Prevention of postoperative hypercoagulation and thromboembolic complications using prolonged adrenoganglioplegia

What is this condition

Hypercoagulation syndrome is not common among the population. According to official statistics, there are 5-7 cases of the disease per 100,000 people. But knowing what it is and how to avoid the risk of the syndrome is absolutely necessary.

The disease is based on a high level of blood clotting due to changes in its composition.

The usual standard for the liquid to solid ratio is 60 to 40%. Due to a lack of fluid, nutrients or other reasons, the plasma in the blood tissues becomes much smaller, and denser elements predominate.

As a result, the blood becomes very thick, loose and sticky. This qualitatively changes its coagulability.

In a normal person, bleeding stops after 2-4 minutes, and a clot remaining on the skin forms after 10-12 minutes. If it occurs earlier, it is suspected that it is prone to hypercoagulability and the necessary tests must be performed to identify the abnormality.

Stages and forms

Hypercoagulation is the initial stage of the development of serious diseases associated with impaired hemostasis - the process of blood clotting. The development of hypercoagulation syndrome is expressed in different ways.

Stages

The first stage is characterized by failures in the formation of blood clots, which entails disruption of the functions of the vascular system.

If this pathology develops, there is a risk that the blood clot completely envelops the blood vessel and stops the blood supply to the body.

The sources of the disease are hidden in the patient’s medical history and have different origins.

Forms

• Congenital pathology. Initially, disturbances in the qualitative or quantitative composition of blood tissue are observed.
• Acquired form. This is a consequence of infectious, viral, cancer and many other diseases.

The second form of structural hypercoagulation occurs mainly in older people. People over 50 are characterized by a physiological age-related decrease in fibrinolysis.

Blood clotting - studies

The necessary diagnosis of hypercoagulable conditions is based primarily on blood tests. In diagnosis, an assessment of the blood coagulation system is carried out; in everyday practice, this is the determination of blood clotting time - prothrombin (PT) and kaolin-kephalin (APTT) - available in any laboratory of a clinic or hospital. To fully assess coagulation, fibrinogen and D-dimers (fibrin breakdown products) levels are measured.

When studying pulmonary complications, computed tomography of the chest is performed in the vascular version, and ultrasound of the heart is performed to assess overload of the right ventricle in case of suspected pulmonary embolism. Ultrasound Dopplerography of the veins of the lower extremities or venography allows you to assess the condition of the venous valves of the extremities and the degree of their damage due to venous disease, and at the same time determine the amount of compression treatment (compression therapy - stockings with the appropriate degree of compression of the veins). Blood morphology determines the platelet coagulation system. Acceptable values ​​are from 150,000 to 450,000. tiles 1 mm thick 3.

Risk factors

These include:

• Unhealthy lifestyle: excessive alcohol consumption, smoking, excess weight.
• Lack of fluid, which entails a lack of complete plasma composition.
• Enzymopathy is a pathological condition associated with improper breakdown of food; dense, unprocessed fragments enter the bloodstream.
• Containing foods in the diet that impair the digestion of foods, especially proteins and carbohydrates.
• Lack of water-soluble vitamins that improve blood quality.
• Liver disease due to impaired biosynthetic function.
• Bacterial infections.
• Dysfunction of the spleen and adrenal glands.
• Damage to blood vessels.
• Diseases such as uterine fibroids, lipoma and leukemia.
• Systemic diseases of the connective tissue of the body (for example, vascular inflammation).
• Misuse of drugs.

There is also a risk of increased blood clotting in patients who have had heart surgery, especially valve or stent implantation. In this case, it is necessary to conduct an additional examination - a coagulogram, and also administer thrombolytic drugs during the operation.

You can reduce the risk of pathology even in the presence of the above diseases through proper nutrition, maintaining the body’s water balance and carefully monitoring the consumption of carbohydrates, sugar and fructose.

Treatment methods for hypercoagulability

Treatment for hypercoagulability involves blocking the function of platelets in the blood or clotting factors produced by the liver. Widely used antiplatelet agents include aspirin or acetylsalicylic acid. The dosage for the prevention of myocardial infarction is 75 mg, stroke ranges from 75–150 mg, higher doses are used in emergency cases after myocardial infarction or ischemic stroke.

To prevent venous thrombosis in the legs, compression stockings with varying degrees of pressure and heparin preparations are used by subcutaneous injection. Currently, there is a very modern treatment for hypercoagulability in patients with atrial fibrillation - the so-called NOAC group of anticoagulants, that is, new oral anticoagulants that have largely replaced the old anticoagulants (acenocoumarol and warfarin). The disadvantage of their use is the relatively high price, the advantage is ease of use - they do not require monitoring of coagulation factors (the so-called INR). Before starting NOAC use, liver and kidney function should be assessed.

