Immune-mediated thrombotic thrombocytopenic purpura: don’t miss the boat

Thrombotic microangiopathy is defined by the association of peripheral thrombocytopenia and microangiopathic hemolytic anemia due to microvascular thrombosis, thus making blood smear the cornerstone of diagnosis. However, several atypical features have been associated with diagnostic and therapeutic delays. Although deep thrombocytopenia in an adult patient with TMA strongly suggests iTTP [1], one third of patients with acquired TTP may present with initially aregenerative anemia. Most importantly, absence of schistocytes on the initial blood smear should not be seen as exclusive of TTP diagnosis but rather as an indication to repeat blood smears. Careful examination of the blood smear can also reveal key features suggestive of a specific TMA entity or an alternative diagnosis: (erythro)myelemia (cancer-associated TMA), hypersegmented neutrophils (vitamin B9/B12 deficiency), and of course severe intra-erythrocytic protozoan infection caused by Plasmodium or Babesia. In addition, up to 10% of iTTP patients have a positive direct antiglobulin test, due to an underlying autoimmune condition [2].

A standardized diagnostic workup has substantial value to identify TMA etiology [3], most often resulting in a diagnosis of acquired TTP, shigatoxin-producing E. coli-associated hemolytic and uremic syndrome (STEC-HUS) or Complement-Mediated Hemolytic Uremic Syndrome (CM-HUS). Other causes of TMA include congenital TTP and secondary TMAs such as the hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, malignant hypertension and cancer-, drug- or autoimmune diseases-associated TMAs.

Clinical examination is often poorly informative Clinical symptoms at the time of TMA onset can hardly differentiate iTTP from other TMA causes. Indeed, serious neurological or cardiac involvement are not only seen during iTTP but can also be encountered in STEC-HUS or CM-HUS [4]. Severe weight loss and/or bone pain suggest the diagnosis of cancer-associated TMA [5]. Although the presence of significant inflammation (elevated white blood cell count and/or fibrinogen) is unusual in iTTP and is mostly seen in STEC-HUS or secondary TMAs

Acute kidney injury is the hallmark of HUS and severe renal failure is unusual in iTTP. Severe hypertension is also suggestive of HUS, but should be interpreted with caution. Hypertension can be a pre-existing comorbidity and, in some cases, the only cause of TMA (malignant hypertension). Alternatively, hypertension is also a frequent finding in secondary TMAs such as scleroderma renal crisis or catastrophic antiphospholipid syndrome [6, 7].

Among the three scoring systems validated in patients with TMA, the French score (creatinine < 200 μmol/L and platelet count < 30 × 10⁹/L) predict severe ADAMTS13 deficiency with 98% (94–100%) specificity, 47% (41–53%) sensitivity, 99% (96–100%) positive predictive value, and 39% (36–42%) negative predictive value. [8] This score is used in most trials recruiting TMA patients likely to have TTP. The point-based ADAMTS13 deficiency prediction score (creatinine > 2 mg/dL, platelets > 35 × 10⁹/L, d-dimer > 4 µg/mL, reticulocytes > 3%, and indirect bilirubin > 1.5 µg/mL) and the PLASMIC score (platelet count < 30 × 10⁹/L, combined hemolysis variables, no active malignancy, no history of transplantation, mean corpuscular volume (MCV) < 9 × 10–14 L, international normalized ratio (INR) > 1.5, creatinine < 2 mg/dL) are less frequently used. Therefore, the Coppo score remains the most suggestive feature of TTP in patients with TMA and should be used to guide initial therapy However, these elements are insufficient to make a definitive diagnosis, making the measurement of ADAMTS13 activity mandatory in all TMA cases.

A severe ADAMTS13 deficiency (activity < 10%) confirms the diagnosis of TTP. However, there is substantial variability in the performance of the ADAMTS13 activity assays and the result is often not available before 2–3 days. Therefore, clinicians should empirically initiate TTP treatment in all patients with a high clinical probability of iTTP while waiting for ADAMTS13 activity results.

The standard of care for iTTP is now well defined (TRIPLET regimen) and includes: (1) ADAMTS13 supplementation using daily plasma exchange, (2) immunosuppression (corticosteroids and rituximab), and (3) VWF inhibition achieved by caplacizumab [9]. Pending ADAMTS13 activity results, a full therapeutic regimen should be initiated in patients with a high clinical probability of TTP while patients with a moderate probability should only receive plasma exchange and corticosteroids. In the sickest patients (in the ICU), caplacizumab is often started just before the first plasma exchange. Plasma exchange must be preferred to plasma infusions in TTP patients. Plasma infusions must be reserved when Plasma exchange is not immediately available [3].

Platelet transfusions might trigger serious complications such as iTTP worsening, relapse, and flare up, status epilepticus or even cardiac accidents. Because microvascular thrombosis is made from unusually large VWF multimers and platelets, the priority should be to avoid platelet transfusion, which should only be used as a rescue strategy in the event of life-threatening bleeding, and always in association with copious plasma supplementation [10, 11]. Moreover, disease severity in iTTP is mostly mediated by ischemia and microvascular thrombosis, rather than by life-threatening bleeding.

In the ICU, clinical severity is often evaluated based on non-specific scores that depict the extent of organ dysfunction. More specific to acquired TTP, age (> 60 years), high LDH, cardiac or central nervous system involvement, delayed diagnosis, initial episode (vs. relapse), platelet transfusion, and the lack of treatment response have been associated with worse outcomes.

Several of the points discussed above should be approached in a more personalized way. For instance, operational definitions for treatment response, exacerbation, remission, and relapse were established at a time when disease understanding and standard of care were behind existing practices. The rate of thromboembolic event and treatment failure are less frequent with the use of the TRIPLET regimen [12]. However, this only applies to TTP and caplacizumab should be withdrawn if ADAMTS13 activity is normal and the diagnosis of TTP ruled out. As shown in Fig. 1, in a close future, a personalized approach will also include patient’s management without plasma exchange, with shorter duration of caplacizumab based on the recovery of ADAMTS13 activity, or longer duration of immunosuppressive drugs. In practice, platelet count could also become the only criterion resuming clinical outcomes. As a reminder, the most common treatment-emergent adverse events of caplacizumab trials include epistaxis (29%), headache (21%), and gingival bleeding (16%). Caplacizumab should be discontinued if a patient experiences a severe bleeding episode, and if necessary, VWF/factor VIII concentrate can be given to correct homeostasis [13].