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Abstract

Acquired thrombotic thrombocytopenic purpura (aTTP) is a very rare life-threatening disorder, which manifests as a profound thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, neurological dysfunction, and other ischemic organ damage. It is caused by antibodies blocking ADAMTS13 metalloprotease. The current standard of the treatment is a triple combination consisting of therapeutic plasma exchange (TPE), immunosuppressive therapy, and caplacizumab, an anti-vWF nanobody. We retrospectively analyzed the medical records and management of three patients with newly diagnosed acute form of aTTP. Three Slovak female patients (mean age at onset 57 years) with severe anemia and thrombocytopenia, one with acute renal insufficiency and two with neurological symptoms were admitted to our institution for suspected aTTP. All patients had ADAMTS13 activity below 2%, laboratory signs of hemolysis, and the presence of ADAMTS13 antibodies. In our laboratory, we also examined the ultra-large high-molecular-weight vWF multimers. The patients were urgently indicated for TPE and high-dose immunosuppressive therapy. Shortly thereafter, caplacizumab was added to the treatment. In the following days platelet count stabilized, ADAMTS13 activity increased and biochemical parameters were gradually adjusted. Two patients experienced exacerbations and one patient experienced relapse of aTTP with mild thrombocytopenia and reduced ADAMTS13 activity, without thrombotic microangiopathy. They were successfully treated with rituximab or cyclophosphamide. Clinical remission was achieved later in all patients. Data collected from our center show that addition of caplacizumab to the standard aTTP treatment helps normalize platelet count faster, reduces the number of TPE sessions and length of hospitalizations, and significantly improves the clinical outcome of patients.

Keywords

a disintegrin and metalloprotease with thrombospondin type 1 motifs acquired thrombotic thrombocytopenic purpura (aTTP)caplacizumab immunosuppressive therapy number 13 (ADAMTS13) activity therapeutic plasma exchange (TPE)

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a very rare life-threatening thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, renal failure, neurological disorders, and other ischemic organ dysfunctions associated with disseminated microvascular platelet-rich thrombi. The prevalence of TTP is 10 cases per million people, and the incidence is approximately 1 new case per million people.^1,2

In comparison to other thrombotic microangiopathies, TTP is defined by a severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 motifs, number 13 (ADAMTS13), which is a specific von Willebrand factor-cleaving protease. ADAMTS13 deficiency can be either inherited via rare biallelic mutations of the ADAMTS13 gene or acquired via ADAMTS13 autoantibodies which neutralize or induce clearance of the ADAMTS13 protein. Without the proteolytic activity of ADAMTS13, the uncleaved ultra-large von Willebrand factor (vWF) multimers accumulate and induce excessive platelet adhesion and aggregation, leading to the formation of disseminated microthrombosis. Acquired TTP (aTTP) may be either idiopathic or secondary to several clinical contexts (e.g., autoimmune disease, infection, organ transplantation, neoplasia, drugs, or pregnancy), and the first acute episode usually occurs in adulthood.^3,4

Clinical symptoms of the acute phase of aTTP may include neurological symptoms (headache, confusion, coma, seizure, stroke, and transient focal defect), renal disorders (proteinuria, moderate acute kidney injury), or ischemia of other organs associated with a disseminated disease, weakness, dyspnea, skin, and mucosal hemorrhage. Laboratory signs are microangiopathic hemolytic anemia (hemoglobin level <100 g/L, typically <70 g/L) and severe thrombocytopenia (platelet count <120 × 10⁹/L, usually <30 × 10⁹/L). Microangiopathic hemolytic anemia is characterized by schistocytes in the blood smear and classic parameters of hemolysis: high reticulocyte count (>120 × 10⁹/L), an undetectable serum haptoglobin concentration, an elevated bilirubin and lactate dehydrogenase (LDH) level.⁵ The diagnosis of aTTP is confirmed by the presence of a severe ADAMTS13 deficiency (activity <10% or <10 IU/dL) and inhibitor or anti-ADAMTS-13 IgG. Blood sample to assess ADAMTS-13 activity should be taken before any therapeutic intervention.

