The Standard of Care for Immune Thrombotic Thrombocytopenic Purpura Today

Summary

Targeted therapy of immune thrombotic thrombocytopenic purpura (iTTP) requires acurate and prompt diagnosis and differentiation from complement-mediated hemolytic uremic syndrome and other causes of thrombotic microangiopathy. ADAMTS13 evaluation (activity and inhibitors or anti-ADAMTS13 IgG) is the key for diagnosis and further management of patients with suspected iTTP during acute episode and in clinical response or remission. Clinical trial results and real-world data have demonstrated the efficacy and safety of the triple therapy consisting of therapeutic plasma exchange, caplacizumab, and immunosuppressives (e.g. corticosteroids and rituximab) for acute iTTP. Such a therapeutic strategy has significantly accelerated the normalization of platelet counts, decreased the length of stays in the intensive care unit and the hospital, but most importantly reduced the mortality rate. The present review highlights some of the important advancements for the diagnosis and management of iTTP and propose the triple therapy as the standard of care for acute iTTP today.

Introduction

Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, primarily caused by acquired deficiency of ADAMTS13^{1, 2}, a plasma metalloprotease that cleaves von Willebrand factor (VWF)^{3, 4}. VWF is a multimeric adhesive glycoprotein, which is synthesized and released from endothelial cells and megakaryocytes/platelets^{5, 6}. The proteolytic cleavage of endothelial ULVWF by plasma ADAMTS13 is essential for normal hemostasis. An inability to cleave the ULVWF anchored on endothelial surface, in circulating blood, and at the sites of vascular injury leads to exaggerated platelet adhesion, agglutination, and formation of occlusive thrombi in small arterioles and capillaries^7–9, a characteristic feature of iTTP pathology¹⁰. Without early recognition and prompt management, iTTP is universally fatal. Therapeutic plasma exchange (TPE) has been the standard of care for nearly three decades, which reduces mortality rate to less than 10–20%^11–13. Remarkable progresses have been made in recent years in rapid diagnosis and prompt management of acute iTTP, which leads to further reduction of the mortality rate.

Early recognition of iTTP

Early recognition of iTTP is the key to reducing mortality and morbidity. All health care providers and trainees should learn how to recognize early signs and symptoms of iTTP. The initial episode of iTTP may occur in patients of all ages and races, but more often seen in African American females of reproductive age in the United States^{14, 15}. The annual incidence of iTTP ranges from 3 to 6 per million residents per year,^{16, 17} while hereditary (hTTP)^{18, 19} or congenital TTP (cTTP)²⁰, resulting from mutations of ADAMTS13, is even more rare, with only one hundred patients registered globally^19–21. Early diagnosis of acute iTTP requires a high index of suspicion, primarily on clinical grounds. Patients may present initially with some nonspecific symptoms including fatigue, headache, fever, pale skin, and rashes; some patients may also experience abdominal pain, extremity weakness, and symptoms of respiratory and urinary infections. In more severe cases, signs and symptoms of ischemic stroke^{22, 23}, myocardial infarction^{24, 25}, seizure, and coma^{26, 27} may be observed in the emergency department.

Laboratory tests may reveal severe thrombocytopenia (usually the platelet counts <30×10⁹/L)^{13, 28} and low hemoglobin and hematocrit, but high white blood cell counts; additionally, serum lactate dehydrogenase (LDH) and bilirubin may be significantly elevated with reduced or undetectable levels or of haptoglobin, suggestive of organ damage and acute hemolysis. Peripheral blood smear examination may reveal the fragmentation of red blood cells (or schistocytes). However, some patients may only have minimal schistocytes, mild thrombocytopenia, and moderate elevation of LDH, an atypical presentation of iTTP²⁹. This may be seen in patients in their early disease course. ~50% of patients with acute iTTP may have elevated levels of serum or plasma troponins^{14, 30–32} and mild to moderate elevation of serum creatine^{14, 17, 28}. A computerized tomography (CT)/magnetic resonance imaging (MRI) scan may reveal large and/or small infarctions in the brain of patients with acute iTTP.^{22, 33, 34} Based on these clinical and laboratory data, a presumptive diagnosis of iTTP can be made.

Clinical risk assessment scores

The diagnosis of iTTP requires first to exclude the secondary causes of TMA, which includes malignant hypertension^{35, 36}, disseminated intravascular coagulation^{37, 38}, disseminated malignancy³⁹, certain medications^40–42, hematopoietic progenitor cell transplantation^{43, 44}, catastrophic antiphospholipid syndrome^{45, 46}, and bone marrow necrosis syndrome^{47, 48}, etc.

