Pain and inflammation are quite often present in chronic venous insufficiency and can vary and intensify with the stage of the insufficiency. The hypertension responsible for the varicose veins induces pain mechanisms, in which cells such as the mast cell and other leukocytes play a role through their ability to roll along the vessel wall and initiate local vessel wall inflammation. (1)
The mast cell is a resident cell of the tunica adventitia (2) This cell is seen as a conductor, orchestrating the endo- and peri-vascular homeostasis and inflammation. (3)
We can quote Jean-Pierre Kinet:
“I argue that Mast Cells play an essential role in ‘orchestrating’ the inflammatory responses that are common in many inflammatory diseases. As such and in spite of their protective roles in some circumstances, Mast Cells represent an attractive therapeutic target for the treatment of these diseases.”
This cell dominates the behaviour of various other adventitial cell types:
1.the microvascular endothelial cells from the vasa vasorum,
2. the small perivascular nerve fibers,
3. the adventitial fibroblasts, and
4, the local lymph microvessels. (4, 5)
The mast cell acts as the first activated inflammatory cell in pathological situations such as in diabetes, chronic hypertension (6) and stress situations (7).The pathogenetic pathways of these pathological conditions are stimuli for activating the mast cell.
Stimulated mast cell are able to trigger a neuroinflammatory cascade, resulting in a progressive activation of vascular vessel wall (aventitia). (8)
The progressive hyper-reactivity of the mast cell thus leads to an induction or deterioration of
Chronic Venous Disease. (9)
Recently it was also suggested that for leg ulcers, often seen in severe CVI:
“Mast cells seem to play an accessory yet important role, on the basis of their number and degranulation index variations and expression of basic FGF.” (10)
Mast cells in general are upregulated in CVI (11).
Controlling the mast cell in CVI: the role of palmitoylethanolamide
The mechanism of ALIA (Autacoid Local Injury Antagonism) is the endogenous body-own mechanism to control overactive mast cells. This mechanism was discovered by the research group of the Nobel laureate professor Rita Levi Montalcini.
The local tissue hormone, or autacoid downregulating the mast cell, and produced “on demand” from the mast cell is Palmitoylethanolamide (PEA). PEA can modulate the overactive mast cells and downregulate those. (12)
Most symptoms in CVI, such as tightness, swelling, and itching. pain on walking and muscle cramps (13) can react positive on the treatment with PEA.
As some inflammatory markers and indicators of endothelial dysfunction are clearly increased in varicose vein blood (14), the administration of the anti-inflammatory compound PEA makes much sense. Reduces of intravascular inflammation is currently one of the inroads in treating CVI. (15)
Treatment of inflammation, pain and itch in CVI: PEA and PEA cream
chronic venous insufficiency
Our recommendations is to use 2-3 times/day 400 mg PEA (for instance as PeaPure), together with 2 times daily PEA cream on the skin, avoiding rubbbing cream into the ulcers.
1. Boisseau MR. Leukocyte involvement in the signs and symptoms of chronic venous disease. Perspectives for therapy. Clin Hemorheol Microcirc. 2007;37:277-90.
2. Chaldakov GN, Fiore M, Ghenev PI, Beltowski J, Ranćić G, Tunçel N, Aloe L. Neuro-immune-adipose interactions. Implication in vascular biology. Front Immunol. 2014;5:130.
3. Kinet JP. The essential role of mast cells in orchestrating inflammation. Immunol Rev. 2007;217:5-7.
4. Swedenborg J, Mäyränpää MI, Kovanen PT. Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2011;31:734-40.
5. Vital A, Carles D, Serise JM, Boisseau MR. Evidence for unmyelinated C fibres and inflammatory cells in human varicose saphenous vein. Int J Angiol. 2010;19:e73-7.
6. Matic P, Jolic S, Tanaskovic S, Soldatovic I, Katsiki N, Isenovic E, Radak D. Chronic Venous Disease and Comorbidities. Angiology. 2014 Jul 8.
7. Alevizos M, Karagkouni A, Panagiotidou S, Vasiadi M, Theoharides TC. Stress triggers coronary mast cells leading to cardiac events. Ann Allergy Asthma Immunol. 2014;112:309-16.
8. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D. Mast cells and inflammation. Biochim Biophys Acta. 2012;1822:21-33.
9. Schönbein GW, Takase S, Bergan New advances in the understanding of the pathophysiology of chronic venous insufficiency. Schmid-Schönbein GW, Takase S, Bergan J. Angiology. 2001;52 Suppl 1:S27-34.
10. Corsi A, Lecci PP, Bacci S, Cappugi P, Pimpinelli N. Early activation of fibroblasts during PDT treatment in leg ulcers. G Ital Dermatol Venereol. 2014 Jun 13.
11. Pascual G, Mendieta C, García-Honduvilla N, Corrales C, Bellón JM, Buján J. TGF-beta1 upregulation in the aging varicose vein. J Vasc Res. 2007;44(3):192-201. Epub 2007 Feb 27.
12. Levi-Montalcini R, SD Skaper, Dal Toso R, L Petrelli, Leon A. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci. 1996;19:514-20.
13. Wrona M, Jöckel KH, Pannier F, Bock E, Hoffmann B, Rabe E. Association of Venous Disorders with Leg Symptoms: Results from the Bonn Vein Study 1. Eur J Vasc Endovasc Surg. 2015 Jun 30. pii: S1078-5884(15)00333-0. doi: 10.1016/j.ejvs.2015.05.013.
14. Poredos P, Spirkoska A, Rucigaj T, Fareed J, Jezovnik MK. Do Blood Constituents in Varicose Veins Differ From the Systemic Blood Constituents? Eur J Vasc Endovasc Surg. 2015 Jun 19. pii: S1078-5884(15)00312-3. doi: 10.1016/j.ejvs.2015.04.031.
15. Urbanek T, Krasinski Z, Begier-Krasinska B, Baum E, Breborowicz A. Sulodexide suppresses inflammation in patients with chronic venous insufficiency. Int Angiol. 2015 Jun 5.