|Year : 2022 | Volume
| Issue : 3 | Page : 145-153
Burden of acquired thrombotic thrombocytopenic purpura: KSA and UAE expert consensus for improved disease management
Hasan AAL-Yaseen1, Amna Al Mehairi1, Mohammed Aldarweesh2, Moussab Damlaj3, Khaled El Tayeb4, Sabir Hussain5, Hani Osman5, Abdulkareem M Almomen6, Mahmoud Marashi7
1 Dubai Health Authority, Hematology Department, Dubai Hospital, Dubai, UAE
2 Hematology Department, King Fahad Specialist Hospital, Dammam, KSA
3 Division of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
4 Department of Adult Hematology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
5 Hematology Department, Tawam Hospital, Abu Dhabi, UAE
6 Hematology Department, King Khalid University Hospital, Riyadh, KSA
7 Department of Hematology, Dubai Health Authority, Mediclinic City Hospital, Dubai, UAE
|Date of Submission||06-Oct-2021|
|Date of Decision||29-Apr-2022|
|Date of Acceptance||30-May-2022|
|Date of Web Publication||15-Sep-2022|
Prof. Mahmoud Marashi
Mediclinic City Hospital, DHCC, Dubai
Source of Support: None, Conflict of Interest: None
BACKGROUND: In Saudi Arabia (KSA) and the United Arab Emirates (UAE), only limited epidemiological data and treatment guidance exist for acquired thrombotic thrombocytopenic purpura (aTTP), a rare, life-threatening blood disorder.
AIMS: Expert insights from KSA and UAE were used to obtain local epidemiological data, to characterize current disease management and unmet needs, and to formulate recommendations for the improvement of the diagnosis and treatment of aTTP. Costs and socioeconomic burden were a secondary focus.
METHODS: Hematologists from KSA and UAE with clinical experience in the diagnosis and management of aTTP individually answered questions on the burden and management of aTTP via an online survey. Based on these insights, a draft consensus was discussed and refined jointly by the hematologists in a live session for each country. Payers provided information on the economic burden and cost of aTTP management.
RESULTS: The experts estimate the incidence of aTTP to 5–6 (KSA) and 1–2 (UAE) per 1,000,000 person-years and anticipate it increasing. Most of the presenting patients are aTTP-naive. Recurrent disease is rare. Diagnosis of aTTP should involve ADAMTS13 activity testing. Plasma exchange and immunosuppression are the current standard of care. Key unmet needs include a lack of awareness of aTTP, access to rapid testing and novel treatments to improve outcomes.
CONCLUSION: The expert consensus to address the unmet needs and improve aTTP outcomes include increasing aTTP awareness and access to ADAMTS13 testing; the development of national guidelines; and, additionally, strategies to improve patients' long-term quality of life.
Keywords: ADAMTS13, acquired thrombotic thrombocytopenic purpura, caplacizumab, diagnosis, hematology, microangiopathic hemolytic anemia, plasma exchange, rituximab, sequelae/comorbidities
|How to cite this article:|
AAL-Yaseen H, Al Mehairi A, Aldarweesh M, Damlaj M, El Tayeb K, Hussain S, Osman H, Almomen AM, Marashi M. Burden of acquired thrombotic thrombocytopenic purpura: KSA and UAE expert consensus for improved disease management. J Appl Hematol 2022;13:145-53
|How to cite this URL:|
AAL-Yaseen H, Al Mehairi A, Aldarweesh M, Damlaj M, El Tayeb K, Hussain S, Osman H, Almomen AM, Marashi M. Burden of acquired thrombotic thrombocytopenic purpura: KSA and UAE expert consensus for improved disease management. J Appl Hematol [serial online] 2022 [cited 2022 Sep 28];13:145-53. Available from: https://www.jahjournal.org/text.asp?2022/13/3/145/356089
| Introduction|| |
Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life-threatening blood disorder, characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ damage and caused by an autoantibody-induced deficiency of ADAMTS13. Disease data, such as epidemiology, diagnosis, and economic burden, and national guidelines for aTTP, are lacking in the Kingdom of Saudi Arabia (KSA) and United Arab Emirates (UAE). Clinical experts collaborated and aimed to illustrate a better understanding of the disease and standardize and improve aTTP management, in their respective countries.
| Methods|| |
The primary focus of this study was to establish the epidemiology of aTTP, the current clinical practice, and unmet needs and to develop local consensus statements on aTTP management in KSA and UAE. Cost of the disease and socioeconomic burden were a secondary focus.
