Coagulation parameters in hyperthyroid cats before and after radioiodine treatment compared with healthy controls

Abstract

Objectives

The aim of the study was to describe the coagulatory state of hyperthyroid cats before and after successful radioiodine therapy (RIT) compared with healthy age-matched controls, using classical coagulation parameters and thromboelastogram (TEG) as a global assessment method. The differences in coagulation activity after RIT, depending on the thyroid hormone (normal vs low total thyroxine [T4]) state, were also evaluated.

Methods

Fifteen hyperthyroid cats and 10 healthy age-matched controls were recruited. Hyperthyroid cats that remained hyperthyroid 14 days after RIT were excluded. Haematology, biochemistry, T4, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and TEG were assessed in control cats and hyperthyroid cats before and 7 and 14 days after RIT. Two weeks after successful RIT, further comparisons were made between cats with normal T4 vs those with low T4.

Results

Fourteen days after successful RIT, 7/15 cats had normal T4 and 8/15 had low T4. Thrombocytosis was noted in 6/15 cats after treatment. Fibrinogen was significantly higher (P <0.001) and PT shorter (P <0.01) in the hyperthyroid cats compared with the healthy controls and these changes persisted after RIT. Persistent increases in fibrinogen, PT, TEG maximal amplitude and TEG clot rigidity, reflecting clot stability, after RIT primarily occurred in the cats with normal T4. TEG-K (time until preset amplitude of 20 mm is reached) and alpha (α) angle reflected impaired fibrin cross-linking ability prior to RIT, which significantly increased after therapy (P <0.05).

Conclusions and relevance

Based on some of the coagulation parameters, cats with hyperthyroidism showed hypercoagulable tendencies, which were mildly increased after RIT, possibly due to transient radiation-induced thyroiditis.

Keywords

Hyperthyroid cats radioiodine treatment coagulatory state thromboelastography

Introduction

Hyperthyroidism is one of the most common endocrinopathies encountered in the geriatric feline population, and it causes a wide range of metabolic changes.¹ In human medicine, hyperthyroidism goes hand in hand with coagulopathies. It can induce a state of hypercoagulability and hypofibrinolysis. Coagulation factors VIII, IX, von Willebrand Factor, fibrinogen, D-dimers and plasminogen activator inhibitor 1 were shown to be increased in some individuals.^2–4 This puts the patient at increased risk of thrombosis.^5,6 In some patients, thrombocytopenia has also been noted.^7–9 After radioiodine (¹³¹I) therapy, some of the increased coagulation factors normalise.⁴

Scarce information is available about the coagulation dynamics in cats with hyperthyroidism. One case showed that feline thyroid disease may pose a risk for development of arterial thromboembolism, independent of cardiac effects.¹⁰ Some hyperthyroid cats can also show prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT) and proteins induced by vitamin K absence or antagonists

clotting times.¹¹ It has been speculated that decreased vitamin K absorption associated with the fat malabsorption seen in some hyperthyroid cats may result in the abnormal clotting times. In another study, 14% of hyperthyroid cats showed thrombocytopenia.¹²

Assessment of coagulation dynamics has mostly been based on PT and aPTT measurements. Thromboelastography (TEG) provides a global assessment of in vivo haemostasis (initiation, amplification, propagation and fibrinolysis). Few studies have suggested that TEG can serve as a valuable diagnostic tool in cats.^13–15

The purpose of this study was to evaluate the coagulatory state of hyperthyroid cats in response to successful radioiodine therapy (RIT) with the classic parameters combined with TEG. Moreover, potential differences in coagulation activity depending on the thyroid hormonal state (normal thyroxine [T4] vs low T4) were of interest. We hypothesised that hyperthyroid cats are in a state of hypercoagulability and that this state could resolve following successful treatment of hyperthyroidism; and that there will be more extreme changes in cats with normal vs low T4 after RIT.

Material and methods

Population and study timeline

This prospective study was conducted from April 2013 until April 2014. Ethical approval was granted by the regional authority (Regierungspräsidium Hessen GI18/17-Nr.A2/2013).

