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THROMBOSIS AS THE MANIFESTATIONS OF HEMOSTASIS PATHOLOGY AFTER TOTAL KNEE REPLACEMENT SURGERY IN OBESE PATIENTS Khelo M.D., Akhtyamov I.F.

Kazan State Medical University,

Republican Clinical Hospital, Kazan, Russia

  

Disorders in hemostasis system (for example, thrombosis) present the common complications after total replacement of big joints. In these circumstances, they present the physiological protective mechanisms for prevention of bleeding and acceleration of wound healing [1, 2]. However orthopedists are not satisfied to the full degree, because protection transforms to harm almost immediately, causing the generalization of the process, disorders in microcirculation and system circulation.

 

Etiopathogenesis, incidence

Massive injuries to tissues and exposure of vascular collagen are the triggering mechanisms in pathogenesis of thrombosis development in arthroplasty [3, 4]. The main stages of pathogenesis are: 1. A surgical intervention activates the Virchow's triad: endothelial vascular injury (intrasurgical vascular injury), decelerating blood flow (with the tourniquet applied), activation of coagulation hemostasis. 2. Alternative inflammation with cascade of cytokines and humoral mediators provoke the tone vascular disorders and migration of leukocytes. 3. As result, the masses of fibrin and formed elements appear in vessels which can separate and cause thromboembolism [1, 3, 5]. Disorders in metabolic processes (including obesity) are considered as the high risk factors in relation to such features as endocrine profile disbalance, decreasing tolerability to glucose, hypodynamia, decreasing elasticity and tone of vessels, tendency and prevalence of hypercoagulation processes. The features of thrombosis pathogenesis in obesity are chronic inflammation, deficiency in fibrinolysis factors, hypodynamia, obstructive sleep apnea (respiratory hypoxia), cardiac insufficiency and venous stasis (Fig. 1).

Figure 1 

The block-scheme of the main stages of thrombosis development in obesity state after knee joint arthroplasty

Chronic inflammation in obesity leads to activation by means of metabolic homeostasis dysregulation, insulin resistance, dyslipidemia, lability of arterial pressure [6-8]. Chronic alternative inflammation is increased by effects of inflammatory cytokines produced by adipocytes. Chronic hypoxia and migration of macrophages worsen. They transform from anti-inflammatory M2-macrophages into M-1 anti-inflammatory macrophages.

The table shows the findings of some clinical studies of thrombosis risk after knee joint replacement (KJR) in obese patients. They produce TNFα, IL-6,IL-8,IL-1β, which cause the systemic inflammatory response syndrome (SIRS) in adipocytes by means of autocrine ways. Adipocytes produce excessive amount of leptin. It increases the level of endothelial adhesive molecules, tissue thromboplastin and platelet adhesion in vessels [8-10]. Moreover, obesity increases the expression of plasminogen activator inhibitor-1. The additional risk factor is joint replacement surgery (especially knee joint) in relation to duration and a technical moment of leg dislocation with maximal compression of vessels in the lower extremity [10].

It is necessary to note that the study groups of the patients (the table) received the modern appropriate preparation for hemostasis normalization in pre-/intra- and postsurgical periods. Despite of this fact, in case of obesity, the risk of hemocoagulation disorders showed 2-3-fold increase in the values in comparison with patients with normal body mass index. Even with adequate methods of thrombosis prevention, the risk of recurrent thrombosis and the urgent type of pulmonary embolism is quite high in the first three months after KJR [10, 11, 17]. Such circumstances cause some systemic complications in the body including chronic pulmonary hypertension and postthrombotic syndrome [17].