A delay in the management of TTP worsens its prognosis. The results of ADAMTS13 activity early in the disease allows for rapid and effective differentiation of TTP from other TMA. However, ADAMTS13 tests are not always directly available in all healthcare facilities, and the initial diagnosis of TTP is frequently based on clinical symptoms. To assist clinicians in predicting the ADAMTS13 activity level, clinical assessment scoring systems (e.g., the French Score or the PLASMIC Score) have been developed. Clinical experience and awareness of TTP as a possible diagnosis is essential to prevent misdiagnosis, delayed treatment, and adverse outcomes due to delayed treatment.⁶

Clinical reports and real-world data have showed the efficacy and safety of the triple therapy consisting of therapeutic plasma exchange (TPE), caplacizumab, and immunosuppressive therapy (corticosteroids, rituximab, or cyclophosphamide. . .) in acute aTTP. Caplacizumab (Cablivi; Ablynx nv, Ghent, Belgium) is humanized anti-vWF nanobody that disrupts vWF-platelet interactions. Such a therapeutic strategy has significantly accelerated the normalization of platelet count, shortened hospital stays and moreover, reduced mortality.^7–9 Mortality of patients with aTTP treated with caplacizumab is below 5% in the acute phase, representing a substantial improvement compared with historical outcomes prior to the introduction of caplacizumab. Untreated aTTP had a mortality rate exceeding 90%, and after the introduction of TPE, mortality remained in the range of approximately 10%—20%.^10,11

Case report 1

A 60-year-old, female patient with newly diagnosed acute renal failure, moderate anemia, and severe thrombocytopenia with bleeding manifestations was urgently admitted to the Department of Hematology and Transfusiology at the University Hospital in Martin in December 2022 due to suspected TTP. She reported subjective symptoms of subfebrility without infectious complications, spontaneous bruising, fatigue, weakness, and mild abdominal pain during the previous 3 days. Initial laboratory results showed signs of acute renal failure (creatinine 181 μmol/L), acute hemolysis, and thrombocytopenia 8 × 10⁹/L. The calculated a PLASMIC score of 5 points (platelet count <30 × 10⁹/L, hemolysis, no active cancer, no history of transplantation, international normalized ratio (INR) <1.5, creatinine <200 μmol/L) indicated intermediate risk of severe ADAMTS13 deficiency. The measured ADAMTS13 activity was significantly reduced to less than 0.2% which confirmed the diagnosis of TTP. All initial laboratory parameters are presented in Table 1. Subsequently examined ADAMTS13 antibodies were detected at level of more than 15 U/mL. We also evaluated the vWF multimer assay in our laboratory (Figure 1). Peak intensity in the Hydrasys 2 scan analysis directly correlates with vWF multimers concentration. When interpreting the results, the multimer bands are classified as follows: 1–3 left to right peaks in the densitogram represent low-molecular-weight multimers, peaks 4–7 represent intermediate-molecular-weight multimers, and peaks above 7 represent the group of high-molecular-weight and ultra-large multimers.¹² Imaging tests including chest X-ray, abdominal ultrasound, and computed tomography (CT) scan of the brain showed no signs of neurological or other pathological conditions.

Table 1.

Initial laboratory parameters in patient 1.

Laboratory parameter	Result	Reference range	Laboratory parameter	Result	Reference range
Hemoglobin (g/L)	93	120–155	Haptoglobin (g/L)	<0,08	0.4–2.68
Platelets (×10⁹/L)	8	140–400	LDH (μg/L)	13.75	1.83–4.12
Reticulocytes (%)	2.8	0.8–2.1	Urea (mmol/L)	18	2.8–7.2
MCV (fL)	91.8	82–98	Creatinin (μmol/L)	181	45–84
MCH (pg)	30.5	26–34	Bilirubin (μmol/L)	31.4	5–21
INR	0.98	0.8–1.2	Direct bilirubin (μmol/L)	8.4	0.1–3.4
Fibrinogen (g/L)	5.31	1.8–4.2	GGT (μkat/L)	1.32	0.07–0.63
d-dimers (mg/L)	2.06	<0.5	ALT (μkat/L)	1.28	0.1–0.6
vWF activity (IU/L)	1.5	0.5–1.4	ALP (μkat/L)	2.68	0.5–2.15
vWF antigen (IU/L)	1.97	0.6–1.5	AST (μkat/L)	0.99	0.1–0.6
ADAMTS13 activity (%)	<0.2	66–136	CRP (mg/L)	21	<5
ADAMTS13 antibodies (U/mL) (later detected)	44.6	<15

ALP, alkaline phosphatise; ALT, alanine transaminase; AST, aspartate transferase; CRP, C-reactive protein; GGT, gamma-glutamyl transferase; INR, international normalized ratio; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; vWF, von Willebrand factor.

