Disturbances of Hemostasis with Vestibulo-Atactic Complications of Chronic Cerebral Ischemia

One of the causes of vestibulopathy in chronic cerebral ischemia (CCI; I67.8 in International Classification of Disease-10) are hemodynamic and hemostatic disturbances systemically and in the inner ear.[1] The vestibulo-atactic syndrome, which reduces the quality of life due to vertigo, poor balance while walking, and coordination disorders, is ranked the second among the main clinical manifestations of CCI.[2] [3] Despite a wide range of neuroprotective and vasoactive medicines, effectiveness of therapeutic measures for CCI is inadequate, prompting the need for better and pathogenetically justified strategies for treating the underlying disease and correcting debilitating symptoms.[4]

One of the key elements in the pathogenesis of CCI is disturbances of cerebral blood circulation or in cellular metabolism of brain structures in association with systemic and local dysfunction of endothelium and, thereby, negative changes in the system regulating the rheology and coagulability of blood.[5] [6]

Therefore, a thorough description of the hemostatic disturbances is paramount for improving prevention and therapy of the vestibulo-atactic syndrome in CCI.

We therefore aimed to evaluate changes/disturbances of the system regulating the rheology and coagulability of blood in CCI complicated by vestibulo-atactic syndrome.

At the clinics of Goldberg Research Institute of Pharmacology and Regenerative Medicine, 50 patients with a previously diagnosed CCI, stages 1 and 2, were examined regarding initial manifestations and functional deficits. The inclusion criteria were: 55 to 66 years of age, a diagnosis of CCI, absence of acute neurological events, hypertension stages 1 and 2 (systolic 140–179/diastolic less than 110 mm Hg), and stable condition. Exclusion criteria were: other brain damage detected with magnetic resonance imaging (tumor, acute disorders of cerebral circulation, head trauma), endocrine diseases, cancer, severe anxiety, and depression. The control group consisted of 20 essentially healthy individuals aged 55 to 66 years.

Patients with CCI were examined to evaluate the severity of the vestibulo-atactic syndrome. Symptoms and medical histories were recorded. Neurological examination, audiometry, and vestibular tests were conducted. Routine laboratory tests were performed. Caloric tests were performed with water at 30 and 44°С.[7] The pendulum test was done using a sinusoidal rotation (0.11 Hz) at maximum speed of 100 degree/s.[8] The horizontal positional test was considered positive when obvious saccades (quick, simultaneous movement of both eyes between two or more phases of fixation in the same direction) were observed.[9] The vestibulo-atactic syndrome was defined as poor balance and/or oscillopsia (objects in the visual field appear to oscillate) during movement and decreased reactivity during the bithermal caloric test.[3]

According to the examination results, the main group of patients was divided into two subgroups: Group 1—with vestibular hypofunction (44%; 10 males and 12 females) and Group 2—without vestibular hypofunction (56%; 15 males and 13 females).

All the patients underwent examination of global hemostatic function. Without tourniquet, 1 mL of blood was taken from the cubital vein in a 3-part syringe (V = 2.5 mL, SFM Hospital Products GmbH) for a single-use cuvette made of medical plastic (V = 0.45 mL, Mednord). The analysis started immediately (10–12 seconds) with the piezothromboelastography method on the hardware and software complex ARP-01M (Mednord).[10] [11]

Statistical analysis was performed using IBM Statistics 22.0 (IBM Inc.). Nonparametric tests were used: Mann-Whitney U test and Kruskal–Wallis analysis of variance. The quantitative data are presented as mean and standard deviation ( ± SD) and as median and interquartile range. Differences were considered statistically significant at p < 0.05.

The patients in Group 1 experienced poor balance/instability in 100% of the cases; oscillopsia was detected in 50% of the patients; 8% suffered from migraine. The bithermal caloric tests demonstrated reduced responses with a summated slow phase velocity of nystagmus less than 20 degrees in all 22 patients. The average value for this group was 9 degrees (range 2–18). According to the results of the additional examination, the positional test was abnormal in 80% of the cases. The rotation test showed reduction in responses in 55% of the cases. According to the results of the tone and speech audiometry, asymmetric hearing loss was identified in 80% of the cases.

