Do patients with immune-mediated thrombotic thrombocytopenic purpura receiving caplacizumab need antithrombotic therapy?

KEYWORDS:

• Anticoagulant
• antiplatelet
• bleeding
• caplacizumab
• thrombosis
• thrombotic thrombocytopenic purpura

1. Introduction

Acquired or immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy with an annual incidence of three cases per 1 million adults [1]. In the pathogenesis, autoimmune inhibition of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) – also known as von Willebrand factor – cleaving protease (vWFCP) takes role in accumulation of ultra-large vWF (ULvWF) multimers, which bond to platelets and induce the formation of microthrombi, causing tissue ischemia, and organ dysfunction [1]. The main causes of morbidity and mortality in iTTP are the thromboembolic complications [2].

Caplacizumab is a bivalent humanized single-variable-domain immunoglobulin that targets the A1 domain of vWF [1]. It inhibits the interaction between vWF and platelet (GP)1b-IX-V receptor, thus, preventing platelet adhesion. Caplacizumab has been introduced as an adjunct to plasma exchange (PEX) therapy and corticosteroids in iTTP [1,3]. In patients receiving caplacizumab, ischemic organ damage-related biomarkers tend to normalize more rapidly [4], and the composite endpoint of iTTP-related death, iTTP recurrence, or major thromboembolic events (TEEs) are reduced significantly [4–8]. Although caplacizumab was recommended to be used in combination with PEX and corticosteroids in iTTP patients experiencing an acute episode of in the current International Society on Thrombosis and Haemostasis (ISTH) guidelines [9] it was also stated that the data informing this recommendation were of moderate certainty and caplacizumab is not yet available worldwide. Besides, the cost-effectiveness of using caplacizumab in this setting is uncertain [5,10].

In this paper, we will first focus on the thrombotic complications and bleeding events observed in TTP patients both in the pre-caplacizumab era and after its introduction. Then, current data in the literature and the recommendations of guidelines on the use of antithrombotic agents (antiplatelets or anticoagulants) in TTP patients will also be evaluated. Finally, we discuss the place of antiplatelet agents and/or anticoagulation in patients receiving caplacizumab based on the literature data available.

2. Thrombotic and bleeding events in TTP in the pre-caplacizumab era

Arterial and venous TEEs can be observed in the course of the disease, and in a large TTP study, arterial thrombosis rate was 10.6% [2] (Table 1). Venous thromboembolism (VTE) rates in iTTP vary from 3.8% to 13% [2,11–14] (Table 1). In a study consisting of 77 patients, one (6%) VTE episode was catheter-related [15]. Rizvi et al. [12] report a VTE incidence of 12.6%, majority of which were catheter-related thrombosis. Deep vein thrombosis (DVT), PE, and superficial venous thromboses are also observed in addition to the catheter-related thromboses [12–14]. Most VTEs occur after platelet normalization, especially in patients who do not receive thromboprophylaxis [13]. The common message from all these 4 studies is that VTE is mostly associated with catheter insertion and VTE prophylaxis is a must during TTP treatment whenever possible.

Table 1. Selected TTP papers reporting data on bleeding and/or thrombotic events and antithrombotic therapies (CNS, central nervous system; LMWH, low-molecular-weight heparin; N/A, not available; NR, not reported; PEX, plasma exchange; TEE, thromboembolic event; VTE, venous thromboembolism)

