Not So Benign
This Is Not Your Father’s Thrombotic Thrombocytopenic Purpura

This year marks 100 years since Eli Moschcowitz, MD, described the first case of what would eventually be named thrombotic thrombocytopenic purpura (TTP). He reported the clinical presentation and pathologic findings resulting from the formation of widespread microthrombi driven by a congenital or acquired deficiency of the ADAMTS13 protease.¹  In the past 20 years, we have seen remarkable progress in the diagnosis and treatment of both immune-mediated (iTTP) and congenital TTP (cTTP). These advances include: the discovery and characterization of the ADAMTS13 protease,^2,3  the use of rituximab to treat and prevent TTP relapses,^4-6  and the regulatory approval of both caplacizumab⁷  and recombinant ADAMTS13⁸  (rADAMTS13) that are drastically changing the treatment paradigm of both iTTP and cTTP. Very soon, caplacizumab or rADAMTS13 – alone, without the need for plasma exchange therapy – could replace emergent plasma exchange therapy as the initial treatment of TTP, pending the results of two ongoing, prospective studies in acute iTTP (evaluating caplacizumab (NCT05468320) and evaluating rADAMTS13(NCT05714969).

This same progress that has increased the numbers of TTP survivors has also transformed our understanding of TTP from an acute, episodic disease to a chronic disease with serious, long-term sequelae.^9-11  The lack of complete recovery after an acute iTTP episode was initially recognized after one of the first patient support group meetings held by the Oklahoma TTP Registry. Surprisingly, patients in this session reported that they had not returned to their previous level of functioning after an acute TTP episode.¹²  Several long-term complications in TTP survivors after recovery from an acute TTP episode have been reported since this initial report. These effects include: neurocognitive deficits (most commonly with short-term memory), mood disorders, chronic headaches, post-traumatic stress disorder (PTSD), and cardiovascular complications (which may be the strongest contributor to the shortened life expectancy seen in survivors of iTTP).^13-17 

iTTP survivors are five times more likely than age- and sex-matched controls to suffer a cerebrovascular accident after achieving remission.¹⁸  In addition, major adverse cardiovascular events (MACE, defined as stroke, myocardial infarction, and any cardiac revascularization) have been reported in approximately 24% of iTTP survivors.¹⁹  To place this in the appropriate context, this rate is more than double the rate of MACE described in traditional cohorts of established patients with known arterial disease (13.6%), multiple cardiovascular risk factors (6.9%), or a genetic predisposition for MACE (14%).^8,20,21  These cardiovascular complications are also reported to occur at a much younger age in iTTP survivors than controls – ranging from one to two decades earlier.³  These differences are most striking in younger female iTTP survivors, who experience stroke and myocardial infarction nearly 20 years earlier than expected when compared with the U.S. reference population. Similarly, patients with cTTP are also at greater risk for cardiovascular complications, including cerebrovascular accidents, during longitudinal follow-up.^22,23  While data suggest that these complications in cTTP may be prevented by prophylactic plasma infusions (or rADAMTS13, by implication), it is unclear if there are other risk factors leading to the development of these cardiovascular complications in patients with cTTP.

While the pathophysiology and diagnosis of both iTTP and cTTP are understood with some certainty, the mechanism (or mechanisms) for the development of these long-term complications in patients with TTP in remission are not well understood. Data suggest that the risk for cerebrovascular accidents may be related to lower levels of ADAMTS13 in remission, but severely deficient ADAMTS13 activity by itself falls short as an explanation for the development of all these seemingly diverse complications in patients with TTP.¹⁸  In research presented at the 2023 ASH Annual Meeting, Senthil Sukumar, MD, MS, and colleagues reported striking rates of inducible ischemia in a younger cohort of patients with asymptomatic iTTP in remission who underwent stress cardiac magnetic resonance imaging.²⁴  These TTP survivors had significantly reduced stress myocardial blood flow that was primarily noted in the subendocardium. Notably, this TTP patient cohort also had significantly reduced myocardial perfusion reserve, which demonstrates the ability of the coronary arteries to dilate in response to stress. These changes were dynamic and not mediated by microthrombotic disease, but rather were suggestive of a vasculopathy in the coronary circulation. Whether this vasculopathy noted in the coronary microcirculation could be the cause of other long-term complications in other organ beds in TTP patients is unknown.

The field of TTP has seen remarkable scientific advances and progress that, without question, have transformed the diagnosis and treatment of this rare blood disease. These answers have also led to even more questions, particularly regarding survivorship issues in patients with TTP. Questions regarding the appropriate screening and prevention (if possible) of these long-term complications in both iTTP and cTTP will become even more important as the number of patients surviving TTP continues to rise going forward. TTP can no longer be viewed as an acute episodic disease, but must be viewed as a chronic illness that requires long-term follow-up and specialized care.