Radoslaw Struniawski

Accelerated thrombus lysis in the blood of plasminogen activator inhibitor deficient mice is inhibited by PAI-1 with a very long half-life

Patients with defective plasminogen activator inhibitor protein (PAI-1) or with PAI-1 deficiency can experience hemorrhage as a result of a hyperfibrinolysis. In these patients, a normal thrombus forms, but endogenous lysis is unchecked as tissue plasminogen activator is unopposed. Treatment includes anti-fibrinolytic agents, including oral tranexamic acid. Another treatment option is the administration of PAI-1, but this serpin rapidly inactivates itself. We have developed a mutant plasminogen activator inhibitor with a very long half life (VLHL PAI-1, t1/2>700 h). Here we investigate VLHL PAI-1 effects in the blood of PAI-1 deficient mice, as a model of human disease. Using a thrombelastograph, we found that blood clots of PAI-1 knockout mice were lysed much more quickly than wild type mice. Additionally, blood clots had less shear elastic modulus strength than clots of normal animals. VLHL PAI-1 treatment of PAI-1 deficient mice extended or prevented thrombus lysis and increased clot strength in a concentration dependent fashion. These two parameters determine the extent of thrombus growth and regression; thus, further testing is anticipated to confirm the effectiveness of plasminogen activator inhibitor with a very long half life in an in vivo model and we hope that this protein can be effective in human PAI-1 deficiency disorder.

The National Alpha-1 Antitrypsin Deficiency Registry in Poland

Abstract The alpha-1 antitrypsin deficiency (AATD) targeted screening program, together with the National Registry, were established in Poland in 2010 soon after the AATD diagnostics became available. Between 2010 and 2014 a total of 2525 samples were collected from respiratory patients countrywide; 55 patients with severe AAT deficiency or rare mutations were identified and registered, including 36 PiZZ subjects (65%). The majority of AATD patients were diagnosed with COPD (40%) or emphysema (7%), but also with bronchial asthma (16%) and bronchiectasis (13%). Therefore, the registry has proved instrumental in setting-up the AATD-dedicated network of respiratory medical centres in Poland. Since augmentation therapy is not reimbursed in our country, the smoking cessation guidance, optimal pharmacotherapy of respiratory symptoms as well the early detection, and effective treatment of exacerbations is absolutely essential.

Pulmonary Langerhans cell histiocytosis — insight into the incidence of alfa-1-antitrypsin (A1ATD) deficiency alleles

INTRODUCTION The alpha-1 antitrypsin deficiency (A1ATD) is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. There is no data regarding prevalence of main, clinically most important A1ATD alleles PI*Z and PI*S in patients with pulmonary Langerhans cell histiocytosis (PLCH). PLCH is not only strongly linked to the cigarette smoking, but is also characterised by polycystic lung lesions. The goal of the study was to assess the incidence of A1ATD alleles in patients with PLCH. MATERIAL AND METHODS Blood samples were collected from 34 adult patients (14 women and 20 men), with histologically confirmed PLCH. AAT serum concentration was assessed by nephelometry and PI-phenotype, identified by isoelectrofocusing. The PI*S and PI*Z alleles were confirmed by genotyping usisng real-time PCR. RESULTS Deficiency alleles PI*Z and PI*S were detected in 3 patients (one woman and 2 men), respectively in 5.88% and 2.94%. The estimated incidence of deficiency alleles was 29.4/1000 (95% CI; 10-69.5) for PI*Z and 14.7/1000(95%CI; 13.9-43.3) for PI*S. According to our previous reports, the expected prevalence of PI*Z and PI*S alleles in general Polish population was 13.7/1000 (95% CI 5.8-21.5), and 7,6/1000 (95% CI 1.7-13.5) respectively. CONCLUSIONS The incidence of main A1AT deficiency alleles in patients with PLCH seems higher than in general Polish population. The study is on-going.

The prognostic importance of the protease-antiprotease imbalance in development of chronic obstructive pulmonary disease comorbid with chronic pancreatitis

Background: chronic obstructive pulmonary disease (COPD) is frequently comorbid with chronic pancreatitis (CP). One of the genes that could play a role in occurrence of that comorbidity by controlling protease-antiprotease balance, is a gene encoding alpha-1-antitrypsin (AAT). Aim: to find markers of susceptibility to CP in COPD patients. Methods: the serum levels of AAT, its genotype, tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9) and MMP-3 in serum were measured in COPD patients with/without CP in equal groups of 60 subjects each. Results: heterozygous carriers of deficient alleles were found in 5% of patients with comorbidity COPD and CP (group 1), while in the group without CP (group 2) - only 1.67%. Moreover, in group 1 there were a large number of people - 18.3% (11 of 60 patients) compared with data of group 2 - 8.3% (5 of 60) in whom the pathology of the respiratory and digestive systems was associated with a lack production of AAT. A significantly higher serum MMP-9 level was observed in patients from group 1 (median - 242.92 ng/ml vs. 131.15 ng/ml). Changes of TIMP 1 had multidirectional character - among 30.56% of patients from group 1 there were increased serum level of TIMP 1, whereas in 16.67% of patients from group 2 this indicator was marked decreased. There were no statistically significant differences in MMP-3 serum levels between the studied groups. Conclusions. Heterozygosity for PiM- polymorphisms and especially both serum AAT and MMP-9 levels are valuable biomarkers for verification predisposition to the occurrence CP among COPD patients.