		Arterial thrombosis n (%)	Venous thrombosis n (%)	Major bleeding n (%)	Minor bleeding n (%)	Ongoing antiplatelet therapy n (%)	Ongoing anticoagulation n (%)	Details
Non-caplacizumab studies
Single-arm
Goel et al., 2015 [2] (n = 10,624)		1138 (10.6)	396 (3.8)	NR 114 (1.1)*	1451 (13.7)	NR	NR	*CNS bleeding
Yarranton et al., 2003 [14] (n = 68)		NR	8 (11.7)*	NR	NR	7(10.2)**	2(3)***	*8 events in 7 patients **Low-dose aspirin ***1 patient was receiving LMWH, 1 warfarin
Rizvi et al., 2000 [12] (n = 71)		None	2	2*	None	NR	NR	*Major hemorrhages were catheter-related
Tse et al., 2020 [13] (n = 77)		NR	16 (13)*	NR	NR	4(5.2)**	1 (1.3)***	*16 events in 14 patients, 2 had a history of VTE, 1 VTE event was catheter-related **Low-dose aspirin ***Warfarin
Benhamou et al., 2020 [11] (n = 314)		NR	48 (12.7)*	NR	NR	142 (45.2)**	None	*48 episodes in 41 patients. 9.7% had a history of VTE **Mostly aspirin
Quintini et al., 2003 [15] (n = 16)		NR	N/A	1 (6.3)	12 (75)	Dipyridamole infusion, 16 (100)	None	N/A
Rosove et al., 1982 [18] (n = 14)		NR	NR	5 (36)	NR	Aspirin + dipyridamole, 14 (100)	None	N/A
Randomized-controlled
Bobbio-Pallaviccini et al., 1997 [16] (n = 72)	Study arm (n = 35)	NR	NR	None	28 (80)	Aspirin + dipyridamole	None	N/A
	Placebo arm (n = 37)	NR	NR	None	30 (81)	None	None
Rock et al., (n = 102) 1991 [17]	PEX arm (n = 51)	NR	NR	1 (1)	7 (7)	Aspirin + dipyridamole, 102 (100)	None	N/A
	Plasma infusion arm (n = 51)
Caplacizumab studies
Single-arm
Völker et al., 2020 [19] (n = 60)		1 (1.6)	None	1 (0.5)	NR	None	None	N/A
Placebo/history-controlled
Phase II TITAN trial, 2017 [4] (n = 72)	Study arm (n = 35)	None*	1 (2.9)	2 (5)	19 (54)	None	None	*TIA were not considered to be major TEE, and were therefore not included in this analysis (1 patient in each group)
	Placebo arm (n = 37)	3 (8.1)?	3 (8.1)	2 (5)	14 (38)	None	None
Phase III HERCULES trial, 2019 [8] (n = 145)	Study arm (n = 72)	6(8)	1(3.6)	8 (10)	46 (65) 22 (78)*	NR	NR**	*Data from the open-label caplacizumab arm of HERCULES study [22] **12 (16.9) from the caplacizumab arm and 9 (12.3) from the placebo arm had bleeding under antithrombotics
	Placebo arm (n = 73)	6(8)	None	1 (1)	35 (48)	NR	NR
Dutt et al., 2020 [6] (n = 124)	Study arm (n = 85)	NR	4 (5)	5 (6)	13 (15)*	None	None	*Primarily gingival bleeding
	Control arm (n = 39)	NR	2 (5)	0	None	None	None
Coppo et al., 2021 [5] (n = 270)	Study arm (n = 90)	NR	11 (12)	2 (2.2)	28 (33)	7 (7.8)	2 (2.2)	N/A
	Control arm (n = 180)	NR	20 (11.1)	N/A	N/A	11 (6.1)	5 (2.8)

There was limited data on bleeding presented in the previous TTP studies, and minor bleeding episode rates were reported to be between 8%–80% (Table 1). These rates were higher especially if antiplatelets were used [15,16]. In the study of Quintini et al. [15], 80% of patients receiving standard therapy plus dipyridamole infusion had bleeding episodes, none of which were severe. In a randomized study, in which patients received either dual antiplatelet therapy (aspirin+dipyridamole) or placebo, treatment efficacy between two arms were comparable with minor and transient bleeding episodes in patients with antiplatelets [16] (Table 1). On the other hand, in a prospective randomized trial comparing PEX therapy with plasma infusion, all patients (n = 102) in both arms received aspirin and dipyridamole [17] (Table 1). Only eight patients had bleeding, one of which was fatal. In another case series, aspirin and dipyridamole combination demonstrated no significant benefit with serious bleeding complications [18] (Table 1). As TTP has been viewed more as a thrombotic disease, bleeding complications may mostly have been neglected in past studies.

3. Thrombotic and bleeding events in TTP patients receiving caplacizumab

The clinical efficacy of caplacizumab in iTTP patients was first tested in the phase II TITAN [4] and phase III HERCULES [8] trials, which were followed by three real-life studies [5,6,19] evaluating the efficacy and safety of caplacizumab in adjunct to PEX therapy and corticosteroids.

