Vol 46, No 7 (2018)


Contraction of blood clots and thrombi: pathogenic and clinical significance

Litvinov R.I., Peshkova A.D.


This review is the frst systematic description of spontaneous blood clot shrinkage, aka clot retraction or contraction. The driver of this process is the contraction of the actin-myosin complex inside activated platelets. The platelet contractile force is transmitted via focal contacts to extracellular fbrin fbers, causing compaction of the three-dimensional fbrin network along with the embedded erythrocytes. The main structural consequences of clot contraction include redistribution of the fbrin-platelet meshwork toward the periphery of the clot and compression of erythrocytes in the core of the clot followed by their deformation into polyhedral cells called “polyhedrocytes”. These structural signatures of clot contraction in ex vivo thrombi and thrombotic emboli derived from various locations indicate that thrombi undergo intravital contraction within blood vessels in vivo. Pathogenic consequences of clot contraction may vary. Thus, contraction of a thrombus changes the vessel lumen, thereby modulating local blood flow in the thrombotic occlusion area. Thrombus shrinkage changes its porosity and permeability for fbrinolytic enzymes. The extent of thrombus compression and densifcation can determine the likelihood of its mechanical rupture, i. e. thrombotic embolization. Several clinical studies have revealed that clot contraction is suppressed in the blood of patients with (pro)thrombotic conditions, such as ischemic stroke, venous thrombosis, and systemic lupus erythematosus. This reduction of clot contraction is due to platelet dysfunction caused by their chronic hyperactivation and energetic exhaustion. Clot contraction depends significantly on cellular and protein composition of the blood; in particular, a high hematocrit and hyperfbrinogenemia both reduce clot contraction, while activated monocytes enhance clot contraction by expressing tissue factor and promoting thrombin generation. The degree of clot contraction abnormalities in thrombotic states generally correlates with disease severity, which confrms the pathogenic importance of clot contraction. In patients with pulmonary embolism clot contraction is decreased signifcantly compared to that in isolated venous thrombosis, indirectly suggesting that a less compacted thrombus is more prone to embolization. This observation points to a potential diagnostic and prognostic value of the clot contraction assay as a novel test for ongoing or threatening thromboembolism. Collectively, contraction of blood clots and thrombi is an underappreciated and understudied process that has a major pathogenic and clinical signifcance in (pro)thrombotic conditions of various etiologies.
Almanac of Clinical Medicine. 2018;46(7):662-671
pages 662-671 views


Evaluation of the morphofunctional state of peripheral blood platelets in sepsis

Koshelev R.V., Vatazin A.V., Zulkarnayev A.B., Faenko A.P.


Background: Sepsis is a severe life-threatening condition characterized by combined dysfunction of the inner organs and systems and by dysregulation of the platelet and coagulation compartments of hemostasis, in particular.

Aim: To assess the character of abnormalities in morphofunctional state of platelets in the pathophysiology of sepsis and the multiple organ failure syndrome by means of coherent interference microscopy.

Materials and methods: This single center, prospective, observational study included 78 hospitalized patients with abdominal sepsis; in 40 of them, the syndrome of multiple organ failure was diagnosed. The causes of sepsis were peritonitis of various etiologies in 55 patients, acute necrotic pancreatitis with suppurative and septic complications in 23. The control group included 25 physically healthy subjects. Coherent interference microscopy was used for vital assessment of the platelet morphofunctional state, with simultaneous analysis of routine coagulogram and platelet aggregation parameters.