Hematologists from KSA and UAE with clinical experience of aTTP took modules via online surveys on burden, management and clinical economics of aTTP. The modules were completed on individual basis. This was followed by a live group session, participated by hematologists, where they agreed on their inputs of the consensus statements for each country. Payers provided information on the economic burden and cost of aTTP management.
A total of nine clinical experts in hematology, who work in specialist centers and have direct experience in treating patients with aTTP, and 2 payers, with experience of healthcare budget management including for aTTP, participated in this study. The data collection was conducted via an online survey, live virtual consensus meetings, and correspondence, between May and July (clinicians) and October (payers) 2020.
The online survey, developed by Ipsos MORI independently from the local experts, referenced the draft International Society on Thrombosis and Haemostasis clinical guideline (2020) and covered the following three topics/modules:
- Epidemiology and diagnosis of aTTP (e.g., incidence, prevalence, recurrence, mortality rate, symptoms, clinical presentation, and diagnosis of aTTP)
- Management of aTTP and unmet medical need (e.g., medical algorithms, standard of care, likely impactful/severe aTTP sequelae, and comorbidities and their management, unmet need, socioeconomic impact, and quality of life (QoL)
- Economic burden of aTTP (e.g., funding and cost of medical services and/or items used to treat aTTP and impact of comorbidities on hospital and long-term treatment costs).
The online survey was completed by four hematologists from the KSA (who answered all 3 modules) and 5 from the UAE (who answered modules 1 and 2). One payer from the KSA and 1 from the UAE answered module 3. All clinical experts also participated in the live country-specific consensus session. The findings were based on the expert clinical knowledge and experience of the participating hematologists and the economic information provided by the payers.
To leverage the individual expertise and establish a consensus of the burden and management recommendations, the clinical experts came together in a virtual working session for each country, moderated by Ipsos MORI. In preparation of the sessions, Ipsos MORI collated, analyzed, and synthesized the findings into a draft consensus document. The clinical experts discussed the content and aligned on the epidemiology, management of aTTP, and unmet needs and came to a consensus for recommendations on aTTP management in their country. Following the live sessions, the revised consensus document was validated by all participating experts.
The established clinical practice, together with cost data from the participating payers, was used to estimate the cost of treating an aTTP episode.
| Results|| |
Epidemiology of acquired thrombotic thrombocytopenic purpura
Robust data on the epidemiology of aTTP in KSA or UAE are missing and registries from which such data could be obtained currently do not exist.
Based on first-hand clinical experience, the four participating clinical experts estimated the aTTP incidence, prevalence, and mortality [Table 1], although highlighted that real rates are likely higher due to the number of undiagnosed cases in KSA. The risk of death is more likely in severe cases that present with comorbidities, and each recurrent aTTP episode increases the risk by 10–20 percentage points.
|Table 1: Acquired thrombotic thrombocytopenic purpura epidemiology across Kingdom of Saudi Arabia according to local clinical experts (n=4)|
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The incidence is expected to increase over the next 5 years in the KSA with better access to earlier diagnosis using ADAMTS13 activity testing and an increased awareness of aTTP among doctors, so patients can be diagnosed and referred earlier. Access to better treatments, and earlier diagnosis, and therefore treatment initiation, should lead to a decrease in mortality. Prevalence is also expected to increase as a result of increased incidence and improved access to treatment and declining mortality.
The 5 participating clinical experts estimated the incidence (equivalent to approximately 10–20 individuals per year, although this could be underestimated as many residents are not UAE nationals and are likely to return to their home country for treatment), prevalence (equivalent to fewer than 60 individuals), and mortality based on their clinical experience, although it was noted that the data supporting the mortality estimate are lacking [Table 2].
|Table 2: Acquired thrombotic thrombocytopenic purpura epidemiology across United Arab Emirates according to local clinical experts (n=5)|
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The incidence is expected to increase in the next 5 years due to increased access to, and awareness of, ADAMTS13 activity testing, as well as increased clinician awareness of aTTP. The prevalence may increase as a result of increased incidence and reduced relapse and mortality rates (driven by better outcomes with earlier diagnosis and novel treatments); alternatively, the prevalence may remain stable as the expatriate population decreases because of COVID-19.
Hematologists from KSA and UAE agreed on definitions of recurrence [Table 3], which can be divided into exacerbation and relapse and refractory disease:
|Table 3: Profiles of patients treated for acquired thrombotic thrombocytopenic purpura (not necessarily mutually exclusive) reported by participating clinical experts (Kingdom of Saudi Arabia=4; United Arab Emirates=5)|
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- Exacerbation: Recurrent disease up to 30 days after the last plasma exchange, requiring re-initiation of plasma exchange
- Relapse: Recurrent disease more than 30 days following the last plasma exchange
- Refractory disease: Failure of platelet response after 4–7 days of plasma exchange or a clinical deterioration in a patient receiving standard treatment.
