|Year : 2022 | Volume
| Issue : 3 | Page : 111-117
Approaches to acquired thrombotic thrombocytopenic purpura management in Saudi Arabia
Ayman AlHejazi1, Amal AlBeihany2, Hani AlHashmi3, Hazzaa Alzahrani4, Ibraheem H Motabi5, Ihab El-Hemaidi6, Khalid Alsaleh7, Khaled El Tayeb8, Magdy Rabea9, Mohamed Khallaf10, Mohammad Hasan Qari11
1 Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
2 Department of Adult Hematology, King Faisal Specialist Hospital and Research Center, Madinah, Saudi Arabia
3 Department of Adult Hematology and Stem Cell Transplantation, King Fahad Specialist Hospital, Dammam, Saudi Arabia
4 Department of Hematology and Bone Marrow Transplantation Section, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
5 Department of Adult Hematology/BMT, King Fahad Medical City, Riyadh, Saudi Arabia
6 Department of Adult Hematology/BMT, King Abdulaziz Medical City, Jeddah, Saudi Arabia
7 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
8 Department of Adult Hematology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
9 Department of Medical Affairs, Sanofi, Jeddah, Saudi Arabia
10 Department of Medical Affairs, Sanofi, Dubai, UAE
11 Department of Hematology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
|Date of Submission||17-Apr-2021|
|Date of Decision||01-Oct-2021|
|Date of Acceptance||18-Oct-2021|
|Date of Web Publication||15-Sep-2022|
Dr. Ayman AlHejazi
Department of Oncology, King Abdulaziz Medical City, Riyadh 14611
Source of Support: None, Conflict of Interest: None
Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening microangiopathy usually characterized by microangiopathic hemolytic anemic, thrombocytopenia, and end-organ ischemia associated with disseminated microvascular platelet-rich thrombi and severe deficiency (activity <10%) of A Disintegrin-like And Metalloprotease with ThromboSpondin Type 1 Motif No. 13 (ADAMTS13). It is a medical emergency, and if left untreated, acute mortality is as high as 90%. This review article is a narrative review based on available literature. In addition, the key discussions of the Kingdom of Saudi Arabia experts and members of “Approaches to aTTP Management” Advisory Board meeting held on October 16, 2020, have been incorporated as expert opinions. It was agreed that treatment should be started based on the presumptive diagnosis and continued until remission or an alternate diagnosis is established. Use of caplacizumab in addition to therapeutic plasma exchange and immunosuppression is recommended in confirmed aTTP episodes.
Keywords: A Disintegrin-Like And Metalloprotease with ThromboSpondin Type 1 Motif No. 13, acquired thrombotic thrombocytopenic purpura, caplacizumab, treatment
|How to cite this article:|
AlHejazi A, AlBeihany A, AlHashmi H, Alzahrani H, Motabi IH, El-Hemaidi I, Alsaleh K, El Tayeb K, Rabea M, Khallaf M, Qari MH. Approaches to acquired thrombotic thrombocytopenic purpura management in Saudi Arabia. J Appl Hematol 2022;13:111-7
|How to cite this URL:|
AlHejazi A, AlBeihany A, AlHashmi H, Alzahrani H, Motabi IH, El-Hemaidi I, Alsaleh K, El Tayeb K, Rabea M, Khallaf M, Qari MH. Approaches to acquired thrombotic thrombocytopenic purpura management in Saudi Arabia. J Appl Hematol [serial online] 2022 [cited 2022 Sep 28];13:111-7. Available from: https://www.jahjournal.org/text.asp?2022/13/3/111/356094
| Introduction|| |
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening microangiopathy usually characterized by microangiopathic hemolytic anemic (MAHA), thrombocytopenia, and end-organ ischemia associated with disseminated microvascular platelet-rich thrombi. TTP could be subclassified into two types, namely congenital TTP (cTTP) and acquired TTP (aTTP). The current review is focused on aTTP. aTTP is immune mediated and accounts for nearly 90%–95% of all TTP., aTTP is a medical emergency, and it needs early medical management. The acute mortality of aTTP if untreated is very high at 90%. The clinical presentation usually includes multivisceral ischemic symptoms (mainly targeting the brain), insidious-onset MAHA with thrombocytopenia occurring in the absence of apparent cause, and severe deficiency (activity <10%) of a metalloprotease enzyme called A Disintegrin-like And Metalloprotease with ThromboSpondin Type 1 Motif No. 13 (ADAMTS13). However, atypical presentations with just neurological symptoms and normal blood counts have also been reported. Thus, atypical presentations and other mimics of aTTP delay the diagnosis. Lack of awareness of the disease further delays the treatment which, in turn, affects the patient outcomes, and therefore, early diagnosis is vital in the management of aTTP.,
The aim of the current review is to summarize the current knowledge regarding the epidemiology, pathophysiology, and management of aTTP, including newer therapies to provide a consensus and recommendations by the authors who are hematology experts in the Kingdom of Saudi Arabia (KSA) with regard to aTTP Management. The experts' recommendations for aTTP were developed as part of their efforts to address the burden and current challenges of aTTP in the KSA and to reach a national consensus in the management of aTTP.
