“Rational” Approach to Caplacizumab Therapy in TTP Outlined in New Article

Judicious use of caplacizumab (Cablivi) can reduce the risk of severe bleeding and help manage costs associated with the therapy in patients living with thrombotic thrombocytopenic purpura (TTP).

Caplacizumab (Cablivi) has become an important disease-modifying agent for the treatment of thrombotic thrombocytopenic purpura (TTP), but the potential for bleeding adverse effects means physicians should carefully consider when—and for how long—to use the therapy, according to a new article published in Transfusion and Apheresis Science.

The piece lays out what its author, Ravi Sarode, MD, professor of pathology at the University of Texas Southwestern Medical Center, calls an individualized “rational” approach.

TTP is marked by a severe deficiency of the enzyme ADAMTS13. The disease is usually caused by autoantibodies (the form known as aTTP), although a minority of patients have congenital TTP caused by genetic mutations.

ADAMTS13 is involved in the regulation of von Willebrand factor (VWF) multimer sizes. Sarode explained that a severe deficiency of the enzyme leads to excessively large VWF multimers that form VWF–platelet-rich microthrombi in smaller blood vessels, which in turn results in microangiopathic hemolytic anemia and thrombocytopenia, the classical features of TTP.

“These microthrombi result in end-organ damage, mainly affecting the heart, brain, and kidneys,” he said.

The first breakthrough in TTP treatment was plasma exchange (PLEX) therapy, which Sarode noted has led to a dramatic reduction in mortality. However, delays in diagnosis or treatment initiation can have deadly consequences, and many patients with aTTP experience long-term neurocognitive and psychological complications, likely resulting from brain damage caused by microthromboses, he said.

The latest innovation in TTP treatment is caplacizumab, a humanized single variable domain immunoglobulin that targets the A1 domain of VWF to inhibit its interaction with platelets. In clinical trials, the therapy has been shown to help correct platelet counts and prevent exacerbations when administered in combination with PLEX.

In the trials of caplacizumab, Sarode said the risk of relapse was associated with ADAMTS13 activity levels: Patients with less than 10% activity had a higher rate of relapses vs those with greater activity.

“In the phase 3 study, during the trial period, about 36% of patients in each arm had ADAMTS13 > 10% when the PLEX was discontinued,” Sarode noted, “and these patients had no exacerbations or relapses.”

However, Sarode noted that patients taking caplacizumab experienced higher rates of severe bleeding compared to the placebo arm, and recent reports have included cases of intracranial hemorrhages in patients treated with caplacizumab. Thus, he said, there may not be a benefit to continuing the use of caplacizumab once a patient’s ADAMTS13 activity exceeds 10%.

Sarode said the data suggest that caplacizumab is a “prudent” choice once a patient gets their TTP diagnosis, but he outlined a treatment plan designed to maximize the therapy’s effect without exacerbating the risk of adverse events. His medical center’s protocol calls for patients with a new diagnosis of TTP to receive a rapid ADAMTS13 assay in house, emergent PLEX, and glucocorticoid and caplacizumab therapy. The latter is monitored by ristocetin co-factor assay (RCo), he said.

“We generally measure RCo to adjust caplacizumab dosing every other day by maintaining RCo < 20 %,” he explained. “Once the ADAMTS13 antibody result is available (within 48-72 h), up-front rituximab (Rituxan) is started.”

Patients are measured for ADAMTS13 twice per week, and caplacizumab is discontinued once the patient has 2 ADAMTS13 readings above 10%. Once the level exceeds 50%, PLEX is also discontinued, he said.

Patients are monitored at regular intervals, and preemptive rituximab is re-started in the patient shows a downward trend, he added.

In summary, Sarode said caplacizumab provides the advantage of a quicker response that can potentially forestall greater long-term neuropsychiatric and psychosocial sequelae.

“Since the efficacy of PLEX depends on supplementing ADAMTS13, it will likely take a few days before it can reverse microthromboses and end-organ damage, especially in the brain,” he said. “Therefore, caplacizumab might be more effective at disrupting the pathophysiology of TTP due to its potent and rapid effect in inhibiting VWF interaction with platelets within 4-6 h,” he said.

He cautioned, however, that because the therapy does not eliminate autoantibodies, it must also “be accompanied by aggressive immunotherapy.”

Such a tailored approach to caplacizumab can help patients capture the benefits of the therapy while reducing the potential for serious bleeding.


Sarode R. Thrombotic thrombocytopenic purpura in caplacizumab era - An individualized approach. Published online March 1, 2023. Transfus Apher Sci. doi:10.1016/j.transci.2023.103682

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