anti-epileptic drugs or other folate antagonists (e.g. sulfasalazine)
Causes of anaemia
Iron deficiency Folate deficiency Vitamin B12 deficiency Haemoglobinopathies Chronic disease Haemolysis
High risk groups that need high dose folic acid
5mg/day
- Women with NTD or with previous child with NTD
- Meds - sodium valproate, AEDs, sulfasalazine
- Women with congenital / hereditary spherocytosis, sickle cell disease, haemolytic anemia, thalassaemia
- Known malabsorption syndrome
- Proven folate deficiency
Vitamin B12 deficiency
Macrocytic anaemia with megaloblastic change in bone marrow
Vitamin B12 decreases in pregnancy
- But rarely ever biochemical vitamin B12 deficiency
Less common
Most commonly due to dietary deficiency, IBD, pernicious anaemia
Erythropoietin for anaemia
Acts to stimulate the bone marrow to make red cells
Mainly used in IDA a/w renal failure
Can be used where blood transfusion has been declined
Need to give with iron
How are sickle cell and thalassaemia different?
Sickle cell - disorder of haemoglobin structure
Thalassaemia - disorder of Hb synthesis
Pathogenesis of sickle cell disease
Point mutation in beta-globin gene –> defective HbA
RBCs can take the shape of a crescent (sickle) when in de-oxygenated state
- Can more easily be destroyed –> anaemia
- aggregates with other HbS –> sickling
Sickling promoted by:
- Acidosis
- Low flow vessels
Repeated sickling –> weakened cell membrane –> intravascular haemolysis
- low haptoglobin level as sign of haemolysis
- Increased unconjugated bilirubin
Sickle blood cells –> vaso-occlusion
Infarcts spleen –> susceptible to encapsulated bacteria
Heterozygous vs. homozygous for sickle cell
Inheritance - Autosomal recessive
Sickle cell carrier / trait
- No health problems unless exposure to extreme conditions, e.g. altitude or dehydration
- Decreases severity of some malaria = beneficial
Homozygous
- chronic haemolytic anaemia
- periods of sickling crisis
- premature death
Pregnancy implications of sickle cell disease
Increased risk: - FGR - VTE / PE - Miscarriage - PET - Abruption - CS - Infection / sepsis - hyposplenism Sickling infarcts in the placenta Crises occur more commonly in pregnancy 35% of women who are pregnant with SCD
Pre-pregnancy management of sickle cell disease
Evaluate risk - Screen for end organ damage.
Counsel on outcomes
- Partner needs to be screened and genetic counselling
Optimise before pregnancy
- Hydroxycarbimide used to prevent crises is teratogenic so should be stopped prior to pregnancy
- Check for iron overload
Advice re avoiding crises - cold, hypoxia, over-exertion and stress
Aspirin in pregnancy
Supplements Folic acid 5mg OD
Routine antenatal care
- Booking bloods and vaccines
- Vaccination advice as per hyposplenic patients - Hep B, influenza, meningococcal, H influenzae
pregnancy management of sickle cell disease
MDT care Uterine artery dopplers + serial growth scans BP and urinalysis with every visit. Penicillin prophylaxis (250mg BD) MSU at every visit
Increased risk of VTE
Monitor for anaemia with Hb at every visit
Avoid precipitating factors to crises such as cold, dehydration, stress.
Crises should be managed aggressively
- Admission, analgesia, rehydration, early use of antibiotics, kept warm and well-oxygenated.
