Severe primary refractory thrombotic thrombocytopenic purpura (TTP) in the post plasma exchange (PEX) and rituximab era
- Sowmya Goranta ,
- Smit S Deliwala ,
- Tarek Haykal and
- Ghassan Bachuwa
- Department of Internal Medicine, Michigan State University at Hurley Medical Center, Flint, Michigan, USA
- Correspondence to Dr Ghassan Bachuwa; gbachuw2@hurleymc.com
Abstract
Acute acquired thrombotic thrombocytopenic purpura (TTP) requires prompt recognition and initiation of plasma exchange (PEX) therapy and immunosuppression. When PEX fails, mortality nears 100%, making finding an effective treatment crucial. Primary refractory TTP occurs when initial therapies fail or if exacerbations occur during PEX therapy, both signifying the need for treatment intensification to achieve clinical remission. Rituximab helps treat most of the refractory TTP cases, except those that are severely refractory. A paucity of studies guiding severely refractory TTP makes management arbitrary and individualised, highlighting the value of isolated reports. We present an extremely rare case of primary refractory TTP with an insufficient platelet response to numerous types of treatments, including emerging therapies such as caplacizumab, on the background of repeated PEX and immunosuppressive therapies.
Background
Microangiopathic haemolytic anaemia (MAHA) is a feature of Coombs-negative haemolysis due to abnormalities in the internal architecture of small arterioles and capillaries leading to features of schistocytes or helmet cells on a blood smear.1 Thrombotic microangiopathy (TMA) describes the specific lesion within the internal architecture leading to haemolysis,2 whereas the vast majority of TMA leads to MAHA and thrombocytopenia, the inverse is not always true.3 Primary TMA includes a variety of syndromes, with acute acquired thrombotic thrombocytopenic purpura (TTP) being its most life-threatening subtype.4 TTP can be hereditary or acquired, and defined risk factors have not been formally parsed out.5 Acquired TTP accounts for over 95% of all TTP cases. In comparison, 50% of the deaths in one registry occurred within the first 24 hours before treatment initiation, alluding to the time-sensitive nature of the disease,6 7 with a predilection for the brain, kidneys and heart while sparing the lungs.8 Acute acquired TTP is due to a deficiency in ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 motif, member 13), a cleaver of ultra-large plasma proteins attached to the endothelial surface called von Willebrand factor (VWF) that serve as sites for platelet attachment.9 In severe TTP, depleting levels of ADAMTS13 promote platelets being consumed into systemic thrombi10 in high shear load areas such as small arterioles and capillaries.2 11 The traditional ‘pentad’ of symptoms has been present in less than 5% of presentations since first being described as a cluster over 50 years ago.12 The evolution of untreated TTP consisted of neurological regression, renal failure, cardiac damage and death.4 In the era preceding plasma exchange (PEX) therapy and rituximab usage,4 13 mortality rates often reached 90%, compared with the manageable 10% seen today8 12 14 effectively relegating splenectomies.9
TTP often requires a presumptive diagnosis based on MAHA and thrombocytopenia with neurological, renal, gastrointestinal or cardiac manifestations. At the same time, ADAMTS13 levels often have prolonged turnaround times, leading to a delay in confirming the diagnosis. This identification is crucial as a presumptive diagnosis has immediate management implications such as PEX and immunosuppression initiation.8 12 Diagnosis is confirmed when ADAMTS13 activity is found to be severely low (<10%).15 16 The PLASMIC (Platelet count; combined hemoLysis variable; absence of Active cancer; absence of Stem-cell or solid-organ transplant; MCV; INR; Creatinine) score was developed to help predict the likelihood of a severe deficiency and is recommended for use in this clinical setting.17 Treatment is often monitored by symptom improvement with correction in platelet counts and lactate dehydrogenase (LDH) levels. Approximately 20% of patients with acute acquired TTP do not respond to a combination of PEX and immunosuppression or experience a worsening during PEX within the first 4 days; these presentations are consistent with the diagnosis of primary refractory TTP.18 Patients who can achieve normalisation in platelet counts with improvement in symptoms after remaining PEX-free for 30 days are considered to be in remission.
