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H.A. van Dorland et al.
period or during childhood.8,11,32,33 As demonstrated for the 111 patients with available information, a substantial number of affected subjects showed thrombocytopenia, hemolysis, jaundice, petechiae and/or anemia during the neonatal period, often leading to therapeutic interventions such as exchange blood transfusion, sometimes many years before clinical diagnosis of TTP (Figure 1). Other patients, however, seemed to present the first signs of TTP only in adulthood. Before the late 1990s cTTP was purely a clinical diagnosis. Today, clarification of its pathophysi- ology,3,34-36 the advent of ADAMTS13 assays, and the pos- sibility of sequencing the ADAMTS13 gene emerging over the past two decades6,7,9,11,12,35-38 allows the diagnosis of both autoimmune and congenital TTP to be quickly and effi- ciently confirmed (for consensus definitions of diagnosis see Scully et al.4,22 and Kremer Hovinga et al.5). During recent years, we have been able to confirm the clinical diagnosis of many of our patients within days or weeks through the use of appropriate assays (Figure 1).
The systematic collection of clinical data in individual patients revealed substantial comorbidities in cTTP patients (Table 2 and Figure 2). Most notable is the high proportion of patients who had suffered from premature arterial thromboembolic events, mainly transient ischemic attacks, ischemic strokes and, to a lesser extent, myocar- dial infarctions. At 40-50 years of age and over, more than 50% of cTTP patients had suffered from at least one arte-
rial thromboembolic event. In addition, several patients seem to suffer from headache, mental or depressive disor- ders, which is similar to the situation in acquired TTP.39,40 Of note, 25% of cTTP patients had renal insufficiency at the time of enrollment and 12.5% had required hemodial- ysis or underwent kidney transplantation (Table 2). Severe and, sometimes transient, renal failure has been described in case reports or series of cTTP patients,41-43 which is dis- tinct from acquired TTP where a creatinine ≥2mg/dL (≥180 μmol/L) is a clear exception.5,22,44
Detailed information on 291 acute episodes in 81 cTTP patients was available at the time of enrollment. The fre- quency of acute manifestations varied considerably in individual patients with a median of approximately 0.1 acute episode per patient-year and a range of 0.02-9 yearly acute episodes per patient (Online Supplementary Table S2). In two-thirds of episodes, the responsible physicians assumed a triggering factor, mainly mild to moderately severe infections, alcohol excess in men, pregnancy in women, and various other potential triggers (Figure 3). Pregnancy is a well-known trigger for acute disease episodes in cTTP13,18-20,45 and it is conceivable that pregnan- cy and other conditions leading to an increased endothe- lial von Willebrand factor secretion may bring about acute disease in the face of absent or severely reduced ADAMTS13 activity. It is generally thought that an acute episode in cTTP is rapidly controlled by simple plasma
Figure 3. Triggers of acute thrombotic thrombocytopenic purpura (TTP) episodes until enrollment in male and female congenital thrombotic thrombocytopenic purpura patients. For 287 of 291 acute TTP episodes documented in the Hereditary TTP Registry information on triggers of the acute bout was known. Seventy-nine patients had episodes with or without presumed triggers: for 97 episodes in 46 patients no trigger was reported; for 190 episodes in 58 patients triggers were reported. Triggers do not sum up as a patient may have had more than one trigger of an acute episode, nor do patients as they may have had episodes with or without triggers.
Table 3. Reported treatment in congenital thrombotic thrombocytopenic purpura patients at enrollment. Variables
Mode of treatment
Patients with regular prophylactic treatment Patients with on demand treatment
Plasma and Factor products applied among regularly treated patients
Plasma products†
Plasma derived FVIII product
Median interval of most recent treatment (days) (n=78)††
All patients (N = 117)*
83 (71%) 34 (29%)
82 (99%)
1 (1.2%)
14.0 [2.0, 14.0, 21.0, 75.0]
N: total number of patients; n: number of patients with available values. Continuous variables are presented as median [(minimum, 25th percentile, 75th percentile, maximum)]. Categorical variables are presented as number and percentage of all patients, or as number (n) of patients. *Information on current treatment missing for two male and four female patients. †Fresh frozen plasma (n=68); fresh frozen plasma and cryo-poor plasma (n=2), solvent/detergent plasma (n=12). ††Interval missing for five patients.
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haematologica | 2019; 104(10)