We analyzed the data coming from these two clinical trials [4,8] together with 3 real-life studies [5,6,19] regarding thrombotic and bleeding complications experienced under caplacizumab therapy.

No arterial thrombotic events occurred in caplacizumab arm of the TITAN trial, to date, three occurred in the placebo arm [4] (Table 1). VTE rates were reported as 5.5% in the entire study population (2.9% and 8.1% in caplacizumab and placebo arms, respectively) [7]. Major TEE rates in the placebo group were consistent with the literature [2]. Bleeding was more common in the caplacizumab arm (54% vs. 38%), most of which were mild to moderate, though 2 cases with serious bleeding in each group were reported [4]. As patients on any antithrombotics were excluded in those trials, we have limited data on the safety and feasibility of concomitant use of caplacizumab and antithrombotics in iTTP.

In the study by Dutt et al. [6], VTE rate was 5% in caplacizumab group, which was the same in historical controls (Table 1). Bleeding rate was 20.9% in patients receiving caplacizumab, of 6% were severe, and there was no bleeding in historical controls. Five patients receiving caplacizumab required blood transfusions due to bleeding. In another caplacizumab study, there were no severe/serious bleeding events, but one major bleeding episode, which was resolved after caplacizumab cessation [19] (Table 1). None of the patients in these three studies were receiving any antithrombotics during the study period [4,6,19].

In the HERCULES trial, major TEE rates were the same in both arms (8%), and one patient in the caplacizumab arm died of hemorrhagic transformation of ischemic stroke after the end of treatment period [8] (Table 1). In the open-label caplacizumab arm of the HERCULES trial, one patient had a major TEE, which resolved after enoxaparin treatment without interrupting caplacizumab [20]. Bleeding rates were 65% and 78% in the caplacizumab and open-label caplacizumab arms, respectively, vs. 48% in the placebo arm [8,20]. Serious bleeding events were also more frequent in patients receiving caplacizumab [20] (Table 1). Safety data from the HERCULES trial demonstrates that, 62% of the patients who received at least one dose of caplacizumab had bleeding events [21]. In the caplacizumab group, 16.9% had a bleeding event with ongoing antithrombotic therapy, whereas this was 12.3% in the placebo group. Three patients with TEE received direct oral anticoagulants while on caplacizumab, and all experienced at least one bleeding event, of which one was serious menorrhagia requiring transfusion [21].

Coppo and colleagues [5] compared 90 patients receiving caplacizumab therapy with 180 historical controls, of which nine patients from the study group and 16 from the historical cohort were on antithrombotic therapy with no details shared on bleeding events (Table 1). Thirty-three patients (37%) received prophylactic antithrombotic agents when platelet counts were > 50 x 10⁹/L. Thirty patients in the study group experienced bleeding events, one of which was a major gastrointestinal bleeding. TEE rates were similar in both groups (12% vs. 11.1%), none of the patients with TEE received thromboprophylaxis (Table 1). Nineteen patients (22%) developed a transient thrombocytosis, although no clear association between elevated platelet counts and TEE occurrence was found [5].

In a recently published case report demonstrating a patient with refractory iTTP, both DVT and arterial thrombosis occurred shortly after caplacizumab discontinuation without TTP recurrence [22]. The patient did not receive any antithrombotic agent while on caplacizumab.

4. What do guidelines recommend on the use of antithrombotic agents in TTP?

The use of antithrombotic agents (antiplatelets or anticoagulants) in TTP was recommended in some practice guidelines [23,24]; however, there is an increased risk of bleeding in iTTP patients receiving caplacizumab [4,8], thus, adding antithrombotics to caplacizumab therapy is controversial.

Low dose aspirin use is recommended both in the British and Japanese guidelines following platelet recovery (>50 x 10⁹/L) [23,24]. On the contrary, in the ISTH Good Practice Statements guidelines [25], antiplatelets were not generally recommended due to the lack of evidence on safety and efficacy. For venous thromboprophylaxis, routine anticoagulant use is recommended once platelet counts are >50 x 10⁹/L [24,25]. However, since there is no precise data about anticoagulation in iTTP, most probably this recommendation is based on the general principles of VTE prophylaxis in acute illness and hospitalization.