Comorbidities and sequelae
The experts identified hypertension, renal insufficiency, neurocognitive impairment, headache, thrombosis, and myocardial infarction as common comorbidities and sequelae with onset occurring during hospitalization. Stroke, sepsis, and paresthesia could also take place during this time period, but are uncommon. After the hospitalization, patients commonly experience headaches, and, uncommonly, strokes.
Diabetes mellitus is a common comorbidity both during and after hospitalization. Hypertension, headache, renal insufficiency, and seizures are also commonly seen during hospitalization, with short-term memory loss, neurocognitive impairment, and depression being common in the period thereafter. Uncommon comorbidities include strokes during both time periods and myocardial infarctions during hospitalization.
Current disease management (including diagnosis and resource use)
In both countries, the clinical experts highlighted the lack of national guidelines for aTTP, instead relying on hematologist colleagues, internal/hospital guidelines, and those from the British Society for Haematology.
ADAMTS13 activity testing is preferred for diagnosis; however, currently, there are challenges with access to this test. A suggested regional initiative to make rapid testing available locally would greatly improve the rate of diagnosis and enable faster treatment initiation.
Plasma exchange and immunosuppressants (such as corticosteroids and rituximab, used commonly off-label) are key elements in aTTP treatment [[Figure 1]a for KSA and [Figure 1]b for UAE]. Plasma infusion is used temporarily if plasma exchange is not immediately available. Once platelet count has improved, clinicians use antithrombotic agents (i.e., aspirin and low-molecular-weight heparins). Packed red blood cells are used to correct for hemolytic anemia, if necessary.
|Figure 1: Part (a) is for KSA; part (b) is for UAE. Elements with a black outline are used for all/nearly all patients and no frame indicates treatments are uncommon. *For refractory patients; †Alternative treatment regimens (e.g., 100 mg per infusion) are also being used. aTTP indicates acquired thrombotic thrombocytopenic purpura; BSA = Body surface area; BW = Body weight; CNS = Central nervous system; CT = Computed tomography; LDH, lactate dehydrogenase; MMF = Mycophenolate mofetil; MRT = Magnetic resonance tomography; PEX = Plasma exchange; PRBC = Packed red blood cells|
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ADAMTS13 testing is not readily available in the KSA and samples are sent abroad for testing with results taking up to 2 weeks. In the absence of ADAMTS13 testing, complete blood count and lactate dehydrogenase are used at diagnosis, after 2–3 weeks of treatment initiation and 2–3 months after treatment.
Fresh frozen plasma or cryodepleted plasma are used for plasma exchange. Until plasma exchange can be initiated, plasma infusion (15–30 ml/kg of body weight, daily) is used. In parallel, corticosteroids (e.g., prednisone) should be used for all patients, bortezomib in refractory patients, and vincristine in relapsed/refractory patients.
ADAMTS13 testing is not easily available and affordable to most patients in the UAE due to samples requiring long turnaround times for results and out-of-pocket payments for patients. All patients with aTTP receive plasma exchange using fresh frozen plasma. Temporary plasma infusion (1–2 l, daily) is used until plasma exchange can be initiated. In parallel, clinicians recommend the use of corticosteroids (e.g., methylprednisolone and prednisolone) and mycophenolate mofetil in all patients, although ciclosporin may be used as an alternative to mycophenolate mofetil. Relapsed/refractory patients are treated with bortezomib.
Cost of disease management
Based on the resource use specified by the clinical experts and the costs provided by payers, the cost of managing an average aTTP episode (without major complications, refractoriness, sequelae, and comorbidities) was estimated.
A conservative estimate of the cost of managing a first aTTP event without complications in KSA came to approximately SAR 139,480 (assuming rituximab was not used). When rituximab was used, the cost increased to SAR 183,480. In both cases, the cost of treatments was the main cost driver [Table 4].
|Table 4: Conservative cost estimate for a first acquired thrombotic thrombocytopenic purpura event without complications in Kingdom of Saudi Arabia|
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The cost calculation was based on the costs provided by a single participating payer and did not include every component associated with aTTP disease management and is likely lower compared to the total cost in practice. Other sources cite higher costs for nursing and intensive care unit (ICU) stay as higher than those reported in the table.
