Bridging the gaps: Towards improved care for immune thrombocytopenia

Abstract

This thesis aimed to address several “gaps” in the care for patients with immune thrombocytopenia (ITP).

FATIGUE In the “PICI”-study, a cross-sectional study with 60 chronic ITP patients, we validated the Checklist Individual Strength (CIS) to measure fatigue in ITP. Furthermore, we found that 56% of the patients was severely fatigued; significantly more than in the general population. Subsequently, we found that fatigue was related to disease activity, skin and organ bleeding, physical, functional, emotional, and social well-being, vitamin D, and physical activity. Disease-specific factors, including disease activity, explained <20% of the variance in fatigue, while non-disease-specific factors, including well-being and activity, played a much bigger role (>50% of explained variance).

FEMALE-SPECIFIC ISSUES In a subset of the PICI-study, including 23 pre-menopausal women, we measured the amount of blood loss and the impact of the menstruation. We found that heavy menstrual bleeding was frequent (42-52%). Furthermore, 78% of the studied patients had experienced clinical menstrual problems in the present or past. Notably, both heavy menstrual bleeding and experiencing a high impact of the menstruation occurred despite normal platelet counts and the use of tranexamic acid or oral contraceptives.

We retrospectively studied the etiological relation between severe postpartum haemorrhage (SPPH) and platelet count, mean platelet volume, plateletcrit, platelet distribution width, and immature platelet fraction in 23205 deliveries. We found that the occurrence of SPPH was independently associated with different degrees of thrombocytopenia, particularly <50*10^9/L, and plateletcrit.

DENTAL CARE In a systematic review, we found that there is alarmingly little research available regarding the risk of bleeding and infection associated with dentoalveolar procedures in ITP patients. However, based on the 17 articles describing 73 dentoalveolar procedures in 49 patients, clinically relevant ITP-related complications seemed rare.

THROMBOPOIETIN RECEPTOR AGONISTS We performed a systematic review to assess whether thrombopoietin-receptor agonists (TPO-RAs) induced changes in the haemostasis that might explain an increased thrombotic risk. Twelve observational studies with a total of 305 patients were included, that were heterogeneous concerning the type of TPO-RA, the timing of assessment during treatment, and the assessed parameters. Overall, TPO-RAs did not seem to influence most markers of platelet function, except for possibly an increase in the levels of platelet-monocyte aggregates, soluble P-selectin, glycoprotein VI expression, and adhesion under flow. Regarding global and secondary hemostasis and fibrinolysis, the literature was scarce, but most studies found no changes, apart from an accelerated clot formation and conflicting data on the levels of plasminogen activator inhibitor (PAI)-1.

Additionally, we performed a prospective study assessing platelet function and coagulation in 16 ITP patients before start of eltrombopag and 2-3 weeks after initiation. We found that ITP patients have a procoagulant state at baseline: pre-activated platelets and elevated levels of factor VIII (FVIII) and Von Willebrand factor (VWF). Eltrombopag treatment did not influence platelet function and the levels of FVIII and VWF, but it did increase plasma thrombin generation potential.

PART V TOPICAL ISSUES We have responded to two topical issues during the writing of this thesis. First, we assessed the chance of relapse after COVID-19 vaccination in a retrospective cohort study using a telephonic questionnaire (n=85): relapse occurred in 8% after the first vaccination. Secondly, we published a response to a recent randomized trial, that found that adding mycophenolate mofetil to steroids in the first-line treatment of ITP led to greater response rates and less relapse. However, they cautioned for a “somewhat decreased quality of life”. In our response, we argued that the latter claim is based on insufficient evidence and, therefore, that the positive trial results should not be disregarded.