The Pathophysiology of Venous Ulceration at the Cellular Level
The paper will explore the biology of wound healing. It will attempt to answer several questions such as why is Mrs. Harrison’s wound taking more than six weeks to heal, how does the varicose vein affect the wound healing process, what is the cause of smell and leakage and also the pathophysiology of venous ulcer.
Venous stasis in varicose disease occurs due to deforming phlebosclerosis and the venous wall loss of its biomechanical properties (damage to contractile structures leads to loss of tone, and damage to supporting structures leads to varicose degeneration), as well as dysfunction of valves as derivatives of the venous wall. Chronic venous insufficiency (CVI) of the lower limbs is, first of all, their insufficient release from venous blood, and not the insufficiency of blood flow to the heart (Martinez-Zapata, Martí-Carvajal, Solà et al. 2012).
The formation of trophic ulcers of the lower extremities with CVI is a complex pathophysiological process. In the last decade, much attention has been paid to conducting fundamental research on the molecular and cellular mechanisms of its pathogenesis.
There are several theories of the formation of trophic venous ulcers of the lower extremities: the theory of microcirculation disorders, the theory of hypoxia, fibrin exudative theory, the theory of leukocyte aggression, microbial theory, the theory of immune disorders (Falanga et al 1987).
The leading mechanism for the formation of trophic ulcers of the lower extremities with varicose disease is impaired microcirculation in the distal extremities. Changes in microcirculation in chronic limbic insufficiency of lower extremities are characterized primarily by local tissue hypoxia in the lower third of the leg, manifested by a significant reduction in tissue oxygen partial tension in the area of ??trophic ulcers against a low functional reserve of microcirculation or ischemic depression of microcirculation
However Green, Jester, McKinley & Pooler (2014) found that changes in microcirculation in the skin and subcutaneous tissue in elderly patients with varicose trophic ulcers of the lower extremities are not only local (in the lower third of the leg), but common, detected in its other segments.
The theory of hypoxia focuses on the formation of trophic venous ulcers of the lower extremities on the violation of the oxygen perfusion of its tissues (Bevis & Earnshaw 2011). Proponents of this theory believe that insufficiency of the venous valves leads to the deposition of blood in saphenous veins with slower blood flow and reduced oxygen partial pressure in skin capillaries. Reduced oxygen content in the deposited blood leads to hypoxic damage to nearby skin.
Fibrin exudative theory associates the pathogenesis of trophic venous ulcers with an increase in venous pressure in the lower extremities, which is transmitted to the microvasculature of the skin and increases the permeability of the skin capillaries (Bevis & Earnshaw 2011).
The increased permeability of the skin capillaries allows macromolecules, such as fibrinogen, to penetrate into the pericapillary tissues. Further transformation of fibrinogen into fibrin leads to the formation of a fibrin “cuff” around the capillaries of the skin.
According to Nash,Thomas & Dormandy (1988), this cuff serves as a barrier to the diffusion of oxygen, which leads to tissue hypoxia and cell damage. Strong chemoattractants, as well as leukocyte and platelet activators can act as substances accumulating in the area of ??fibrin deposits that form around the capillaries. This leads to chronic inflammation, exacerbating chronic venous insufficiency. However, in subsequent studies by Bollinger et al (1982), it was shown that fibrin cuffs cannot cause a significant decrease in oxygen diffusion.
Theories of the Formation of Trophic Venous Ulcers
In recent years, papers have been published in which leukocytic aggression (the theory of leukocyte aggression) is considered the basis for the formation of trophic ulcers in patients with varicose disease. Its authors propose a scheme for the formation of trophic ulcers in the form of a dynamic process shown in the chart below
Indeed, with CVI of the lower extremities, the phenomenon of activation and endothelial adhesion of leukocytes with their subsequent migration into paravasal tissues was discovered.
According to Braide et al (1984), it is macrophages fixed in capillaries that cause vessel obstruction, a decrease in capillary blood flow and the development of micronecrosis of tissues. Further penetration of leukocytes into tissues subjected to anoxia and ischemia causes their pathological activation with the release of cytokines (leukotrienes, thromboxane, interleukins, tumor necrosis factor). Cytokinins have a different effect: 1) to increase vascular permeability, contributing to the progression of the edema of the lower limb, 2) cause adhesion of blood cells to form a leukocyte and platelet plugs in microvessels with the subsequent formation of blood clots in the venous line, the release of lysosomal enzymes, active radicals, toxic metabolites oxygen. The ongoing processes further damage the microvasculature, contributing to the development of chronic inflammation, local and systemic allergic reactions, reducing cell proliferation and recovery. This is the cause of long-term healing of venous ulcers. Simultaneously with the described processes in lower extremity CVI, the activity of skin fibroblasts decreases in the latter: the ability to cytokinesis and growth.
