Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel), wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis).
Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and, therefore, the best-understood.
Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium (lining of the vessel). Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: Proteins in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands, which strengthen the platelet plug (1)
Figure 1. Blood Coagulation Cascade
The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as the intrinsic pathway), and the tissue factor pathway (formerly known as the extrinsic pathway), which merge at the formation of thrombin from prothrombin and they lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form (1)
Abstract: Mechanisms of blood coagulation by direct contact of non-thermal atmospheric pressure dielectric barrier discharge plasma are investigated. This study shows that no significant changes occur in pH or calcium concentration of blood during discharge treatment. Thermal effects and electric field effects are also shown to be negligible. Investigating the hypothesis that the discharge treatment acts directly on blood protein factors involved in coagulation, we demonstrate aggregation of fibrinogen, an important coagulation factor, with no effect on albumin. We conclude that direct dielectric barrier discharge treatment triggers selective natural mechanisms of blood coagulation.
Introduction: Over the past few years non-thermal atmospheric pressure plasma has emerged as a novel promising tool in medicine. Compared to the effects of the more conventional thermal plasma (2), non-thermal plasma is selective in its treatment since it does not burn tissue. This enables many new medical applications including sterilization of living tissue without damage (3), blood coagulation (3), induction of apoptosis in malignant tissues and (4, 5) modulation of cell attachment (6, 7, 8).
Two different approaches to the use of non-thermal plasma effects in medicine have been pursued. In one approach, plasma is created remotely and its afterglow is delivered by a jet to the desired location. In this indirect approach relatively long living active plasma species do most of the desired work, while most of the charged particles do not survive outside the plasma generation region. Alternatively, non-thermal atmospheric pressure plasma has been generated in direct contact with living tissue. Here it has been shown that treatment produces various effects much faster due to direct contact with charged species (9).
Although blood coagulation by direct non-thermal plasma treatment has been reported before (3), the bio-chemical pathways (mechanisms) through which such coagulation occurs remain largely unclear. In this paper several possible mechanisms are investigated. We demonstrate that direct plasma triggers natural, rather than thermally induced, coagulation processes. We also demonstrate that release of calcium and changes of blood pH level are insignificant. Instead, the evidence points to selective action of direct non-thermal plasma treatment on blood proteins involved in the natural coagulation processes.
Figure 3. (a) Non anticoagulated donor blood treated with e-plasma for 15 s exhibits immediate clot layer formation (b) Citrated whole blood treated with e-plasma for 15 s exhibits immediate clot layer formation
Figure 5. Treatment of buffered solution of fibrinogen (a (control), b (30 sec) and buffered solution of albumin (c (control), d (30 sec)). Figs. a-b show change in opacity of fibrinogen solution after treatment whereas Figs. c-d show no change in opacity of albumin solution
Figure 6. (a) Comparison of control and treated solution of fibrinogen, (b) Comparison of control and treated solution of albumin. Treated and untreated albumin show the same size distribution with average size of about 6nm, which corresponds well to the published albumin size of around 8 nm 
Figure 4. (a) Citrated whole blood (control) showing single activated platelet (white arrow) on a red blood cell (black arrow) (b) Citrated whole blood (control) showing many non-activated platelets (black arrows) and intact red blood cells (white arrows) (c) Citrated whole blood (treated) showing extensive platelet activation (pseudopodia formation) and platelet aggregation (white arrows) (d) Citrated whole blood (treated) showing platelet aggregation and fibrin formation (white arrows)
Conclusions: It has been demonstrated earlier that non-thermal plasma coagulates blood rapidly  and the results presented in this article indicate that non-thermal dielectric barrier discharge treatment is capable of coagulating anti-coagulated blood. This discharge appears to promote rapid blood coagulation by enhancing the natural coagulation processes. Previously it was hypothesized that direct contact non-thermal e-plasma treatment initiates blood coagulation by an increase in the concentration of Calcium ions , an important ion in the coagulation cascade. Experiments performed by us show no significant change in calcium concentration during the time of coagulation in discharge treated blood. E-plasma treatment does not coagulate blood due to change in pH, as we observe no significant change in pH of blood during the time of treatment in which blood coagulates. We hypothesize that e-plasma treatment may activate some of coagulation proteins. E-plasma treatment of a buffered solution of human fibrinogen results in rapid fibrinogen aggregation. Interestingly, this non-thermal plasma treatment is selective, as a similar buffered solution of human serum albumin shows no change even after a longer treatment. The results presented in this paper indicate that direct conversion of fibrinogen into fibrin may be one of the mechanisms by which non-thermal plasma initiates coagulation. Further investigations are necessary to determine other pathways of activation of coagulation by non-thermal plasma treatment.