Figure 1.

Analysis of vWF multimers at National Centre of Hemostasis and Thrombosis in Martin by the Hydrasys 2 scan. (a) Hydragel analysis (left—patient; right—control); (b) densitometric analysis (blue—patient; yellow—control).

Immediately after confirmation of the TTP diagnosis, the central venous catheter for dialysis was inserted and on day 5 after the first symptoms appeared, we immediately initiated the TPE treatment at a volume of 1.5 times the estimated plasma volume, per day, using plasma products from healthy donors in combination with high-dose corticosteroids (1 g methylprednisolone intravenously daily). Anemia was treated with two red blood cell transfusions and hemoglobin levels subsequently rose above 100 g/L. On day 6 after initial symptoms, we started to administer caplacizumab at a dose of 10 mg as an initial intravenous injection before the first TPE, and then 10 mg daily subcutaneous injections after completion of each TPE. It was the first use of caplacizumab in Slovakia. ADAMTS13 activity (Figure 2) and titer of inhibitor were monitored once a week and platelets were monitored per day.

Figure 2.

Monitoring of ADAMTS13 activity, platelets, and LDH in patient 1 from day 5 after the first symptoms.

The clinical response—platelet count above 150 × 10⁹/L for two consecutive days, together with normal or normalizing LDH (4.57 μg/L) and clinical recovery was achieved on day 10 (4 days after the initial caplacizumab dose). We stopped TPE (the total number of plasma exchange sessions was 6) and slowly reduced the dosage of corticosteroids. The patient received further subcutaneous administrations of caplacizumab. Platelet count steadily improved, biochemical parameters progressively stabilized and ADAMTS13 activity significantly increased to 82%.

On day 16 after the first symptoms, moderate prolonged epistaxis occurred. Laboratory tests confirmed an exacerbation of aTTP with ADAMTS13 activity at 5% without thrombocytopenia and microangiopathic hemolytic anemia, and vWF activity at 0.03 IU/L. 12.5 IU/kg IU of human plasma-derived FVIII/vWF concentrate (Haemate P; CSL Behring, Hattersheim am Main, Germany) together with etamsylate and tranexamic acid were administered and caplacizumab was temporarily stopped for 1 day. Rituximab (700 mg intravenously) was added to the treatment once a week for the following 4 weeks. One week later, ADAMTS13 antibodies were negative and ADAMTS13 activity was 47.7%. Due to a good clinical condition patient was discharged from hospital on the 20th day of hospitalization. Daily subcutaneous injections of caplacizumab continued in combination with prednisone in the outpatient care and the total number of administrations was 43 (38 after discontinuation of TPE). The patient underwent regular check-ups, initially once a week, then once every 2 weeks, and finally once a month. Long-term remission was successfully achieved.

Case report 2

In August 2024, a 44-year-old, female patient with newly diagnosed bicytopenia (severe anemia and severe thrombocytopenia), fever and behavioral disorder (disorientation, psychomotor impairment and left-sided hemiparesis) was first admitted to the neurology department at a peripheral hospital and, a day later, she was admitted to the Department of Hematology and Transfusiology of the University Hospital in Martin. Due to suspected TTP we calculated a PLASMIC score of 7 points (platelet count <30 × 10⁹/L, hemolysis, no active cancer, no history of transplantation, MCV <90 fL, INR <1.5, creatinine <200 μmol/L) which indicated high risk of severe ADAMTS13 deficiency. Analyzed ADAMTS13 activity was significantly reduced to 0.2% and ADAMTS13 inhibitor was 113.1 U/mL. Other laboratory parameters showed signs of hemolysis (reticulocytosis, decreased haptoglobin, increased LDH, and bilirubin). The initial laboratory parameters are presented in Table 2.

Table 2.