Unlike the previous ones [23,24], in the most recent ISTH guidelines for the treatment of TTP [9], caplacizumab use in acute iTTP is recommended, though no recommendations on antithrombotic use either with or without caplacizumab are included. What’s more, there is no statement to withhold or continue caplacizumab in case of adding an antithrombotic agent due to a new thrombotic event [9].

5. Discussion and conclusion

Although caplacizumab seems to prevent arterial thrombotic events, current evidence does not support using caplacizumab as an anticoagulant agent in iTTP, since the rates of VTE in both caplacizumab and no-caplacizumab groups are similar [10].

Bleeding events were more frequent in patients with caplacizumab than that of controls, and most patients receiving caplacizumab did not concomitantly use antithrombotics. Since caplacizumab inhibits platelet adhesion at high-shear rates, but not at low-shear rates, there may be a lower bleeding risk when compared to other antiplatelets [10,26]. Supporting this, in the pre-caplacizumab era, TTP patients receiving aspirin and/or dipyridamole had higher rates of minor bleeding events than observed in caplacizumab-treated patients; however, although rare, major bleeding episodes seem to be more frequent in cases with caplacizumab than that of historical controls receiving antiplatelets (Table 1). One must keep in mind that studies from the pre-caplacizumab era do not emphasize bleeding as it was considered as a complication of the disease and not the treatment. However, in patients receiving caplacizumab bleeding is reported as a treatment adverse event, which may cause a bias.

Despite limited data, iTTP patients treated with caplacizumab should probably receive anticoagulant prophylaxis especially when platelet counts are > 50 x 10⁹/L, if not contraindicated. When platelet counts are < 50 x 10⁹/L, the indication for anticoagulant prophylaxis could be assessed on a patient-by-patient basis. Recommendations solely based on platelet numbers are on the other hand not practical, because platelet functions are compromised under caplacizumab therapy, which may create a therapeutic dilemma. This problem is similar to the ones encountered in treating cirrhosis, disseminated intravascular coagulation or patients with prostetic heart valves who bleed, since these patient groups are prone to both bleeding and thrombosis. As patients on antithrombotic therapy were excluded from HERCULES and TITAN trials, data from a very small number of patients among the literature [6] show that if strongly indicated, they can be used safely concomitantly, yet careful monitorization is mandatory. The best would be to weigh the risk of hemorrhage vs. thrombosis and decide to use concomitantly or to avoid either of them.

Putting all these together, there is a need to ascertain the thromboprophylaxis strategy among iTTP cases receiving caplacizumab. Available guidelines are falling short to settle on the concomitant use of antithrombotics and caplacizumab, and whether to withhold caplacizumab to commence anticoagulation treatment in the occurrence of VTE. In the absence of clinical indication, concomitant use of caplacizumab and antiplatelet drugs should not be encouraged. With the growing experience in caplacizumab use, these issues should be addressed in future.

6. Expert Opinion

In iTTP, there is an increased risk of venous thrombotic events (VTEs) as well as arterial thrombotic events. The use of antiplatelet and/or anticoagulant therapy during disease course, especially in the thrombocytopenic phase, has been controversial yet encouraged in some older guidelines. Two major clinical trials have introduced caplacizumab as a first line drug candidate, but they reported an elevated bleeding risk compared to standard care. In the absence of clinical indication, concomitant use of caplacizumab and antiplatelet drugs should not be encouraged. iTTP patients should probably receive anticoagulant prophylaxis, especially when the platelet counts are >50 x 109/L. When the platelet counts are <50 x 109/L,the indication could be assessed on a patient-by-patient basis by weighing the risk of hemorrhage vs. thrombosis. Further studies are needed for the necessity, safety and management of antiplatelet and anticoagulant therapy in patients receiving caplacizumab.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer of this manuscript discloses receiving funds from Sanofi and Alexion. A separate reviewer discloses being a principal investigator and one of the authors of the manuscript on the HERCULES trial. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.