| Methods|| |
This review article is a narrative review based on the available literature. The literature search was done using Medical Subject headings terms or equivalent such as “Purpura, Thrombotic Thrombocytoenic,” “ADAMTS13 Protein” and “Microangiopathic Hemolytic Anemia, Congenital” in PubMed, PubMed Central, Medline and Google Scholar. In addition, the key discussions of the KSA experts and members of “Approaches to aTTP Management” Advisory Board meeting held on October 16, 2020, were incorporated as expert opinions on aTTP Management in the KSA. A total of nine experts from Riyadh, Jeddah, Dammam, and Madinah attended the meeting. The statements presented in this article reflect the authors' analysis, evaluation, and opinion, and the management recommendations were formed by a panel of aTTP experts in the KSA during the advisory board discussions and deliberations, based on Delphi's technique, which was subsequently drafted and peer-reviewed by the authors.
aTTP is a rare condition with an annual global incidence of 1–2 cases per million people. However, in countries such as the USA (3–4 cases/million),, England (6 cases/million), France (2–4 cases per million), Germany (2.1 cases/million), the incidence is slightly higher than the global incidence. Epidemiological studies from the KSA are limited. Iqbal et al. have reported a single tertiary care center experience of 24 patients, and this was the total number of patients who undertook treatment in their hospital over an approximately 10-year period from October 2006 to April 2015. This suggests that aTTP is also rare in the KSA. The experts' consensus also was that the estimated incidence of aTTP was approximately 1–2/million in the KSA.
The median age of diagnosis of the first episode is usually in the fourth decade of life and is quite rare in children. In Saudi Arabia, the median age at diagnosis is in the third decade based on the expert's experience. The annual incidence of aTTP in children <18 years of age is nearly one in ten million. Females and Black race have higher risk of aTTP. In England, the UK TTP Registry had 75% of cases occurring in women. Similarly, in the Oklahoma TTP-HUS Registry, 76% were women and 36% were Blacks. Obesity and human leukocyte antigen DR isotype 11 positivity are the other predisposing risk factors. Besides these risk factors, a lot of conditions predispose to aTTP. An acute aTTP episode can be triggered by many conditions that increase the von-Willebrand factor (VWF) levels, such as infection, chronic inflammation, pregnancy.,
The main components in the pathophysiology of TTP is VWF and ADAMTS13 which is the size regulator of VWF. ADAMTS13 cleaves the ultra-large polymers of activated VWF to smaller forms which are less sticky. Thus, when ADAMTS-13 is deficient, VWF-rich platelet thrombi are formed in the microvasculature that heralds TTP. In the case of cTTP, there is a primary deficiency of ADAMTS13. However, in case of aTTP, there are antibodies against ADAMTS13, therefore, causing decreased ADAMTS13 activity.
Antibodies against ADAMTS13 are broadly classified into two types, namely inhibitory and noninhibitory, both of which enhances ADAMTS13 clearance. These antibodies are mainly of the IgG subtypes, the most abundant classes being IgG4 and IgG1. However, 20% of patients contain IgA and IgM isotypes as well. Those with IgA or IgG1 at presentation during an acute episode of aTTP were associated with a higher death rate. However, IgG4 was associated with disease relapse and often is the only isotype present in relapsed patients.,
Early diagnosis is vital for better patient outcome and hence a presumptive diagnosis is made based on the clinical and laboratory abnormalities. Since typical presentations of aTTP is not always the case, clinical scores such as the PLASMIC score [Table 1] and the French thrombotic microangiopathy (TMA) reference center score [Table 2] that predict ADAMTS13 reduced activity are recommended to make a presumptive diagnosis and commence early treatment. This is true for the KSA as well, as opined by the advisory board members. The French score has a sensitivity of 98.8% and a specificity of 48.1% if at least one criterion is fulfilled. When all three criteria are fulfilled, although the sensitivity decreases to 46.9%, the specificity increases to 98.1%. The main challenge is in the diagnosis and to rule out other TMAs such as drug induced, complement mediated, Shiga toxin related, disseminated intravascular coagulation, malignancy, severe hypertension, anti-phospholipid syndrome, HELLP, eclampsia, and stem cell or solid organ transplantation.
