Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP.
Methods
Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] (n = 87) and HC (n = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI < 3). Amplitude, area under the curve (AUC) and 50% clot lysis time were determined.
Results
At baseline, psoriasis patients had higher median amplitude and AUC compared with HC (p < 0.0001). After correction for possible confounders (BMI, smoking behavior, psoriatic arthritis, arterial hypertension, diabetes and coronary artery disease), the increased amplitude in psoriasis patients compared to HC remained significant. Successful anti-inflammatory treatment resulted in a significant decrease in amplitude (p = 0.0365).
Conclusion
This is the first prospective study comparing the CLP of psoriasis patients with that of HC. A significant increase in both amplitude and area under the curve, indicative of a hypercoagulable CLP, was observed in psoriasis patients compared to HC. After successful anti-inflammatory treatment, amplitude significantly decreased.
Psoriasis has been linked to an increased risk of venous thromboembolism
Here, we report a significant increased amplitude (marker for coagulation) in 87 uncontrolled psoriasis patients compared to 87 matched healthy controls
Successful anti-inflammatory treatment results in a decrease in amplitude
These findings indicate that uncontrolled psoriatic inflammation predisposes patients to a hypercoagulable state
Introduction
Psoriasis, an immune-mediated inflammatory disease, manifests commonly as erythematosquamous plaques with a predilection for extension sites [1]. Although historically assessed as a Thelper (Th) 1-driven disease, interleukin (IL) 23-driven Th17-cells have more recently been indicated as key players. These inflammatory mediators are present in skin but also in the peripheral blood of psoriasis patients [2, 3]. These findings have been translated to the use of therapeutic monoclonal antibodies targeting tumor necrosis factor alpha (TNFα), p40-subunit of IL12 and IL23, IL17(A and/or F) or IL17-receptor, or the p19-subunit of IL23 [4, 5].
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An important comorbidity in psoriasis patients is metabolic syndrome: in a disease severity-dependent way, the risk is increased [6, 7]. Associated with these findings is the increased risk of myocardial infarction (stroke) in psoriasis patients [8, 9].
In addition to the previously described arterial ischemic events, an increased incidence rate of venous thromboembolism (VTE) has also been described in psoriasis patients [10‐12]. In a systematic review we previously reported a non-significant increased incidence of VTE in the overall psoriasis population, suggesting that only a sub-group of the overall psoriasis population is at risk to develop VTE [13]. Since VTE is associated with increased morbidity and mortality, as well as a high burden on the health care budget, identification of the subgroup at risk is of interest to target preventive measures [14‐17]. Retrospective attempts to identify psoriasis patients at risk of developing VTE have already been made [18, 19].
Factors predisposing to VTE are captured in Virchow’s triad: hypercoagulability, endothelial injury and venous stasis [20]. Chronic systemic inflammation may affect both hypercoagulability and endothelial injury [21]. In vitro information on hypercoagulability activity can be obtained through a functional clot lysis profile (CLP) assay. In this assay, both amplitude and area under the curve (AUC) provide information on coagulation activity [22]. Additionally, 50% clot lysis time (50%CLT) (time point at which 50% of maximal optical density or turbidity is reached) provides information on the lysis activity: a longer 50%CLT correlates with decreased lysis activity.
The aim of this project was to investigate whether the CLP in psoriasis patients might exhibit features of hypercoagulability (e.g., increased amplitude and/or AUC) or decreased lysis (e.g., increased 50%CLT) compared to HC and whether anti-inflammatory treatment impacts these features.
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Methods
Study Design and Study Population
After approval of this study by the institutional review board, eligible patients were informed and asked to participate. Psoriasis patients with active disease (defined as PASI or BSA ≥ 10) before initiation of a systemic treatment were eligible for inclusion: 126 uncontrolled psoriasis patients signed informed consent and baseline blood samples were obtained. The first 87 responders were selected and matched according to age and sex to HC. HCs were selected from patients presenting without diagnosis of any inflammatory disease. The psoriasis cohort was followed up after initiation of treatment. When skin clearance was obtained (absolute PASI < 3), new blood samples were drawn.
Blood Sampling and Clot Lysis Profile
Plasma samples were isolated from blood collected in citrate tubes. After blood withdrawal, the samples were stored for maximum 5 h at 4 °C before plasma isolation. To obtain platelet-poor plasma, blood samples were centrifuged at 1800 rpm, 4 °C for 20 min. Plasma was stored in aliquots at −80 °C. All aliquots were stored in the UZ/KUL biobank.