Results: The group of patients with sepsis (n = 38) had higher fbrinogen levels, compared to that in the control (4.5 ± 1 g/L, p = 0.0001), with mild thrombocytopenia (238 ± 12 × 109/L, p = 0.0001). Platelet aggregation was also increased (48 ± 3%, p = 0.0001). Assessment of circulating platelets by coherent interference microscopy showed a progressive increase of the mean populational morphodensitometrical parameters, such as the diameter (p = 0.0002), perimeter (p < 0.0001), and area (p = 0.0002), as well as a decrease in mean values of the phase height (p = 0.0002) and volume (p = 0.0002). There was an increase in the proportion of activated cells to 41% (vs. 33% in healthy control) and the proportion of degenerative cells up to 8%. The patients with severe sepsis complicated by multiple organ failure (n = 40), compared to the control ones, demonstrated exhausted of compensatory mechanisms with the development of consumption coagulopathy: prolonged activated partial thromboplastin time (57 ± 2 s, p = 0.0001), increased prothrombin index (117 ± 4, p = 0.0025), decreased fbrinogen level (1.6 ± 2 g/L, p = 0.0001) and platelet counts (110 ± 9 × 109/L, p = 0.0001), and their lower aggregation (24 ± 3%, p = 0.0001). According to the results of the coherent phase microscopy, the types of the morphodensitometrical abnormalities were similar to that in the main group, albeit they were more signifcant. The proportion of the activated cells was 43%, while that of the degenerated and functionally incompetent platelets, 15%. There were signifcant correlations between the morphodensitometrical parameters of the platelets and basic parameters of their aggregation induced by adenosine diphosphate and collagen.

Conclusion: Sepsis is associated with advanced abnormalities in the morphofunctional state of peripheral blood platelets progressing concomitantly to the deterioration of the patient's state. Coherent interference microscopy allows for a real-time assessment of the morphological particulars and functioning of circulating thrombocytes. Further studies are required to validate the results of this method.
Almanac of Clinical Medicine. 2018;46(7):672-681
pages 672-681 views

The role of ultrastructural abnormalities of the blood-brain barrier in the development of brain glioblastoma radioresistance

Balkanov A.S., Chernikov V.P., Golanov A.V.


Background: Glioblastoma (GB) is the most commonly diagnosed brain tumor. Its management involves adjuvant therapies, such as radiation. The cause of high probability of GB local relapse is its radioresistance related to hypoxia arising from abnormal blood-brain barrier permeability in GB vessels and in the peritumoral zone (PZ).

Aim: To study pathophysiology of hypoxia in the residual GB based on the abnormalities of the morphological elements of the capillary walls building up the blood-brain barrier in GB and PZ capillaries.

Materials and methods: Samples for morphological evaluation were taken during surgery for GB in 5 patients. The samples were prepared for transmission electron microscopy according to the standard technique with fixation in 2% glutaraldehyde in phosphate buffer, post-fixation with osmium tetroxide, embedding in the epon-araldite mixture, and contrast staining of ultrathin sections with uranylacetate and lead citrate. Abnormalities of the capillary cells (mitochondrial vacuolization and vacuolization of endoplasmic reticulum in endothelial cells, pericytes and astrocytes), as well as of the acellular element of the capillary wall, i.e. basement membrane, were assessed in two groups of capillaries – those of GB (n = 38) and those of PZ (n = 32).

Results: Abnormalities characteristic for apoptosis and oncosis were found in the cells of the GB and PZ capillaries of the blood-brain barrier, such as endothelial cells and pericytes. However, in the GB capillaries these abnormalities were signifcantly more frequent (р < 0.001). Only half (52.6%) of the GB capillaries had an edematous pericapillary astrocyte layer. In all other capillaries, astrocyte sprouts either were visualized as separate morphological elements (13.2%) or were not visualized at all (34.2%). All PZ capillaries had the astrocyte layer, being edematous in 68.8% of the capillaries and totally edematous only in 25%. Thickened basement membrane was found in the vast majority (89.5%) of the GB capillaries and only in 25% of the PZ capillaries (р < 0.001).

Conclusion: Findings of abnormal cell elements in the GB capillaries leading to peritumoral edema and consequent hypoxia are highly likely to be the cause of the remnant GB radioresistance.
Almanac of Clinical Medicine. 2018;46(7):682-689
pages 682-689 views

Soluble forms of immune checkpoint receptor PD-1 and its ligand PD-L1 in plasma of patients with ovarian neoplasms

Gershtein E.S., Utkin D.O., Goryacheva I.O., Khulamkhanova M.M., Petrikova N.A., Vinogradov I.I., Alferov A.A., Stilidi I.S., Kushlinskii N.E.