Twenty-five hyperthyroid cats referred to the Justus-Liebig University Giessen for RIT were potential candidates. Inclusion criteria were confirmed diagnosis of hyperthyroidism based on: typical history; physical examination; routine laboratory (haematology, biochemistry) findings; increased serum T4 concentration; and increased thyroid-to-salivary gland ratio derived from thyroid scintigraphy.¹⁶ All cats had their medical treatment (methimazole or carbimazole) for hyperthyroidism discontinued 1 week prior to the RIT. Exclusion criteria were concurrent disease, pretreatment with heparin or its derivatives, glucocorticoids administered in the most recent 3 months and those that remained hyperthyroid 14 days post-RIT. Owing to the influence of cardiac diseases on coagulation, cats with an echocardiographic ratio of left atrium to aorta >1.48 were also excluded.¹⁷ Cats weighing <2.5 kg were excluded according to the guidelines of the ethics committee.

Ten healthy, euthyroid cats presented for a routine check-up served as age-matched controls. The inclusion criterion was a minimal age of 8 years. Exclusion criteria were any medication administered within the past 2 weeks and a body weight <2.5 kg.

Work-up

Full work-up of both study and control cats consisted of routine haematology (ADVIA 2120; Siemens Healthcare Diagnostics) and biochemistry (ABX Pentra 400; ABX Horiba), serum T4 concentration, coagulation panel (PT, aPTT, fibrinogen and TEG), thoracic radiographs, echocardiography, electrocardiogram and blood pressure measurement. Additionally, plasma thyroid stimulating hormone (TSH) was assessed in the study cats 14 days after RIT to further assess thyroid hormone status.

Blood samples were collected via direct venepuncture from the vena cephalica antebrachii or vena femoralis using a 20 G or 22 G needle and passively dropped into the Vacutainer. Blood for laboratory analysis, including haematology, clinical chemistry and coagulation parameters, was collected in 1.2 ml tubes coated with EDTA, heparin and 3.18% trisodium citrate. Citrated tubes were filled such that a ratio of 9:1 whole blood to anticoagulant was obtained. The tubes were inverted multiple times to ensure adequate mixing of the blood and anticoagulant. Serum and citrated plasma for measurement of T4 and TSH, respectively, were shipped to a commercial laboratory (Biocontrol, Ingelheim, Germany). Total T4 was measured with a chemiluminescent immunoassay, while TSH was assessed with a human chemiluminescent assay, previously validated in cats.¹⁸

Coagulation panel

Citrated plasma was prepared after centrifugation at 3000 g for 10 mins. Fibrinogen, PT and aPTT were assessed in citrated plasma using an automated coagulation analyser (STA Compact; Roche Diagnostics). PT and aPTT were measured as clotting times using human assays; that is, STA Neoplastin Plus and STA APTT Kaolin (both Roche Diagnostics). Fibrinogen concentration was determined with the Clauss method applying a human calibration curve (STA Fibrinogen and STA Unicalibrator; both Roche Diagnostics).

TEG was performed with non-activated citrated whole blood using a computerised thromboelastograph (TEG 5000 Thrombelastograph TEG Analyser Software Version 4.2.10; Haemonetics). Citrated plasma tubes were left in a standing position for 1 h at room temperature. TEG cups were filled with 20 µl calcium chloride (0.2 M CaCl₂) and 340 µl whole blood. Duplicate measurements were performed using two TEG devices and mean values were used for further statistical analysis. Six TEG variables were investigated: R, K, alpha (α) angle, MA, G and LY30. R is defined as the time span from initiation until the first fibrin polymers are produced. K is the time until preset amplitude of 20 mm is reached; it represents the speed of clot formation based on fibrin production and cross-linking, coagulation factors and platelet count. α is closely related to the K value and is influenced by the same factors. MA is the maximal amplitude reflecting the maximal clot strength. G reflects clot rigidity and represents the global coagulation activity. It is calculated from the MA. LY30 is the percentage of fibrinolysis 30 mins after attaining the MA.¹⁹

Results were compared with in-house reference intervals obtained in young adult European Shorthair cats.^15,20

RIT and follow-up

Each cat received an individual dose of ¹³¹I, depending on severity of clinical signs, T4 concentration and scintigraphic picture of thyroid glands. Follow-up haematology, biochemistry, T4 concentration and coagulation panel were performed 7 and 14 days post-treatment in the hyperthyroid cats.

Statistics

Statistical analyses were performed using commercial software GraphPad Prism Version 6.0. Owing to the relatively small size of the groups, non-parametric tests were used.