Table

Rate of thrombosis in obese patients after arthroplasty

Studies	Short description of patients	Incidence
Dore NK et al., 2017 [11]	40 patients with KR
	2 patients with BMI < 18.5 kg/m2	for patients with BMI < 18.5 – 0.99 %
	18 patients with BMI 18.5-25 kg/m2	for patients with BMI 18.5-25 – 1.98 %
	113 patients with BMI 25-29.9 kg/m2	for patients with BMI > 25 – 4.95 %
	7 patients with BMI > 30 kg/m2
Friedman RJ et al., 2013 [6] (review study), with consideration of classic thrombosis and pulmonary embolism	5,485 patients after KR
	825 patients with BMI < 25 kg/m2	5.4 %
	2,116 with BMI 25-29 kg/m2	7.3 %
	2,222 with BMI 30-39 kg/m2	9.3 %
	322 with BMI > 40 kg/m2	9.1 % high risk of symptomatic pulmonary embolism
Amin et al., 2006 [12]	41 patients with BMI 25-39 kg/m2	0.1 %
	41 patients with BMI > 40 kg/m2	9.75 %
Dowsey et al., 2010 [13]	211 patients with BMI 25-39 kg/m2	0.47 %
	57 patients with BMI > 40 kg/m2	5.26 %
Krushell et al., 2007 [14]	39 patients with BMI 25-39 kg/m2	2.56 %
	39 пациентов с ИМТ > 40 кг/м2 39 patients with BMI > 40 kg/m2	2.56 %
Kang J et al., 2015 [15]	543 patients with BMI 26.4 ± 3.2 kg/m2	14.1 %
	175 patients with BMI 31.2 ± 5.2 kg/m2	100 %
Wallace G et al., 2014 [16]	32,485 patients with primary KR
	Patients with BMI 20-25 kg/m2	2 %
	Patients with BMI ≥  26 kg/m2	3.3 %

The differences in incidence of postsurgical thrombosis in different populations are interesting: the mean rate is about 100 : 100,000 in the European countries and Russia, 10-20 : 100,000 in the Southeastern Asia [18, 19]. Possibly, it is associated with higher predisposition to thrombophilia in white population by means of more frequent mutations of Factor Five Leiden (4.8 % in healthy European individuals vs. 0.2 % in Asians) and G20210A locus prothrombin mutation (2.7 % in healthy European individuals vs. 0.2 % in Asians) [20, 21].

 

Thrombosis diagnosis

Diagnosis of thrombotic complications is complex. It includes the clinical and instrumental methods of examination.

Among the clinical symptoms and life quality criteria which give only indirect assumption of the diagnosis, attention is given to Homans’ symptom, edema in the lower extremity and increasing skin turgor in the leg veins, soft tissue edema in the leg ≥ 3 cm as compared to the healthy leg, petechiae and collateral superficial venous veins, immobilization ≥ 3 days after intervention [22, 23]. The common symptoms in suspicious pulmonary embolism are heart rate > 95 per minute, cough and blood in sputum, shortbreathing, chest pain, syncope [24, 25].

Among the diagnostic tests, the important one is biochemical D-dimer test for estimation of blood fibrin byproducts [26, 27]. If it shows negative results, thrombotic complications are almost impossible. If results are positive, subsequent diagnostic search for pathological conditions is continued. Comparing the clinical symptoms, the clinical physicians add ultrasonic examination of lower extremity vessels, pulmonary scintigraphy or computer angiography to the data of laboratory tests [28].

One should note that life style and its quality are to be modified for realization of extensive planned surgery. Particularly, the patient has to change his/her dietary habits and try to decrease body mass (nutritional specialist’s consultation), with daily simple remedial gymnastics (physiotherapist’s consultation), examination of glucose and lipid fractions (endocrinologist’s consultation) and compensation of concurrent somatic pathology [29].

Patients are distributed into three groups according to risk (low, middle, high) depending on presence and combination of identified genetic or acquired factors (primary and secondary) [30]. The primal causes are mutation variations in hemostasis system predisposing to thrombophilia: Leiden factor mutation, G20210A locus prothrombin mutation, deficiency of C/S proteins, deficiency of antithrombin III and others. The secondary predisposing factors are surgical and non-surgical factors (Fig. 2).