Initial laboratory parameters in patient 2.

Laboratory parameter	Result	Reference range	Laboratory parameter	Result	Reference range
Hemoglobin (g/L)	65	120–155	Haptoglobin (g/L)	<0,08	0.4–2.68
Platelets (×10⁹/L)	15	140–400	LDH (μg/L)	13.75	1.83–4.12
Reticulocytes (%)	8.8	0.8–2.1	Urea (mmol/L)	18	2.8–7.2
MCV (fL)	86.5	82–98	Creatinin (μmol/L)	99	45–84
MCH (pg)	30.2	26–34	Bilirubin (μmol/L)	61	5–21
INR	1.19	0.8–1.2	Direct bilirubin (μmol/L)	10	0.1–3.4
Fibrinogen (g/L)	3.06	1.8–4.2	GGT (μkat/L)	0.3	0.07–0.63
d-dimers (mg/L)	33.05	<0.5	ALT (μkat/L)	0.39	0.1–0.6
ADAMTS13 activity (%)	<0.2	66–136	AST (μkat/L)	1.28	0.1–0.6
ADAMTS13 antibodies (U/mL)	113.1	<15	CRP (mg/L)	10.2	<5

ALT, alanine transaminase; AST, aspartate transferase; CRP, C-reactive protein; GGT, gamma-glutamyl transferase; INR, international normalized ratio; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume.

After consultation with a nephrologist, a central venous catheter for dialysis was inserted, and on day 3 after the onset of initial symptoms, TPE started at a volume of 1.5 times the estimated plasma volume, per day, using healthy donor plasma products in combination with high-dose corticosteroids (1 g of methylprednisolone intravenously daily with a slow dose reduction). On day 4, we started to administer caplacizumab, first 10 mg intravenously prior to TPE, then subcutaneously after each TPE. On day 13 (8 days after the initial dose of caplacizumab), the platelet count was above 150 × 10⁹/L for two consecutive days, the LDH level was 2.35 μg/L and other parameters gradually normalized. We found significantly increased ADAMTS13 activity (100.2%) and an insignificant titer of ADAMTS13 inhibitor (9.8 U/mL), so we stopped plasma exchange (the total number of plasma exchange sessions was 11), reduced the dose of corticosteroids and continued daily subcutaneous administration of caplacizumab for up to 30 doses after stopping the TPE therapy (the total number of administrations was 38). No side effects of caplacizumab were observed, and remission was achieved. Monitoring of ADAMTS13 activity, platelets, and LDH is depicted in Figure 3. The patient was discharged from the hospital on the 16th day of hospitalization.

Figure 3.

Monitoring of ADAMTS13 activity, platelets, and LDH in patient 2 from day 2 after the first symptoms.

However, in January 2024, 3 months after the caplacizumab treatment, the patient experienced a clinical relapse. Laboratory results showed mild thrombocytopenia (112 × 10⁹/L), normal ADAMTS13 activity (50.1%), but positive ADATMTS13 antibodies (84.4 U/mL), with no signs of hemolysis. The relapse was successfully treated with rituximab (700 mg intravenously), once weekly for the next 4 weeks in combination with prednisone and platelet count steadily improved. Patient had no clinical symptoms of TTP during the relapse.

Case report 3

A 66-year-old, female patient with acute dysarthria, expressive aphasia, moderate normocytic anemia, severe thrombocytopenia with spontaneous petechiaes, and mild hematuria was admitted to the Department of Hematology and Transfusiology of the University Hospital in Martin in October 2024 with suspected TMA. The patient subjectively reported blurred vision lasting 1 week. First, a neurological examination and CT scan of the brain and coronary arteries were performed. The results showed no signs of acute ischemia, only a focal epileptic seizure, which was most probably associated with thrombocytopenia. Antiepileptics were added to the therapy. The calculated PLASMIC score of 7 points (platelet count <30 × 10⁹/L, hemolysis, no active cancer, no history of transplantation, MCV <90 fL, INR <1.5, creatinine <200 μmol/L) indicated a high risk of severe ADAMTS13 deficiency. We found significantly reduced ADAMTS13 activity (1.7%) and a positive ADAMTS13 inhibitor (19.8 U/mL) which confirmed the diagnosis of aTTP. Other initial laboratory parameters showed normal renal function and signs of acute hemolysis (reticulocytosis, decreased haptoglobin, increased LDH, and bilirubin; Table 3).