The impact of RIT on coagulation variables with focus on time point (7 vs 14 days after RIT) and thyroid hormone status (normal T4 vs low T4) vs the age-matched controls was assessed with a Kruskal–Wallis test and Dunn’s Multiple Comparison post-test. Level of significance was set at P <0.05.

Results

Animals

Fifteen hyperthyroid cats met the inclusion criteria. All of them were European Shorthair cats with a median age of 11 years (range 9–16 years) and a median weight of 3.8 kg (range 3.0–5.8 kg). Seven of 15 were male castrated and 8/15 were female spayed. The control cats consisted of eight European Shorthair cats, one Maine Coon and one Angora cat. Median age was 8 years (range 8–10 years) with a median weight of 4.7 kg (range 3.3–7.7 kg). Four of 10 were male castrated and 6/10 were female spayed. The hyperthyroid cats were treated with a median activity of 148 MBq ¹³¹I (range 74–222 MBq).

T4 and TSH concentrations

The median T4 concentration in the hyperthyroid cats (17.8 µg/dl; range 5.5–37.5 µg/dl [reference interval (RI) 1.0–4.0 µg/dl]) decreased significantly 7 days (4.5 µg/dl; range 0.7–8.8 µg/dl) and 14 days (0.9 µg/dl; range 0.5–3.5 µg/dl) after RIT (P <0.05 and P <0.001, respectively) (Figure 1). Seven days after RIT, 6/15 cats had normal T4 concentration, 1/15 had low T4 concentration and 8/15 were still hyperthyroid. One week later, 7/15 cats had normal T4 concentrations, of which five had TSH concentrations <0.03 µU/ml, one of 0.03 µU/ml and another of 0.05 µU/ml. Eight of 15 cats had low T4 concentrations, of which seven had TSH concentrations <0.03 µU/ml and one had a TSH concentration of 0.04 µU/ml (RI 0.04–0.44 µU/ml).

Figure 1

Effect of radioiodine therapy (RIT) on thyroid hormone status vs healthy controls. Blue diamonds indicate cats with normal thyroxine (T4) 14 days post-RIT; red diamonds indicate cats with low T4 14 days post-RIT. Data are shown as a scatter plot. The central line indicates the median; *P <0.05; **P <0.01; ***P <0.001; ****P <0.0001. The grey area represents the reference interval

Haematology

RIT did not have a significant impact on haematocrit and platelet count (Figure 2a) and there was no difference between study and control cats. However, platelet count showed a marked inter-individual variation in the study cats 14 days following RIT, which was present in cats with normal and low T4; thrombocytosis was seen in 6/15 cats.

Figure 2

Impact of time and thyroid hormone status after radioiodine therapy (RIT) on (a) thrombocytes, (b) fibrinogen concentration, (c) prothrombin time (PT) and (d) activated partial prothrombin time (aPTT) in hyperthyroid cats in comparison with healthy controls. Blue diamonds indicate cats with normal thyroxine (T4) 14 days post-RIT; red diamonds indicate cats with low T4 14 days post-RIT. Data are shown as a scatter plot. The central line indicates the median; *P <0.05; **P <0.01; ***P <0.001; ****P <0.0001; the blue asterisk is the significant difference (P <0.05) between the cats with normal T4 14 days post-RIT and the other group. The grey area represents the reference interval

Coagulation panel

Median fibrinogen concentration in hyperthyroid cats (2.57 g/l; range 1.63–5.5 g/l) was 1.8-fold higher than the age-matched controls (1.42 g/l; 1.19–3.09 g/l; P <0.001) (Figure 2b). Within 14 days following RIT, fibrinogen concentration remained increased. However, the persistent hyperfibrinogenaemia was mainly seen in cats with a normal T4 vs cats with a low T4.

Hyperthyroidism was associated with significantly shorter median PT (10.1 s; range 9.4–10.9 s) compared with the age-matched controls (10.95 s; range 10.1–11.3 s; P <0.01) (Figure 2c). Significantly shorter PT than the controls was still present 7 days – and to a lesser extent 14 days – after RIT. The shorter PT was mainly based on the findings in the cats with normal T4, rather than the cats with low T4.

Hyperthyroidism and RIT did not have a significant impact on the aPTT (Figure 2d).

TEG

Six cats showed an R value above the RI prior to RIT. RIT resulted in a significant (P <0.05) decrease in median R value (P <0.05) 7 days (9.7 mins; range 3.95–19.2 mins) but not 14 days after RIT compared with pretreatment results (17.0 mins; 6.35–35.6 mins) (Figure 3a).

