Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19.

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.

A collaborative study by the Working Group on Hemostasis and Thrombosis of the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) on the interference of haemolysis on five routine blood coagulation tests by evaluation of 269 paired haemolysed/non-haemolysed samples.

INTRODUCTION: Haemolysis is the leading cause of sample rejection in laboratory haemostasis. Most studies focused on artificially haemolysed samples. The aim of this study was a prospective assessment of spontaneous haemolysis on haemostasis tests, by comparing results of haemolysed (H) versus new, non-haemolysed (NH) specimens, collected within 4hrs. As new coagulometers can identify interfering substances, visual assessment of haemolysis was also compared with instrumental haemolysis index and stratified in subclasses. MATERIALS AND METHODS: Two hundred and sixty nine paired samples were collected and analysed using ACL TOP750-CTS (Instrumentation Laboratory, Bedford, USA), for prothrombin time (PT), activated partial thromboplastin time (aPTT), D-Dimer (DD), fibrinogen (Fib) and antithrombin (AT). Bias between H and NH was calculated and compared with the respective critical difference (CD). RESULTS: Mean bias was - 0.1 s for PT (P = 0.057), - 1.1 s for aPTT (P < 0.001), 1025 ng/mL for DD (P < 0.001), - 0.04 g/L for Fib (P = 0.258) and 1.4% for AT (P = 0.013). Bias exceeding the CD varied according to the method, with larger differences for aPTT (36.1%) and DD (17.1%) and < 8% for PT, Fib and AT. No correlation emerged between free haemoglobin values and difference in haemostasis tests in H and NH samples for any tests. Moderate/severe haemolysis involved > 95% of samples. The agreement between visual assessment and instrumental evaluation of haemolysis was 0.62. CONCLUSION: Spurious haemolysis deeply influences aPTT and DD, and to a lesser extent AT and Fib. Prothrombin time seems only slightly influenced, suggesting that PT can be accepted also in haemolysed samples. Although a good inter-observer correlation of haemolysis evaluation was found, the instrumental assessment of haemolysis seems recommendable.

Maternal serum protein S forms in pregnancies complicated by intrauterine growth restriction.

OBJECTIVES: The clinical relevance of protein S deficiency in pregnant women remains controversial. Major debate exists regarding which parameter (total protein S antigen, free protein S antigen or functional protein S) should be evaluated in order to define protein S deficiency. The present study aimed to identify which of these parameters correlate with intrauterine growth restriction (IUGR). STUDY DESIGN: A retrospective case-control study of women with IUGR (n=27) and healthy controls (n=123) in the third trimester of pregnancy. RESULTS: The maternal serum of women in the IUGR group had significantly lower levels of functional and free protein S compared with the control group: 54.07 ± 24.72% vs 65.20 ± 17.95% (p<0.005) and 42.88 ± 11.01% vs 56.64 ± 13.30% (p<0.0001), respectively. No significant correlation was found between total protein S and IUGR. CONCLUSIONS: Levels of functional and free protein S are correlated with IUGR.

A cohort mortality study of leather tanners in Tuscany, Italy.

BACKGROUND: Work in leather tanning may involve exposure to a wide range of chemicals. Some of these are carcinogens or suspected carcinogens. Increased risk for a number of cancers have been reported, although there are considerable inconsistencies between studies. The present study investigates the mortality of leather tanners in Tuscany, Italy. METHODS: Tanneries were selected from the 1996 Valdarno Inferiore Tanneries Census and were in operation since December 31, 1970. Employees were followed until December 31, 1998 through company records, and the National and Regional Death Index. Demographic and work history data were abstracted from company payrolls. Regional mortality rates were used to calculate Standardized Mortality Ratio (SMR). Analyses were completed for the overall cohort (men and women) and for men who ever worked as of finisher, chrome tanners, and vegetable tanner (only men). RESULTS: The cohort consisted of 4,874 workers (4,150 males and 724 females) employed in 92 tanneries active in 1996 and operating on December 31, 1970. Ascertainment of vital status and cause of death were completed for all individuals by the end of follow-up, December 31, 1998. Males showed increases for cancer of the endocrine glands (SMR 5.67, 4 observed (obs), 90% Confidence Intervals (CI) 195-1,308), blood diseases (SMR 3.29, 4 obs, 90% CI 112-753), mental disorders (SMR 1.95, 6 obs, 90% CI 85-385), violence and accidents (SMR 1.30, 54 obs, 90% CI 102-163). Mortality from myeloid leukemia was increased in males (SMR 2.08, 5 obs, 90% CI 82-437) and in females (SMR 5.99, 2 obs, 90% CI 106-1,887). One death from nasal cancer was observed versus 0.2 expected. Mortality from lung cancer was increased among finishers (SMR 1.45, 19 obs, 90% CI 95-212), an increase was observed also for bladder cancer (SMR 1.25, 2 obs, 90% CI 22-393) and pancreatic cancer (SMR 1.20, 2 obs, 90% CI 21-379). CONCLUSIONS: The study confirms previous observations among tanners of increased mortality from lung, bladder, and pancreatic cancer. Noteworthy are the increased mortality from myeloid leukemia together with the new findings of an increased mortality from endocrine glands tumors, blood diseases, and psychiatric disorders which should be considered with caution because of the small number of cases and the novelty of the observation.