Von Willebrand disease (VWD) is not uncommon in Taiwan. In type 2 or type 3 VWD hemorrhagic symptoms are severer and laboratory data relatively more distinctive. De novo mutation and somatic mosaicism of type 2 VWD gene were rarely reported. Therefore clinical, laboratory and genetic studies of only type 2A, 2B and 2M VWD will be presented and issues of de novo mutation and somatic mosaicism will be explored. Fifty-four patients belonging to 23 unrelated families from all around the country in whom type 2 VWD exclusive of type 2N has been diagnosed not only by clinical and routine laboratory studies but also by genetic confirmation during 1990–2015 were investigated. A novel technique named amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) was used to confirm the presence of somatic mosaicism. Informed consent was obtained for study. De novo mutation was identified in 4 families among 15 families (26.7 %) in whom family members including parents were available for examination. All their parents were free from bleeding symptoms and had no similar mutation as their respective affected daughter. An interesting example of somatic mosaicism of VWF gene mutation was found in a large family with type 2A VWD. The father carrying a mutated VWF gene, p.Arg1597Trp, transmitted this mutation to his 3 daughters, 1 son, 3 granddaughters and 2 grandsons. However, the father had normal laboratory findings and experienced no abnormal bleeding, while his offspring who inherited the mutation showed abnormal laboratory findings compatible with type 2A VWD and had history of abnormal bleedings. ARMS-qPCR revealed that the father had only 25.5 % mutant in his blood cells and 31.1 % mutant in his oral mucosal cells, while all his offspring had about 49 % mutant in their blood cells. De novo mutation of type 2 VWD gene was identified in 4 out of 15 families (26.7 %) examined. Since only one child was affected in each family, germline mosaicism was not likely. A somatic mosaicism of type 2A VWD gene was documented in a big family by a newly in-house developed technique ARMS-qPCR.

Acquired factor XIII (FXIII) inhibitor is a rare but possibly underdiagnosed bleeding disorder. To date, less than one hundred cases have been reported, but the number has increased rapidly in recent years, especially in Japan. Because of the rarity of this disorder, no treatment guidelines are available. In some reports, physicians treated the bleeding with cryoprecipitate or factor XIII concentrate and eradicated the inhibitor with various immune suppressants. From January 2015 to December 2018, we collected consecutive patients diagnosed as having acquired FXIII inhibitor. FXIII activity and inhibitor were measured by a fluorescent factor XIII assay using isopeptidase reaction catalyzed by activated factor XIII and the Bethesda method, respectively. Factor XIII antigen was measured by latex-enhanced immunoassay. We found five adult patients with detectable FXIII inhibitor. Four of them were older than 70. Two had systemic lupus erythematosus. All the patients presented with ecchymosis and intramuscular hematoma. No life-threatening bleeding was observed. Delayed diagnosis was common with varied time periods needed to achieve a correct diagnosis. All bleedings were treated and improved by cryoprecipitate. Steroids were given to all patients and cyclophosphamide, rituximab, and other immune suppressants were also used. FXIII inhibitor was totally resolved in three, partially resolved in one, and persisted in one patient. We documented five patients with acquired FXIII inhibitor, found over 4 years. The most common presentations were ecchymosis and intramuscular hematomas. Cryoprecipitate was effective in controlling most bleeds. Steroid, cyclophosphamide and rituximab were effective in eradicating inhibitor in some patients.

Hemophilia A (HA), an X-linked bleeding disorder caused by Factor VIII (F8) gene mutations, persists in the population due to sporadic cases arising from de novo mutations. This study analyzed 24 pedigrees from hemophilia registries of multiple medical centers in Taiwan to assess whether sporadic non-inversion variants (NIVs) recur in the same generation within families. Linkage analysis using intragenic and extragenic markers combined with amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) revealed that among 16 individuals inheriting the same X chromosome as the one bearing the sporadic HA-causing mutation, none carried the F8 variant. These findings strongly suggest that sporadic NIVs exhibit very low risk of recurrence. Our results provide critical information for recurrence risk assessment and counseling strategies for HA sporadic NIVs.