Clinical assessment scoring system (e.g., the French score or the PLASMIC score) has been developed and validated, which may aid in the initial diagnosis and urgent management of patients suspected with iTTP. Table 1 describes the parameters and scores between the French score^{17, 49} and the PLASMIC score⁵⁰. As you can see, both scoring systems emphasize two key parameters for a high score: the severity of thrombocytopenia and the levels of serum creatine in the presence of microangiopathic hemolytic anemia^{17, 49, 50}. Both scoring systems require ruling out the possibility of disseminated malignancy and the history of hematopoitic progenitor transplantation. Several other studies have independently validated the PLASMIC score^51–54. Paydary et al. performed a meta analysis of 970 cases from 13 eligible studies published and demonstrated that a PLASMIC score ≥5 has a sensitivity and specificity of 0.99 (0.91–1.0, 95% CI) and 0.57 (0.41–0.72, 95% CI), respectively⁵³. These results suggest that a patient with a PLASMIC score <5 may not have iTTP and does not need urgent TPE and/or caplacizumab; a patient with a PLASMIC score ≥5 does not always have iTTP because of its low specificity. Kim et al. demonstrated that the PLASMIC score combined with an in-house ADAMTS13 test may increase the cost-effectiveness in managing patients with suspected iTTP⁵².

Table 1.

Clinical scoring systems for assessing the probability of severe ADAMTS13 deficiency in patients with suspected TTP

Parameters	French Score	PLASMIC Score
Platelet count	<30×109/L (+1)	<30×109/L (+1)
Serum creatinine level	<2.25 mg/dL (+1)	<2.0 mg/dL (+1)
Hemolysis
Indirect bilirubin > 2 mg/dL	✓	+1
or rculocyte count > 2.5 %	✓
or undetectabel haptoglobin	✓
No active cancer in previous year	✓	+1
No history of solid organ or SCT	✓	+1
INR < 1.5	✓	+1
MCV < 90 fL	ND	+1
Likelihood**	0: 2%	0–4: 0–4%
	1: 70%	5: 5–24%
	2: 94%	6–7: 66–82%

Each item is associated with one pint (+1); INR, international normalized ratio; MCV, mean corposcular value; SCT, stem cell transplanation;

^✓indicates the response that is consisent with the statement in French score in patients with TTP. There was no history or clinical evidence for associated cancer, transplantation or disseminated intravascular coagulation. Therefore, these items were intrinsic to the scoring system. ND indicates that MCV is not part of the French score.

^**The likelihood of severe deficiency of plasma ADAMTS13 deficiency (<10 IU/dL or 10% of normal), which is diagnostic for TTP.

The role of ADAMTS13 evaluation

Plasma ADAMTS13 evaluation (e.g., ADAMTS13 activity and inhibitor or anti-ADAMTS13 IgG) is crucial for confirming the initial diagnosis of iTTP, which guides urgent and further management^{17, 37}. Thus, before any therapeutic intervention, a blood sample for ADAMTS13 evaluation should be obtained. The International Society on Thrombosis and Haemostasis (ISTH) guidelines recommend an ADAMTS13 activity cutoff at 10 IU/dL (or 10% of normal) for distinguishing iTTP from other causes of TMAs^{17, 55}. When plasma ADAMTS13 activity is <10 IU/dL (or <10%) with a detectable inhibitor or positive anti-ADAMTS13 IgG in the proper clinical context, a diagnosis of iTTP is confirmed. When plasma ADAMTS13 activity is ≥20 IU/dL (or ≥20% of normal), iTTP can essentially be ruled out, and other diagnoses such as complement-mediated hemolytic uremic syndrome (cHUS)^{9, 56} should then be considered. When plasma ADAMTS13 activity falls between 10 IU/dL and 20 IU/dL (or between 10% and 20%), clinical judgement is required for reaching the final diagnosis, and other diagnoses should be considered as well (Figure 1)^{17, 57}.

Figure 1.

Diagnosis and management pathways for a patient with a confirmed iTTP and for a patient with suspected iTTP when ADAMTS13 test is available. Not shown here is the management pathway when ADAMTS13 test is not available. In this case, TPE, steroids, and rituximab may be offered, but caplacizumab should not used with a concern of potential risk of bleeding.

*In most initial iTTP cases, plasma ADAMTS13 activity is less than 5% of normal or undetectable. Those with a relapsing episode may have higher ADAMTS13 activity.

