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