In contrast, patients manifesting thrombocytopenia and MAHA after a period of remission, with symptoms consistent with recurrence of an acute episode, are termed TTP in relapse. Asymptomatic and isolated variations in ADAMTS13 is not enough to establish TTP in relapse or remission. Rituximab has quickly established itself as a frontline therapy for refractory TTP, often after hepatitis B has been ruled out, and recommendations for its use in the initial stages with PEX and immunosuppression have been delineated.19–22 Fewer than 6% of refractory TTP cases fail PEX, immunosuppression and rituximab, and the scarcity of reports makes clinical decision making more arbitrary, highlighting the importance of isolated instances in guiding more resistant TTP.20 A review of the literature revealed numerous therapies with varying levels of success in treating refractory TTP, such as mycophenolate mofetil (MMF), cyclophosphamide, intravenous immunoglobulin (IVIG), plasma infusions, cyclosporine, vincristine, bortezomib and newer therapies such caplacizumab. It is our understanding that a case of highly refractory TTP requiring multiple therapies is an infrequent presentation. Parsing out refractory TTP cases based on the extent of treatments used over the years, we report the first case of severe refractory TTP displaying resistance to over nine therapies (figure 1).
Timeline of various treatments used. LDH, lactate dehydrogenase; TTP, thromboticthrombocytopenic purpura; VWF, von Willebrand factor.
Case presentation
A 48-year-old man was brought to the emergency department (ED) after experiencing fluctuating levels of consciousness and persistent presyncopal symptoms interspersed with symptoms of malaise and weakness for the past few days described by family. Emergency medical services noted orthostatic vital signs on-site with an initial blood pressure reading of 118/78 mm Hg and a blood pressure of 86/45 mm Hg upon standing. On arrival, he was afebrile, normotensive and respiring at 18 breaths/min on room air without appearing ill on physical examination. His medical history was significant for diabetes, hypertension and chronic venous stasis ulcers. His laboratory values revealed severe anemia with a haemoglobin (Hgb) of 51 g/L, platelets of 2.2×109/L without leucocytosis, and rising troponins in the absence of renal damage (table 1). He received 4 units of red blood cells and was transferred to the intensive care unit (ICU). The constellation of findings and a 72% calculated risk for severe ADAMTS13 deficiency based on a PLASMIC score of 6 prompted the initiation of daily PEX with fresh frozen plasma and corticosteroid therapy. His mentation improved within 24 hours, and he was at his baseline level of cognition confirmed by family within 48 hours. Drawn before PEX initiation, his ADAMTS13 registered below 3%, whereas inhibitor levels were over measurable levels, confirming the diagnosis. After 96 hours of PEX and immunosuppression, his platelet counts remained unchanged at 3.5×109/L, whereas ADAMTS13 continued to be unmeasurable with high inhibitor levels (19.2 BEU). A short PEX-free course resulted in a further drop in platelets, prompting re-initiation. ADAMTS13 profile reassessed a week after the first rituximab dose demonstrated severely low ADAMTS13 levels continued while inhibitor load reduced to 7.6 BEU. Forty-eight hours after the second rituximab injection, his platelet levels were 3.3×109/L. Two more agents with daily IVIG injections and MMF were added to his regimen. Despite instituting five different therapies and infusions of cryoprecipitate, his platelets continued declining, reaching their nadir at 1.7×109/L. ADAMTS13 and inhibitor levels drawn after continued to demonstrate undetectable ADAMTS13 activity with high circulating inhibitor levels. During these treatments, he tolerated PEX without any haemodynamic compromises. Complete differential blood counts and LDH levels were serially drawn to ascertain treatment functionality, whereas weekly ADAMTS13 protease and inhibitor levels had a 1-week turnaround (table 2). After maximising therapies, a tertiary centre was consulted to manage the refractory nature of his TTP further. During his admission, he never developed any electrolyte or renal abnormalities. At the same time, platelet counts varied between 1.7×109/L and 4.0×109/L, LDH between 300 U/L and 500 U/L, and Hgb between 90 g/L and 110 g/L after the initial transfusion.
Baseline laboratory characteristics
| Baseline laboratory characteristics | Status |
| Red blood cell | Marked anisocytosis with schistocytes |
| Alkaline phosphatase | 89 U/L |
| % Iron saturation | 53 |
| Total bilirubin | 3.7 mg/dL |
| Bilirubin direct | 0.4 mg/dL |
| International normalised ratio | 1.32 |
| High-sensitivity troponin-I (first) | 0.23 ng/mL |
| High-sensitivity troponin-I (second) | 1.02 ng/mL |
| High-sensitivity troponin-I (third) | 1.47 ng/mL |
| Activated partial thromboplastin time | 30.9 s |
| Fibrinogen | 220 |
| Haptoglobin | <7.9 mg/dL |
| Haemoglobin | 51 g/L |
| Haematocrit | 16.2% |
| Platelet count | 3.3 ×109/L |
| Reticulocytes | 10% |
| Lactate dehydrogenase | 929 U/L |
| Peripheral smear | Schistocytes |
| Direct antiglobulin test (Coombs) | Negative |
| Antinuclear antibody | 1:320 |
| Anion gap | 10 mEq/L |
| Potassium | 3.9 |
| Creatinine | 1.1 mg/dL |
| Protein electrophoresis | No monoclonal proteins seen |
Treatment response
| VWF protease activity (%) | VWF protease inhibitor | Lactate dehydrogenase (U/L) | Platelet count (×109/L) | |
| Month 1 (week 1) | <3 | >32 BEU | 929 | 3.3 |
| Month 1 (week 2) | <3 | >32 BEU | 929 | 3.3 |
| Month 1 (week 3) | <3 | >32 BEU | 929 | 3.3 |
| Month 1 (week 4) | <3 | >32 BEU | 929 | 3.3 |
| Month 2 (mean) | <3 | 19.2 BEU | 429 | 4.4 |
| Month 3 (mean) | <5 | >56% | 400 | 9.5 |
| Month 4 (mean) | <5 | 110% | 421 | 6.4 |
| Month 5 (mean) | <5 | 105% | 159 | 8.0 |
| After (discharge) | 27 | 65% | 177 | 1.9 |
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VWF, von Willebrand factor.