The clot profile was generated through a functional clot lysis assay, in which the speed of clot formation and dissolution is measured. Briefly, CaCl2 (to induce clot formation) and tissue-type plasminogen activator (to induce lysis) are added to diluted plasma (final concentration 30%; 10 mM Tris, 0.01% Tween 20, pH 7.5). By measuring the optical density at 405 nm every 2 min for 300 min, the clot lysis turbidity profile is determined. Next, the amplitude, AUC and 50%CLT are calculated. The amplitude (maximal clot absorbance) is an indication for clot formation or coagulation tendency. The AUC reflects the overall coagulation/fibrinolysis profile. Finally, the 50%CLT is the time point between maximum turbidity and clear transition, representing the fibrinolysis rate [23].
Sample Size Justification and Statistical Analysis
A preliminary power calculation was performed for AUC, 50%CLT and amplitude (power = 0.8; alpha = 0.05) resulting in a sample size of at least 34 subjects and 34 controls to detect a significant difference. Using preliminary estimates of the standard deviations of 16 HC and 14 psoriasis patients, an unblinded sample size recalculation was performed, and a new target of 83 subjects and 83 HC was advised.
Comparison of AUC or amplitude between patients and matched controls or between time points within patients was performed using the Wilcoxon signed rank test. The outcome measure quantifies the time until 50%CLT is reached. In some cases 50%CLT was not reached at the end of the observation time (300 min), resulting in a censored observation. The presence of censored observations was handled by analyzing the data using time-to-event or survival analysis techniques. Kaplan-Meier estimates were used for descriptive statistics, and a Cox proportional hazards model was used for statistical inference, using the robust sandwich estimator of Lin and Wei (1989) to account for data clustering due to matching of patients with controls or repeated measurement of patients. Analyses have been performed using SAS software (version 9.4, SAS System for Windows).
To correct for possible confounders, linear mixed models were used to analyze the difference in mean AUC or amplitude between patients with or without a given comorbidity. Random effects account for clustering by patient or patient-control match. Cox proportional hazards models were used for the analysis of the difference between patients with or without comorbidity in time to 50%CLT. Clustering was accounted for by using the robust sandwich estimator.
Ethical Approval
This study was approved by the institutional review board (s62301). Patients were informed about the study. Informed consent was obtained according to good clinical practice. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Results
Demographics
The mean age of psoriasis patients and HC was 52 and 52.7 years, respectively, and 70% (n = 61) were male in both cohorts. Mean body mass index (BMI) was 28.83 (SD 5.156) in the psoriasis cohort compared with 25.96 (SD 4.076) in HC (p < 0.001). An overview of comorbidities is presented in Fig. 1.
Fig. 1
Presence of comorbidities in the psoriasis cohort and healthy controls. Among psoriasis patients, arterial hypertension (p < 0.001), diabetes (p = 0.002), psoriatic arthritis (p <0.001) and coronary artery disease (p = 0.002) were significantly more present compared to HC. Within the psoriasis cohort, comorbidities were similarly present in all psoriasis treatment groups. IBD inflammatory bowel disease; PsA psoriatic arthritis; aHT arterial hypertension; CAD coronary artery disease; HC healthy controls; Pso psoriasis patients
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Clot Lysis Profile: Psoriasis Patients Versus HC
The CLP of 87 psoriasis patients and 87 age- and sex-matched HC was determined.
At baseline, psoriasis patients had significantly higher amplitude levels (%) (median 160.5 [IQR, 135.3–182.3]) (Fig. 2, panel A) and AUC (%) (median 266.8 [IQR, 183.4–391.3]) (Fig. 2, panel B) compared to HC (%) (median amplitude 129.1 [IQR, 111.8–152.5] (p < 0.0001); median AUC 188.2 [IQR, 133.4–284.9]) (p < 0.0001).
Fig. 2
Indicators of clotting tendency derived from the clot lysis profile. A Amplitude was significantly higher in psoriasis patients versus healthy controls (*p < 0.0001). B Area under the curve was significantly higher in psoriasis patients versus healthy controls (*p < 0.0001). Box represents interquartile ranges. Black triangles represent the median values. Whiskers mark minimal and maximal values. HC = 87; Pso-BL = 87
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There was no difference in 50%CLT between patients and HC at baseline.
Impact of Comorbidities and Treatment Modality
Given the high prevalence of comorbidities in the psoriasis cohort compared to the HC, we corrected for these differences using linear mixed models including the following variables in the model: BMI, smoking, psoriatic arthritis, arterial hypertension, diabetes and coronary arterial disease. After correction for these possible confounders, the increased amplitude in psoriasis patients compared to HC remained significant.
