Haemophilia A and von Willebrand disease (VWD) are the most common bleeding disorders in man. Diagnosis relies on the measurement of factor VIII (FVIII) and von Willebrand factor (VWF), respectively, in blood plasma.
The WHO 6th IS Factor VIII / von Willebrand factor, plasma (07/316) supports global harmonisation of diagnosis by defining the International Unit (IU) for:
The measurement of factor V (FV) in plasma is undertaken to support:
The IU for FV clotting activity is defined by the WHO 1st IS Factor V, plasma (03/116).
ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 motifs 13), also known as ‘von Willebrand factor (VWF) cleaving protease’ is responsible for modulating the range of multimeric species of VWF in the circulation. Acquired or congenital deficiency of ADAMTS13 is associated with:
Diagnosis of deficiency includes tests for ADAMTS13 function and antigen. The proposed WHO 1st IS ADAMTS13, plasma is scheduled for establishment by WHO in 2014 and will define the IU for ADAMTS13 function and antigen so promoting harmonisation in the calibration of secondary (local) reference plasmas. Further studies into the causes of inter-laboratory variability for patient plasma containing ADAMTS13-antibody complexes are required.
Inhibitory antibodies to FVIII develop in around 30% of Haemophilia A sufferers as a result of exposure to infusions of FVIII concentrates:
The WHO 2nd IS Factor VIIa Concentrate (07/228) defines the IU for clotting activity in FVIIa therapeutic concentrates.
Replacement therapy for the bleeding disorder, von Willebrand disease (VWD) is undertaken using purified concentrates of VWF, some of which also contain coagulation factor VIII. The WHO 2nd IS VWF Concentrate (09/182) is used for the potency labelling and characterisation of VWF in these products by defining the IU for:
NIBSC acts as custodian of the Secondary Coagulation Standard Plasma (Lot #4) on behalf of the International Society on Thrombosis and Haemostasis. This lyophilised plasma reference is calibrated for 21 coagulation-related analytes and is available to manufacturers for the calibration of plasma calibrants and reference materials.
Despite the introduction of improved screening tests for infectious diseases in blood donors there is still a residual risk of virus transmission from fresh, frozen plasma (FFP) derived from single donors. This issue has been addressed by the introduction of a virus-inactivation step (solvent-detergent exposure), in the manufacture of commercial sources of FFP.
These products comprise blood group-specific plasma pools prepared from several hundred donors and are presented as frozen units of approximately 200ml volume. These products are subject to European Official Control Authority Batch Release (OCABR) procedures and undergo the following tests to ensure quality and safety:
In addition, the manufacturing plasma pools undergo the following tests for viral safety:
Accurate potency labelling of therapeutic FVIII concentrates is crucial for maintaining product consistency and hence reliability of dosing for replacement therapy. The current system of potency labelling has worked well for the last 40 years:
However there have been issues relating to the use of 2 different assay methods for potency labelling:
Our studies have shown that for the majority of products there is no difference in measured potency when the two methods are used, however, for others there is a significant discrepancy. This can lead to confusion when:
We are now entering a new era of replacement therapy which will see the introduction of ‘longer-lasting’ products specifically designed to prolong the plasma half-life, so reducing the frequency of infusion, through chemical and genetic modifications:
In many cases these modifications have resulted in methods-related potency discrepancies when measured relative to the WHO IS FVIII concentrate and this raises the possibility of alternative approaches to potency labelling. The Section is ideally placed to support a harmonised approach to potency labelling and several initiatives are ongoing:
Decision tree for potency labelling new FVIII therapeutics (Hubbard et al J Thromb Haemost 2013; 11, 988)
Dr Anthony R Hubbard, Section Leader