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What age-related parameters increase the risk of thrombosis?

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 10, 2020
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Question: What age-related parameters increase the risk of thrombosis?

Thrombosis is the formation of a blood clot in the circulatory system. The thrombus or the clot attaches to the inner wall of the blood vessel and hinders the blood flow. Blood clotting is the usual response of the body to injury. A part of this clot separates and lodges into the blood vessels. If lodged near an organ, it may disrupt the blood flow to the organ and have dangerous consequences. It may lead to an heart attack, a stroke, or a pulmonary embolism.

Risk factors for thrombosis include obesity, pregnancy, recent surgery, etc. Most articles have listed "age" as a risk factor. What age-related factors cause thrombosis and how can we eliminate it?
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Involvement of SASP in age-related thrombosis

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Apoorva Kulkarni Aug 10, 2020
A recent study identified 44 senescence-associated secretory phenotype (SASP) proteins that participate in hemostasis, the first step in wound healing where the body prevents blood from escaping the vessels. The authors reported that the expression of these proteins was 2-fold in the senescent cells when compared to the quiescent cells. Also, mice treated with doxorubicin, a DNA-damaging chemotherapeutic agent that induces cellular senescence, showed increased blood clotting. The authors checked the expression of blood-clotting factors – SERPINE1, SERPINE2, SERPINB2, SERPINB6, thrombospondin 1, tissue inhibitor of metalloproteinase 1, and filamin A-alpha, and found that their mRNA levels were elevated following doxorubicin treatment. And selective removal of senescent cells attenuated the increased clotting caused by doxorubicin. [1] Senescence irreversibly arrests cell proliferation and is accompanied by SASP that participates in several age-related diseases. As the number of senescent cells accumulated increases with age, so does the risk of thromboisis and other age-related diseases. However, SASP proteins may constitute only a part of the factors responsible for thrombosis in the elderly. Other factors need to be identified. Reference: 1. Wiley CD, Liu S, Limbad C, Zawadzka AM, Beck J, Demaria M, et al. SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells. Cell Rep [Internet]. 2019 Sep;28(13):3329-3337.e5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2211124719310976
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Serotonin and ROC induce platelet activation

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Apoorva Kulkarni Aug 10, 2020
Serotonin is a vasoactive hormone, which is stored in the platelets in granules and is released in the plasma when the platelets are activated. Serotonin induces changes in platelet shape and boosts platelet aggregation. [1] A study reported that platelets from patients aged between 72 and 86 years old have a higher sensitivity and an increased responsiveness to serotonin than platelets from subjects 18 to 27 years of age. [2] The authors suggest that increased sensitivity can be an important contributing factor of increased platelet aggregability in the elderly. [3] It has been reported that platelet serotonin content decreases with age. [1,4] Reduced serotonin platelet content and an increased plasma serotonin level is also observed in patients with type 2 diabetes and in patients suffering from peripheral vascular diseases when compared with correspondingly aged healthy volunteers. [1] This suggests that platelet hyperactivity can cause an increased release of serotonin in the plasma, which then positively feeds back to platelet hyperactivity and may play a role in the pathogenesis of thrombotic diseases. [3] Reactive oxygen species modify the protein structures using carbonylation and these proteins accumulate leading to increased carbonyl content in platelets with age. [5] Altered protein activity in the platelets may lead to altered thrombotic susceptibility. [6] Senescent cells also play a role in activation of the platelets. [7] References: 1. BARRADAS MA, GILL DS, FONSECA VA, MIKHAILIDIS DP, DANDONA P. Intraplatelet serotonin in patients with diabetes mellitus and peripheral vascular disease. Eur J Clin Invest [Internet]. 1988 Aug;18(4):399–404. Available from: http://doi.wiley.com/10.1111/j.1365-2362.1988.tb01030.x 2. GLEERUP G, WINTHER K. The effect of ageing on human platelet sensitivity to serotonin. Eur J Clin Invest [Internet]. 1988 Oct;18(5):504–6. Available from: http://doi.wiley.com/10.1111/j.1365-2362.1988.tb01047.x 3. Le Blanc J, Lordkipanidzé M. Platelet Function in Aging. Front Cardiovasc Med [Internet]. 2019 Aug 7;6. Available from: https://www.frontiersin.org/article/10.3389/fcvm.2019.00109/full 4. Flachaire E, Beney C, Berthier A, Salandre J, Quincy C, Renaud B. Determination of reference values for serotonin concentration in platelets of healthy newborns, children, adults, and elderly subjects by HPLC with electrochemical detection. Clin Chem [Internet]. 1990 Dec;36(12):2117–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2253357 5. Alexandru N, Constantin A, Popov D. Carbonylation of platelet proteins occurs as consequence of oxidative stress and thrombin activation, and is stimulated by ageing and type 2 diabetes. Clin Chem Lab Med [Internet]. 2008 Jan 1;46(4). Available from: https://www.degruyter.com/doi/10.1515/CCLM.2008.104 6. Levin L, Zelzion E, Nachliel E, Gutman M, Tsfadia Y, Einav Y. A Single Disulfide Bond Disruption in the β3 Integrin Subunit Promotes Thiol/Disulfide Exchange, a Molecular Dynamics Study. Sadoshima J, editor. PLoS One [Internet]. 2013 Mar 18;8(3):e59175. Available from: https://dx.plos.org/10.1371/journal.pone.0059175 7. Wiley CD, Liu S, Limbad C, Zawadzka AM, Beck J, Demaria M, et al. SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells. Cell Rep [Internet]. 2019 Sep;28(13):3329-3337.e5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2211124719310976
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