About

Symptoms and signs

The main principle of healthy blood and the whole body is timely treatment. If there are precipitating bleeding disorders or questionable tests, it is necessary to conduct a proper interview and study the accompanying symptoms.

Symptoms of the pathology include:

• Fatigue, “flies in the eyes”, blurred vision due to lack of oxygen.
• Evenly throbbing headaches.
• Dizziness with short-term loss of coordination.
• Muscle weakness and tremors.
• Severe nausea.
• Loss of sensation in the limbs, tingling, burning and complete disappearance.
• Dry skin and mucous membranes, frequent bruises (even with light).
• A noticeable reaction to cold is trembling, brooding.
• Poor sleep, attacks of shortness of breath.
• Painful sensations in the heart area - tingling, rapid heartbeat, shortness of breath, shortness of breath.
• Depression with accompanying nervous disorders, tearfulness.
• Burning of the mucous membrane of the eyes, sensation of excess particles.
• Slowing down blood flow in wounds, causing rapid “clotting”.
• Multiple terminations of pregnancy.
• Systemic diseases.
• Frequent urge to yawn.
• Cold extremities, heaviness in the legs, venous pathways are clearly visible.

Only the presence of several of the above symptoms at the same time allows one to think about blood clotting disorders among other pathologies. However, to make a correct diagnosis, a number of specialized medical examinations are necessary.

Diagnostics

Along with the first symptoms that appear in your appearance and well-being, changes in blood tests also appear. Signs of hypercoagulability are also visible in many ways.

Blood parameters

• CIC analysis. The presence confirms the progression of foreign bodies in the body, indicating activation of complement C1-C3.
• Erythrocytosis - an increase in the number of red blood cells from 6 T/l.
• Hyperthrombocytosis - platelet count 500,000 per cubic mm.
• Hemoglobin 170 g/l.
• Fluctuations in blood pressure, tendency to low readings.
• Increased prothrombin index (more than 150%).
• Symptom of platelet aggregation (sticking).

Also, clinical examination of plasma reveals the formation of spontaneous clots. This indicates a clear course of hypercoagulation.

Sometimes diagnostic difficulties arise due to the complete absence of specific clinical symptoms, since most symptoms are characteristic of other cardiovascular diseases, for example, the central nervous system.

Discussion

We found that patients with sepsis who have the same TEM pattern of hypercoagulation, nevertheless, have a different combination of thrombophilia markers, which casts doubt on attempts to replace coagulopathy with any one single-component drug. When planning studies to correct septic coagulopathy, it is necessary to take into account the heterogeneity of this group of patients. As critics point out, the failure of clinical trials of various anticoagulants in sepsis stems from a failure to identify patients who are more likely to respond positively to the test drug. Examples include studies of activated protein C (except PROWESS), antithrombin, tissue factor pathway inhibitor. The history of the thrombomodulin study (SCARLET), which ended negatively quite recently, is interesting [12]. The criterion for inclusion in the study was an increase in the international normalized ratio to 1.4 with a platelet level from 30 to 150·109/l. In most cases of sepsis, this combination will be observed with the development of overt DIC. It turns out that the drug, the main (but not the only) effect of which is the launch of natural anticoagulant mechanisms, was proposed to be administered already in the hypocoagulation phase of DIC. It may be better to select a more appropriate therapeutic window during the hypercoagulable phase for administration of the drug, and also to first test the highly variable effect of thrombomodulin in vitro (for example, in the thrombin generation test with thrombomodulin).

We believe that when identifying hypercoagulability in sepsis, it is necessary to measure the level of physiological anticoagulants (antithrombin, protein C), as this potentially opens up new therapeutic options. D-dimer, factor VIII, von Willebrand factor and a decrease in the level of thrombin generation have a certain prognostic value. However, the number of factors studied, their sequence and frequency of tests remain unknown and require further analysis, since the direct process of transition from hypercoagulation to overt DIC in a clinical setting has not been studied in detail.

Prevention and treatment

The causes of vascular diseases often lie in late diagnosis and lifestyle provocations. Addiction to smoking, alcohol, junk food and sugar are harmful to your health. Therefore, prevention is important to prevent disease and blood clots.

Prevention

• Diet.
• Quitting smoking and drinking alcohol.
• Avoid intense physical activity.
• Walking through a coniferous forest or just in a green park.