Background: Ovarian cancer is one of the most common oncologic diseases holding the frst place in mortality related to neoplasms of female genitalia. Along with active surgical intervention, contemporary ovarian cancer treatment includes various chemotherapeutic regimens which in many cases are quite effective, but relapse and death rates still remain high. In the recent years, major attention has been paid to the possibility of ovarian cancer immunotherapy associated with the discovery of the so-called “immune checkpoint” signaling, i.e. programmed cell death-1 / programmed death-ligand 1 (PD-1/PD-L) pathway, controlling intensity and duration of autoimmune response at physiologic conditions. Tumor PD-1 and/or PD-L1 expression is being actively studied as a predictor of anti-PD-1/PD-L treatment efficacy; however, this approach has certain limitations and problems that might be probably bypassed by determination of soluble PD-1 (sPD-1) and its ligand (sPD-L1) in serum or plasma.

Aim: Comparative evaluation of sPD-1 and sPD-L1 content in plasma of healthy women and of patients with benign or borderline ovarian tumors and ovarian cancer, as well as the analysis of associations between these markers and main clinical and pathologic characteristics of ovarian cancer.

Materials and methods: Sixty two (62) patients with ovarian neoplasms aged 32 to 77 (median, 56.5) years were enrolled into the study. Fifteen (15) patients had benign tumors, 9 had borderline, and 38, ovarian cancer. The control group included 17 healthy women aged 24 to 67 (median, 49) years. Plasma sPD-L1 and sPD-1 concentrations were measured with standard enzyme immunoassay kits (Afmetrix, eBioscience, USA).

Results: Plasma sPD-L1 and sPD-1 levels in ovarian cancer patients (median, 41.3 and 48.0 pg/ml, respectively) did not differ significantly from those in the control group (49.5 and 43.8 pg/ml). sPD-L1 level in the patients with benign tumors (median, 22.2 pg/ml) was signifcantly lower than in the control (p < 0.01). The lowest sPD-1 level in plasma was found in the patients with borderline ovarian neoplasms, the difference with the ovarian cancer group being statistically signifcant (p < 0.05). No correlations between sPD-L1 and sPD-1 plasma levels were found in any of the study groups. sPD-L1 level signifcantly increased with disease stage (R = 0.44; p < 0.01), the most signifcant increase being observed at the most advanced IIIC stage (p < 0.05 as compared to all other stages). sPD-L1 was also signifcantly higher in the patients with ascites than in those without ascites. Plasma sPD-1 concentration was not associated with the indices of ovarian cancer progression, though its median was 1.3–1.44 times lower in the stage I than in the stage II–III patients, and decreased in those with the tumor size above 10 cm (assessed by ultrasound examination) and in the patients with ascites. No statistically signifcant associations of the markers' levels with tumor histological type and differentiation grade of ovarian cancer were found.

Conclusion: sPD-L1 level in ovarian cancer patients correlates with disease progression and can be considered as a promising marker for monitoring of anti-PD-1/PD-L1 treatment efficacy. Potential clinical implications of sPD-1 require further studies.

Almanac of Clinical Medicine. 2018;46(7):690-698
pages 690-698 views

Reduction in the incidence of postoperative cognitive impairment after hysterectomy with inhalational sevoflurane anesthesia

Akimenko T.I., Zhenilo V.M., Zdiruk S.V., Aleksandrovich Y.S.


Background: The term “postoperative cognitive dysfunction (POCD) syndrome” is applied to an impairment of higher mental functions that may occur postoperatively and are related to the surgery and anesthesia. Medical and social impact of POCD is undoubted due to its high incidence (up to 30% after non-cardiac surgery), high expenses related to the restoration of cognitive functions, as well as the need in social adaptation of the patients.

Aim: To decrease the risk of POCD after subtotal hysterectomy through optimization of anesthesiological care.