Fridman, G., Peddinghaus, M., Ayan, H., Fridman, A., Balasubramanian, M., Gutsol, A., Brooks, A. & Friedman, G., Blood Coagulation And Living Tissue Sterilization By Floating Electrode Dielectric Barrier Discharge In Air, Plasma Chemistry and Plasma Processing 2006. 26: p 425-442
Fridman, G., Shereshevsky, A., Jost, M.M., Brooks, A.D., Fridman, A., Gutsol, A., Vasilets, V., Friedman, G., Floating Electrode Dielectric Barrier Discharge Plasma in Air Promoting Apoptotic Behavior in Melanoma Skin Cancer Cell Lines”, Plasma Chemistry and Plasma Processing, 27(2): p163-176.
Kieft, I. E., Kurdi, M., and Stoffels, E., Reattachment and Apoptosis after Plasma-Needle Treatment of Cultured Cells, IEEE Tans. Plasma Sci. 2006 34(4): p 1331-1336
Fridman, G., Brooks, A.D., Balasubramanian, M., Fridman, A., Gutsol, A., Vasilets, V.N., Ayan, H., Friedman, G., Comparison of Direct and Indirect Effects of Non-Thermal Atmospheric Pressure Plasma on Bacteria, Plasma Process. Polym., 2006, 10.1002/ppap.200600217.
Relevant Publications, Talks and Posters
Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge Plasma, S.U. Kalghatgi, G. Fridman, M. Cooper, G. Nagaraj, M. Peddinghaus, M. Balasubramanian, V.N. Vasilets, A. Gutsol, A. Fridman, G. Friedman, IEEE Transactions on Plasma Science, Volume 35, Issue 5, Part 2, Oct. 2007, pp. 1559-1566. FULL TXT(PDF).
Blood Coagulation and Living Tissue Sterilization by Floating-Electrode Dielectric Barrier Discharge in Air, G. Fridman, M. Peddinghaus, H. Ayan, A. Fridman, M. Balasubramanian, A. Gutsol, A. Brooks, G. Friedman, Plasma Chemistry and Plasma Processing, 26, 425-442 (2006). FULL TXT (PDF)
Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge Plasma, Gayathri Nagaraj, Sameer Kalghatgi, Andrew Wu, Gregory Fridman, Moogega Cooper, Marie Peddinghaus, Manjula Balasubramanian, Ari Brooks, Victor Vasilets, Alexander Gutsol, Alexander Fridman, Gary Friedman, American Society of Hematology Annual Meeting, Dec 7-11, 2007. Atlanta. USA
Mechanism of Blood Coagulation by Non-Thermal (Cold) Atmospheric Pressure Dielectric Barrier Discharge Plasma, S. Kalghatgi, G. Fridman, G. Nagaraj, M. Cooper, M. Balasubramanian, A. Brooks, V. Vasilets, A. Gutsol, A. Fridman, G. Friedman, First International Conference on Plasma Medicine (ICPM-1), October 15th - 18th, 2007, Corpus Christi, Texas
Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge, Sameer Kalghatgi, Gregory Fridman, Moogega Cooper, Gayathri Nagaraj, Marie Peddinghaus, Manjula Balasubramanian, Victor Vasilets, Alexander Gutsol, Alexander Fridman, Gary Friedman, In Abstracts and full papers 18th International Symposium on Plasma Science, Aug 26th-Aug31st, Kyoto University, Kyoto, Japan : Kyoto University, 2007
Mechanism of Blood Coagulation by Non-Thermal Atmospheric Pressure Dielectric Barrier Discharge Plasma (Contributed Talk), S. Kalghatgi, Gregory Fridman, Moogega Cooper, Gayathri Nagaraj, Marie Peddinghaus, Manjula Balasubramanian, Victor Vasilets, Alexander Gutsol, Alexander Fridman, Gary Friedman, 34th IEEE International Conference on Plasma Science, June 17-22 2007, Albuquerque, New Mexico, USA
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