Figure 3

Effect of time and thyroid hormone status after radioiodine therapy (RIT) on thromboelastography (TEG) values (a) TEG-R, (b) TEG-K, (c) TEG-α, (d) TEG-MA, (e) TEG-G and (f) TEG-LY30 in hyperthyroid cats compared with healthy controls. Blue diamonds indicate cats with normal thyroxine (T4) 14 days post-RIT; red diamonds indicate cats with low T4 14 days post-RIT. Data are shown as a scatter plot. The central line indicates the median; *P <0.05; **P <0.01; ***P <0.001; ****P <0.0001; the blue asterisk is the significant difference (P <0.05) between the cats with normal T4 14 days post-RIT and the other group. The grey area represents the reference interval

Prior to RIT, median K time (8.0 mins; range 2.05–20.45 mins) was significantly (P <0.05) shorter than median K time seen 14 days after treatment (3.85 mins; 1.45–8.5 mins). The decreased K time observed after RIT was mainly due to a decrease in the cats with normal T4. Overall, more than half of the cats (7/10 controls, 11/15 pre-RIT, 7/15 7 days post-RIT and 8/15 14 days post-RIT) had a K value exceeding the RI (Figure 3b).

The median α value (Figure 3c) was at the lower end of the RI in the hyperthyroid cats prior to RIT (25.7°; range 10.8–61.3°) and significantly (P <0.05) increased 14 days after treatment (46.4°; range 26.0–72.3°). This difference could be mainly attributed to the cats with normal T4.

The median MA and G values increased transiently 7 days after RIT and decreased again 14 days after treatment. They were significantly (P <0.01) lower in the control cats (MA 35.8 mm [range 29.2–58.1 mm] and G 2.8 kd/s [range 2.1–7.0 kd/s]) compared with the hyperthyroid cats 7 days after RIT (MA 53.3 mm [range 32.1–69.0 mm] and G 5.7 kd/s [2.4–11.1 kd/s]) (Figure 3d,e). Fourteen days after RIT, only the cats with normal T4 showed a significantly (P <0.05) higher median MA and G value (MA 50.25 mm [range 44–60.05 mm] and G 5.1 kd/s [range 4.0–7.6 kd/s]) when compared with the controls.

Hyperthyroidism and RIT did not have a significant impact on fibrinolysis as reflected by LY30 (Figure 3f).

Discussion

Overall, this study demonstrated hypercoagulable tendencies in hyperthyroid cats prior to RIT as reflected by increased fibrinogen concentration and shortened PT. However, despite the hypothesis, fibrinogen concentration and PT did not normalise after successful therapy. In contrast, overall coagulation activity demonstrated by TEG variables reflecting overall clot stability, such as MA and G, increased transiently 7 days after RIT.

After RIT, cats were divided into those with normal T4 and those with low T4. This was done to take the effect of thyroid hormone concentration on the coagulation process into account. The overall low TSH values were measured 2 weeks after RIT vs the 1–3 month timeline published in the literature.^21,22 Thus, TSH could not be used to differentiate euthyroid cats from subclinical or overt hypothyroidism. To avoid misclassification due to uncertainty concerning the recovery capacity of the pituitaries’ thyrotroph function after prolonged suppression, the terms ‘normal T4’ and ‘low T4’ were used. Another factor potentially influencing T4 and TSH concentrations is euthyroid sick syndrome. Concurrent disease was an exclusion criterion, but, after RIT, radiation-induced thyroiditis could occur with secondary inflammation, influencing the function of the thyroid axis.²³

Regarding fibrinogen plasma concentration, the results of the hyperthyroid cats observed here are in agreement with findings in people after RIT. As in cats, increased fibrinogen plasma concentration has been demonstrated in human hyperthyroid patients, reflecting hypercoagulability in this catabolic state.^2,4,24 Surprisingly, in the hyperthyroid cats evaluated here, fibrinogen concentrations did not normalise after RIT. This could be partially explained by the fact that 53% of the cats were still hyperthyroid 7 days after treatment. Most likely, however, is that the fibrinogen concentration needs more than 14 days to normalise. In hyperthyroid people treated with RIT, normalisation of the fibrinogen plasma concentration required 12 weeks – much longer than our study period of 2 weeks.⁴ That the thyroid hormone state after RIT has an impact on the fibrinogen level could be demonstrated by the difference in cats with normal vs low T4 14 days after treatment. The difference between control cats and hyperthyroid cats 14 days after RIT was only significant in the cats with normal T4. In the cats with low T4, a declining tendency was shown.