The definitive diagnosis is by testing the ADAMTS13 activity which is now considered the gold standard for diagnosis. ADAMTS13 activity <10% when compared to the control (pooled plasma) is 97% sensitive and 100% specific to diagnose aTTP. However, interpretation of ADAMTS13 activity assay must be correlated clinically as there are many conditions in which there is either under- or over-estimation of reduced ADAMTS-13 activity or an actual decrease in the activity secondary to other medical conditions. An actual reduction in the ADAMTS-13 activity could be due to hepatic necrosis, graft versus host disease, sepsis, human immune-deficiency virus infection, Kaposi sarcoma. Besides ADAMTS-13 activity, another objective modality of diagnosis is to detect the presence of antibodies against ADAMTS13. Neutralizing (inhibiting) antibodies are present in 65%–95% of cases and considered to be positive if the Bethesda inhibition assays are >0.4 Bethesda units. Nonneutralizing (noninhibiting) antibodies are detected using enzyme-linked immunosorbent assays and are found to be positive in 97% of aTTP.
Based on the consensus from the experts, diagnosis of aTTP is challenging and requires ruling out all other TMAs. The predictive scores such as PLASMIC and French scores are recommended to make a presumptive diagnosis of aTTP diagnosis to initiate early treatment. The definitive aTTP diagnosis is by testing the ADAMTS13 activity, which is now considered the gold standard for diagnosis. However, in the KSA, the availability of in-house testing of ADAMTS13 activity is lacking in majority of the hospitals, causing a delay in the definitive diagnosis which is, therefore, considered as a key unmet need in the management of aTTP in the KSA. This is further complicated by lack of clinical suspicion, delayed referral, and lack of treatment options such as apheresis and access to newer biologicals such as caplacizumab at all centers.
Traditional standard of care treatment
As soon as the presumptive/confirmed diagnosis of aTTP is made, therapeutic plasma exchange (TPE) is to be administered and is to be continued daily till the platelet count recovers or an alternate diagnosis is established and TTP is ruled out.,, TPE is a process by which the patient's plasma is removed by apheresis and is replaced with donor plasma, thereby removing the antibodies against ADAMTS13 along with the residual ultra-large VWF multimers and simultaneously replacing it with donor ADAMTS13. The donor plasma products that could be used include fresh frozen plasma (FFP), thawed plasma (FFP that has been thawed and stored for up to 5 days at 1°–6°C), cryo-poor plasma (cryoprecipitate has been removed and is also called cryoprecipitate reduced plasma), and pathogen-inactivated plasma such as amotosalen-UVA-treated plasma or solvent/detergent-treated, and the choice of the product used is determined by the clinician. Besides TPE, the next main stay of treatment is immunosuppression, and corticosteroids have been traditionally used to suppress the production of autoantibodies.,, The recommended dose is prednisolone 1–2 mg/kg/day or equivalent. However, there are no controlled trials to prove the efficacy of corticosteroids in the treatment of aTTP. Moreover, TPE with immunosuppression is still the recommended standard of care in aTTP treatment which should be started directly after diagnosis of aTTP.
The unmet needs
Despite TPE and immunosuppression, aTTP patients remain at high risk for thrombotic complications such as myocardial infarction, ischemic stroke, renal failure, or other end-organ damage.,, Acute mortality is still seen in up to 20% of aTTP cases and the median time from diagnosis to death is 9 days., Further, up to 42% of all cases experience unpredictable refractoriness to treatment with TPE and corticosteroids, up to 50% experience exacerbations, and up to 84% remain at long-term risk of relapse. The hospitalization is often lengthy with TPE treatment which can last 2 weeks or even more, and they take a longer time to start working, thereby increasing the risk of patients to additional complications due to microthrombi even after diagnosis., Although various treatment options such as mycophenolate mofetil, cyclophosphamide, intravenous (IV) immunoglobulin, plasma infusions, cyclosporine, vincristine, and bortezomib have been tried in refractory/relapsed diseased status with varying levels of success, mortality rates are as high as 40%. This scenario was no different in the KSA where Iqbal et al. have reported that the mortality was 16.7% (n = 4/22) where n = 3 died during the acute episode either due to severity of the disease or delayed treatment. There were no relapses reported during the 22 months of follow-up and 20.8% (n = 5/24) were early refractory to standard treatment with TPE.