Table 3.

Initial laboratory parameters in patient 3.

Laboratory parameter	Result	Reference range	Laboratory parameter	Result	Reference range
Hemoglobin (g/L)	81	120–155	Haptoglobin (g/L)	<0,08	0.4–2.68
Platelets (×10⁹/L)	10	140–400	LDH (μg/L)	19.45	1.83–4.12
Reticulocytes (%)	4.1	0.8–2.1	Urea (mmol/L)	7.1	2.8–7.2
MCV (fL)	88.1	82–98	Creatinin (μmol/L)	57	45–84
MCH (pg)	30.4	26–34	Bilirubin (μmol/L)	72.5	5–21
INR	1.07	0.8–1.2	Direct bilirubin (μmol/L)	14.2	0.1–3.4
Fibrinogen (g/L)	3.18	1.8–4.2	GGT (μkat/L)	1.42	0.07–0.63
d-dimers (mg/L)	4.83	<0.5	ALT (μkat/L)	0.94	0.1–0.6
vWF activity (IU/L)	1.51	0.5–1.4	ALP (μkat/L)	1.26	0.5–2.15
ADAMTS13 activity (%)	1.7	66–136	AST (μkat/L)	1.11	0.1–0.6
ADAMTS13 antibodies (U/mL)	19.8	<15	CRP (mg/L)	26.6	<5

We inserted a central venous catheter for dialysis, treated anemia with red blood cell transfusions and started TTP treatment with corticosteroids (500 mg of methylprednisolone intravenously with a slow dose reduction). On day 8 after the initial symptoms, we started at a volume of 1.5 times the estimated plasma volume, per day, using healthy donor plasma products, and on day 9, we added caplacizumab to the therapy, administered according to the protocol. After five plasma exchanges, on day 12 after the first symptoms (3 days after the initial caplacizumab dose), the platelet count was above 150 × 10⁹/L for two consecutive days, ADAMTS13 activity improved to 41.9%, the ADAMTS13 inhibitor was negative, and neurological symptoms were no longer present. We stopped TPE, reduced the dose of corticosteroids and continued the administration of caplacizumab. The patient tested positive for hepatitis B antibodies (HBsAb), an infectologist confirmed chronic hepatitis B infection, and entecavir was added to the treatment. Corticosteroid therapy was complicated with steroid-induced diabetes mellitus requiring insulin therapy. Screening tests for oncological, rheumatic, and immunological disorders were negative, and the cause of aTTP has not yet been determined.

On day 16, the patient experienced an acute intestinal infection, which can be followed by exacerbation of aTTP, so we examined all laboratory parameters and found that the patient had ADAMTS13 activity of 4.4%, ADAMTS13 inhibitor of 23 U/mL, mild thrombocytopenia, and moderate anemia. We started another daily TPE sessions and increased the dose of methylprednisolone. Rituximab was contraindicated because of positive HBsAb; therefore, 1 g of cyclophosphamide was administered intravenously on day 20. In following days, the platelet count stabilized, ADAMTS13 activity increased, ADAMTS13 antibodies were negative again, and clinical remission was reached. Monitoring of ADAMTS13 activity, platelets, and LDH is shown in Figure 4. The total number of plasma exchange sessions during hospitalization was 16. Due to her good clinical condition, the patient was discharged from the hospital stay on the 28th day of hospitalization, but due to the high risk of relapse, daily subcutaneous administration of caplacizumab in combination with prednisone continued and the total number of caplacizumab doses was 43 (23 after stopping TPE). The patient then underwent regular check-ups and achieved complete remission.

Figure 4.

Monitoring of ADAMTS13 activity, platelets, and LDH in patient 3 from day 8 after the first symptoms.