In addition to plasma ADAMTS13 activity and inhibitors, assessing ADAMTS13 conformations via a monoclonal antibody binding assay may also aid the diagnosis and differential diagnosis of iTTP^{58, 59}. Plasma ADAMTS13 in patients with acute iTTP appear to exhibit an “open” conformation, resulting from the binding of an IgG antibody or autoantibody to the distal domains of ADAMTS13^{59, 60}. The levels of the “open” ADAMTS13 were significantly reduced during clinical response/remission, and were undetectable in patients with aHUS and healthy individuals^{58, 59}. These findings indicate that conformational change of plasma ADAMTS13 may be a diagnositic marker for acute iTTP. It may also serve as a predictive marker for the early disease relapse as the “open” conformation of ADAMTS13 occurs prior to the decline of plasma ADAMTS13 activity and the detection of anti-ADAMTS13 IgG⁵⁹.

Moreover, longitudinal assessment of plasma ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 antigen in patients with acute iTTP, particularly prior to discharging patients home and during remission, may also help predict clinical exacerbation and relapse^{13, 61, 62}, and guide an additional immunosuppressive^{63, 64} or a targeted therapy⁶⁵.

Therapeutic strategy for acute iTTP

With advancement of targeted therapies in TMA, it is crucial to differentiate iTTP from cHUS after excluding the other secondary causes. Clinical experience and studies have shown that TPE is essentially ineffective for cHUS resulting from mutations in complement or complement regulatory genes. Eculizumab, an anti-complement C5 monoclonal antibody, is the treatement of choice, which reduces the mortality and prevents or reverses the end-stage renal disease^{66, 67}.

In contrast, patients with iTTP should be treated with the triple therapy consisting of TPE, caplacizumab and immunosuppressives (e.g., corticosteroids and rituximab). This is now considered to be the standard of care for confirmed iTTP and for those with high probability of iTTP^{17, 55, 68, 69}. However, rituximab and caplacizumab may be withheld or delayed for those with intermediate to low probabilities of iTTP until a positive ADAMTS13 result (e.g., ADAMTS13 activity <10 IU/dL or <10% of normal) is obtained^{17, 55}. Caplacizumab is generally not recommended to be prescribed to a patient with a suspected iTTP but without an obtainable ADAMTS13 test for its confirmation, citing the concern of potential bleeding complications^{17, 55}.

Daily TPE is thought to remove autoantibodies against ADAMTS13 while replenishing the missing or inhibited ADAMTS13 enzyme from donor plasma as the replacement fluid.^{11, 13} Corticosteroids may not only inhibit acute inflammation⁷⁰, but also suppress the immune system, which works in concert with rituximab, to reduce the formation of anti-ADAMTS13 IgGs.^{13, 71} Rituximab should be given as soon as the diagnosis of iTTP has been made to accelerate the cessation of autoantibody production, which may shorten the disease course⁷² and prevent it from relapse⁷³.

Caplacizumab, a newly FDA-approved drug, is an anti-VWF nanobody that disrupts VWF-platelet interactions,^{65, 74} thus preventing platelet adhesion, aggregation, and thrombus formation at the sites of vascular thromboses. Several studies have demonstrated the therapeutic efficacy and safety of the triple therapy (TPE, caplacizumab, and immunosupressives), which is shown to accelerate the time for platelet count normalization, reduce the number of TPE and volume of plasma, and hospital stay; most importantly, this therapeutic strategy reduced thromboembolic complications, exacerbation, and in-hospital mortality rate (Table 2).^{65, 69, 74, 75} Only mild to moderate bleeding complications were observed,^{65, 69, 74, 75} which in most cases did not require stopping the medication and/or administrating a reversal agent such as the VWF concentrate.

Table 2.

Efficacy and safety of using caplacizumab in conjunction with therapeutic plasma exchange, corticosteroids, and rituximab