Materials and methods: This prospective, single blind study performed from May 2016 to October 2017 included 67 middle-aged women with large uterine myomas or multimodal myomas, who underwent subtotal hysterectomy (through laparotomic Pfannenstiel incision) under general anesthesia. The patients were divided into two groups depending on the anesthesia method. The patients from group 1 (n = 35) were operated under inhalational sevoflurane anesthesia with micro-bolus fentanyl infusion (100 to 300 µg/h). In the patients from group 2 (n = 32), micro-boluses of dexmedetomidine were started 15 minutes before intubation at doses of 0.4 to 1.1 µg/kg/h, ending at the time of the wound closure. Cognitive functions were assessed with MMSE (Mini Mental State Examination) and МОСА (Montreal Cognitive Assessment) scales preoperatively and in the early postoperative period (at days 1 and 5).

Results: There was a signifcant difference in cognitive functions between the groups at days 1 and 5 after surgery. In the dexmedetomidine group, the cognitive parameters were signifcantly better: median MOCA score was 26 vs 25 (p < 0.001) at day 1 and 27 vs 26 (p < 0.001) at day 5. MMSE scores at day 1 were 27 vs 25 (p < 0.005) and at day 5, 28 vs 27 (p < 0.001). The group 2 patients also had lower opioid requirements (p < 0.001).

Conclusion: The use of dexmedetomidine for hysterectomy under inhalational sevoflurane anesthesia allows for reduction of postoperative cognitive impairment in the early postoperative period.
Almanac of Clinical Medicine. 2018;46(7):699-707
pages 699-707 views

Results of coronary bypass surgery of the arteries with extended atherosclerotic abnormalities

Rafaeli Y.R., Pankov A.N., Rodionov A.L., Pekarskaya M.V.


Background: In multi-vessel atherosclerotic coronary artery disease, coronary artery bypass grafting remains the method of choice and allows for the best possible revascularization and maximal continuity of the results. Conduit functioning to a large extent depends on the coronary artery (CA) diameter and on the severity of atheromatous involvement and anatomic abnormalities of its walls. However, there is no consensus on what minimal diameter and extent of CA lesions could provide robust long-term results of bypass surgery. Consequently, surgical strategy for bypass grafting in diffuse coronary involvement and small vessel diameters has not been clearly defned.

Aim: To perform a comparative analysis of the bypass grafts functioning depending on CA anatomy and methods of revascularization.

Materials and methods: The study included 98 patients, who, irrespective of their clinical condition, had a control coronary angiography (CAG) with shuntography (SHG) between 6 months to 5 years after they had undergone direct myocardial revascularization by coronary artery bypass grafting. In total, 215 anastomoses were assessed. The bypassed CAs were divided into two groups according to their diameters and into two subgroups depending on the severity of the coronary vasculature involvement. When bypassing an artery with diffuse involvement, angioplastic anastomoses were done in 52.5% of the cases. Long-term graft functioning was assessed by shuntography.

Results: Conduit functioning after bypassing of CA >1.5 mm in diameter and with local CA narrowing did not depend on the graft type and was 95.1% for the internal thoracic artery (ITA) grafts and 90.1% for the great saphenous vein (GSV) grafts. With diffuse lesions, these values decreased to 68.4% for ITA and 69.1% for GSV (р < 0.05). Long-term revascularization results for coronary arteries with a diameter of ≤ 1.5 mm were signifcantly lower for all types of conduits: with local stenosis, 78.6% ITA and 68.4% GSV grafts were patent, whereas in diffuse coronary bed involvement, 50 and 33.3%, respectively (р < 0.05). After placement of an angioplastic anastomosis to the CA with diffuse lesions, 79.3% of the ITA and 69.2% of the GSV grafts were functioning, whereas after the use of the standard technique, such were 55.6 and 40%, respectively (р < 0.05).

Conclusion: Bypass grafting of CA with local lesions and > 1.5 mm in diameter, the graft type has not signifcant impact on its long-term functioning. In diffuse CA involvement, angioplastic anastomoses should be used.
Almanac of Clinical Medicine. 2018;46(7):708-715
pages 708-715 views

Specifics of acute coronary syndrome associated with atrial fibrillation in real world clinical practice (based on the registry of the Krasnodar Region)

Tatarintseva Z.G., Kosmacheva E.D., Raff S.A., Kruchinova S.V., Porkhanov V.A.