At the same time, a number of researchers believe that the term “leukocyte aggression” should cause great doubts (Kang et al 2012). In their opinion, leukocyte and macrophage reactions cannot in principle be called aggression. They should be considered as a defense reaction, and their imperfections or side effects do not give grounds for a change in the established and correct.
According to Belcaro, Christopoulos & Nicolaides (1991), the formation of trophic ulcers is due to prolonged venous stasis and constant hydraulic load, which disrupt the processes of capillary permeability. It is a long venous stasis and a constant hydraulic load that violate the processes of capillary permeability. The erythrocytes, which, disintegrating, create hemosiderosis, release large protein molecules and lipid complexes, go into extravasal space. All of this, by denaturing, forms complexes that are subject to resorption. According to biological laws, it can be carried out only through an inflammatory reaction, mainly through its cellular phase – acute (leukocyte) and chronic (macrophage). Chronization occurs because the factors causing this process cannot be eliminated.
Isolation of the so-called toxic substances in other conditions would be useful. Thus, the release of oxygen free radicals by macrophages, as well as the release of enzymes by neutrophils, provides phagocytosis and protects the body against bacteria. If leukocytes did not secrete destructive enzymes, they would never pass through the endothelium and would not fulfill their function. However, the presence of immune changes and the presence of a constant factor that causes and maintains inflammation leads to the formation of a continuous cascade of perivascular cellular reactions with pathological transformation of the substances secreted by this
The Theory of Hypoxia
Proponents of the microbial theory of the development of venous trophic ulcers emphasize that bacterial contamination and colonization of trophic venous ulcers always occurs. Differences in the microbial spectra of trophic ulcers in varicose disease and in PTFS of the lower extremities have been established.
When varicose veins in 75% of patients staphylococcus and their combinations are sown. Gram-negative microorganisms were found in 25% of patients (Franzeck et al 1984). At PTFS, the percentage of detection of gram-negative flora increases to 41%. It was found that the microbial spectrum depends on the duration of the ulcer. So, with an ulcer lasting up to a year, saprophytic or staphylococcal microorganisms dominate in the microbial spectrum. With PTFS and long-term existence of the ulcer pathogenic Gram-negative bacteria and anaerobes are sown. However, an inflammatory reaction in a trophic ulcer of any size almost never makes it possible to develop a common surgical infection, despite the presence of diverse microflora (Jawien, Szewczyk, Kedziora-Kornatowska et al. 2006). Obviously, microbes simply vegetate in an ulcer, like on the skin, and the attachment of the microbial component to the course of a trophic ulcer is important for maintaining inflammation.
The role of immune disorders in the development and recurrence of trophic ulcers of the lower extremities has been little studied. In most of the publications available, systemic immune changes are assessed in isolation from local changes in soft tissue. At the same time, Banys, Kazmierski & Jaszewski (2011) identified the relationship between the immune status, the clinic, and the course of venous ulcers of the lower extremities, and the time frame for their healing. The authors showed that in patients with trophic ulcers of the lower extremities of venous etiology there are marked disorders of systemic and local immunity, expressed in an increase in the blood from the cubital vein content. An increase in the concentration of circulating immune complexes (in 84%), an increase in activity, an increase in population cells of the immune system (monocytes / macrophages, MK-cells, neutrophils), hyperplasia of CD4 + 45RO + T-cells “memory” in 64% of patients, increased expression of CD25 molecules (a-chain of the interleukin-2 receptor) on CD4 + T-cells, ESR in 68%, C-reactive protein in 38%. At the same time, in capillary blood near the ulcer, a significant decrease in the number of CD16 + 56 MK cells, a decrease in the number of MKT cells, as well as CD8 + T cells with an a-chain of interleukin-2 receptor on the cell membrane was observed (Sindrup et al 1987). This indicates the participation of these cells in the pathological process. At the same time, immunological disorders were directly related to trophic lesions of the skin and did not depend on the underlying disease. Significant differences in immune status, depending on the duration of the underlying disease before the first appearance of trophic ulcers have been identified, Studies of recent years obtained information about the possible role of tissue proteases (metalloproteases) in the development of trophic disorders in the CVI of the lower extremities (Nicolaides, Christopoulos & Vasdekis 1989). It was found that the synthesis of matrix metal proteases (MMP) and their tissue inhibitors (T1MP) occurs in all patients in the area of ??impaired trophism. The most well studied MMP-1, MMP-2, MMP-9, T1MP-1, T1MP-2. However, their relationship and role in the pathological process are not completely clear. Matrix metalloprotease-9 is synthesized directly around the trophic ulcer, and metal proteases 1 and 8 are found in the usually not healing venous trophic ulcers. A decrease in the amount of the T1MP-1 inhibitor is noted.
