Journal Club – TTP

By Brian Carney

Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019; 380(4): 335-346.

Clinical Question:

In patients with thrombotic thrombocytopenic purpura (TTP), does addition of caplacizumab to plasma exchange improve time to normalization of platelet count?


A combination of plasma exchange and immunosuppression with corticosteroids and rituximab is widely accepted as standard first-line therapy for acute TTP. Despite high response rates to this combination, there are definite concerns regarding slow time to response and risk of exacerbation (recurrence within 30 days) and relapse (recurrence after 30 days). Slow responses, exacerbations, and relapses put patients at high risk of morbidity and mortality given the potential for catastrophic complications with TTP. Caplacizumab is an antibody fragment (nanobody) that targets the A1 domain of von Willebrand factor (vWF), preventing the interaction of vWF with the platelet glycoprotein Ib-IX-V receptor. By antagonizing vWF and platelet interaction, caplacizumab prevents the microvascular thrombosis which is the basis of the pathophysiology of TTP. Caplacizumab was evaluated in the phase II TITAN study and found to significantly improve time to response in platelet count and exacerbation rate compared to placebo [1]. The phase III HERCULES study was undertaken to confirm and extend these findings in a larger clinical trial.


An ISTH guideline recommends considering early addition of caplacizumab to plasma exchange and corticosteroids for management of acute TTP [2].

Study Design:

  • Multicenter, randomized, double-blind, placebo-controlled clinical trial
  • n = 145
    • Caplacizumab: 72
    • Placebo: 73
  • Setting: 92 study sites worldwide
  • Enrollment period: November 2015 through April 2017
  • Follow-up period: Treatment period (30-58 days) + 28 days after completion of treatment
  • Analysis: Intention-to-treat
  • Primary efficacy outcome: Time to response. Defined as time from first administration of caplacizumab to normalization of platelet count.
  • Key secondary outcomes:
    • Composite of TTP-related death, recurrence, and major thromboembolic events
    • Recurrence of TTP during treatment and follow-up
    • Refractory TTP. Defined as lack of doubling of platelet count after 4 days of treatment and LDH persistently above upper limit of normal.
    • Time to normalization of serum creatinine, LDH, and troponin I
  • Primary safety outcome: Adverse events


Inclusion Criteria:

  • 18 years or older (although some sites enrolled children 2-18 years)
  • Suspected TTP on the basis of thrombocytopenia and microangiopathic hemolytic anemia with schistocytes
  • Patients had received exactly one session of plasma exchange
  • Notably, severe ADAMTS13 deficiency was NOT an eligibility criterion

Exclusion Criteria:

  • Suspected thrombotic microangiopathy other than TTP (e.g., HUS)
  • Congenital TTP

Baseline Characteristics:

  • Initial TTP episode in 67% of patients in caplacizumab vs. 47% in placebo arm
  • Recurrent TTP episode in 33% of patients in caplacizumab vs. 53% in placebo arm
  • Rituximab used in 39% of patients in caplacizumab vs. 48% in placebo arm


  • Patients were randomized 1:1 to plasma exchange and corticosteroids with either caplacizumab or placebo
  • Caplacizumab was administered as a 10 mg IV loading dose given immediately prior to the first session of plasma exchange after randomization. Subsequent doses of 10 mg SQ were administered daily for 30 days after the final session of plasma exchange.
  • Caplacizumab could be continued for an additional 28 days in response to persistent severe ADAMTS13 deficiency
  • In the event of TTP recurrence, patients were switched to open-label caplacizumab

Outcomes (comparisons are caplacizumab vs. placebo):

            Primary Outcome:

  • Rate ratio for normalization of platelet count: 1.55, P=0.01 (caplacizumab superior)

Secondary Outcomes:

  • Efficacy
    • Composite of TTP-related death, recurrence, and major thromboembolic events: 12% (n = 9) vs. 49% (n = 36), P<0.001 (caplacizumab superior)
      • TTP-related death: 0% vs. 4% (n = 3)
      • Recurrence of TTP (exacerbation): 4% (n = 3) vs. 38% (n = 28)
      • Major thromboembolic event: 8% (n = 6) vs. 8% (n = 6)
    • Recurrence of TTP of during treatment and follow-up: 12% vs. 38%, P<0.001 (caplacizumab superior)
    • Refractory TTP: 0% vs. 4% (n = 3), P=0.06
  • Safety
    • Treatment with caplacizumab was associated with increased risk of epistaxis and gingival bleeding. Serious adverse events of bleeding were reported in 11% of patients who received caplacizumab and 1% of patients who received placebo. Fewer patients who received caplacizumab developed hypocalcemia, which was likely due to them undergoing significantly fewer sessions of plasma exchange.


In the HERCULES study, caplacizumab was observed to improve time to normalization of platelet count and reduce rates of TTP exacerbation. No statistically significant differences in TTP-related death, major thromboembolic events, or refractory TTP were reported. Caplacizumab was associated with an increased risk of hemorrhage, although most events were mild and of limited clinical significance.

There are several limitations that warrant mentioning. Confirmation of ADAMTS13 deficiency was not an eligibility requirement, thus potentially exposing patients without a true diagnosis of TTP to caplacizumab. This issue was mitigated to some extent by limiting enrollment to patients who had already initiated plasma exchange. A greater proportion of patients in the placebo arm had recurrent and potentially more difficult to treat disease. Finally, fewer than half of patients in each arm were treated with rituximab, which is largely considered standard-of-care first-line therapy for TTP.

Caplacizumab improves time to response when added to standard therapy for TTP. This may reduce the risk of severe complications. In view of these findings, it is reasonable to consider adding caplacizumab in patients with confirmed or strongly suspected TTP. Additional studies further exploring clinical outcomes such as TTP-related mortality and long-term neurologic sequelae of TTP in caplacizumab-treated patients will be of interest.


  1. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016; 374(6): 511-522.
  2. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020; 18(10): 2496-2502.