Using high sensitivity cardiac troponin values in patients with SARS-CoV-2 infection (COVID-19): The Padova experience.

BACKGROUND: The spectrum of Coronavirus Disease 2019 (COVID-19) is broad and thus early appropriate risk stratification can be helpful. Our objectives were to define the frequency of myocardial injury using high-sensitivity cardiac troponin I (hs-cTnI) and to understand how to use its prognostic abilities. METHODS: Retrospective study of patients with COVID-19 presenting to an Emergency Department (ED) in Italy in 2020. Hs-cTnI was sampled based on clinical judgment. Myocardial injury was defined as values above the sex-specific 99th percentile upper reference limits (URLs). Most data is from the initial hospital value. RESULTS: 426 unique patients were included. Hs-cTnI was measured in 313 (73.5%) patients; 85 (27.2%) had myocardial injury at baseline. Patients with myocardial injury had higher mortality during hospitalization (hazard ratio = 9 [95% confidence interval (CI) 4.55-17.79], p < 0.0001). Multivariable analysis including clinical and laboratory variables demonstrated an AUC of 0.942 with modest additional value of hs-cTnI. Myocardial injury was associated with mortality in patients with low APACHE II scores (<13) [OR (95% CI): 4.15 (1.40, 14.22), p = 0.014] but not in those with scores > 13 [OR (95% CI): 0.48 (0.08, 2.65), p = 0.40]. Initial hs-cTnI < 5 ng/L identified 33% of patients that were at low risk with 97.8% sensitivity (95% CI 88.7, 99.6) and 99.2% negative predictive value. Type 1 myocardial infarction (MI) and type 2 MI were infrequent. CONCLUSIONS: hs-cTnI at baseline is a significant predictor of mortality in COVID-19 patients. A value < 5 ng/L identified patients at low risk.

Correlation between ADAMTS13 activity and neurological impairment in acute thrombotic microangiopathy patients.

Differential diagnosis between thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMA) is usually difficult because of frequently overlapping clinical presentations. Severely depressed ADAMTS13 activity (<10 %) seems distinctive for TTP because of its pathogenetic role. However a long debate exists in the literature about its sensibility and specificity. Our aim was to search for clinical differences between TMA patients referred to our laboratory, comparing them for protease activity <10 versus ≥10 %. ADAMTS13 activity ≥10 % patients (n = 73) showed a higher prevalence of drug- (p = 0.005) and cancer-associated (p < 0.001) TMA. Mean platelet count and renal dysfunction prevalence was lower (p < 0.001), while neurological impairment was more frequent (p = 0.001) in the <10 % ADAMTS13 activity group (n = 109), confirming previous literature findings. When taken neurological manifestations singularly, epilepsy (p = 0.04), focal motor deficit (p < 0.001) and cranial nerve palsy (p = 0.007) were more frequent in the <10 % activity group. In our case series, a <10 % ADAMTS13 activity depicts a group of patients with clinical features similar to TTP patients. Focal motor impairment or epileptic manifestations could further address toward a TTP diagnosis. Studies about treatment efficacy and follow-up are advised to determine whether laboratory findings can guide therapeutic decisions.

Defective ADAMTS13 synthesis as a possible consequence of NASH in an obese patient with recurrent thrombotic thrombocytopenic purpura.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a rare and devastating hematologic disorder frequently associated with multiple organ failure and sometimes death. This syndrome is mainly associated with severe deficiency of ADAMTS13, a disintegrin and metalloprotease with thrombospondin (TSP)-1 repeats, cleaving high molecular weight von Willebrand Factor (ULVWF) multimers. Decreased plasma ADAMTS13 activity results in the accumulation of ULVWF multimers with consequent platelet activation. Recently, obesity has been considered as a potential independent risk factor for TTP, but the reason of this association is still unknown. METHODS AND RESULTS: We describe an unusual case of fatal recurrent TTP in a morbid obese female with non-alcoholic steatohepatitis (NASH) and severe ADAMTS13 activity deficiency due neither to an inhibitory autoantibody nor to a gene mutation. CONCLUSIONS: Visceral obesity is associated with non-alcoholic fatty liver disease (NAFLD) and NASH: we hypothesized that these conditions can influence ADAMTS13 antigen and activity. In fact, hepatic stellate cells (HSC) are the main producers of ADAMTS13, and a decrease in ADAMTS13 activity has been reported in liver disease.

Discrepant ratios of arterial vs. venous thrombosis in hemophilias A and B as compared to FVII deficiency.

