Our case represents a rare clinical presentation of acquired TTP revealing an AML. It highlights the importance of having a clinical flare of TTP and a high clinical suspicion of a neoplastic etiology of TTP.
Thrombotic microangiopathy syndrome (TMA) is defined by the combination of mechanical hemolytic anemia, thrombocytopenia, and variable organ failures often reflecting severe underlying conditions like TTP and hemolytic uremic syndrome (HUS). (3) TTP is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction due to disseminated microvascular platelet rich-thrombi. (4) When vascular injury occurs, von Willebrand Factor (VWF) enables platelet adhesion and aggregation in the microcirculation. ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), an enzyme, cleaves VWF multimers to reduce their size and adhesive capacity. (4) A deficiency in ADAMTS-13 leads to ultralarge VWF multimers that bind spontaneously to platelets forming microthrombi in small vessels and causing tissue ischemia, platelet consumption, and hemolytic anemia. (5,6) TTP is primaly an autoimmune disease, with anti-ADAMTS13 IgG present in about 75% of acute cases. Rarely, anti-ADAMTS13 IgM and IgA are also found. In 20–25% of cases, anti-ADAMTS13 IgG is not detectable, possibly due to assay sensitivity or involvement of other immunoglobulin isotypes (Ig A or Ig M). Severe ADAMTS13 deficiency, can also be inherited via ADAMTS13 gene mutations (less than 2% of cases).(6) Established predisposing factors for acquired TTP include female sex, black ethnicity, HLA-DRB1*11, and obesity. Conditions that increase plasma VWF levels can precipitate acute TTP episodes. Approximately 50% of precipitating factors are idiopathic, while the other 50% are due to factors like inflammation, cancer, HIV, autoimmune diseases, sepsis, medications, and pregnancy. (5,7)
TTP should be considered in all patients presenting with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. (8) TTP often presents with severe thrombocytopenia (platelet counts of 10–17 × 10^9/L), though higher counts do not rule out TTP. Bleeding symptoms include ecchymoses, petechiae, and menorrhagia, observed in 46% of TTP cases.(9) The nervous system is affected organ,40%-80% of cases, with symptoms ranging from headaches to seizures and coma. A Glasgow Coma Scale score of 14 or less significantly increases mortality risk. (10) Gastrointestinal symptoms (nausea and abdominal pain) are seen in 35%-40% of cases. Renal dysfunction is less common in TTP than in HUS, though acute renal failure requiring dialysis in 4%-15% of patients. Elevated troponin levels found in 68% of TTP patients, indicate a worse prognosis. (10) Rarely, TTP may present with acute pancreatitis or bloody diarrhea, which can be mistaken for Shiga toxin–associated HUS. (9) TTP must be differentiated from various conditions, including other primary TMAs like complement-mediated HUS, Shiga toxin-associated HUS, and drug-induced TMA from drugs like calcineurin inhibitors, quinine, and chemotherapeutics. TTP can also be associated with pregnancy-related disorders, transplantation, malignancy, infection, disseminated intravascular coagulation, connective tissue disease, severe hypertension, and cobalamin deficiency. ADAMTS13 levels may be normal or reduced in these conditions, severe deficiency (< 10%) is rare. (11)
The laboratory diagnosis of TTP involves testing ADAMTS13, a VWF-cleaving enzyme, through several assays that measure its activity, antigen levels, and autoantibodies. The ADAMTS13 activity assay evaluates the enzyme's ability to cleave VWF while autoantibody assays detect antibodies against ADAMTS13. Neutralizing antibodies are measured using a functional inhibitor assay, with results are reported as Bethesda units (BU), ≥ 0.4–0.5 BU/mL considered positive. High-titer inhibitors (≥ 2 BU/mL) are common in TTP patients. Non neutralizing antibodies, which increase ADAMTS13 clearance, are detected by ELISA or western blotting. In severe ADAMTS13 deficiency without inhibitors, genetic sequencing for congenital TTP is recommended. (11) During acute TTP episodes, ADAMTS13 typically shifts to an open conformation, a potential diagnostic marker for acute TTP. This conformational change is not observed in remission TTP, HUS, or sepsis (18). Severe ADAMTS13 deficiency (< 10% activity) strongly suggests TTP but can also occur in conditions like hepatic necrosis and severe sepsis. (11)