You should exclude sweets, pickles, salty and fried foods, as well as bananas, potatoes and carbonated drinks from your diet. Carbohydrates can be obtained in the form of vegetables, fruits and natural juices.

Tea should be unsweetened, marmalade and sweets are allowed to a minimum.

Protein - in the form of porridges and cereal soups, lean meat and fish. For oils, it is better to use butter and olive oil in small quantities.

Medicines

Don't forget to schedule medical help. There is no need to look for substitutes; you should only take what the doctor prescribed.

During treatment, drugs that dilute platelets are often used: aspirin, heparin, fragmin, clopidogrel, chimes, pentoxifylline, etc. To this are added physiotherapy and injections of vitamins E, C, P (or taking them in tablets).

Folk remedies

Treatment at home is allowed only in combination with a therapeutic regimen. Folk recipes are based on the medicinal effects of plants - grapes, string, licorice, etc.

Also, take 1-2 tablespoons of honey in the morning on an empty stomach, and also use garlic and any raspberry jam.

Literature

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8): 801. DOI: 10.1001/jama.2016.0287
2. Iba T., Levy JH, Raj A., et al. Advance in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation. J. Clinical Medicine. 2019; 8(5): 728. DOI: 10.3390/jcm805072
3. Scarlatescu E., Juffermans NP, Thachil J. The current status of viscoelastic testing in septic coagulopathy. Thrombosis Research. 2019; 183: 146–153. DOI: 10.1016/j.thromres.2019.09.029
4. Saito S., Uchino S., Hayakawa M., et al. Epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems. J. Critical Care. 2019; 50: 23–30. DOI: 10.1016/j.jcrc.2018.11.009.
5. Ostrowski SR, Windeløv NA, Ibsen M., et al. Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality: A prospective study. J. Critical Care. 2013; 28(3): 317.e1–11. DOI: 10.1016/j.jcrc.2012.09.003
6. Hincker A., ​​Feit J., Sladen RN, et al. Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Critical Care. 2014; 18(5): 549. DOI: 10.1186/s13054-014-0549-2
7. Dimitrova-Karamfilova A., Patokova Y., Solarova T., et al. Rotational thromboelastography for assessment of hypercoagulation and thrombosis in patients with cardiovascular disease. J. Life Sci. 2012; 6:28–35.
8. Müller MC, Meijers JC, Vroom MB, et al. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review. Critical Care. 2014; 18(1): R30. DOI: 10.1186/cc13721
9. Gonzalez E., Kashuk JL, Moore EE, et al. Differentiation of Enzymatic from Platelet Hypercoagulability Using the Novel Thrombelastography Parameter Delta (Δ). J. Surgical Research. 2010; 163(1): 96–101. DOI: 10.1016/j.jss.2010.03.058
10. Collins PW, Macchiavello LI, Lewis SJ, et al. Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. British J. Haematology. 2006; 135(2): 220–227. DOI: 10.1111/j.1365-2141.2006.06281.x.
11. Gamzatov Kh.A., Gurzhiy D.V., Lazarev S.M. and others. Use of the thrombin generation test to assess the coagulation and anticoagulant activity of the hemostatic system in patients with abdominal sepsis. Bulletin of surgery named after. I.I. Grekova. 2013; 172(5): 66–70. DOI: 10.24884/0042-4625-2013-172-5. [Gamzatov Kh.A., Gurzhy DV, Lazarev SM, et al. Ispol'zovanie testa generacii trombina dlya ocenki koagulyacionnoj i antikoagulyantnoj aktivnosti sistemy gemostaza u bol'nyh s abdominal'nym ​​sepsisom. Vestnik hirurgii im. II Grekova. 2013; 172(5): 66–70. (In Russ)]
12. Vincent J.-L., Francois B., Zabolotskikh I., et al. Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy. JAMA. 2019; 321(20): 1993–2000. DOI: 10.1001/jama.2019.5358

Consequences and complications

The consequences of the disease are very serious and in advanced stages leave no chance for a healthy lifestyle.

The most common complications include congestion and the formation of blood clots in the blood vessels. The vascular canal or coronary artery may be completely closed. This leads to cardiac arrest in vital systems.

• Severe hypertension.
• Impaired elasticity of the arteries, accompanied by the deposition of cholesterol plaques.
• Phlebeurysm.
• Stroke and heart attack.
• Systemic migraine.
• Thrombosis.
• Thrombocytopenia.
• Systematic and isolated cases of abortion.
• Preservation of intrauterine development.
• Infertility.