Severe anaemia, acute chest, stroke or splenic sequestration should be treated with blood transfusion or exchange transfusion
- Routine exchange transfusion not recommended
Deliver by 38-40 weeks
Deliver in tertiary unit with appropriate specialist support
CEFM - Increased risk of c-section and abruption
Thalassaemia
- Inheritance
Pathogenesis
Autosomal recessive
Reduced globin chain synthesis (beta in beta-thalassaemia with excess of faulty alpha, and alpha in alpha-thalassaemia with excess of faulty beta) –> red cells with insufficient haemoglobin levels
Ineffective red cell production –> release of damaged red cells into the peripheral circulation –> extravascular haemolysis
Alpha thalassaemia
Severity correlates with the number of affected alpha globin genes
1 - alpha thalassaemia trait
2 - alpha thalassaemia minor
- Mild microcytic hypochromic anaemia
- In pregnancy, can give po iron if iron deficient
3 - haemoglobin H disease
- Microcytic hypochromic anaemia
- Heinz bodies
- Pregnancy:- Folic acid 5mg/day, Transfusions may be offered to correct anaemia
4 - Haemoglobin Barts –> IUFD
Beta thalassaemia
Beta globin chain deficiency –> clumping of free alpha chains –> damage RBC membrane –>
- Haemolysis –> iron (causes secondary haemochromatosis) and unconjugated bilirubin (causes jaundice)
- Extravascular haemolysis in the spleen
Thalassaemia trait or minor
Thalassaemia intermedia
Thalassaemia major
Thalassaemia major
Most common and most severe form of beta thalassaemia
Iron overload
Haemochromatosis –> arrhythmias, pericarditis, cirrhosis, hypothyroidism, diabetes
Diagnosis:
- Low Hb, MCV
- Blood smear - microcytic, hypochromic, target cells
- Diagnosis confirmed with Hb electrophoresis = low HbA, increased HbF and HbA2
Present within first 2y of life
- Usually at 3-6 months when switch from HbF to HbA occurs
Treatment:
- Requires lifelong blood transfusion
- chelation therapy
- Splenectomy
Pregnancy management of thalassaemia major
Chelating agents are contraindicated in pregnancy
Require extra transfusions when pregnant –> increased risk of iron overload
Assess organ damage Folic acid 5mg/day MDT - obs, haematology Partners should be tested Avoid iron supplementation Monitor feta growth Increased incidence of red cell antibodies because of number of previous transfusions (~15%) Check TFTs - frequently hypothyroid VTE prophylaxis Cardiac failure is the primary cause of death
Most women subfertile - require OI
ECHO at 28/40 - risk of cardiomyopathy
Haemophilia carriers
Daughters are obligate carriers
May have reduced levels of factor VIII or IX - 1/3
May have bleeding tendency - e.g. dental work, surgery
During pregnancy, FVIII levels rise, therefore no bleeding problems occur
- However fall dramatically within 48h of delivery, therefore risk of secondary PPH
FIX levels do not rise, therefore may need factor replacement during labour
Consider cfDNA to reduce need for invasive testing
Factor VIII levels should be checked before invasive procedures
If male fetus
- Deliver at tertiary centre for NICU support
- Avoid FBS, forceps, ventouse, FSE
- Elective CS does not eliminate risk of ICH
If female fetus
Delivery at tertiary centre if women is a carrier of severe factor VIII or IX deficiency
Aetiology / incidence of vWD
Affects up to 1% of population
Autosomal dominant
vWF = plasma protein
- Stabilises factor VIII
- Adheres platelets to injured vessel walls
Diagnosis - prolonged APTT and low vWF
- vWF and FVIII both increase in pregnancy, therefore difficult to diagnose
- Refer to haem PP
management of vWD
Pre-conception
- Assess type of vWD and if they respond to desmopressin (DDAVP)
- Genetic counselling
- Discuss potential risks of pregnancy and delivery
Antenatal:
- Prenatal testing (with haemostatic cover if required)
- Von Willebrand screen in 1st and 3rd trimester
- Anaesthetic assessment
- Consider haemostatic correction before invasive testing
Intrapartum
- Avoid FSE, FBS, ventouse, rotational forceps
- CS only for normal obstetric reasons
- Baby’s vWF levels increase at delivery / in response to stress
- IV access, FBC, G&H
- Avoid IM infections if abnormal vWF levels
- Liaise with haematology
- DDAVP, factor support, TXA (TXA 5/7 PP)
- Active third stage
Neonatal alert
- Cord blood to diagnose vWD
Differential diagnoses of low plt in pregnancy
Spurious result - repeat the test Gestational thrombocytopenia (75%) PET (15-20%) Infection DIC Thrombotic thrombocytopenia purpura Acute fatty liver APS / SLE Idiopathic immune thrombocytopenic purpura (ITP)
Idiopathic thrombocytopenia purpura
- definition and presentation
Isolated low plt count with normal bone marrow and absence of other causes of thrombocytopenia
Autoantibodies against platelet surface antigen cause peripheral platelet destruction
2 in 10,000 pregnancies
Purpuric rash
Increased tendency to bleeding
Diagnosis of ITP
Diagnosis of exclusion Examination of peripheral blood film U&E, urate LFTs +/- LDH, reticulocytes and direct Coombs test if haemolysis is suspected Coags Lupus anticoagulant, anticardiolipin antibodies, antinuclear antibodies Virology screen - TORCH, EBV, HIV +/- malaria
Thrombocytopenia in the first half of pregnancy is more likely to be ITP
Management of ITP
Usually conservative / observation If very low: - Corticosteroids - IV immunoglobulin - Immunosuppressive drugs (cyclosporin)
Refractory ITP may require splenectomy
- If have had, then should have penicillin prophylaxis in pregnancy
Aim for plt >80x109/l at delivery
- >50x109/l - safe of CS or normal delivery, but >80 required for epidural / spinal (d/w anaesthetics)
Avoid ventouse
Caution with FBS and forceps
Cord bloods for platelet count
- Avoid IM vitamin K if low
Small risk of PPH
f/u as per haematology
Neonatal implications of ITP
Risk of neonatal platelet count <50 is 5-15%
Non-immune thrombocytopenia (NAIT)
Neonatal autoimmune thrombocytopenia
- Occurs if mothers have ITP or SLE
- Antibodies directed against platelets
- Clinical manifestations less severe than NAIT
- NB: Platelet nadir occurs at day 5
What is HUS/TTP?