BACKGROUND: The occurrence of a thrombotic event in congenital bleeding disorders has drawn considerable attention in recent years. Both patients with hemophilia and patients with von Willebrand disease and even those with rare coagulation disorders have been shown to present occasional thrombotic events. Little is known on the comparative prevalence of arterial vs. venous thrombosis in these patients. OBJECTIVES: The purpose of the present investigation was to evaluate the prevalence of arterial vs. venous occlusions in hemophilia A and B vs. FVII deficiency. METHODS: A time unlimited search of the literature was carried out using pertinent key words. Arterial or venous occlusions had to be proven by objective methods. RESULTS: Eighty-five patients with hemophilia A or B have been reported to have had an arterial occlusion vs. six cases of FVII deficiency. On the contrary, 34 patients with hemophilia A or B and 32 cases with FVII deficiency have been reported to have presented with a venous thrombosis. The ratios of arterial vs. venous thrombosis are 3.72, 1.13, and 2.50 for hemophilia A, hemophilia B, and hemophilia A + B combined, respectively, and 0.19 for FVII deficiency. CONCLUSIONS: Hemophilia A and hemophilia B do not protect from arterial occlusions (mainly acute coronary syndromes), whereas they assure some protection from venous thrombosis. The opposite seems true for FVII deficiency. The potential significance of this discrepancy is discussed.

Presence of anti-ADAMTS13 antibodies in obesity.

BACKGROUND: The low-grade chronic inflammation present in obesity has been recognized as a risk factor for thrombosis, atherosclerosis and cardiovascular complications. In this context, production by adipose organ of a number of inflammatory adipokines could play a crucial role. It has been reported that obesity represents a risk factor for acquired thrombotic thrombocytopenic purpura (TTP), a disease caused by ADAMTS13 deficiency because of anti-ADAMTS13 antibodies, but the pathophysiological link between obesity and TTP is still unknown. We aimed to investigate mechanisms linking obesity to risk of TTP. MATERIALS AND METHODS: Eighty obese patients consecutively admitted to Bariatric Unit of Padua between 2006 and 2009, and 39 lean subjects were characterized by anthropometric, metabolic and inflammatory parameters. ADAMTS13 autoantibodies, activity and antigen levels, and several cytokines including thrombospondin-1 were measured. RESULTS: 21.3% of obese patients were positive for noninhibitory ADAMTS13 autoantibodies, while all lean subjects were negative (P<0.01). No differences in ADAMTS13 activity and antigen levels were found. Thrombospondin-1 levels were significantly higher in obese than in lean subjects (974.4 ± 592.7 vs. 318.9 ± 202.1 ng/mL; P<0.001) and were inversely correlated with ADAMTS13 activity (R=-0.4853; P<0.001). Dot blot suggests that anti-ADAMTS13 antibodies in obese patients bind recombinant thrombospondin-1. CONCLUSIONS: We suggest that anti-ADAMTS13 antibodies are directed against thrombospondin domains shared between ADAMTS13 and thrombospondin-1 and that their generation may be sustained by high levels of thrombospondin-1. This phenomenon could be of relevance, because little is known on the pathogenesis of TTP and its possible link with obesity.

Myocardial infarction in two cousins heterozygous for ASN41HIS autosomal dominant variant of Bernard-Soulier syndrome.

Bernard-Soulier Syndrome is characterized by thrombocytopenia with large platelets and defective aggregation to ristocetin. The bleeding tendency is variable but may be severe. The syndrome is due to genetic defects of the GPIb-V-IX complex and it has been maintained to be protective from thrombotic events. Here we present the first two cases of documented M.I. in two cousins, heterozygous for the Arg41His mutation which is responsible for a dominant form of Bernard-Soulier Syndrome. In one of the two patients an aneurysm of the aorta was also present. The patients had a mild bleeding tendency which was severely aggravated by treatment with antiplatelet drugs. These clinical observations are in contrast with experimental studies which demonstrate that Bernard-Soulier-like strains of mice show a decreased thrombus generation in several experimental settings.

Worldwide diffusion of FVII Arg304Gln coagulation defect (FVII Padua).

FVII Padua is a Type 2 defect owing to an Arg304Gln substitution in exon 8. The defect was originally discovered in an isolated valley in northeastern Italy. Subsequently, it was described in several other countries of the Mediterranean basin and Middle East. Recently, several proven or suspected cases have been described among Afro-Americans in the USA. This study has demonstrated the existence of at least a two-founder effect for this FVII abnormality, Mediterranean countries, and USA Afro-Americans. Patients are usually asymptomatic or only paucisymptomatic. The defect is characterized by low FVII activity when rabbit brain thromboplastins are used in the assay system. On the contrary, FVII levels are normal when ox-brain thromboplastins are used. FVII antigen is always normal.