Pathology during pregnancy

The serious danger of hypercoagulability during pregnancy is obvious. By the way, this syndrome most often occurs in older men and pregnant women.

In the history of pregnant women, hypercoagulability syndrome is often referred to as “moderate hypercoagulability” or “chronometric hypercoagulability.”

In both cases, we are talking about the “activation” of special mechanisms in the mother’s body. Their task is to avoid large blood loss during childbirth, which requires constant monitoring.

Danger for baby

In case of increased blood density and viscosity, the fetus does not receive adequate nutrition. As a result of lack of control or untimely administration of treatment, serious consequences will occur for the child.

Deviations in the physiological development of the fetus and cessation of vital activity in the womb are possible.

Risks for a pregnant woman

These include:

• Miscarriage.
• Bleeding from the uterus.
• Placental abruption.
• Active forms of late toxemia, etc.

Multiple myeloma (MM) accounts for about 10% of all hematological tumors. Despite the fact that the disease remains incurable, modern therapeutic approaches have significantly improved the overall survival of patients. As a result of the use of “new” drugs (proteasome inhibitors, immunomodulators) in combination with chemotherapy drugs and glucocorticosteroids (GCS), as well as high-dose therapy and transplantation of autologous hematopoietic stem cells, the median total life expectancy increased from 24-30 to 60 months [ 1].

The course of the disease is accompanied by disturbances in the blood coagulation system, which can lead to thrombotic or (less commonly) hemorrhagic complications [2].

The highest incidence of thrombosis is recorded in patients with MM during the first year after diagnosis of the disease and during antitumor therapy without appropriate prophylaxis can reach 34-58% [3, 4].

It is reasonable to believe that understanding the mechanisms of disruption of the coagulation system would make it possible to anticipate possible complications and take preventive measures in a timely manner. That is why many specialists have shown increased interest in this issue in recent decades. Thanks to several dozen studies, it has been shown that patients with MM have a combination of various factors affecting hemostasis.

As with many other malignant neoplasms, the risk of thrombosis in MM is associated with the circulation of proinflammatory cytokines. So,

A. Palumbo et al. [5] assign a significant role to interleukin-6, tumor necrosis factor, and C-reactive protein. An increase in the concentration of these proteins can lead to activation of the coagulation system due to interaction with coagulation factors, blood cells (platelets, monocytes), as well as with the vascular wall and endothelial damage [6, 7].

One of the mechanisms of tumor growth (both in solid tumors and in MM) is neoangiogenesis [8]. Circulating vascular endothelial growth factor (VEGF), as well as the formation of a complex of tissue factor with factor VIIa, triggers the extrinsic mechanism of the blood coagulation cascade [9, 10].

M. Zangary [7] and J. Aurwerda [9] note an increase in the activity of circulating factor VIII and von Willebrand factor in patients with MM in the advanced phase of the disease. Moreover, a correlation was revealed between an increase in the number of inflammatory cytokines and an increase in the activity of these factors. The authors also note that one of the reasons for the increased risk of thrombotic complications is the emergence of resistance to activated protein C (anticoagulant), which disappears as the tumor mass is reduced [10-13].

One of the main distinguishing features of MM is paraproteinemia, which leads to essentially different hemostasis disorders - both hemorrhagic and thrombotic conditions. One of these symptoms is increased blood viscosity. The pathogenesis of hyperviscose syndrome is explained not only by an increase in the concentration of pathological protein, but also by excess plasma, which always accompanies hyperproteinemia [14].

Light chains of immunoglobulins can form complexes with platelets and coagulation factors - V, VII, VIII, prothrombin and fibrinogen, thereby disrupting the function of these factors and potentiating bleeding. At the same time, paraproteins “envelop” the proteins of the fibrinolysis system, preventing the timely lysis of fibrin and dissolution of the thrombus [15].

The proliferation of plasma cells in the bone marrow increases the activity of osteoclasts, resulting in bone tissue resorption, which leads to the redistribution of calcium and an increase in its amount in the blood serum [16]. In this case, the development of thrombosis can be facilitated by both hypercalcemia and prolonged immobilization of patients due to pathological bone fractures. In addition, there are studies that reveal increased levels of heparinase, which is synthesized in plasma cells and destroys both endogenous heparin and heparin administered to patients for prophylactic purposes [16]. However, apparently, the role of this factor is not so significant.

