Are Age Appropriate Ranges Needed In Coagualtion Testing For The Elderly?
by Donna Castellone, MS, MT(ASCP)S • July 05, 2023
INTRODUCTION:
We all know that 30 is the new 20, 50 the new 40 etc, but what you may be able to mask or enhance on the outside may not translate to physiology. What age is considered elderly? While there is no standard definition for the term elderly, according to the United States Social Security Administration anyone age 65 or older is elderly.1 How does this category translate in the medical setting, and in particular regarding coagulation testing. If our hemostatic system is different at a young age, what are the differences that may be seen in an older population?
Should this be something coagulation laboratories should be concerned with? According to the census the elderly population is increasing globally. The US population age 65 and over grew from 2010-2020 at the fastest rate since the end of the 1800's, translating to a 38.6% increase in just 10 years.2 The global population of people aged 80 and older is expected to triple between 2015 and 2050. In 2020 the number of people aged 60 years will double from 12% to 22% by 2050. On the flip side, the birth rate in the US has been falling over the last 20 years. It is projected there will be three million people worldwide aged 100 and over by 2050.2
Reference ranges (RR) are one of the most important tasks in any laboratory. They are vital for interpreting results. In coagulation, most of the upper limits of ranges state they are appropriate for adults > either 18 or 21 years of age. Manufacturer's ranges do not state at what age category represents adult.3 Reference intevals are defined in relation to a healthy population to include the values that 95% of apparently healthy individuals would fall into and 2.5% of results in the lower range and 2.5% of values in the upper range will be out of the reference interval.3
Based on this information, is it time to investigate reference ranges for coagulation testing in this aging population to enable detection of coagulation abnormalities for both bleeding and clotting disorders?
ROUTINE TESTING:
A study looked at coagulation results from healthy subjects aged 60 and older and compared them to current adult reference intervals to determine any differences.
The aPTT results (90%) were below the reference ranges, while 6.7% of results were outside the range, indicating increased procoagulant effects. But PT results were within the verified adult ranges, this suggested that the extrinsic and common pathways are functionally competent. When looking at fibrinogen levels, results (98%) were within the adult RR, however females presented with significantly higher levels.3 Vessel wall stiffness which has been reported in older adults as a phenomenon of aging can contribute to a procoagulant state. However, increases have been seen in factors V, VII, VIII, IX, XII, von Willebrand factor and platelet function.3
Based on these findings, questions arise as to the suitability of a general adult reference interval for elderly patients. Based on these results, it may suggest that if the general adult aPTT reference intervals are applied, more elderly patients may be defined as hypercoagulable. However, whether they are truly hypercoagulable or the shorter aPTT is part of normal aging remains unclear.3
SPECIALTY TESTING
A study looked at 120 subjects with an average age of 78.6 years (26 males 94 females). In 25.8% to 93.3% of the subjects, the results of the tests, except for prothrombin time and thrombin-antithrombin III complex, deviated from reference intervals obtained from young healthy subjects. Results also showed that fibrinolysis was more activated than coagulation. The study showed that RR for AT, PC, D-dimer and thrombomodulin should be established for the elderly (65 -74) as well as those over 75.4
Thromboelastography (TEG) studies have shown that females have lower clotting values, longer time for clot formation and higher maximum amplitude. These results suggest that females have a more hypercoagulable picture which may be attributed to hormonal differences. Aging has also been associated with hypercoagulability which results in a great risk for VTE. A study showed that the clotting kinetics of both older males and females were not within manufacturers RR but were elevated.3 This suggests that clot formation in healthy older adults is slower despite having fibrinogen levels within the RR. However, there are no validated RR on the elderly. Results showed that the majority of clot kinetics were in the upper half of the manufacturers RR with the maximum amplitude in the lower half of the RR, which suggests hypercoagulability and contradict aging is associated with a procoagulant status. A more comprehensive study of healthy elderly adults is needed to determine if these results are part of normal aging or are pathological.3
COAGULATION ISSUES IN THE ELDERLY:
Venous thrombosis and coagulation factor levels increase with age. Understanding the association between levels of procoagulant factors and the risk of a first VT in the elderly is important. Higher levels of VIII, IX and XI but not prothrombin were associated with a risk of VT. A study of 401 patients and 431 controls aged 70 and older were included in the Age and Thrombosis, Acquired and Genetic risk factors in the Elderly (AT-AGE) study.5 In this study, mean age of 78, the population risk for VT with elevated factor levels was 37.6% for FVIII, 23.3% for FIX and 12.4% for FXI, however prothrombin was not associated with a risk of VTE.5
Studies that have treated traumatic hemorrhage and coagulopathy have relied on data from patients 35-45 years. A study looked at age related changes. THe same patterns of coagulation changes were seen in response to injury such as low fibrinogen levels and high APC and hyperfibrinolysis. However, fibrinogen levels and greater thrombin generation and greater fibrinolysis were seen as age increased.6
Looking at traumatic coagulopathy in the cohort of patients (1576) older than 65, there is an increase in the number of patients seen in this situation. Many protein levels alter significantly with normal aging and as a result traumatic coagulopathy looks different in an aging population. It strongly correlated with higher fibrinogen and greater fibrinolysis. Knowing that thresholds for clotting factors are different based on ages should be considered when evaluating possible clinical treatments.6
ANTICOAGULATION IN THE ELDERLY:
Data from clinical trials as well as clinical evaluations have determined that elderly patients on direct oral anticoagulants (DOACs) are at the greatest risk for bleeding. Again, it is not clear if age intrinsically affects this response.