The data demonstrated that the indicators were within the reference values in the control group and patients with CCI without vestibulo-atactic syndrome.

In the analyses of hemostasis, thrombin time, activated partial thromboplastin time (aPTT), prothrombin time, fibrinogen level, antithrombin activity, and soluble fibrin-monomer complexes in plasma were within normal range in all cases. However, the mean values of the recorded indices in the patients of Group 1 were the closest to the reference boundary of hypercoagulability. The same group demonstrated a slight increase of D-dimer ([Table 1]).

Table 1 Results of the analyses of hemostasis[a]

Hemostasis test	Control (n = 20)	Group 1 (vestibular hypofunction) (n = 22)	Group 2 (no vestibular hypofunction) (n = 28)
TT, s	15.0 ± 1.0	15.0 ± 1.0	14.0 ± 1.0
aPTT, s	32.0 ± 8.0	27.0 ± 8.0	30.0 ± 7.0
PT, s	14.0 ± 2.5	11.0 ± 3.0	13.0 ± 2.0
Fibrinogen, g/L	3.0 ± 1.0	3.3 ± 1.0	3.1 ± 0.9
Antithrombin (%)	95.0 ± 29.0	78.0 ± 27.0	100.0 ± 28.0
D-dimer (ng/L)	450 ± 50	520 ± 55	470 ± 55
SFMC (mg/100 mL of plasma)	3.68 ± 0.32	4.20 ± 0.35	4.11 ± 0.35

Abbreviations: aPTT, activated partial thromboplastin time; PT, prothrombin time; SFMC, soluble fibrin monomer complexes; TT, thrombin time.

^a Results are provided as mean ± standard deviation.

Thus, according to the clinical hemostasiogram, it is possible to conclude that there is a tendency toward coagulation activation in the group with vestibulo-atactic syndrome.

According to the data of low-frequency piezothromboelastography, all the patients with CCI had an increase in the intensity of blood coagulation, which was accompanied by an increase in the value of the intensity of total coagulation by 1.25 times in Group 1 and 1.2 times in Group 2 in comparison with the control group (p < 0.001; [Table 2]).

Table 2 Results of the assessed parameters of low-frequency piezothromboelastography, provided as median (interquartile range)

Parameter	Control (n = 20)	Group 1 (vestibular hypofunction) (n = 22)	Group 2 (no vestibular hypofunction) (n = 28)
t1 (min)[a]	1.7 [1.3; 2.3]	0.9 [0.4; 1.5]***	1.8 [0.6; 2.9]*,∆∆
ICC (r.u.)	14.6 [9.4; 18.4]	32.8 [16.4; 56.25]**	28.4 [16.5; 40.4]**
CTA (r.u.)	33.3 [24.9; 40]	66.24 [51.4; 76.9]***	40 [30.3; 45.4]∆∆∆
t3 (min)[b]	9.2 [8.2; 12.5]	5.4 [4.6; 9.3]***	10.4 [8.7; 12.8]∆∆∆
ICD (r.u.)	38.9 [29.8; 44.6]	71.6 [46.8; 86.9]***	41.4 [34.2; 48.9]∆∆∆
ICP (r.u.)	13.4 [12.3; 19.5]	19 [17.8; 21.1]**	19.2 [18; 20.6]**
t5 (min)	38.5 [31.4; 44.3]	35.5 [30.5; 43.4]	37.4 [32.3; 46.1]
MA (r.u.)	569 [433; 673]	709.5 [614.3; 743.2]*	709 [651.5; 768.5]*
ITC (r.u.)	15.8 [14.5; 16.9]	19.8 [17; 20.6]***	19 [16.1; 22.4]***
RICL (%)	0.3 [0.2; 0.4]	1.6 [0.5; 3]**	0.6 [0.23; 2.4]
CAC (r.u.)	2.4 [2.2; 2.9]	3.6 [2.5; 4.4]***	2.2 [1.7; 2.8]∆∆∆

Abbreviations: CAC, coefficient of anticoagulant activity; CTA, constant thrombin activity; ICC, intensity of coagulation contact; ICD, intensity of coagulation drive; ICP, intensity of clot polymerization; ITC, intensity of total coagulation; MA, maximum amplitude; RICL, retraction intensity and clot lysis value.