Differential diagnosis
On initial arrival to the ED, his dramatic haematological profile for severe anaemia and thrombocytopenia in the presence of presyncope with positive orthostatic vital signs was concerning for an acute gastrointestinal bleed prompting a bedside stool guaiac study that was eventually negative. The degree of anaemia and thrombocytopenia was enough to consult the staff haematologist that ultimately drove most of his medical management and attributed his syncopal like symptoms as an evolving sign consistent with TTP. At the same time, the troponin leak was considered a severe feature of his disease state. A smear revealed MAHA and thrombocytopenia, concerning for primary TMA. Sepsis, malignancy, drug-induced thrombotic microangiopathy (DITMA), drug-induced thrombocytopenia (DIT) and other potential confounders were ruled out before formally diagnosing him with TTP. Autoimmune workup was unremarkable, a feature that usually differentiates TMA syndromes from disseminated intravascular coagulation (DIC). We presumptively treated him for TTP once his calculated PLASMIC score was 6. ADAMTS13 came back with levels below 3% with high circulating antibody titres, confirming the diagnosis. Upon a sustained lack of response to the initial combination therapy with PEX and corticosteroid, and after ruling out other conditions with similar features, he was diagnosed with primary refractory TTP.
Treatment
His initial Hgb of 51gL prompted a transfusion of 4 units of packed red blood cells. Prompt initiation of daily PEX and immunosuppression was initiated once a presumptive diagnosis of TTP was established, based on clinical and laboratory findings supported by a PLASMIC score of 6. After not responding to the initial combination therapy and having confirmed refractory TTP, rituximab injections given weekly was the first in a series of treatments, followed by a short course of IVIG infusion. The continued lack of response prompted the use of MMF 1000 mg two times per day for 9 days. Neither of these therapies resulted in sustained rises in platelet count. During these treatments, he tolerated PEX without any haemodynamic compromises, whereas biological therapies were sequenced after daily PEX completed. Daily complete differential blood counts with LDH levels and weekly ADAMTS13 protease and inhibitor levels were serially drawn to ascertain treatment functionality.
Outcome and follow-up
After transferring to a tertiary centre, he had a 4-month hospitalisation. After his transfer, PEX and corticosteroids were continued daily, whereas therapies used at our facility were not reinitiated. Cyclophosphamide was added and maintained for the entirety of his stay except for a period of myelosuppression. Bortezomib, another advanced therapy, was given. Still, his course was complicated by an episode of pulseless activity arrest and episodes of septic shock prompting transfer to the ICU, often requiring supplemental oxygen. During these episodes, he underwent multiple plasma infusions. A decision to undergo laparoscopic splenectomy occurred due to the putative effects of the therapies, with a considerable rise in platelets ranging between 9.0×109/L and 1.1×109/L afterward. Caplacizumab was the final therapy that was added to his regimen after achieving clinical equipoise from experiencing a cardiac arrest and multiple subsequent episodes of sepsis that was initially precluding him from receiving the novel therapy. ADAMTS levels were repeated every week, although median values have been reported (table 2). He was maintained on daily caplacizumab 11 mg subcutaneous injections, prednisone 50 mg and cyclophosphamide 100 mg, whereas daily PEX was transitioned to three times a week with a goal of complete liberation before discharge. Notable laboratory values on release were platelets 1.9×109/L, Hgb 87 g/L, ADAMTS13 27%, inhibitor level 65% and LDH 177 U/L, whereas on a physical examination, he was conversational, not ill-appearing, ambulating and breathing on room air. His postdischarge plan included a 10 mg prednisone taper every subsequent week while continuing cyclophosphamide 100 mg daily for a minimum of 6 months, caplacizumab 11 mg subcutaneous daily for 30 days and a follow-up with the haematologist with regular blood count profiles. Postsplenectomy immunisations were administered in the form of Pneumovax, meningococcal B and meningococcal conjugate ACYW vaccines.