Clot Lysis Profile: Impact of Treatment
Disease Evolution
Mean psoriasis area severity index (PASI) and body surface area (BSA) at baseline were 13.3% and 24.4%, respectively. The mean time to follow-up sample was 6.1 months (SD 3.8 months). At follow-up, mean PASI and BSA decreased to 1.3% and 2.1%, respectively.
Clot Lysis Profile: Baseline Versus Follow-up
Overall, the amplitude (%) (median 149.1 [IQR, 124.0–175.5]) of the CLP was significantly lower at follow-up compared with baseline (%) (median 160.5 [IQR, 135.3–182.3]) (p = 0.0365) (Fig. 3, panel A).
Fig. 3
Evolution of indicators of clotting tendency derived from the clot lysis profile before and after psoriasis treatment. A Amplitude significantly decreased in psoriasis patients after successful anti-inflammatory treatment (*p = 0.0365). B No significant changes in AUC were observed after successful anti-inflammatory treatment. C 50%CLT significantly increased at follow-up compared to baseline (p = 0.0052). A and B Box represents interquartile ranges. Black triangles represent the median values. Whiskers mark minimal and maximal values. AUC area under the curve; Pso-BL psoriasis baseline; Pso-FU psoriasis follow-up
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No difference was observed between AUC at baseline (%) (median 266.8 [IQR, 183.4–391.3]) compared to follow-up (%) (median 276.7 [IQR, 188.0–407.3]) (Fig. 3, panel B).
When looking at 50%CLT, a significant increase in 50%CLT was observed at follow-up compared to baseline (p = 0.0052) (Fig. 3, panel C).
Patients were treated with conventional therapies or biological treatments. The treatment modalities did not affect amplitude or area under the curve. In contrast, however, treatment with selective IL23-antibodies was associated with a significantly prolonged 50%CLT (p = 0.0007) (see supplementary material Appendix A).
Focus on the Impact of Disease Severity Represented by BSA
In our cohort we observed significantly higher levels of hsCRP in patients with higher BSA (p = 0.033). We also performed a subanalysis of the CLP in patients with BSA > 10, > 15 and > 20 and their matched HC: at baseline we found similar results for the overall group compared to the different subgroups. Next, we investigated the effect of psoriasis treatment on CLP in the subgroups with BSA > 10, > 15 and > 20 (baseline and follow-up). Also here the findings were in line with the results of the CLP evolution in the overall group. In conclusion, we could not demonstrate an additional effect of higher baseline BSA on the CLP (see supplementary material Appendix B).
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Discussion
In this study we show for the first time the effect of psoriatic disease activity and subsequent treatment on the CLP. We found a CLP with hypercoagulable characteristics (high amplitude and AUC) in active psoriasis patients compared to HC. Successful anti-inflammatory therapy resulted in a significant tendency towards normalization of this hypercoagulable CLP. The 50% clot lysis time was not different between patients and HC, although an increase was observed within patients over time despite controlling for disease activity.
In line with reports in the literature, our psoriasis patients had a high prevalence of comorbidities and risk factors for vascular events. Each of these factors can independently predispose patients to the development of VTE. However, even after correction for each of these possible confounders, the CLP amplitude remained significantly higher in psoriasis patients compared to HC. This suggests that merely the presence of active uncontrolled psoriasis—even in the absence of any comorbidity—is a risk factor for VTE.
Since inflammation and hypercoagulation are intertwined, we investigated the effect of anti-inflammatory treatment on the clot lysis profile. The majority of psoriasis patients (85%) were treated with biologics (anti-IL17/IL23/TNFα) and only a minority (15%) with conventional therapies (methotrexate or cyclosporine). All patients had to achieve an absolute PASI and/or BSA < 3 for inclusion. After a median follow-up of 6 months, we observed a significant decrease in amplitude but not AUC. We showed that the treatment modality did not influence amplitude or AUC.
Von Stebut et al. observed that improvement in flow-mediated dilation became significant only after 52 weeks [24]. Similarly, Elnabawi et al. showed a significant improvement in total coronary plaque burden, primarily driven by a reduction in non-calcified plaque burden 52 weeks after start of biologic therapy in psoriasis patients [25]. These findings suggest that a longer follow-up would have been interesting the effects of long-term remission.