Both are manifestations of microvascular platelet aggregation
Common features are thrombocytopenia and microangiopathic haemolytic anaemia
Thrombotic thrombocytopenic purpura
- systemic and extensive, particularly CNS involvement
Haemolytic Uraemic syndrome
- Predominantly affects kidneys
No effect on foetus
Similar presentation to PET but no HTN
Treatment = supportive
+/- steroids +/- plasmaphoresis
Don’t deliver foetus
Gestational thrombocytopenia
Benign, self-limiting condition
Most common at delivery, can occur at any time
Mild thrombocytopenia
- Rarely <70x109/l
Diagnosis confirmed when plt normalises outside of pregnancy
VTE incidence
incidence of non-fatal DVT and PE in pregnancy is 0.1%
- 75% DVT, 25% PE
- RR of VTE in pregnancy is increased 4-6 fold (further increase PP - up to 20-fold)
Risk of DVT after CS 1-2%
If DVT remains untreated, ~20% will develop PE
PE may be fatal in almost 15%
Thromphilias in order of severity for VTE risk
Those with prior VTE and
- Anti-thrombin deficiency
- APS
- Recurrent unprovoked VTE
–> treatment dose clexane AN + 6 weeks PN
Also FHx of VTE but no personal Hx with antithrombin deficiency
Others - standard prophylactic dose AN + 6 weeks PN
- prev VTE, recurrent provoked VTE, single unprovoked VTE
FHx of VTE but no PMHx, with weak lab thrombophilia (FVL heterozygous, Prothrombin heterozygous) - observe, consider PN prophylaxis
FHx of VTE but no PMHx, with significant thrombophilia (FVL homo, protein C or S deficiency, FVL + PT mutation) - consider AN prophylaxis if risk factors, given PN
Post-natal clexane
5 days
- All women who have emergency CS
- 2 major risk factors or 1 major + 2 minor
Major
- CS
- BMI >30
- Immobile
- comorbidity
- PET
- Sepsis
Minor
- > 35y
- Prolonged labour
- Smoker
- PPH
- Extensive perineal trauma
- Varicose veins
BMI >40 should have 10 days
Risks of LMWH
Lumps and itching at the injection site
- May be due to technique or allergy
Heparin induced thrombocytopenia –> pro-thrombotic state
- Check FBC on commencement and 7-10 days later
- HIT risk is substantially lower than with UFH
Osteoporosis
- Only reported with therapeutic doses
- More common with UFH
Management of DVT in pregnancy
Full length compression stockings
Should be worn in the acute period and for 12/12 after the event to reduce the incidence of post-thrombotic syndrome
LMWH
- Consider BD dosing because increased renal clearance in pregnancy
- Treatment should continue for the remainder of pregnancy and at least 6/52 PN and until at least 3/12 of treatment has been given in total
It takes 2-3 weeks for a clot to organise
- Consider insertion of IVC filter if birth is imminent and risk of bleeding is significant and would contraindicate LMWH / UFH
If women very high risk of thrombosis, can use UFH peripartum
UFH vs. LMWH for VTE prophylaxis
LMWH is preferred as:
- It has a lower risk of heparin-induced thrombocytopenia
- It doesn’t require routine monitoring, unlike UFH
- Patient can be taught to self administer
- Lower risk of osteoporosis and bone fractures
- LMWH has a longer half life than UFH so can be OD or BD dosing