Authors	Year	Study design	N	Time to platelet normalization (days)	# TPE (days)	Volume of plasma (L)	Hospital stay (days)	ICU stay (days)	Exacer/rel. n (%)	Thrombosis n (%)	Bleed-ing* n (%)	TTP-related death, n (%)
Peyvandi et al.	2016	Prospective, phase 2, randomized, and controlled	36	2.4 (1.9–3.0) median (95% CI)	7.7 (3–21) mean (range)	ND	ND	ND	ND	ND	19 (54)	0 (0)
Scully et al	2019	Prospective, phase 3, double-blind, randomized, and controlled	72	2.7 (1.9–2.8) median (95% CI)	5 (1–35) median (range)	18.1 (5.3–102.2) median (range)	9 (2–37) median (range)	3.0 (1.0–10.0), median (range)	3 (4)	6 (8)	46 (65)	0 (0)
Dutts et al	2020	Retrospective, observational, and multicentral	85	3 (2–4) median (IQR)	7 (5–14) median (IQR)	ND	12 (8–24) median (IQR)	ND	5 (7)	5 (7)	17 (20)	5 (6)
Volker et al	2020	Retrospective, observational, and multicentral	60	3 (1–13) median (range)	9 (2–41) median (range)	ND	18 (5–79) median (range)	4 (0–46) median (range)	4 (6.7)	ND	1 (1.7)	1 (1.7)
Coppo et al	2021	Prospective, observational, and multicentral	90	5 (4–6) median (IQR)	5 (4–7) median (IQR)	24.2 (18.3–30.2) median (IQR)	13 (9–19) median (IQR)	ND	4 (4.4)	11 (12)	13 (14.4)	1 (1.1)
Peyvandi et al.	2021	Prospective, combined phase 2 and phase 3, and controlled	108	2.8 (2.7–2.9) median (95% CI)	ND	ND	ND	ND	19 (17.6)	8(7.4)	62 (58.5)	0 (0)

N, number of patients treated with caplacizumab;

^*clinically relevant major and minor bleeding; ND, not determined; CI, confident interval; n, number of patients having the event; TPE, therapeutic plasma exchange; IQR, interquartile range; ICU, intensive unit.

While caplacizumab is now incorporated into the standard of care for iTTP in several European countries including England,^{65, 76} France,^{68, 69} and Germany⁷⁵, many health care providers in North America, including my own institution in Kansa City, are somewhat reluctant to prescribe this novel and effective drug to our patients as the first-line treatment, citing the added cost that may be substantial⁷⁷. However, the cost effectiveness analysis should include the length of stay in intensive care unit and hospital, the number of TPE and the volume of plasma used, but most importantly the prevention of death and any potential long-term sequalae that might occur form ongoing microvascular thromboses. Prior to caplacizumab, 10 to 20% of patients died and nearly 50% of patients experienced exacerbations or refreactoriness despite daily TPE, steroids, and rituximab^{14, 24}. Many patients who survive the acute episode may suffer from cognitive decline and depression⁷⁸, as well as ischemic stroke^{22, 79}. Thus, it is important to stop microvascular thrombosis with caplacizumab as early as possible, while trying to address the underlying autoantibody-mediated inhibition of ADAMTS13 activity with immunosuppressives, which may take weeks to months. Most recent studies have demonstrated that adding caplacizumab to TPE and immunosuppressives is cost-effective^{69, 80}. It allows the hospital to achieve a greater efficiency in managing the life-threatening disease like iTTP.

The other questions have been the proper duration of caplacizumab therapy and the best time to safely stop it. Initial clinical trials require daily caplacizumab for 30 days after stopping TPE, followed by a 28-day extension^{65, 74}. One can assume that caplacizumab may be safely stopped once clinical remission and at least partial biochemical (ADAMTS13) recovery are achieved. This includes normalization of platelet counts, reduction of LDH to <2 x upper limit of normal (ULN), and plasma ADAMTS13 activity (>20 IU/dL or >20% of normal) according to the expert concensus⁸¹. In almost all cases who experienced an exacerbation of iTTP prior to the use of caplacizumab in our previous cohort⁶¹ or after stopping of caplacizumab^{65, 74} had their plasma ADAMTS13 activity at the levels of <10 IU/dL (or 10% of normal) while platelet counts were in the normal range.

Conclusions

The triple therapy consisting of daily TPE, caplacizumab, and immunosuppressives (e.g., steroids and rituximab) should be considered the standard of care today for all patients with confirmed iTTP or those with high probability of iTTP as long as plasma ADAMTS13 evaluation is obtainable for confirmation. Therapy with TPE can be safely discontinued once platelet counts are normalized for two days, but caplacizumab should not be discontinued until clinical remission and at least partial ADAMTS13 remission is achieved.

Perspective

Future study should be designed to test if caplacizumab, steroids, and rituximab without TPE would be safe and sufficient for curing acute iTTP. Several anecdote case reports have demonstrated the safety and efficacy of using such a new strategy for managing acute iTTP^82–85. Additionally, recombinant ADAMS13^{86, 87} and its potentially antibody-resistant ADAMTS13 variants^{88, 89} should be developed for clinical use. This will change how we treat iTTP tomorrow.