More recently, marked differences have been observed between results obtained with ELISA, latex immunoassay and aggregometry methods in a patient with type 2 VWD (Table 2). These discrepancies require further investigation, but highlight problems in the diagnosis of certain VWD defects. Another challenge for laboratories in emerging countries is the diagnosis of rare bleeding

disorders (RBDs). A higher prevalence of some of these disorders is expected in cultures where consanguineous marriage is common (e.g. type 3 VWD was noted to be the most common subtype in India [31]). Although this may partly reflect ‘easier’ diagnosis (both clinically and by laboratory testing) than type 1 VWD, others report that 60–70% of type 3 VWD cases arise from consanguinity [30]. EQA demonstrates the capacity of laboratories INCB024360 cell line to identify patients with RBDs, and can identify methodological issues.

For example, 50% of established centres and 53% of emerging centres report a lower limit of reference range for FXI:C assay ≤ 60U dL−1 [33], despite evidence that patients with FXI deficiency and levels of up to 70 U dL−1 may bleed [34]. Consequently, 3/37 centres (8%) reported a normal FXI:C level, and a further 8% reported borderline levels in a patient with factor XI deficiency and a median FXI:C level of 43 U dL−1. EQA has also demonstrated variation in the ability of laboratories to identify FXIII deficiency. Clot solubility screening tests show variable sensitivity depending on the reagents used, and this can affect diagnostic efficacy [35]. Current guidelines buy Romidepsin recommend the use of specific activity

assays in the diagnosis of FXIII deficiency, but cost and availability of reagents is beyond the scope of some emerging centres. Careful adoption and evaluation of a suitably sensitive screening test is important. A major issue for laboratories in emerging centres Thiamet G is access to and funding for reagents to perform the full range of assays in the investigation of bleeding disorders [27]. However, it is possible to identify areas for improvement in diagnostic accuracy that will lead to improved patient care. Factor XIII (FXIII) circulates in plasma as a tetramer of two catalytic A-subunits and two carrier B-subunits (A2B2). In plasma, all A-subunits exist in complex form, whereas there are free B2 homodimers. In platelets, monocytes and macrophages, cellular FXIII occurs only as A2 homodimer. The B-subunits are synthesized in the liver by hepatocytes. The A-subunits are assumed to be mainly of bone marrow origin, but hepatocytes might also contribute [36,37]. In plasma, thrombin, together with cofactors fibrin(ogen) and Ca2+, activates FXIII by cleavage of the activation peptide from the A-subunit, followed by dissociation of the A- and B-subunits [38]. Congenital FXIII deficiency is a rare (1 in 2–5 million), autosomal recessive inherited disease that affects all races and both sexes [39].