Question 1
Give a differential diagnosis for a FVIII:C of 0.15 iu/ml
Mild haemophilia A
Haemophilia A on factor concentrate prophylaxis
Von Willebrand Disease
Type 1 or 2
Combined FV + FVIII deficiency
Discrepant 1-stage / 2-stage assays
Question 2a
A pregnant woman tells you she has a family history of ‘haemophilia’. How would you proceed?
Explore pedigree
Who is the index case and are they still alive / contactable?
Patient’s bleeding history (Score >7 significant in women)
Bloods
Check VIII, IX, XI, VWF & others based on ethnicity
Genetic sequencing – only takes 2 weeks
Question 2b
You find nothing from the above, what possibilities remain?
Rare coag disorder
Platelet function disorder
3-5% of Haemophilia A families do not have a detectable mutation
Question 3a
In an asymptomatic woman, whose father has severe haemophila A and mother is normal, what is the risk that her daughter is a carrier of severe haemophilia A?
Superficially the daughter will be an obligate carrier, having taken X from father
But the quoted non-paternity rate in the UK is 1%
Question 3b
The daughter is a carrier (FVIII 0.68 iu/ml). She goes on to have two twin girls of her own. One twin has a FVIII of 0.69 iu/ml. What would you predict the levels to be in the other twin?
Could be the same
Or could be very low due to mirror image lyonisation between the twins
Question 4
In which situations can you be sure someone is an obligate carrier?
If they are a daughter of an affected mother
If they are the mother of two affected children
(not if they are the daughter of an affected father for reasons of non-paternity)
Question 5
A. List the differential diagnosis for these clotting results in isolation
Pre-analytical error, e.g. overfilled sample tube
Drugs, e.g. heparin
Deficiencies of factors VIII, IX, XI, XII
Acquired Inhibitors, e.g. lupus anticoagulant, acquired haemophilia
B. Describe the principle of the dRVVT test for lupus anticoagulant
RVV activates Factor X
Added to phosphoplipid, prothrombin and calcium it will clot fibrinogen to fibrin
This test is unaffected by deficiencies of VIII, IX, XI and XII
Step 1:
Normal plasma + DRVV + dilute phospholipid + calcium —> time to clot
Patient plasma + DRVV + dilute phospholipid + calcium —> time to clot
Calculate the ratio between the two clotting times
If ratio is elevated, step 2:
Attempt correction with normal plasma (if successful, suggests II, V, X or FGN deficiency)
Attempt correction with additional phospholipid. A greater than 10% correction with additional phospholipid is indicative of a lupus anticoagulant.
C. State the final diagnosis in this case and briefly summarise your initial management of this patient
Acquired haemophilia A with a co-existing lupus anticoagulant. (Explanation: The lupus anticoagulant is shown by the dRVVT correction with the use of excess phospholipid. The factor VIII inhibitor is demonstrated by the very low factor VIII level and the time dependent nature of the inhibitor on mixing studies. The lupus anticoagulant is also interfering with the mixing studies, as shown by the lack of a full correction on the immediate 50:50 mix (Factor VIII inhibitors are typically time dependent with a correction of APTT on immediate mix, becoming prolonged again following a 2-hour incubation)).
Brief management plan:
Local bleeding control, e.g. nasal pack
Stop apixaban
Limit procedures that risk bleeding, e.g. reduce phlebotomy, manual BP cuff, falls prevention
Tranexamic acid
Consider need for bypassing agents, e.g. FEIBA, rFVIIa
Consider need for neuro imaging, ?intracranial bleeding
Consider options for eradicating the inhibitor, e.g. steroids, rituximab, alternative immunosuppression
question 6
Mr Cobblepot is a 65 year old man admitted for an elective right total knee replacement. He has a fall post-operatively which delays his rehabilitation and as a result he is making good progress but remains an inpatient seven days after the procedure. On day 8 post-op he reports a painful, swollen, red left leg.
Current medications: Lisinopril, Atorvastatin, Paracetamol, Oxycodone liquid, Prophylactic Tinzaparin
Bloods pre-op: Hb 135, WBC 5.5, Platelets 230, Creatinine 60, ALT 10, Bili 5
Bloods on day 8: Hb 115, WBC 11, Platelets 45, Creatinine 65, ALT 11, Bili 6, CRP 30
a) What test(s) would you perform next?
Coagulation screen – PT / APTT / Fibrinogen
US doppler left leg
Septic screen
Screening test for heparin induced thrombocytopenia (HIT), i.e. Heparin-PF4 antigen assay
b) Briefly describe the principles of one laboratory assay, of your choice, that can be used to confirm the suspected cause of thrombocytopenia
e.g. Lateral flow immunoassay
Qualitative test using fresh citrated plasma
Detects Heparin-PF4 complexes bound to gold nanoparticles as they move along a membrane, with IgG complexes immobilised onto the membrane to generate a visible line
c) Recommend a management plan
Switch to an alternative non-heparin anticoagulant immediately
In this clinically stable patient I recommend switching to once daily, subcutaneous, treatment-dose fondaparinux
Continue anticoagulation for three months, switching to warfarin after a minimum of five days overlap with fondaparinux
Provide patient with an HIT alert card
Avoid future heparin exposure
(N.B. Answer does not have to be fondaparinux, there are other appropriate options)
d) Three years later, the patient requires cardiac bypass surgery. The cardiothoracic team would prefer to use unfractionated heparin to support the surgery. They request your advice regarding his suitability to receive this.
Test for persistent antibodies with a functional assay prior to procedure
If still present, use a non-heparin anticoagulant (e.g. argatroban)
If antibody negative, proceed with intra-op UFH but use non-heparin alternatives pre- and post-op