Along with venous thrombosis, patients with MM have an increased incidence of arterial thrombosis (including myocardial infarction and stroke). As is known, arterial thrombi consist mainly of platelets and fibrin strands (while venous thrombi consist mainly of erythrocytes and fibrin). This is a consequence of increased platelet activation [15, 17].

Against the background of secondary immunodeficiency, patients with MM often experience infectious complications that support systemic inflammation, and in the case of sepsis, they can lead to disseminated intravascular coagulation syndrome. Under the influence of the lipopolysaccharide complex of a number of bacteria, a sharp intensification of the cyclooxygenase metabolic pathway occurs. Increased activity of thromboxane A2 leads to massive platelet aggregation. The interaction of microorganisms with blood cells (platelets, monocytes) and endothelium leads to the expression of tissue factor and the initiation of blood clotting. In this case, phospholipids of bacterial cell membranes are a catalyst that accelerates the coagulation reaction. The biological meaning of microthrombosis during infection is to limit the inflammatory focus. However, in conditions of an infectious process poorly controlled by the immune system, activation of the blood coagulation system can become uncontrollable and lead to both severe thrombotic complications and bleeding as it enters the hypocoagulation phase as a result of massive consumption of factors [18, 19].

Antitumor therapy makes a separate contribution to thrombus formation. A. Palumbo et al. [20] showed a high risk of thrombosis due to the use of immunomodulators—thalidomide and lenalidomide—in treatment regimens, especially in combination with high doses of dexamethasone.

It should be noted that there is no increase in the incidence of thrombosis during therapy with bortezomib (in monotherapy, as well as in combination with chemotherapeutic drugs and corticosteroids). Even the possibility of leveling procoagulant activity due to bortezomib therapy is being discussed, but this assumption requires further study [6, 21].

To date, recommendations have been developed and adopted for the prevention of thrombosis in patients with MM. It is recommended, along with laboratory tests, to take into account additional risk factors (RF), such as age, obesity and lipid metabolism disorders, diabetes mellitus, a history of thrombotic episodes, heart disease, arrhythmias and the presence of an artificial pacemaker, kidney disease, immobilization, acute infection, installation of a central venous catheter, therapy with erythropoietin, corticosteroids, anthracyclines, immunomodulators. It has been shown that in the presence of one of the risk factors, it is sufficient to prescribe aspirin as a prophylaxis for thrombosis. In the presence of 2 of the listed factors, it is more advisable to carry out anticoagulant therapy with low molecular weight heparin or warfarin [20, 22].

Despite the interest of clinicians in the problem of hemostasis disorders in patients with MM, many mechanisms remain unclear, and the detection of thrombotic complications even against the background of anticoagulant therapy prompts an even more thorough analysis of risk factors.

Standard coagulation tests to identify disorders in the coagulation system are assessments of clotting time: activated partial thromboplastin time (aPTT), reflecting the state of the internal coagulation pathway, prothrombin index (PTI), characterizing the work of the external pathway, and thrombin time (TT), characterizing the final phase of the coagulation cascade - the rate of fibrin formation. To conduct research, platelet-poor plasma is used, to which an activator (kaolin and thromboplastin), phospholipids and calcium chloride are added, which immediately starts the coagulation process. The result of these tests is the time interval between recalcification and the appearance of a fibrin clot [19, 23]. The advantage of these tests is the ability to simply and quickly assess directly the result of the interaction of most coagulation factors. However, the addition of high concentrations of the activator used in these methods leads to very rapid clot formation, which does not always reflect the processes occurring in vivo

[23]. Changes in APTT and TV indicators occur with a significant deficiency or excess of factors.

One of the methods for integral assessment of hemostasis is the study of thrombin generation. The principle of the method is based on recording the concentration of thrombin in the sample at each time point by measuring fluorescence during the cleavage of a thrombin-specific fluorogenic substrate by the resulting thrombin after adding a coagulation activator (thromboplastin or koalin) to recalcified platelet-poor plasma. The dynamics and amount of thrombin formed determines the rate and intensity of the conversion of fibrinogen into fibrin, and, consequently, the entire process of thrombus formation [23-25].

Another method for global assessment of hemostasis is thromboelastography (TEG). The technique is performed using a small amount of whole blood, which is placed in a cuvette, recalcified, and then an activator is added. A sensor placed in a cuvette that makes slow oscillating movements records the rate of formation and physical properties (strength, elasticity) of the forming clot. The fundamental difference between TEG and standard coagulation tests is that of the known components of the hemostatic system, TEG evaluates 4 main ones: the coagulation cascade, platelets, anticoagulation mechanisms and the fibrinolysis system [23].

