A 38 year old man has a routine coagulation test prior to surgery which reveals a prolonged APTT. He has had a major haemostatic challenge without any problems (orthopaedic surgery).
First things first – we checked the sample wasn’t clotted, underfilled or haemolysed. Then we performed other investigations including mixing studies to test for an inhibitor (A lupus insensitive reagent such as Actin FS is a suitable test when thinking about a lupus anticoagulant; FVIII inhibitors won’t be revealed by this test but then they would be vanishingly rare in an asymptomatic young man anyway). We also excluded heparin effect by doing a TT and RT, which were normal. We checked that the patient wasn’t taking a novel oral anticoagulant, and took a good bleeding history while we were at it (though it didn’t reveal much).
We went on to test his intrinsic factors and extablished that he had an isolated FVIII deficiency (level of 17%). This was a bit surprising given the major surgery he had undergone previously. Many people wondered whether the patient may have Type 2N VWD, which is certainly possible in this context, but was not the diagnosis here. A VW:FVIII binding assay could be used to look for this, although many centres would now just request gene sequencing if Type 2N VWD is suspected. In our patient FVIII gene sequencing gave us the answer however, as he was found to have the Tyr365cys mutation.
This mutation affects the thrombin binding site of FVIII, although the actual mechanism by which thrombin generation is affected is complex and not entirely elucidated. This abnormal thrombin binding has no real clinical effect – as evidenced in this case – bleeding is minimal if noted at all. It does effect in vitro testing however. The key in these cases is to check both a one stage and two stage assay; the one stage assay (which is the routine test in most labs as it is easily automated and accurate in most cases) gives a misleadingly low result. The two stage assay (or to be correct, most labs will actually perform a chromogenic assay in these situations, which can be automated and is more reproducible than the traditional two stage assay) gives much higher FVIII results – in this case 78%. Published case series show that the Two stage/chromogenic assay best reflects the bleeding phenotype of these patients – i.e. most do not bleed.
Whilst this kind of inverse/reverse discrepancy is beloved of examiners and pedants (!) Bowyer et al suggest that in the UK this mutation is actually reasonably common. The consequences of missing it are not dire – after all we will be erring on the side of over-treating – but we shouldn’t over treat if it can be avoided. Whilst many Haematologists would be a little anxious about not giving any prophylaxis before major surgery, it is probably safe to take this approach. It would certainly be reasonable to perform a DDAVP challenge, assessed by serial chromogenic FVIII assays, and plan to use DDAVP to cover surgery.
It should also be remembered that if a patient with the Tyr365cys mutation does bleed there is probably something else going on – VWD, another FVIII mutation or other bleeding disorder.
Thanks for following Case 26; we hope it was a useful guided walk through the possible causes of a prolonged APTT and how these patients should be investigated, with a sprinkle of laboratory knowledge to top it off.
Join us for Case 27 soon!
Bowyer, A. E., Goodeve, A., Liesner, R., Mumford, A. D., Kitchen, S. and Makris, M. (2011), p.Tyr365Cys change in factor VIII: haemophilia A, but not as we know it. British Journal of Haematology, 154: 618–625. doi: 10.1111/j.1365-2141.2011.08688.x