Another possible reason for the persistently increased fibrinogen plasma concentration could be radiation-induced thyroiditis, a known side effect of RIT in people²⁵ characterised by an inflammatory reaction with increase in acute-phase proteins.²⁶ Fibrinogen is a positive acute-phase protein in various species and can rise significantly during an inflammatory process.²⁷ A significant increase of the acute-phase protein α-acid glycoprotein in cats 6 days after RIT has already been shown by our group.²³ As an acute-phase protein, fibrinogen could remain increased after RIT due to the inflammation. Further studies are needed to evaluate the fibrinogen level over a longer observation period.

A prolonged PT has been described previously in 1/20 hyperthyroid cats prior to treatment with methimazole,¹¹ which could not be confirmed in our study. Caution should be exercised when interpreting the results of this one cat as it was also under glucocorticoid treatment for inflammatory bowel disease, which could have influenced the coagulation dynamics. Overall, the median PT in the previous study was bordering the lower limit of the RI. This tendency of shortening was also observed in our study.

Similar to hyperfibrinogenaemia, the shortened PT might also indicate hypercoagulability. This could be caused by the hyperthyroid state of some of the cats after RIT and/or the inflammation caused by thyroiditis secondary to RIT. Interestingly, hyperthyroidism did not have an impact on aPTT. The shortened PT despite a normal aPTT observed in hyperthyroid cats is surprising as, in people, a shortened aPTT is a more common indicator for hypercoagulability in thromboembolic events than PT.^28–30 However, the hyperfibrinogenaemia itself could also be the reason for PT shortening. A shortening of PT and aPTT after adding incrementing levels of fibrinogen in an in vitro test has been reported previously.³¹ Perhaps a higher degree of fibrinogen increase is needed to cause a shortening in the aPTT compared with the PT.

TEG was performed in non-activated citrate plasma as use of an activator is known to accelerate the coagulation reaction and thus potentially masks mildly hypercoagulable patterns.^32,33 The TEG variables were less transparent to interpretation. The median MA and G values reflecting overall coagulation activity support the findings of increased fibrinogen and shortened PT indicative of a hypercoagulatory state in hyperthyroid cats prior to and after RIT. Although not significant, TEG MA and G were higher in hyperthyroid cats than in the controls. Inflammation in combination with a hyperthyroid state in the cats 7 days after RIT might even further increase median MA and G value, while it decreases again 14 days after RIT when there is less inflammation.

While overall coagulation activity indicated by MA and G values suggests a more hypercoagulable tendency, this does not apply for all phases of the global coagulation process. The increased R and K value, as well as decreased α angle, indicate decreased coagulation activity, especially during fibrin cross-linking. It might be hypothesised that hyperthyroid cats have an impaired ability of forming a clot, but once it is formed, it remains strong, even with increased viscosity, as demonstrated by the MA and G values. It remains questionable as to whether these tendencies have clinical repercussions, such as higher thrombotic risks. Further research is needed to shed light on this matter.

The limitations of this study are the small study population with consequently low power so that significant findings might have been missed. It would be interesting to have a longer follow-up in the cats. Another important limitation is the RI used for the different coagulation parameters. As RIs for feline coagulation variables are scarce and highly method-dependent, we used published in-house RIs.^15,20 However, the feline population used to establish these RIs included young adult cats and was therefore not representative of the study population. We overcame this problem by using age-matched control cats. Lastly, we are aware that many hyperthyroid cats might also suffer from comorbidities such as masked concurrent chronic kidney disease (CKD). Owing to the short follow-up time, we were not able to see how many of the treated cats had masked CKD.²¹ Whether this condition could influence coagulation activity in cats is unknown. However, despite thorough examination, similar, masked comorbidities might also be present in the age-matched control cats so that differences between controls and hyperthyroid cats described here can be considered significant.

Conclusions

Coagulation parameters reflect a hypercoagulable tendency during hyperthyroidism that remains or is even transiently augmented after RIT, possibly due to transient radiation-induced thyroiditis. The clinical relevance of these tendencies remains questionable and long-term changes are unknown.

Footnotes

Accepted: 23 November 2018

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Yi Cui

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