All patient data have been anonymized, patient consents for treatment and consents to publish were obtained, and the reporting of these cases is in accordance with CARE guidelines.¹³

Discussion

TTP is a medical emergency which requires rapid diagnosis, urgent management, and treatment, usually in intensive care units. A clinical response to treatment is defined by a platelet count above 150 × 10⁹/L for two consecutive days, together with normal or normalizing LDH levels and clinical recovery. A durable clinical response lasts at least 30 days after discontinuation of TPE and caplacizumab administration (clinical remission) which can be accompanied by ADAMTS13 activity ⩾50% (complete ADAMTS13 remission). Recurrence of disease within 30 days after achieving response to treatment is defined as exacerbation, and recurrence of disease 30 days or longer after reaching response to treatment is defined a relapse.¹

According to the latest studies, TPE remains the cornerstone and first-line therapy for patients with aTTP and should be initiated immediately after the diagnosis of TTP or even when TTP is suspected. It is performed at a volume of 1.5 times the estimated plasma volume, per day, using plasma from a healthy donor or derived products until clinical remission is achieved. The main mechanisms of action of TPE in TTP are thought to be both replenishment of the missing or inhibited functional ADAMTS13 enzyme from donor plasma and the removal of anti-ADAMTS13 autoantibodies and abnormally large vWF multimers.^1,8,14

ISTH (International Society on Thrombosis and Haemostasis) guidelines recommend the addition of corticosteroids to TPE over TPE alone in patients experiencing a first acute event of aTTP. They may moderately reduce the mortality and complications in a life-threatening situation, whereas adverse events for short-term corticosteroid use are not severe. The preferred dosage is 1 mg/kg.¹⁴

Rituximab is anti-CD20 monoclonal antibody whose primary effect is the prevention or treatment of relapses.¹⁵ Relapse in aTTP can manifest either as a “clinical relapse” associated with thrombocytopenia (platelets <150 × 10⁹/L) or as an “ADAMTS13 relapse” with ADAMTS13 activity levels of <20%, without thrombocytopenia or microangiopathic hemolytic anemia. ADAMTS13 relapse usually progresses to clinical relapse if treatment is not initiated.¹⁶ The mechanism of action of rituximab is to remove anti-ADAMTS13 autoantibodies and increase ADAMTS13 enzyme activity. Physicians may consider the benefits of using rituximab in cases such as the presence of a known comorbid autoimmune disorder. The long-term outcomes and potential adverse events of adding rituximab need to be determined.^8,15

Caplacizumab is humanized, bivalent, variable-domain-only immunoglobulin fragment which targets the A1 domain of vWF and prevents interaction with the platelet glycoprotein Ib-IX-V receptor12 and the subsequent microvascular thrombosis.^11,17 A phase III HERCULES trial (a randomized, double-blind, multicenter, and placebo-controlled trial) showed that caplacizumab was effective in the treatment aTTP, significantly shortening the time to platelet count normalization compared to placebo, and reducing the incidence of mortality, exacerbations, and major thromboembolic events during the treatment period by 74% and the overall number of TTP exacerbations/relapses by 67%. The study also evaluated the potential of caplacizumab to reduce the risk of recurrence by allowing for treatment to continue until immunosuppressive therapy resolve the underlying autoimmune disease. Although treatment with caplacizumab can stop the formation of microthrombi, it has no effect on the autoimmune component of the disease.^11,18,19

If caplacizumab is added to treatment within 3 days of confirming the diagnosis, patients can reach better clinical outcomes. The recommended caplacizumab dosage regimen in patients with aTTP is an initial intravenous injection of caplacizumab 10 mg prior to TPE, followed by a daily subcutaneous injection of 10 mg of caplacizumab after each TPE, followed by daily subcutaneous injection of 10 mg of caplacizumab for 30 days after the end of TPE treatment. ADAMTS13 activity should be monitored once a week. If at the end of this period, there is evidence of unresolved immunological disease, it is recommended to continue daily subcutaneous administrations of caplacizumab 10 mg together with corticosteroids until the signs of underlying immunological disease are resolved and ADAMTS activity is >10%.^20–22 Early relapses after stopping caplacizumab, occurring within less than 10 days, which correspond to the duration of the drug’s effect, in patients with persistent undetectable ADAMTS13 activity, suggest an unresolved autoimmune process. The optimal frequency for monitoring ADAMTS13 activity during remission is once in every 3 months for the first 2 years.^19,23