Figure 2

The main clinical factors of venous thromboembolic complications for traumatology and orthopedics, where A – unrelated, B – directly related to intervention [30]

Currently, there are detailed protocols of prevention of thromboembolic complications after surgical interventions. For example, we would like to mention the Russian Clinical Recommendations of Traumatologist-Orthopedists (2012) and Phlebologists of Russia (2015) [30, 31]; the National Standard of RF – Clinical Recommendations (treatment protocols) “Prevention of Thromboembolic Syndromes” (2016) [32]; ACCP recommendations (American College of Chest Physicians) and AAOS recommendations (American Academy of Orthopaedic Surgeons) for prevention of symptomatic thromboembolic complications in patients after total knee or hip replacement (2012) [33]; European Anesthesiological Clinical Recommendations for Prevention of Thromboembolic Complications (2018) [34]. All recommendations are almost identical and include the methods for non-pharmacological and pharmacological support.

There are some intrasurgical general procedures for decreasing risk of clot formation: 1) realization of maximally sparing approaches to surgical field and reduction of intervention time, prevention of wound surface contamination (rational antibiotic therapy), efficient analgesia, prevention of hypovolemia and dehydration; 2) prevention of cardiovascular and respiratory failure; 3) use of regionary (spinal or epidural) intrasurgical anesthesia; 4) administration of pharmaceuticals only into the upper extremity veins [30-34].

 

Drug-free prevention of clot formation

The active measures for tone increase are used for normalizing venous blood flow: static elastic compression of lower extremities, intermittent pneumatic compression, cava filters [35].

Cava filters are implanted into the inferior vena cava for prevention of pulmonary embolism. It is the long term measure for preventing and decreasing risk of sudden cardiac death. They are recommended for cases when anticoagulation therapy is contraindicated and for cases with anamnestic data of risk of thromboembolic complications, but the data on efficiency in obese patients is contradictive (according to the metaanalysis and the clinical recommendations) [36, 37].

Intermittent pneumatic compression (IPC) for the lower extremities with pressure of 40-50 mm Hg is realized with the compression cuffs. It is considered as the most efficient mechanic preventive methods, especially in combination with pharmacological prevention [37]. The round-the-clock application is preferable. Static elastic compression of the lower extremities with compression dressing or elastic bandage is conducted immediately after hospital admission of a patient with limited moving activity [30, 37]. It is necessary to note that the presurgical bed-day was reduced to 24 hours in some hospitals; it is also the technique for prevention of hemocoagulation. The special preventive compression dressing (dosed compression hoses) is more efficient and more simple to use, with independent pressure gradient. Elastic compression is to be realized only for non-operated extremity during surgical intervention. For the operated extremity, the bandage (hose) is applied on the surgical table immediately after surgery. Elastic compression for the lower extremities is conducted before return to common moving activity of the patient, with continuation in outpatient conditions [30-34].

The mechanical techniques are sometimes used as the single preventive measure in patients with contraindications to pharmacological prevention due to high risk of bleeding [37]. Recently, electrostimulation for leg muscles for prevention of thrombosis in the lower extremity has become popular in general surgery, traumatology and orthopedics [38]. The technique allows efficient preventing the venous stasis and can be used at hospital and outhospital stages of treatment of patients receiving arthroplasty. Active clinical implementation included it into the recommendations 2015 for thrombosis prevention of Association of Phlebologists of the Russian Federation.

 

Pharmacological prevention of thrombosis

For planned total knee replacement, the anticoagulants are used in the perisurgical period in all patients without contraindications [30-34, 37]. On average, the use of the anticoagulants is 5-6 weeks, but the results from various association of orthopedists, cardiologists and anesthesiologists of Europe and Southeastern Asia are different [8]. For example, European anesthesiological clinical recommendations for prevention of thromboembolic disorders, and American associations of orthopedists recommend to individualize the time of administration of the agents; Russian recommendations adhere to 5-6 weeks [33, 37]. The wide-scale study from the Korean orthopedists (after replacement of big joints in 306,912 patients) approved the time of drug prevention of thrombosis from 10 to 20 days after surgery, and up to 90 days in some cases [37]. The selection of an anticoagulant has to consider the some factors: possibilities of hospital, indications and contraindications of the agent in relation to the risk for the patient, quality of evidences for a medical agent.