*In comparison with the control group, the p-value is ≤0.05; **p ≤ 0.01; ***p ≤ 0.001.

^∆ In comparison with Group 1, the p-value is ≤0.05; ^∆∆ p ≤ 0.01; ^∆∆∆ p ≤ 0.001.

^a t1 indicates the time from the beginning of the study to the achievement of the maximum amplitude of piezothromboelastogram (A1). This indicator is used to evaluate the total influence of the suspense stability of blood and intensity of the background aggregating activity of blood corpuscles.

^b t3 indicates the time when the blood starts to thicken (“gelling point”). The gelling point reflects blood transition from sol into gel-like state. On the curve of the piezothromboelastogram, t3 is determined automatically when the tangent of the slope of the curve changes by 60% relative to the abscissa.

The analysis of the initial stages of coagulation demonstrated differences in the parameters characterizing the suspension stability of blood t1 and the intensity of coagulation contact (ICC). t1 was 1.88 times lower in Group 1 (p < 0.001) and 1.05 times higher in Group 2 (p < 0.05) in comparison with the control group. In Groups 1 and 2 there was a statistically significant increase in the intensity of contact coagulation and aggregate activity (the activity that enables aggregation) of the blood corpuscles: ICC in Groups 1 and 2 exceeds the control by 2.24- and 1.94-fold, respectively (p < 0.05). The examined patients also showed an increase in thrombin activity—a universal enzyme of blood coagulation—upon which the adhesive-aggregate activity of the blood corpuscles, secretion of pro- and anticoagulation factors from the cellular storage pools, clot density, and structure depend on.[12]

The parameter describing thrombin activity—constant thrombin activity—was significantly increased in Group 1 (by 1.98 times, p < 0.001). It was at the upper boundary of the control values for Group 2 (by 1.2 times) demonstrating that the balance of the hemostatic potential of the patients in this group is between the normal and pathological. The differences in the clotting time—t3 reduced by 1.7 times in Group 1 (p < 0.001)—were similarly reduced in comparison with Group 2 and the control group. In the absence of statistically significant differences in t3 between the control group and Group 2, the clotting time tended to lengthen (by 1.13 times). While evaluating the proteolytic stage of fibrinogenesis, Group 1 demonstrated increased intensity of the coagulation drive (ICD), reflecting the intensity of proteolysis of fibrinogen, 1.84 times higher than in the control group (p < 0.001) and 1.72 times higher than in Group 2 (p < 0.001). The ICD values for Group 2 did not differ significantly from the control group. Analysis of the fibrin polymerization stage in the studied subgroups demonstrated the increase in its intensity (ICP) by 1.41 and 1.43 times in Group 1 and Group 2, respectively, in comparison with the control group (p < 0.01). Both groups experienced the increase in the clot density confirmed by the greater maximum amplitude value, which was 1.24 times higher in Group 1 and 1.24 times higher in Group 2 in comparison with the control group.

While evaluating the lytic activity characterized by the retraction intensity and clot lysis value, increased intensity of fibrinolysis was detected in Group 1 by 5.33 times that in the control (p < 0.01) but did not differ significantly from Group 2, for which only a tendency to increased clot lysis was seen. Moreover, increase in the coefficient of anticoagulant activity was observed in Group 1 by 1.5 times higher than in the control (p < 0.001) and 1.63 times higher than in Group 2 (p < 0.001).

The application of the global test of the low-frequency piezothromboelastography in the evaluation of the hemostatic potential of whole blood in CCI patients allowed us to see severity of disorders at all stages of the formation of cross-linked fibrin: initiation, amplification, propagation, and lateral assembly. Thus, according to the clinical hemostasiogram and results of the analysis of the characteristics of the low-frequency piezothromboelastography, we can conclude that there is a decrease in the suspension stability of blood cells with increased thrombin activity leading to chronometric and structural hypercoagulation at the initial stages of fibrinogenesis in CCI. The presence of vestibulo-atactic syndrome in CCI is accompanied by a pronounced procoagulant shift in the phenotype of hemostatic potential.

The obtained results demonstrate the need for further studies to substantiate the possibility of applying anticoagulant therapy to prevent and treat the vestibular dysfunction evolved in CCI.

Publication History

Article published online:
20 July 2020

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