Caplacizumab has an acceptable safety profile, with mild-to-moderate mucocutaneous bleeding as the most common side effect. The contraindications for the use of caplacizumab are as follows: recent major surgery, life-threatening bleeding, or formal indication for therapeutic dose anticoagulation. Additionally, it remains unclear whether we should consider the risk of hemorrhagic transformation of brain ischemic lesions, in a context of severe thrombocytopenia. The best strategy to manage bleeding when administering caplacizumab remains uncertain. Although discontinuation of treatment is mandatory during surgery or life-threatening bleeding, the administration of vWF concentrates should antagonize the effect of caplacizumab.^19,24–26

Our patients started initial treatment with corticosteroids and TPE immediately after we diagnosed suspected TTP and examined ADAMTS13 activity, which was less than 2%. On day 6 after the initial symptoms, caplacizumab was added to the therapy. First patient reached clinical remission on day 10 after the first symptoms, but on day 16, there was an exacerbation of aTTP with ADAMTS13 activity of 5% without thrombocytopenia and microangiopathic hemolytic anemia. Rituximab was added to the treatment, the patient was discharged from the hospital on the 20th day of hospitalization, and continued with daily subcutaneous injections of caplacizumab, for a total of 38 doses. Complete long-term remission was achieved. The second patient achieved clinical remission on day 13 after the first symptoms, but the clinical relapse occurred 3 months after the end of the caplacizumab treatment. Laboratory results showed mild thrombocytopenia, reduced ADAMTS13 activity, and positive ADAMTS13 inhibitor with no sign of hemolysis. The relapse was treated with rituximab and complete remission was achieved. The third patient reached remission on day 12 after the first symptoms, but on day 16, she had acute intestinal infection, followed by an exacerbation. ADAMTS13 activity was 4.4%, ADAMTS13 inhibitor was 23 U/mL, and mild thrombocytopenia with moderate anemia was detected. We started another daily TPE, increased the dose of methylprednisolone and administered cyclophosphamide. Later, platelet counts was stabilized, ADAMTS13 activity increased, ADAMTS13 antibodies were negative again, and clinical remission was achieved.

In the future, it is important to study the risk factors for developing relapses and the optimal time to discontinue the treatment based on the detailed monitoring of ADAMTS13 activity during remission, which is a predictive marker to identify patients at risk for relapse.²¹ According to the single group, treatment, phase III, open-label, single-arm MAYARI study it was demonstrated that caplacizumab and immunosuppressive therapy without initial TPE, has been shown to be safe and effective in more than 95% patients with aTTP without severe symptoms. A new hope in TTP treatment presents the recombinant human ADAMTS13 (rhADAMTS13), which was approved as prophylactic or on-demand enzyme replacement therapy in adult and pediatric patients with congenital TTP.²⁷ However, in aTTP rhADAMTS13 needs to be resistant to a large fraction of the patients’ autoantibody mixtures, while its intrinsic activity cannot be lost.⁶

Conclusion

TTP is rare life-threatening disorder, which requires quick hematological management and treatment in collaboration with other specialists. ADAMTS13 activity level of <10% confirms the diagnosis, but TPE as initial treatment should be started as soon as TTP is suspected based on clinical condition. In 2021, new monoclonal antibody, caplacizumab, was added to the first-line of treatment, which significantly improved the morbidity and mortality by shortening the time needed to normalize platelet count and reducing the incidence of exacerbations and major thromboembolic events. Prospectively, it may be an option to start the treatment with caplacizumab and immunosuppressive therapy without TPE. Another advance in TTP treatment is rhADAMTS13, which was approved as prophylactic and on-demand treatment for congenital TTP, but the potential benefits in patients with aTTP remain unknown. Our case reports present the effective administration of caplacizumab, immediately after starting TPE therapy in patients with newly diagnosed acute form of aTTP, including the first administration of caplacizumab in Slovakia. There was a rapid response to treatment and complete long-term remission was achieved.

Footnotes

Acknowledgements

The work was supported by Vega 1/0059/25 project and Vega 1/0250/22.

Declarations

ORCID iD

Kristina Maria Belakova

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Effectiveness of caplacizumab in the first-line treatment for acquired thrombotic thrombocytopenic purpura: single center experience

Abstract

Keywords

Introduction

Case report 1

Case report 2

Case report 3

Discussion

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References