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Additionally, information on the lysis tendency was obtained from both 50%CLT and AUC. Surprisingly, we found an increase in 50%CLT (a marker for a reduced fibrinolytic activity) after treatment in psoriasis patients. In particular, this was noted in the patient group treated with IL23 antagonists. In a recent publication, Yumeng et al. demonstrated that in Kc-Tie2 mice, a well-established mouse model of psoriasis, targeting IL-17A or IL23 not only resulted in skin clearance but also increased the time to occlusive thrombus formation after 6 weeks of treatment, resulting in reduced risk of thrombosis [26]. This suggests that targeting psoriasis by blocking IL23 or IL17A may lower the risk of cardiovascular events in patients. The explanation for our finding of an increase in 50%CLT in patients treated with IL23-blockers is unclear and may be explained by low sample size and type 1 error.
In clinical practice the most commonly used score is BSA. We observed significantly higher levels of hsCRP in patients with higher BSA (p = 0.033), confirming the link between cutaneous and systemic inflammation. However, higher thresholds of body surface involvement (e.g., > 15%; > 20%) did not additionally affect the CLP, and body surface involvement of 10% already results in increased risk of VTE. We also investigated the effect of psoriasis treatment on CLP correcting for BSA but also here the findings were in line with the results of the overall group, indicating that reduction of cutaneous psoriasis with body surface involvement of 10% already improves the CLP.
Overall, our results are important in an era in which new potent anti-inflammatory drugs with a potential pro-thrombotic risk profile are introduced in the treatment of multiple inflammatory diseases. Safety signals of increased risk of VTE with the use of JAK inhibitors resulted in additional post-marketing studies such as ORAL surveillance and boxed warnings from the US Food and Drug Administration [27]. Future research should address the utility of the CLP assay in clinical practice for patient risk stratification and personalized medicine.
Previous studies have linked CLP parameters to the risk of arterial and venous events in certain groups of patients [28, 29]. However, CLP assays are not standardized or automated and are not routinely available in most clinical laboratories. Therefore, it is currently not feasible to use CLP routinely to stratify patients with psoriasis. Future research should address the use of CLP in clinical practice, focusing on the predictive value for clinical events.
The above findings raise the question whether thromboprophylaxis in uncontrolled psoriasis patients is warranted. Overall, there is little evidence to support this claim. However, it seems reasonable to identify uncontrolled inflammation as an additional risk factor for VTE, therefore lowering the threshold to start thromboprophylaxis when high risk situations such as immobilization or hospitalization occur.
Our study has strengths and limitations. Strengths are the prospective set up, the selection of age- and sex-matched HC and correction for potential confounders. Given the nature of the disease, some confounders (e.g., obesity) are more present in the psoriasis cohort which could be considered a limitation. However, those confounders are present at baseline and follow-up in the psoriasis group, therefore providing intrinsic correction when evaluating the impact of systemic inflammation on CLP. The relatively short follow-up of 6 months is a limitation as explained above. Additionally, due to the inclusion criteria no information on partial responders was obtained. Lastly, we found that body surface involvement of ≥ 10% is linked to changes in the clot lysis profile. The true cut-off may be even be < 10%; however, due to the inclusion criteria (baseline PASI or BSA > 10%), we could not investigate the impact of less extensive psoriasis.
Conclusions
In conclusion, we identified a CLP with hypercoagulable characteristics in uncontrolled psoriasis patients compared to age- and sex-matched HC. After correction for confounders, this finding remains robust. Furthermore, successful systemic treatment regardless of treatment modality was associated with a normalization of this hypercoagulable profile, suggesting that inflammation is an important driver in this hypercoagulability. Even though measuring CLP is currently not feasible in daily practice, our findings underline the importance of dermatologists' awareness about VTE as a comorbidity in psoriasis patients.
Acknowledgements
We thank the participants of the study. We thank Annouschka Laenen (Interuniversity Institute for Biostatistics and statistical Bioinformatics).
Declarations
Conflict of Interest
Tom Hillary has received consultancy from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Janssen, Leo Pharma, Eli Lilly, Novartis, Sandoz, UCB Pharma; speaker fees from AbbVie, Almirall, Amgen, Biogen, Celgene, Janssen, Leo Pharma, Eli Lilly, Novartis, Sanofi, UCB Pharma; research funding from AbbVie, Almirall, Amgen, Janssen, Leo Pharma, Eli Lilly, Novartis, UCB Pharma. SV Has received grants from: AbbVie, J&J, Pfizer, Galapagos, Takeda and Has received consulting and/or speaking fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma. Tine Vanhoutvin, Miet Peeters, Maya Imbrechts, ThomasVanassche and Marjan Garmyn have nothing to disclose.
Ethical Approval
Institutional Board Approval (s62301) was obtained prior to the start of this project; prior to enrolment, all patients signed informed consent. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
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