One of the qualitatively new, as close as possible to in vivo

tests for studying hemostasis can be a method for studying the spatial dynamics of fibrin clot formation (thrombodynamics - TD), developed at the Federal State Budgetary Institution State Scientific Center of the Ministry of Health of Russia. A series of experiments has shown its high sensitivity to conditions of both hypo- and hypercoagulation. The method not only allows one to estimate the rate of formation of a fibrin clot upon activation with immobilized thromboplastin (imitation of vessel damage), but also records the formation of spontaneous clots in the plasma volume away from the activator, which obviously play an important role in the readiness of plasma for thrombus formation. This method also measures the optical density of the clot, which makes it possible to assess the binding density of fibrin strands and, accordingly, the potential for fibrinolysis [23].

The purpose of this prospective study was to determine the frequency and nature of disorders in the blood coagulation system in patients with MM and to assess the adequacy of preventive anticoagulant/antiplatelet therapy.

Materials and methods

A prospective study conducted in the department of high-dose chemotherapy and bone marrow transplantation of the Hematological Research Center of the Ministry of Health of the Russian Federation from March 2012 to May 2013 included 25 patients with newly diagnosed MM (13 men and 12 women) aged 29-72 years ( median 54 years). The immunochemical variant of the disease in 16 (64%) patients belonged to class G, in 2 (8%) to class A, in 6 (24%) Bence-Jones MM was diagnosed, and in 1 (4%) solitary plasmacytoma. According to the Durie-Salmon criteria, the stage of the disease at the time of examination was determined as III in 13 (52%) patients, II in 9 (36%), and I in 2 (8%). According to the international system, stage I was diagnosed in 9 patients, stage II in 11 and stage III in 5 patients. In 7 patients, renal dysfunction was detected. The diagnosis was made according to the IMWG criteria.

Paraprotein in the blood serum of 3 (12%) patients was detected only in trace amounts; in 16 (64%) its concentration was above 30 g/l, with a maximum value of 78 g/l. At the same time, the amount of total protein was normal in 9 (36%) patients, high in 16 (64%), with the highest indicator being 145 g/l. In 9 (36%) patients, the albumin level was reduced (20-33 g/l), in 7 (28%) the calcium level in the blood serum was increased. In 16 (64%) patients, the amount of β2-microglobulin (β2-MG) was increased, the maximum value of which (31.2 mg/l) was noted in a patient with renal failure. C-reactive protein exceeded the norm (6.61-57.5 mg/l) in 4 patients. The number of plasma cells in the bone marrow ranged from 2 to 74%. Extramedullary plasmacytomas were detected in 8 (32%) patients.

The state of hemostasis was assessed according to the results of tests: aPTT, TV, time of XIIa-dependent fibrinolysis, PTI according to Quick and INR, fibrinogen and D-dimer content. In addition, integral methods for studying hemostasis were used, two of which are classical - the thrombin generation test and TEG, as well as a new method for determining the spatial growth of the clot - the TD test.

The obtained data were regarded as normocoagulation if their numerical value fell within the control framework.

The norm for APTT (from 25 to 38 s) was determined by the time of clot formation in standardized lyophilized plasma; the norm for TV was from 12 to 19 s. The proper PTI indicator according to Quick was 70-130%. The normal amount of fibrinogen was estimated at a level of 1.8-3.5 g/l. The time of XIIa-dependent fibrinolysis was considered normal in the range of 4-12 minutes, the concentration of D-dimer was less than 500 μg/L.

According to the results of the study of the thrombin generation test, the normal value of endogenous thrombin potential (ETP) was considered to be 760-1450 nM min; The maximum thrombin concentration was normally 140-270 nM.

When analyzing TEG data, the normal “reaction time” (R) corresponded to a period from 9 to 27 minutes, the reference time of the “amplification phase” (k) - from 2 to 9 minutes. The rate of clot formation was assessed by the angle α, which normally could range from 22 to 58°. The norm of the maximum amplitude of curve divergence (MA) was 44-64 mm.

In the TD study, the reference values ​​for the initial and steady-state clot growth rates were 36-56 and 20-30 µm/min, respectively (the range of clot growth rates in 50 healthy volunteers). Clots of spontaneous (outside the activator) thrombus formation were normally absent.

“Hypocoagulation” was recorded in the case of an increase in APTT and TV, a decrease in fibrinogen concentration, and PTI; reduction of ETP and maximum thrombin concentration (in the thrombin generation test); lengthening of R, k, decrease in angle α and maximum amplitude (in thromboelastography); and also when the clot growth rate in the TD test decreases.