ADAMTS13 deficiency occurs in 13–75% of TMA. Early detection of severe, antibody-mediated ADAMTS13 deficiency allows for targeted therapies such as B-lymphocytes-depleting monoclonal antibodies. (11) In evaluating patients with TMA, the primary goal is rapid plasma exchange initiation for suspected TTP, guided by ADAMTS13 activity measurement. Clinical prediction models to assess pretest probability of TTP like the Bentley score, requiring d-dimer measurement, lacks validation and adoption. The French TMA score offer a high negative predictive value (93.3%) for excluding acquired ADAMTS13 deficiency. Key predictors include platelet count < 30 x 10^9/L, serum creatinine ≤ 200 µmol/L, and detectable antinuclear antibodies.(12) The PLASMIC score categorizes patients into low-risk (0–4), intermediate-risk (5), and high-risk (6–7) groups. (13) Superior to the modified French score, PLASMIC supports immediate plasma exchange for high-risk scores.(11)
The primary treatment for TTP involves plasmapheresis, with or without steroids, to remove ultralarge VWF multimers and supplement deficient ADAMTS13 enzyme. Plasmapheresis is initially conducted daily until clinical remission is achieved, usually within 7–9 days, indicated by platelet counts > 150,000/µL and LDH levels < 1.5 times the upper limit of normal. After remission, sessions continue every 2–3 days for two weeks to prevent recurrence of microvascular thrombosis. Additional treatment includes high-dose methylprednisolone, rituximab administered weekly for four weeks and possibly Caplacizumab. The latter was associated with faster normalization of the platelet count; and reduce the risk of TTP-related death and recurrence, and thromboembolic event (14). For refractory cases, more aggressive treatments such as twice-daily plasma exchange, cyclophosphamide, vincristine, or cyclosporine A, or splenectomy may be considered. (5) Platelet transfusion are generally avoided unless necessary, and folate supplementation is recommended. (15)
Interpreting ADAMTS-13 levels in AML patients requires caution, as levels are significantly reduced, especially with infections, correlating inversely with inflammatory markers like CRP, IL-6, TNFα, and IL-1β. (16) A study evaluated ADAMTS-13 activity post- Bone Marrow Transplantation (BMT) in AML patients, revealing that low ADAMTS-13 post BMT is associated with prolonged APTT, PT, elevated CRP, and D-Dimer, and increased mortality rates over one to two years. (17)
To our knowledge, this case report is the third globally to describe the association of TTP with AML.
KUCHARIK et al. described the first case where AML with myelodysplasia-related changes initially manifested as TTP. Despite typical TTP symptoms, the patient rapidly deteriorate and did not respond to plasmapheresis, revealing the diagnostic challenges when TTP masks an underlying hematologic malignancies such as AML.(23) This case emphasized the need to consider secondary TTP in leukemia patients, even without ADAMTS13 testing.(18). Another case by Adimora et al described a 71 year old with TTP complicating his AML, who died within one day of diagnosis. (19)
Our report represents the second known case of TTP revealing an AML. It highlights the importance of suspecting secondary causes, particularly neoplastic ones, in TTP cases with atypical features. Although the AML - TTP association is rare, the presence of unusual clinical indicators – such as atypical skin lesions in a 65-year-old with constitutional symptoms – prompted further investigation, leading to AML diagnosis. The pathophysiology behind acquired TTP in AML remains unclear, but possible mechanisms include erratic production of anti-ADAMTS13 antibodies or ADAMTS13 deficiency, similar to other leukemia-associated conditions. No treatment protocol has been validated due to the rarity of these cases. The remains standard treatment for TTP is (corticosteroids, plasmapheresis, Rituximab, and eculizumab in refractory cases) along with the etiological treatment. In our case, despite having the high clinical suspicion and establishing the diagnosis and initiating rapidly the right treatment, the patient deceased highlighting challenges in concurrent TTP and hematologic malignancies (24)