Discussion
The approach to refractory TTP presumes an accurate diagnosis of acquired TTP and prompts initiation of appropriate therapy, whereas conditions such as DIT, DITMA, infections and malignancy are ruled out. PEX is usually an indicator of a favourable prognosis with mortality rates approaching 100% in patients who fail therapy,18 placing importance on the need to treat refractory TTP effectively. Platelet counts are the primary indicator for monitoring response to treatment: a favourable response is defined as a platelet count above 1.5×109/L for at least 2 days. Neurological symptoms and LDH are the first to improve, followed by platelets during serial PEX exchanges.9 10 The mainstay of refractory TTP therapy is rituximab, with extensive studies demonstrating platelet recovery in over 90% of all patients with better outcomes,19 and 43% of relapses arise when rituximab is not used.23 Rituximab decreases the duration of PEX and is recommended for patients without immediate ADAMTS13 levels, and a minimum calculated PLASMIC score of 5. Accumulating evidence of its effectiveness in refractory TTP has shifted practice patterns, with previous approaches reserving rituximab for select cases.15 21 22 Failure to respond to these therapies is rare, and managing the disease is much more challenging, with an emphasis on individualised treatment.15
We selected MMF as the initial agent for our patient’s rituximab refractory TTP and continued it for 9 days. Despite being used with success in two other reports,24 our patient failed to mount an adequate platelet response. Following MMF, a short course of IVIG was used. Despite multiple reports of it being successfully used as salvage therapy by binding antibodies to ADAMTS13,25 our patient failed to demonstrate a similar response. Once transferred to a tertiary centre, daily PEX and corticosteroids were kept ongoing with incremental additions of advanced therapies. The first advanced therapy was cyclophosphamide. A popular treatment in the pre-rituximab days in patients with refractory TTP, its use has now evolved to include TTP resistant to rituximab,15 26 with an average time of 10 days for platelet recovery. A majority of cyclophosphamide guiding reports come from patients with systemic lupus erythematosus (SLE) who developed acute TTP.27 A diminutive response to cyclophosphamide paved the way for bortezomib in our patient, a 26S proteasome inhibitor causing apoptosis. A similar case of TTP being refractory to PEX, corticosteroids, rituximab and cyclophosphamide finally responding to bortezomib has been reported.28 During this time, plasma infusions were administered, which are often considered temporary measures rather than a remission-inducing strategy.29 After exhausting multiple options and engaging in shared decision making, our patient decided to undergo a laparoscopic splenectomy. Splenectomies were much more common in the pre-PEX era with varying reports of success, and its sparse use is highlighted with one large centre not having to resort to the procedure in over a decade of treating TTP patients since the emergence of effective therapies.9
Following the procedure and recovery from multiple acute episodes of illness, caplacizumab, an anti-VWF that blocks downstream interactions promoting platelet aggregation, was initiated to liberate him off his PEX and minimise immunosuppression. Caplacizumab was approved in the USA in February 2019 and is slowly gaining traction as a constituent of initial therapy in refractory or severe TTP characterised by neurological findings, high troponin (another initial finding in our patient) or critical findings. Studied outcomes such as survival, duration of PEX, rate of exacerbations and duration of hospitalisation from two major trials, TITAN30 and HERCULES,31 provide caplacizumab these indications. Caplacizumab is recommended not to be discontinued after PEX until ADAMTS13 has normalised; this lowers the risk of exacerbations and accelerates recovery time.
Learning points
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Rituximab should be part of the initial cluster of therapies with plasma exchange (PEX) and immunosuppression to treat acute acquired thrombotic thrombocytopenic purpura (TTP).
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Identification of refractory TTP requires that other causes such as sepsis, malignancy, drug-induced thrombocytopenia or drug-induced thrombotic microangiopathy be ruled out before initiating refractory TTP therapies.
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Platelet counts are the primary indicator of disease response combined with clinical recovery. Lactate dehydrogenase and schistocytes can often persist after the acute episode resolves.
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Primary refractory TTP that has failed PEX therapy has a mortality rate nearing 100%, making effective treatment imperative.
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Consider caplacizumab as initial therapy in severe primary TTP or refractory TTP as it is known to improve survival, duration of PEX and duration of hospitalisation.
Footnotes
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Contributors SG: conception, design, acquisition of data and manuscript. SSD, TH and GB: conception, design, acquisition of data, edit and manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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