“Hypercoagulation” was assessed by accelerating APTT, TT, slowing XIIa-dependent fibrinolysis, increasing PTI, fibrinogen and D-dimer concentrations; increase in ETP and maximum thrombin concentration; acceleration R and k, increasing angle α, and MA; an increase in the rate of clot growth, as well as the formation of spontaneous fibrin clots in the plasma that form far from the immobilized thromboplastin.

Statistical analysis was carried out using the multiple linear regression method (with a stepwise elimination procedure). Statistically significant factors associated with the concentration of D-dimer (a marker of completed microthrombosis) were identified. We assessed the adequacy of the regression model (the distribution of residuals is normal, the coefficient of determination is 0.65; p

=0.05). Graphs of correlations between the concentration of D-dimer and the identified significant predictors were constructed (taking into account that the values ​​of the partial and pairwise correlation coefficients practically coincided). Statistical packages SAS 9.3 and SPSS 16.0.2 were used for calculations.

Results and discussion

When studying hemostasis in primary patients with MM, in 19 (76%) cases the aPTT was normal.

The remaining 6 (24%) patients showed hypocoagulation (40-56 s). TV remained normal in 14 (56%) patients, and in 11 (44%) it also indicated a state of moderate hypocoagulation (20-29 s).

PTI according to Quick and INR were shifted towards hypocoagulation in 5 patients, reaching extreme values ​​of PTI 48% and INR 1.55. In the remaining 20 patients, PTI and INR values ​​remained within normal limits.

In 7 (28%) patients, an increase in fibrinogen concentration was determined: 3.6-5.4 g/l, in 2 (8%) - its amount was reduced (1.0 and 1.3 g/l).

In 11 (44%) patients, an increase in D-dimer content was detected; Moreover, in 2 patients this figure only slightly exceeded the upper limit of normal: 534 and 614 μg/l, and in the rest it exceeded the permissible limit by 4-17 times, reaching 16,722 μg/l. High (1000 μg/l or more) concentration of D-dimers was statistically significantly 2 times more common in men and in stage III of the disease than in women and patients with stage II MM. In patients with stage I of the disease, the concentration of D-dimers did not exceed the norm.

According to the thrombin generation test, in 19 (76%) patients the ETP corresponded to the norm, in 5 (20%) it moderately exceeded the norm (1456-2120 nM·min), and in 1 patient it was reduced to 600 nM·min. Peak thrombin concentration was increased (278-390 nM) in 6 patients and remained decreased (80 and 99 nM) in 2.

When studying TEG, normocoagulation was recorded in 13 (52%) patients, moderate hypocoagulation - in 4 (16%). In 8 (32%) patients, the parameters were shifted towards hypercoagulation, and MA was mainly increased, reaching a maximum level of 88.2 mm.

The initial rate of clot growth was increased in 10 (40%) patients, and the stationary rate was increased in 7 (28%). In 4 plasma samples, active formation of spontaneous clots was detected, which merged with each other and with a clot growing from the activator, characterizing a state of hypercoagulation. Despite this, in 12 (48%) patients a decrease in the density of the fibrin clot was detected (from 2951 to 14,757 conventional units).

In the table

The results of assessing hemostasis using various methods are presented.
It should be noted that, despite the normal (or shifted towards hypocoagulation) aPTT, in 17 (68%) patients at least one of the methods used revealed hypercoagulation.
The identification of a high concentration of D-dimer and the relationship of this parameter with other factors deserve special attention. Multiple linear regression analysis revealed a correlation between D-dimer concentration and ETP value (Pearson's partial correlation coefficient R

0.61;
regression coefficient 0.48; p
=0.01)
(Fig. 1)
.
Figure 1. Positive correlation of D-dimer concentration with ETP.
The amount of thrombin determines the intensity of the conversion of fibrinogen to fibrin. That is why the study of the thrombin generation test (the key enzyme of hemostasis) is an important part of the work. Despite the fact that the upper limit of normal was exceeded in only 20% of patients, we identified a connection between this parameter and the concentration of D-dimer.

An interesting finding was the presence of a direct correlation between the concentrations of D-dimer and β2-MG.