The cost of managing a first aTTP event without complications, from the perspective of a single participating private insurer, was estimated to be approximately AED 209,412 (assuming no need for rituximab). When rituximab was used, the cost increased to AED 238,030. In both cases, the main cost driver was the treatment [Table 5]. These costs did not include the costs for diagnostic testing as ADAMTS13 tests are not available/reimbursed in the private setting.
|Table 5: Conservative cost estimate for a first acquired thrombotic thrombocytopenic purpura event without complications in United Arab Emirates|
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The sequelae and comorbidities associated with aTTP lead to an increase in patient burden and, consequently, a reduction in QoL. Although anuria and renal insufficiency are rare, participating clinical experts estimated that they still affect ~ 5% of patients with aTTP which negatively impacts QoL (especially if dialysis is required). In more severe cases, patients may also suffer from neurologic complications.
The participating clinical experts reported that it is common for patients in the UAE to experience psychological problems including depression and memory loss. This severely impacts patient QoL and increases burden of the disease, as it can further deteriorate patient health and lead to loss of independence.
Participating experts stated that the main financial impact of aTTP on patients is loss of income. Treatment is not associated with co- or out-of-pocket payments. The average male salary is ~10,000 SAR/month, with women earning less on average, and most jobs will give sick leave for ~10 days; however, the time period for hospitalization and recovery of an aTTP period is generally longer than 10 days. In the KSA, many families are large and are dependent on one family member's income, usually the father or son; losing the only source of income can therefore be devastating for some families.
As aTTP is very rare, the data on the financial impact of the disease are very limited. UAE nationals' treatment is fully funded by the government; however, nationals only represent ~5% of the population. Nonnationals without insurance or with insufficient insurance face considerable out-of-pocket costs and there are no programs for financial support; however, charities can provide limited financial relief.
Current unmet needs
Considering the differences in the patient population and health-care system across both countries, clinical experts reported quite diverging perceptions of unmet needs in aTTP patients [Table 6].
|Table 6: Current unmet needs in Kingdom of Saudi Arabia and United Arab Emirates as reported by local clinical experts|
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Expert recommendations to improve acquired thrombotic thrombocytopenic purpura management
Due to the absence of local guidelines, the management of aTTP is not standardized across KSA and UAE, which can result in less optimal results in less specialized centers. To improve the diagnosis and treatment of aTTP in both countries, the clinical expert panels agreed on key recommendations to optimize management and long-term outcomes for patients with aTTP in KSA [Table 7] and UAE [Table 8], while also encouraging nationwide initiatives (i.e., registries) and access decisions for more innovative treatments.
|Table 7: Expert (n=4) consensus recommendations to improve management of acquired thrombotic thrombocytopenic purpura in Kingdom of Saudi Arabia (rationale in italics)|
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|Table 8: Expert (n=5) consensus recommendations to improve management of acquired thrombotic thrombocytopenic purpura in United Arab Emirates (rationale in italics)|
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| Discussion|| |
The burden of aTTP in 2 Gulf states, KSA and UAE, is not well characterized and there are no national guidelines for how it should be managed, and additionally, access to ADAMTS13 activity testing is challenging. These factors contribute to a low awareness of the disease among doctors who are not hematology specialists, resulting in delays in referrals, diagnosis, and treatment initiation, with consequently poor patient outcomes. In addition, local experts suggest that caplacizumab along with adding rituximab as early as possible can help improve patient outcomes as it has been shown to have a positive impact on thromboembolic event rate, death rate, relapse rate, hospitalization/ICU time, days of plasma exchange, and time to normalization of markers of end-organ ischemic damage., The participating clinical experts provided a consensus on epidemiology disease characterization, current management, and holistic recommendations for improved aTTP management (that consider the addressing of unmet needs from both a hematologist and patient perspective) and constitutes the foundation for national guidelines for management of aTTP in the UAE and KSA.
The article represents the opinion and insights of 9 hematologists and 2 payers which may impact the full representation of disease details in UAE and KSA.
The research upon which this manuscript is based was funded by Sanofi S.A. None of the authors received additional payment (outside of their regular salary for Sanofi employees) for the development of this manuscript. Ruth Zeidman, Matteo Fabiani, and Christopher Sayadian from Ipsos MORI supported data collection and analysis, as well as the development and writing of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood 2017;129:2836-46.
Alharthy A, Karakitsos D. King Saud Medical City Intensive Care Unit: A critical and cost-focused appraisal. Saudi Crit Care J 2019;3:19-23. [Full text]
Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al.
ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020;18:2486-95.
Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, et al.
Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012;158:323-35.
Hanlon A, Metjian A. Caplacizumab in adult patients with acquired thrombotic thrombocytopenic purpura. Ther Adv Hematol 2020;11:1-10.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]