ATTP: Acquired Thrombotic Thrombocytopenic Purpura; TMA: Thrombotic MicroAngiopathies; ADAMTS13: A Desintegrin and Metalloproteinase with ThromboSpondin 1 - motifs - member 13; TTP: Thrombotic Thrombocytopenic Purpura; LDH: Lactic Dehydrogenase; HIV: Human Immunodeficiency Virus; DNA: Deoxyribonucleic Acid

Acquired Thrombotic Thrombocytopenic Purpura (aTTP) belongs to thrombotic microangiopathies (TMA). It is caused by antibodies aimed at A Desintegrin and Metalloproteinase with ThromboSpondin 1 - motifs - member 13 (ADAMTS13), a metalloprotease designed to shorten von Willebrand factor multimers, which accumulation leads to enhanced platelets aggregability. Clinical symptoms of Thrombotic Thrombocytopenic Purpura (TTP) consists of a pentad: mechanical hemolytic anemia, thrombopenia, neurologic impairment, renal failure and fever.

A 47 year’s old Turkish patient was referred to the emergency department for bronchospastic respiratory failure. She was only treated with salbutamol for asthma since childhood and was not vaccinated against influenza virus. She was admitted to intensive care unit and an infection by influenza virus was rapidly diagnosed using immunochromatography on rhino pharyngeal secretions.

On admission, her blood pressure was normal, she presented a tachycardia (110 beats/min) and tachypnea (40 breaths/min). Examination revealed bilateral diffuse wheezing and clinical signs of respiratory distress.

Initial laboratory test results were: hemoglobin level, 15 g/dL; platelet count, 57×10³/mm³; blood urea nitrogen and serum creatinine level, 15.6 mmol/L and 65 μmol/L, total protein, 5.7 g/dL; albumin, 3.7 g/dL; LDH, 200 UI/L, PaO₂ = 52 mmHg, PaCO₂ = 28 mm Hg; pH = 7.43, bicarbonates = 22 mmol/L. Chest radiography was normal. Treatment was initiated with high-flow oxygen, aerosols of β2-agonist, systemic corticosteroids (prednisone 1 mg/kg/day) and oseltamivir (150 mg/kg/day for 5 days). She did not require mechanical ventilation.

On the 6^th day, a post-influenza bacterial pneumonia was diagnosed and intravenous antibiotherapy with cefotaxime and linezolide was started. Moderate ultrasensible troponin elevation (199 ng/mL, cut-off value 50 ng/ml) was noted, without electrocardiographic modification. Echocardiography revealed global hypokinetic left ventricle with ejection fraction measured at 40%.

A diagnosis of TMA was promptly made based on the occurrence of acute renal failure and deep thrombopenia on the next day (Figure 1). Her ADAMTS13 activity was depressed (<5%) with positive anti- ADAMTS13 dosage (70 UI/L). Alternative complement pathway was normal. Antinuclear and antiphospholipid antibodies were absent, and HIV status was negative.

Figure 1: Evolution of platelet count and serum creatinine level.

The patient required twelve plasma exchanges, progressively spaced after normalization of platelet counts (>150 G/L) for two successive days. Furthermore, she received intermittent renal replacement therapy with hemodialysis for 6 days and four red cells units were transfused. Despite thrombocytopenia as low as 6 G/L, she was not supplied with platelet units and did not suffer from hemorrhagic complication. Early relapse after withdrawal of corticosteroid therapy administered for asthma (diminution of platelet count and rise of LDH) required administration of rituximab and reintroduction of corticosteroids. Sixteen days after her admission, renal function fully recovered and TMA’s signs totally disappeared, enabling her transfer out of the intensive care unit.

Acquired TTP is considered an autoimmune disease [1] and can be triggered by bacterial [2] or viral [3] infections, stress, pancreatitis [4] or an immune stimulation such as vaccination [5].

To our knowledge, only 2 cases of aTTP triggered by influenza infection were reported. The first case was described by Wasserstein in 1981. Diagnosis was made retrospectively based on chronic glomerulonephritis, sudden onset aphasia and hemolytic anemia following infection by the influenza virus [6]. The second reported case was a 67 years old Japanese patient presenting both intravascular disseminated coagulation and fatal TMA with ADAMTS13 deficiency, following recent seasonal flu diagnosis [7].

Correlation between infection and acquired TTP and the pathophysiology of anti-ADAMTS13 antibodies production is not completely understood. Given the diversity of triggering factors, molecular mimicry is unlikely to play a role. The hypothesis can be made that DNA-histone complexes and myeloperoxydase produced by polynuclear neutrophils lead to endothelial activation which exposes ADAMTS13 antigen and enhances autoantibody production in predisposed patients. This was shown in a study by Fuchs [8], in which the rise in DNA-histone complexes and myeloperoxydase correlated with disease activity in TTP patients.

Plasmapheresis was used in this case to remove anti-ADAMTS13 antibodies and provide fresh ADAMTS13 proteins. Introduction of rituximab is based on recent studies demonstrating its efficacy in cases of relapse [9].

This case shows the importance of viral triggering factors. Testing for influenza virus should be considered in epidemic situations when aTTP is diagnosed.