Elderly people were not well represented in the major clinical trials evaluating the safety and efficacy of DOACs and this is of concern for clinicians prescribing these agents. The mean age of patients on rivaroxaban was 73, and only a quarter of patients were 78 or older. A study of rivaroxaban pharmacokinetics in healthy subjects, for example, noted that the area under the concentration-time curve of rivaroxaban was 41% higher in those over 75 years than in those aged 18–45. It is difficult to determine if the pharmacological effect is due to age or confounding clinical issues including decreased renal function, comorbidities and medications.6
To determine if this response is age related, an ex-vivo comparison was conducted between 36 fit elderly (75-87) and 30 fit young (26-38) subjects. Blood samples were incubated with rivaroxaban. There was a greater prolongation of PT and mPT in the elderly when compared to younger subjects. There was a difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). It was also noted that FX and FII activity was significantly lower in the elderly in the presence of rivaroxaban. This may call for lower doses of the drug due to the increased sensitivity of the elderly to DOACs.6
CONCLUSION:
The absence of age specific coagulation reference intervals for older adults (>60 years) makes it difficult for the clinician to determine whether reported results outside the general adult reference intervals are interpreted as a patient being at a risk for bleeding or thrombosis or if the result is a normal variable associated with aging. These findings support that based on census data and serving an elderly population, laboratories may need to take steps to ensure they have age-appropriate coagulation reference intervals to best service an increasingly older population.
Despite that you may feel that elderly is based on a feeling and not an age, coagulation results may have it's own opinion!
REFERENCES:
- Leandra Beabout, What age is considered elderly? Experts weigh in
May 14, 2022, https://www.care.com/c/what-age-is-considered-elderly/ - Older Population and Aging - Census.gov
https://www.census.gov/topics/population/older-aging.html - Rebecca Donkin⇑ and Yoke-Lin Fung, Investigating Age Appropriate Coagulation Reference Intervals to Support Patient Blood Management in the Elderly: A Verification Study, Association of Clinical Scientists, 2020.
http://www.annclinlabsci.org/content/50/4/545.long - A Deguchi 1, H Wada, H Shiku, H Hamaguchi, Y Kawamura, Coagulation/fibrinolysis disorders in telderly, 2000 Mar;48 (3):217-21.
- Huijie Wang 1, Frits R Rosendaal 1, Mary Cushman 2, Astrid van Hylckama Vlieg, Procoagulant factor levels and risk of venous thrombosis in the elderly, J Thromb Haemost, 2021 Jan;19(1):186-193.
- NicolaS. Curry, Ross Davenport, Henna Wong, Christine Gaarder, Pär Johansson, NicoleP. Juffermans, Marc Maegele, Jakob Stensballe, Karim Brohi, Mike Laffan, Simon J. Stanworth Traumatic coagulopathy in the older patient: analysis of coagulation profiles from the Activation of Coagulation and Inflammation in Trauma-2 (ACIT), Journal of Thrombosis and Haemostasis, Volume 21, Issue 2, February 2023, Pages 215-226
- Emmanouela Kampouraki, Salah Abohelaika, Peter Avery, Tina Biss, Paul Murphy, Hilary Wynne & Farhad Kamali , Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing. Journal of Thrombosis and Thrombolysis, volume 52, pages170–178 (2021).