Welcome to a second themed issue of Seminars in Thrombosis and Hemostasis dedicated to laboratory diagnostics. In this issue, we will present several state-of-the
art reviews highlighting hemostasis/thrombosis testing aspects relevant to a spectrum
of bleeding and thrombotic disorders and treatments. The issue begins with a contribution
by Adcock et al summarizing the performance of mixing studies to further evaluate
the etiology of prolonged clotting times and differentiate factor deficiencies from
factor inhibitors, inhibitor anticoagulants, and lupus anticoagulants.[1] Due to technical and interpretive non-standardization, combined with patient variables,
there is no single approach to mixing studies that will correctly classify all cases
as a deficiency or an inhibitor. Because mixing study results are often used as an
early test to help determine what additional specialized testing is needed, it is
vitally important to understand the pre-analytical, analytical, and post-analytical
variables that affect the testing, including when the result patterns may be misleading.
This review is an excellent summary of the variables that must be considered with
each situation.
The second manuscript, by Saadalla and colleagues, provides an informative review
of traditional and partially automated von Willebrand factor multimeric analysis,
and the role of multimers in discriminating different subtypes of von Willebrand disease
(VWD).[2] The review includes discussion of VWD subtypes, underlying pathophysiology, and
abnormalities of triplet or quintuplet structure that can be seen on multimer gels.
The third contribution, authored by Keiji Nogami, describes clot waveform analysis
(CWA), an information analysis method that is available on certain coagulation laboratory
instruments.[3] The method deconstructs the coagulation pathway of the prothrombin time or activated
partial thromboplastin time into phases such as the pre-coagulation phase, coagulation
phase, and post-coagulation phase. Potential applications of CWA mentioned in the
review include predicting the phenotype of inherited or acquired coagulation factor
abnormalities. CWA is a global coagulation assay that may provide useful information
in several challenging hemostasis settings, although standardization of testing and
additional study is necessary to move the application forward in clinical practice.
The fourth manuscript, by Larsen and colleagues, focuses on the current status of
platelet function testing in the diagnosis of bleeding disorders and to monitor the
efficacy of antiplatelet therapy, including descriptions of available methods and
advantages and disadvantages of each.[4] Pre-analytical variables affecting platelet function are discussed in detail and
can help the reader address common practical challenges in their own laboratories.
The subsequent manuscript, by Bowyer and Gosselin, focuses on factor VIII and IX activity
measurements for hemophilia diagnosis and treatment.[5] The article opens with a summary of the impressive advances in hemophilia care over
the last decade and then transitions to discussion of types of coagulation factor
assays and the variables that can impact results. Importantly, the discordance between
the one-stage and the two-stage chromogenic assays seen in a subset of nonsevere hemophilia
patients is described, as it relates to testing approaches for diagnosis of mild hemophilia.
The manuscript then summarizes the currently available modified, extended half-life
factor replacement products and the recommended (and not recommended) laboratory methods
for monitoring these products, information of great value to clinical hemostasis laboratories.
In the next manuscript, authors Warkentin and Greinacher provide an excellent review
on laboratory testing for heparin-induced thrombocytopenia (HIT), including the autoimmune
and spontaneous forms, as well as vaccine-induced immune thrombotic thrombocytopenia
(VITT).[6] While these highly prothrombotic conditions share the characteristics of thrombocytopenia
and increased thrombotic risk, the antibodies in HIT and VITT are distinct in their
recognition of distinct PF4 epitopes, which impacts the sensitivity and specificity
of laboratory assays. In particular, while ELISA methods are typically able to identify
both types of antibodies, rapid immunoassays have high sensitivity for HIT but poor
sensitivity for VITT. This is an incredibly importance difference in laboratory practice,
with potential to significantly impact patient diagnosis and care, and readers are
urged to read this manuscript carefully. An excellent figure demonstrating the HIT
and VITT antibody differences was selected as the cover art for this issue.
The next article in this issue, from Gardiner et al, delves into the discussion of
laboratory developed tests (LDTs), assays that are more commonly performed in highly
specialized hemostasis/thrombosis laboratories, and that fill an important niche for
patient testing when there are no commercially available options approved by local
regulatory authorities, or the commercial options are of substandard quality.[7] The manuscript provides important background context on differences in laboratory
regulation in different parts of the world, and explores the challenges associated
with increasing LDT regulation with potential impacts to patient care. The manuscript
provides helpful tables that summarize studies that should be performed during the
validation of a high-quality LDT.
In the next review, Richard Marlar expertly discusses diagnosis of inherited defects
in the natural anticoagulants antithrombin, protein C, and protein S.[8] Deficiencies in these proteins are prominent inherited causes of increased thrombotic
risk. However, diagnostic testing is not always necessary for patient management and
the tests are greatly affected by pre-analytical variables, technical challenges including
assay interference by anticoagulant medications, and problems with interpreting results
and applying these results to patient care. The author thoughtfully discusses testing
approaches and algorithms recommended by the International Society on Thrombosis and
Hemostasis (ISTH) for evaluating these deficiencies[9]
[10]
[11] and arms the reader with practical knowledge to avoid common pitfalls.
In the last manuscript, authors Pruthi and Chen discuss the bypassing agents used
to treat hemophilia A and B patients with factor inhibitors, including treatments
currently used and those in development.[12] The review focuses on what is known about the effects of these agents on routine
and specialized coagulation assays.
We are thrilled to present this issue of Seminars in Thrombosis and Hemostasis composed of an excellent collection of laboratory state-of-the-art reviews. We thank
the expert authors for their contributions and hope the readers find great value in
the content.