Treatment-related complications further add to the misery of aTTP patients. The need for a long duration of TPE predispose the patients to high risk of plasma exchange-related complications such as allergic reactions, alkalosis, volume depletion, infection, and hypotension.,, TPE is almost always done using a central venous catheter and the procedure of catheter placement also comes with complications associated with the insertion procedure, infection, thrombosis, and hemorrhage.,,
Beside short-term complications, long-term consequences of aTTP episodes result in decreased quality of life. The risk of morbidity and mortality increases with every episode of aTTP. Besides ischemic complications, patients suffer from cognitive deficits, mood disorders, arterial hypertension, and increased risk of other autoimmune diseases such as SLE and Sjogren's syndrome. In summary, the traditional treatment with TPE and corticosteroids has delayed onset of action, need for prolonged duration of treatment, and treatment-related adverse events, which leads to significant patient numbers having refractoriness, relapses, and exacerbations. Hence, the hunt for newer modalities of treatment beyond TPE and immunosuppression is warranted.
Newer approaches for treatment in acquired thrombotic thrombocytopenic purpura
With this background, the urge to invent newer modalities of treatment to resolve unmet needs of TPE and corticosteroids were on the rise. With the advent of the biologicals' era, rituximab had been in use for a while as an immunosuppressive agent with aTTP as an off-label indication. Rituximab is a chimeric monoclonal antibody against CD20 proteins present on the mature B cells, and in aTTP, it is given at a dose of 375 mg/m2 body surface area, once weekly for 4 weeks. The International Society on Thrombosis and Hemostasis (ISTH) has issued a conditional recommendation to use rituximab over corticosteroids during the first event or relapse, conditional in the context of very low certainty evidence. The authors recommend the use of rituximab in aTTP treatment in addition to TPE and corticosteroids.
The recent addition to the biologicals that can be used in the management of aTTP is caplacizumab. Caplacizumab was the first agent that was exclusively approved for the treatment of adult patients with aTTP, in combination with TPE and immunosuppressive therapy by the European Medicines Agency (EMA) in September 2018, the United States Food and Drug Administration in February 2019, and the Saudi Food and Drug Authority in October 2020. The use of caplacizumab has also been recommended for use with moderate certainty evidence by the ISTH guidelines in case of first event or relapse. The ISTH guidelines panel also believed that caplacizumab should be started in the early phase of an acute TTP event, as soon as possible after the diagnosis is confirmed. Caplacizumab has also been accorded the orphan drug status by EMA as aTTP is a rare disease.
Caplacizumab in acquired thrombotic thrombocytopenic purpura
Caplacizumab is a VWF-directed antibody fragment that is administered (IV) upon the initiation of TPE. It is available as a white lyophilized powder which has to be reconstituted with a solvent before use. The first dose is 10 mg IV before TPE followed by daily subcutaneous administration of 10 mg after completion of TPE so that TPE does not remove caplacizumab from the plasma. This subcutaneous administration has to be continued till 30 days after stopping TPE. The efficacy and safety of caplacizumab have been proven by TITAN (Phase II) and HERCULES (Phase III) study. In the TITAN trial, 72 patients were randomized to receive either caplacizumab (n = 36) or placebo (n = 39) during TPE and for 30 days afterward. Approximately 90% of patients received steroids in both groups and 5.6% in the caplacizumab group and 23.1% in the placebo group received rituximab. There was a 39% reduction in the median time to a response in the caplacizumab group (P = 0.005) with an event ratio of 2.20 (95% confidence interval (CI), 1.28–3.87, P = 0.005). Complete remission after initial course of TPE was seen in 81% of patients treated with caplacizumab versus 46% of patients treated with placebo. The common adverse events encountered were headache and epistaxis. There were no deaths in the treatment group when compared to two deaths in the placebo group; however, bleeding-related complications were more in the caplacizumab-treated group when compared with placebo. A post hoc analysis further revealed that the mean number of days of TPE and the mean volume of plasma used were lower in the treatment group during daily TPE (5.9 vs. 7.9 days, and 19.9 vs. 28.3 L, respectively) and during the entire treatment period, including exacerbations (7.7 vs. 11.7 days, and 25.8 vs. 41.8 L, respectively).