Fibrin Exudative Theory
Damage to tissues by leukocytes includes a number of pathogenetic mechanisms. With venous hypertension, there is an expansion of the capillaries and a significant reduction in the blood flow velocity in them (Labropoulos et al 2012). Under these conditions, intravital microscopy showed that leukocytes in the capillaries move more slowly than red blood cells, which is explained by their large volume and spherical shape. This leads to the accumulation of red blood cells behind each white blood cell as it passes through the capillaries. Getting into the postcapillary venule with a large diameter, red blood cells shift white blood cells to the periphery of the vessel, where some of them stick to the endothelium, the phenomenon of “marginal standing” of leukocytes occurs.
Adhesion of leukocytes to the endothelium leads to their activation, release of free radicals, proteolytic enzymes and tissue damage. Neutrophils can also migrate through the vascular wall to the extracellular space. Continuing for a long time, this leads to deep trophic disorders of the soft tissues. It should be noted that extravasation of blood cells is a multi-step process, including activation and release of adhesive molecules by both leukocytes and endothelial cells, the interaction between these cells and their release of reactive substances (leukotrienes, interleukins, oxygen free radicals, etc.)
Rational nutrition involves controlling body weight, eliminating fatty, spicy and salty foods (excessive water load provokes edematous syndrome), eating bread from wholemeal bran and buckwheat, vegetable oil up to 50 ml daily, increasing diets from raw vegetables and fruits correction of beriberi and micronutrient deficiencies. Vitamin C and B complex are the recommended nutrients (Hudson et al 2013).
Currently, the indisputable fact is that without compression, none of the known methods of treating diseases of the veins of the lower extremities can be successfully implemented. Moreover, it can be said that compression treatment is the only pathogenetically justified, safe and practically non-contraindicated method.
In chronic venous insufficiency with severe trophic disorders of the soft tissues of the limb, as a rule, elastic bandages of short extensibility and class III compression knitwear are used. Compression products in patients with trophic ulcers should be applied on top of dressings containing topical medicines. In this case, an inelastic cotton-gauze bandage serves as an adsorbent material in case of a pronounced exudation from the surface of a trophic ulcer. The formation of an elastic bandage should be carried out in the Trendelenburg position (with the lower limbs raised above head level) (Christopoulos et al 1989). It is also important to create a uniformly decreasing degree of compression of the limb from the ankle to the knee joint. After relief of acute inflammation in the area of ??trophic ulcers and, accordingly, reduction of exudation, It is advisable to use with the purpose of compression special medical knitwear. Its undoubted advantages are simplicity and aesthetics of use. A variation of elastic compression is a zinc-gelatin dressing, proposed by PG Unna more than 100 years ago. The therapeutic effect of the zinc-gelatin dressing consists in the segmental compression of the enlarged superficial veins, the prevention of retrograde blood flow through them, the local effect on trophic ulcer (the bactericidal effect of zinc on certain types of microorganisms, the osmotic effect, etc.).
Leukocyte Aggression Theory
Regardless of the cause of venous trophic ulcer, its size and phase of the wound process, treatment should begin with a set of conservative measures aimed at healing or reducing the area of ??ulceration, arresting inflammatory reactions and complications, preoperative preparation, improving quality of life.
Conservative treatment should begin with providing the necessary therapeutic regimen for the patient. Staying in bed with a 25-30 ° raised foot helps to improve venous outflow, and often this already leads to a reduction in trophic ulcers and the relief of cellulite. Postural drainage can also be provided with a roller evenly placed under the affected lower limb (Dowsett, Grothier, Henderson et al. 2013).
In case of varicose veins, superficial veins may be recommended for surgical treatment, which is effective in case of detection of pathological blood reflux. It is also advisable to use compression knitwear, prophylactic (Snyder 2005).
Currently, the pharmacotherapy of chronic venous insufficiency has firmly taken its topical position as one of the main types of treatment for this pathology. In patients with trophic ulcers of the lower extremities, particular attention should be paid to the choice of a program of conservative therapy (Carter, Fylling & Parnell 2011). The severity of trophic changes of the skin dictates the need for the appointment of drugs of various pharmacological groups, and the staging of the wound process and the tendency of patients to allergic reactions is a careful individual selection of drugs. Unfortunately, some patients with pathology of the lower limbs for various reasons cannot be performed radical surgery, or their implementation should be divided into several stages.
Conclusion:
The paper has demonstrated why Mrs. Harrison’s wound has took more than 6 weeks to heal. trophic venous ulcers of the lower extremities are formed as a result of a complex set of changes in venous and arterial hemodynamics, lymphatic drainage, biophysical, biochemical and immunological processes in the lower extremities, which realize their influence through the violation of reparative processes in the tissues. However, the exact mechanisms of the formation of venous trophic ulcers are not finally revealed. The complexity of the pathogenesis of trophic venous ulcers of the lower extremities requires the development and use in clinical practice of a multi-faceted concept of their treatment.
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