Hemostatic changes by thrombopoietin-receptor agonists in immune thrombocytopenia patients

Dijk, Wobke E.M. van; Brandwijk, Odila N.; Heitink‐Pollé, Katja M. J.; Schutgens, Roger E.G.; Galen, Karin P M van; Urbanus, Rolf T.

doi:10.1016/j.blre.2020.100774

Cited by 15 publications

(14 citation statements)

References 104 publications

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“… 1 – 3 , 43 , 44 Certain treatments are associated with a further increase in thromboembolic risk. 2 , 9 , 45 Eleven publications of TPO-RA treatment of ITP ( Table 3 ) have reported randomized, controlled registrational clinical trials and/or their long-term rollover studies in ITP. The incidence of TEEs reported in these studies of TPO-RA ranged from 0% to 9.4% in studies up to 7 months in duration and from 2.6% to 8.9% in studies of 2–8 years’ duration ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Cooper

Altomare

Thomas

et al. 2021

Therapeutic Advances in Hematology

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Background: Patients with immune thrombocytopenia (ITP) are at risk of bleeding and, paradoxically, thromboembolic events (TEEs), irrespective of thrombocytopenia. The risk of thrombosis is increased by advanced age, obesity, and prothrombotic comorbidities: cancer, hyperlipidemia, diabetes, hypertension, coronary artery disease, and chronic kidney disease, among others. Certain ITP treatments further increase the risk of TEE, especially splenectomy and thrombopoietin receptor agonists. Spleen tyrosine kinase (SYK) is a key signaling molecule common to thromboembolic and hemostatic (in addition to inflammatory) pathways. Fostamatinib is an orally administered SYK inhibitor approved in the USA and Europe for treatment of chronic ITP in adults. Methods: The phase III and extension studies included heavily pretreated patients with long-standing ITP, many of whom had risk factors for thrombosis prior to initiating fostamatinib. This report describes long-term safety and efficacy of fostamatinib in 146 patients with up to 5 years of treatment, a total of 229 patient-years, and assesses the incidence of thromboembolic events (by standardized MedDRA query). Results: Platelet counts ⩾50,000/µL were achieved in 54% of patients and the safety profile was as described in the phase III clinical studies with no new toxicities observed over the 5 years of follow-up. The only TEE occurred in one patient (0.7%, or 0.44/100 patient-years), who experienced a mild transient ischemic attack. This is a much lower rate than might be expected in ITP patients. Conclusion: This report demonstrates durable efficacy and a very low incidence of TEE in patients receiving long-term treatment of ITP with the SYK inhibitor fostamatinib. identifiers: NCT02076399, NCT02076412, and NCT02077192.

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Section: Discussionmentioning

confidence: 99%

Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Cooper

Altomare

Thomas

et al. 2021

Therapeutic Advances in Hematology

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“…42 Conversely, a systematic review of 12 observational studies, including 305 patients receiving either eltrombopag or romiplostim, found some evidence for increased platelet activity, with increased soluble P-selectin, glycoprotein (GP) IV and adhesion under flow identified. 43 Considering avatrombopag, a placebo-controlled study of 30 patients with thrombocytopenia secondary to chronic liver disease rather than ITP, showed that while avatrombopag induced an increase in absolute platelet numbers, there was no change in platelet reactivity by flow cytometry. 44 Whether these agents increase clinical thrombosis risk in ITP patients has been assessed via prospective data collected from patients enrolled onto pivotal phase 2 and 3 TPO-RA clinical trials, mainly conducted for indication approval by the regulatory agencies [European Medicines Agency (EMA) and FDA].…”

Section: Do Thrombopoietin -Receptor Agonists Cause Thrombosis?mentioning

confidence: 99%

Thrombosis in immune thrombocytopenia — current status and future perspectives

Swan

Newland

Rodegheiro³

et al. 2021

Br J Haematol

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Immune thrombocytopenia (ITP) is an autoimmune disorder in which a combination of defective platelet production and enhanced clearance leads to thrombocytopenia. The primary aim for therapy in patients with this condition is the prevention of bleeding. However, more recently, increased rates of venous and arterial thrombotic events have been reported in ITP, even in the context of marked thrombocytopenia. In this review we discuss the epidemiology, aetiology and management of thrombotic events in these patients. We consider the impact of ITP therapies on the increased thrombotic risk, in particular the use of thrombopoietin-receptor agonists (TPO-RAs), as well as factors inherent to ITP itself. We also discuss the limited evidence available to guide clinicians in the treatment of these complex cases.

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“…In vivo, the CWA demonstrated that increased platelet counts were associated with enhanced blood coagulation using PRP [5]. Although thrombosis in ITP patients is an important problem, thrombosis generally occurs in the recovery phase, such as when using the thrombopoietinreceptor agonists [24]. Microvesicle-associated thrombin generation in ITP patients was reported to be increased after the initiation of thrombopoietin receptor agonists [25].…”

Section: Discussionmentioning

confidence: 99%

Clot Waveform Analysis Demonstrates Low Blood Coagulation Ability in Patients with Idiopathic Thrombocytopenic Purpura

Wada

Ichikawa

Ezaki

et al. 2021

JCM

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Background: Although platelets, which contain large amounts of phospholipids, play an important role in blood coagulation, there is still no routine assay to examine the effects of platelets in blood coagulation. Methods: Hemostatic abnormalities in patients with thrombocytopenia, including those with idiopathic thrombocytopenic purpura (ITP), were examined using clot wave analysis (CWA)–small-amount tissue-factor-induced FIX activation (sTF/FIXa) and thrombin time (TT). Results: Although there were no marked differences in the three parameters of activated partial thromboplastin time (APTT) between normal healthy volunteers and typical patients with ITP, the peak heights of the CWA-sTF/FIXa were markedly low in patients with ITP. The three peak times of the CWA-sTF/FIXa in patients with a platelet count of ≤8.0 × 1010/L were significantly longer than those in patients with a platelet count > 8.0 × 1010/L and the peak heights of the CWA-sTF/FIXa in patients with a platelet count of ≤8.0 × 1010/L were significantly lower than those in patients with >8.0 × 1010/L. The peak heights of the CWA-APTT in patients with ITP were significantly lower than in patients with other types of thrombocytopenia. The three peak heights of the CWA-sTF/FIXa in ITP patients were significantly lower than those in patients with other types of thrombocytopenia. The CWA-TT showed lower peak heights and longer peak times in patients with ITP in comparison to patients with other types of thrombocytopenia. Conclusions: The CWA-sTF/FIXa and CWA-TT results showed that blood coagulation is enhanced by platelets and that the blood coagulation ability in ITP patients was low in comparison to healthy volunteers and patients with other types of thrombocytopenia.

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Hemostatic changes by thrombopoietin-receptor agonists in immune thrombocytopenia patients

Cited by 15 publications

References 104 publications

Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Thrombosis in immune thrombocytopenia — current status and future perspectives

Clot Waveform Analysis Demonstrates Low Blood Coagulation Ability in Patients with Idiopathic Thrombocytopenic Purpura

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