HERCULES study was a phase III, double-blind, parallel group, multicenter, randomized placebo-controlled trial. A total of n = 145 participants were randomized in a 1:1 ratio to receive caplacizumab or placebo over and above the standard of care that was predefined. The median time to normalization of the platelet count was lower with caplacizumab when compared with placebo (2.69 days [95% CI = 1.89, 2.83] vs. 2.88 days [95% CI, 2.68, 3.56], P = 0.01). The percentage of patients with a composite outcome event (TTP-related death, recurrence of TTP, or a major thromboembolic event) was 12% with caplacizumab versus 49% with placebo (P < 0.001). Recurrence of TTP at any time during the study was 12% in caplacizumab versus 38% in placebo group (P < 0.001). There were no patients in the caplacizumab group who developed refractoriness when compared to three patients in the placebo group. A total of 65% in the treatment group experienced mucocutaneous bleeding, while only 48% experienced it in the placebo group. Mortality was seen in three patients in the placebo group and one patient in the caplacizumab group who died of cerebral ischemia after completing the treatment period.
The results of the randomized controlled trials (RCTs) have been confirmed by the real-world evidence data including 85 patients receiving caplacizumab from 22 hospitals in the United Kingdom published by Dutt et al. Glucocorticoids and rituximab with TPE was received by n = 84/85 patients. The median time to normalization of platelet count (3 days), duration of TPE (7 days), and duration of hospital stay (12 days) were comparable with the results of the RCTs. However, the median duration of TPE and the time from TPE initiation to normalization of platelet count were favorable when compared with the historical data (P < 0.05). Recurrence was noted in n = 5/85 (6%) of patients, all of whom had persistent ADAMTS13 activity <5 IU/dL and mortality occurred in n = 5/85 (6%) of patients, and none of them attributed to caplacizumab.
Recommendations for acquired thrombotic thrombocytopenic purpura treatment
- aTTP is a rare condition with diagnostic challenges, and early treatment is the key to better patient outcome. We endorse the ISTH guidelines on aTTP management to start treatment based on the presumptive diagnosis and continue treatment until remission or aTTP is ruled out and an alternate diagnosis is established
- Given the proven efficacy of caplacizumab in the TITAN and HERCULES trial, we recommend the use of caplacizumab in addition to TPE and immunosuppression in confirmed aTTP episodes. A national consensus be drawn to guide the physicians on the diagnosis and treatment of aTTP incorporating the newer treatment modalities, curated for the patient population of the KSA
- We further recommend that long-term follow-up studies and real-world evidence be gathered to generate evidence on the efficacy of caplacizumab in mitigating long-term morbidity and improving the health-related quality of life.
| Conclusions|| |
We have attempted to summarize the current knowledge, unmet clinical needs, and recent advances in the management of aTTP in this article. We have also drawn consensus statements and provided recommendations pertaining to KSA based on the experience of the hematology experts of the country who routinely manage aTTP patients and who were also the members of “Approaches to aTTP Management” meeting held on October 16, 2020. Every nation has unique hurdles with regard to availability and affordability of various treatment options. In the KSA, it is the late presentation, with higher prevalence of neurological complications, nonavailability of diagnostic tests or treatment options in most of the centers, and delayed referral to tertiary centers where such facilities are available. Therefore, it is important that the KSA also has recommendations curated to the needs of its people. Such population-specific recommendations would guide the entire medical community of the nation, enabling them to aid in the early initiation of treatment in patients with aTTP, by prompt referral to a specialist, which is the key to better patient outcomes.
Sanofi Genzyme offered logistical support for the development of this consensus statement.
Financial support and sponsorship
Sanofi Genzyme has provided Advisory Board Honoraria for authors.
Conflicts of interest
The research upon which this manuscript is based was funded by Sanofi Genzyme. The meeting of the expert group was organized and funded by Sanofi Genzyme. All authors were paid honoraria for attending the advisory board. No additional payment was provided for authorship. Magdy Rabea and Mohamed Khallaf are employees for Sanofi Genzyme.
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[Table 1], [Table 2]