In patients with elevated levels of D-dimer, high concentrations of β2-MG were determined in 50% of cases (on average 9.7 mg/l). Moreover, the levels of β2-MG in patients with normal D-dimer levels were statistically significantly different from those in patients with high D-dimer concentrations ( p

<0.05)
(Fig. 2)
.
Figure 2. Association of β2-MG with normal (n=15) and increased (n=9) D-dimer concentrations.
Based on this, it can be assumed that β2-MG may also play a role in the procoagulant status of patients. With TEG, almost a third of patients have increased MA, which may reflect increased activation of the platelet unit.

When studying hemostasis using the TD method, despite the increase in the rate of fibrin clot formation, its insufficient density was shown. When analyzing the results obtained, an inverse correlation was revealed between the concentration of paraprotein (as well as total protein) and the density of the fibrin clot. Based on this, it can be assumed that the pathological protein can be integrated into the structure of the fibrin clot, leading to the formation of an incomplete thrombus (Fig. 3)

.
Figure 3. Negative correlation of M-gradient with fibrin clot density.
Patients received induction therapy using PAD (bortezomib + doxorubicin + dexamethasone) or VCD (bortezomib + cyclophosphamide + dexamethasone) regimens. To prevent thrombosis, a round-the-clock intravenous infusion of unfractionated heparin was administered at a dose of 500 U/h or aspirin was prescribed at a dose of 100 mg/day.

At the stage of induction therapy, hemorrhagic complications were absent in all patients; in one case (a 71-year-old man) ileofemoral thrombosis developed. The disease manifested itself with ossalgic syndrome at the beginning of 2012. The patient independently took non-steroidal anti-inflammatory drugs with a temporary effect. In May 2012, computed tomography revealed tumor formations in the ThVI and ThIX vertebrae. Histological examination of a biopsy specimen of the formation revealed a tumor substrate: plasma cells. Upon further examination, multiple foci of osteodestruction were discovered in other bones of the skeleton, as well as soft tissue components in the area of ​​the ribs. An immunochemical study revealed monoclonal secretion of Bence-Jones-λ paraprotein in blood serum (800 mg/l) and urine (traces). The number of plasma cells in the bone marrow was 8.6%. Kidney function is not impaired (blood creatinine 87 µmol/l). Based on the examination, a diagnosis was made: MM, occurring with paraproteinemia and Bence-Jones-λ proteinuria, stage IIIA, low-secreting form, occurring with multiple osteodestructions and the presence of extramedullary soft tissue components (in the ThVI and ThIX vertebrae, protruding into the spinal canal, as well as in areas of the VI ribs on the right, VII and VIII ribs on the left). The course of the disease was complicated by lower paraparesis and dysfunction of the pelvic organs.

During the initial assessment of hemostasis in this patient, APTT, PTI, fibrinogen concentration, TEG parameters and ETP indicator were normal, but a high concentration of D-dimer (8116 μg/l), prolongation of XIIa-dependent fibrinolysis (15 min), and an increase in the growth rate of fibrin clot (Vinit. 62 µm/min, Vst. 32 µm/min). The first induction course of VCD for the patient was carried out in the hospital with accompanying therapy with unfractionated heparin 500 units/hour.

As a result of the first course of therapy, a reduction in the size of the soft tissue components was achieved, as a result of which movements in the lower extremities were restored and dysfunction of the pelvic organs regressed. To perform stabilizing surgery for complete destruction of the ThIV vertebra, the patient was transferred to a neurosurgical hospital. Aspirin was discontinued before surgery. 3 days after discontinuation of the drug, the patient developed ileofemoral thrombosis. The operation has been postponed to a later date. Anticoagulant therapy with dalteparin was carried out for 3 weeks at a dose of 11.4 thousand IU/day, as a result of which vascular recanalization was achieved. The metal structure was successfully installed. Subsequently, the patient constantly took aspirin, which allowed him to continue induction therapy and achieve a stable partial remission of the disease. Thrombotic complications did not recur.

Conclusion

Analysis of laboratory data made it possible to note that, despite the normal result of the standard APTT test, hypercoagulation was detected in 68% of patients by at least one of all studied methods, which indicated an increased readiness for thrombus formation. At the same time, in 50% of patients, the formation of a blood clot with low optical density was noted. An inverse correlation was found between the density of the fibrin clot and the content of pathological protein in the blood.

Heparin infusion at a dose of 500 U/h or aspirin at a dose of 100 mg/day were adequate prevention of thrombosis.

Along with laboratory assessment of the hemostasis state of each patient, it is important to take into account additional risk factors, such as old age and prolonged immobilization.

Despite the fact that some mechanisms of disorders in the coagulation system leading to excessive thrombus formation are now known, and most patients receive preventive therapy, cases of thrombosis that have occurred prompt further research.