Currently, the following basic pharmacological groups are used for thrombosis prevention: unfractionated heparin (UH), low molecular weight heparins (LMWH), vitamin K antagonists (VKA) and disaggregants (aspirin) and the new oral anticoagulants (NOAC) [31].

UH and LMWH present the group of heparin derivatives. This group of the anticoagulants is usually called as direct ones, in contrast to indirect anticoagulants – vitamin K inhibitors.                                         

The pharmacodynamics profile of heparin is determined by its ability to activate antithrombin (AT) by means of specific pentasaccharide part of heparin molecule which provides the association with AT-3 [39]. This part is located in LWMH, presenting fondaparinux in reality [40]. The complex “heparin + AT-3” inhibits thrombin (factor II) and activated factor Xa, and factors IX, XI, XII (procoagulants). Development of fractioned or low molecular weight heparins resulted in more comfortable and safer use of direct anticoagulants. Often clinical administration of LMWH does not require for laboratory control. It is not surprisingly that these agents became the standard for thrombosis prevention in various categories of patients, mainly surgical and orthopedic patients and patients in ICU [39].

The fundamentally other mechanism of anticoagulant activity is associated with VKA. These agents (currently, warfarin is mainly used) suppress the recyclic formation of vitamin K, and block formation of some clotting factors in the liver [41]. Despite of the indirect mechanism, delayed beginning and completion of action, warfarin is irreplaceable anticoagulant in some situations, particularly in orthopedic patients [39].

Some patients receive antiplatelet (antiaggregant) agents (acetylsalicylic acid, clopidogrel or their combination) according to therapeutic indications. Their uptake does not provide appropriate prevention of thrombosis [8, 41]. Therefore, patients with constant receive of antiaggregants should receive preventive dosages of anticoagulants. At the same time, their use in combination with anticoagulants increases the risk of bleeding, and it is necessary to control the course of INR in the coagulogram.

However NOAC agents are dominant in prevention of thrombotic conditions in planned KJR, particularly in obese patients [32, 39]. Currently, the good basis of evidences has been collected for such NOAC as dabigatran, rivaroxaban and apixaban. Currently, their absolute predominance is associated with some evident advantages: oral administration, absent necessity for dose titration (except for patients with renal diseases) and continuous control of INR, independence from food uptake and chemical neutrality in combination with different food products [31, 40-42]. It is not recommended to use NOAC for valval pathology of the heart and for renal failure, but it is a rare event in candidates for arthroplasty.

 

CONCLUSION

Therefore, on the basis of the literature data, we would like to accentuate some moments:

1. Clot formation is an evolutional protective mechanism of the body which cannot be completely excluded from a surgical intervention (as a bleeding source), but some stages are possible to control with various pharmacological agents, which are similar with native anticoagulants in structure and action.

2. Obesity is an unfavorable factor of thrombosis hyperactivation in total knee replacement due to latent chronic inflammation, hypoxia, intense activity of adipocytes in view of stimulation of cascade of proinflammatory cytokines from macrophages and expression of plasminogen activator inhibitor-1.

3. The risk of thrombosis in obese patients is 1-2 times higher than in patients with normal body mass (except for genetic thrombophilia), in patients with comorbid obesity – 2-4 times higher, according to multiple clinical studies.

3. The existing polymodal thrombosis prevention (mechanic + pharmacological) allows total knee replacement without significant risks for patients. However excessive body mass after surgery is still the source of significant risk of delayed hemocoagulation disorders.

 

Information on financing and conflict of interests

The study was conducted without sponsorship.

The authors declare the absence of clear or potential conflicts of interests relating to publishing this article.