Table 2.

Gaps in knowledge and potential solutions.

Research gap	Description	Implications for future research
Sex as a biological variable	Most studies did not use both male and female mice, and many did not report mouse sex.	Include both male and female mice in studies to account for and compare sex differences in VWF-mediated thrombosis.
Age as a biological variable	Significant variation in the age of mice used across studies, and many did not report mouse age.	Standardize age selection criteria to improve comparability and manipulate to clarify age-related differences in VWF-mediated thrombosis.
Impact of mouse strain on VWF-mediated thrombogenicity	The majority of single-vessel models used C57BL/6 mice, whereas TTP models generally used a mixed CASA/Rk-C57BL/6J-129X1/SvJ strain. It is known that CAST/Ei and CASA/Rk strains have altered VWF biology.	Further exploration of single-vessel thrombosis models using mice with genetic backgrounds of CASA/Rk and/or CAST/Ei is warranted, given that these strains yield improved replication of clinical TTP signs in TTP models when compared with C57BL/6-129/Sv alone.
Heterogeneity in model choice and methodology	A large number of models were used, all with varying methods and choice of arterial or venous circulation.	Standardize thrombosis model methodologies, with inclusion of both venous and arterial assessment when able, to improve comparability of studies and further clarify the role of VWF across the vasculature. Justification for choice of model is warranted given their varying pathogenic mechanisms and clinical applicability.
Thrombus composition	A minority of studies investigated the composition of formed thrombi, with many identifying varying distribution and proportion of VWF and platelets vs fibrin and RBCs.	The clinical importance of thrombus composition (ie, white vs red thrombi) is increasingly apparent, with known differences in response to thrombolysis in mice and humans. Studies should assess thrombus composition within their model for improved clinical translation.
Underreporting of mouse characteristics and detailed methodologies	Mouse characteristics were underreported across studies. Numerous studies were omitted from methodological variation assessment as they did not report detailed methods.	Standardize required reporting of key variables that can influence outcomes, validity, and comparability of studies (ie, mouse age, sex, weight, strain, supplier, and detailed methodology).

RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura; VWF, von Willebrand factor.