Background: Coronary heart disease is the most common cardiovascular disorder, while atrial fibrillation (AF) is the most common heart arrhythmia.

Aim: To perform a comparative analysis of the coronary substrate assessed by coronary angiography in patients with acute coronary syndrome (ACS) in combination with various AF types, as well as to analyze abnormal electrocardiographic findings and blood troponin levels in patients with ACS and AF versus ACS patients with sinus rhythm.

Materials and methods: We retrospectively analyzed medical files 13,244 ACS patients entered into the total ACS registry in the Krasnodar Region from 20.11.2015 to 20.11.2017. In 1204 (9%) of them ACS was associated with AF (ACS + AF group, n = 119), the remaining 12 040 (91%) patients had sinus rhythm (ASC + SR group, n = 120).

Results: Compared to the ACS + SR group, the troponin levels were significantly (р ≤ 0,05) higher in the ACS + AF group. No statistically significant differences between two groups were found for localization of hemodynamically significant coronary stenoses at coronary angiography. Only 25.0% (p = 0.1689) of patients with ACS + AF without ischemic electrocardiographic changes (ST depression or elevation) had no hemodynamically significant coronary stenoses at coronary angiography.

Conclusion: AF in ACS patients is an important factor in the course of the disease and is characterized by higher blood troponin levels and significantly more frequent absence of ischemia-related electrocardiographic changes, compared to the ACS patients with sinus rhythm.

Almanac of Clinical Medicine. 2018;46(7):716-724
pages 716-724 views

Computed tomography and magnetic resonance imaging in the diagnosis of the small and large intestine strictures in Crohn’s disease. Radiological semiotics and assessment of the inflammation activity

Dubrova S.E., Stashuk G.A., Nikitina N.V., Bogomazov Y.K.


Rationale: Crohn's disease is characterized by continuous severe course, and in a half of the patients is associated with formation of strictures that are difcult to treat and significantly decrease quality of life. Difficulties during the differentiation between inflammation-related and fbrostenotic strictures and divergent approaches to their treatment in patients with Crohn's disease indicate the need in precise diagnostics and systematization of the radiological semiotics of strictures.

Aim: To propose radiological semiotics of the small and large intestine strictures based on the results of multiaxial computed tomography (MACT) and magnetic resonance imaging (MRI).

Materials and methods: MACT and MRI visualization was performed in 40 patients with a stenotic type of Crohn's disease.

Results: The radiological signs of the strictures were classifed into two main groups: intestinal and extra-intestinal. They were systematized according to nine criteria, such as character of formation, etiology, number, inflammation grade, extension, shape, and location, presence of ileus and presence of other complications. The inflammation activity in the intestinal wall was evaluated during the postcontrast assessment: active inflammation in the arterial phase (at 25 seconds after administration of the contrast agent), chronic inflammation in the delayed phase (at 10 minutes). The MRI results were cross-checked with those of MACT. At the precontrast stage, MRI was more informative as per the width of the intestinal lumen, whereas MACT was preferential in the diagnosis of fat infltration of the intestinal wall. Post-contrast MACT and MRI were diagnostically equivalent. The most indicative for active inflammation were diffuse weighed MRI images, arterial phase MACT and MRI, whereas chronic inflammation and wall fbrosis were better diagnosed at the delayed phase (at 10 minutes) of MACT and MRI. Both methods (MACT and MRI) could not differentiate between the submucous and muscular layers of the intestinal wall. Mixed type of inflammation was seen in the walls of intestinal strictures: chronic inflammation dominated in the intermediate, most extensive part of a stricture and remained stable during the dynamic follow-up, whereas active inflammation was found in the marginal parts of the strictures, which were most susceptible to changes during the follow-up.

Conclusion: Based on a set of certain signs obtained by radiological visualization, we propose a registry for stricture assessment based on evaluation of the inflammation activity.

Almanac of Clinical Medicine. 2018;46(7):725-733
pages 725-733 views

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