Microangiopathic Anemia

Abstract

Background: Patients suffering from hemolytic anemia, thrombocytopenia, and organ damage may suffer from microangiopathic anemia, also called thrombotic microangiopathy (TMA). This condition is caused by many different pathogenic mechanisms and is always life-threatening due to vessel occlusion in vital organs. Rapid and careful workup is mandatory to identify the cause of TMA. To identify patients suffering from immune-mediated thrombotic thrombocytopenic purpura (iTTP), ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) measurement is mandatory. All patients with ADAMTS13 activity below 10 IU/dL are assigned to the diagnosis iTTP and need urgent targeted treatment. Meanwhile, caplacizumab - an anti-von Willebrand factor humanized single-variable-domain immunoglobulin fragment - is approved for the treatment of iTTP. Patients with TMA and ADAMTS13 activity>10 IU/dL can be assigned to other forms of TMA such as hemolytic uremic syndrome (HUS), complement-mediated TMA (cmTMA) - previously assigned to the term atypical HUS (aHUS) - or TMA secondary to underlying diseases such as autoimmune disorders, cancer, or infectious diseases. Complement inhibition with C5 targeted treatment, such as eculizumab or ravulizumab, is approved for the treatment of cmTMA. Even more challenging may be the differential diagnosis in pregnancy, in cancer patients with complex medication and the need to rule out conditions imitating TMA such as Evans syndrome, intoxication, infection, or severe vitamin B12 deficiency.

Summary: Identifying TMA and defining the pathophysiology of TMA is urgently necessary in patients with thrombocytopenia and hemolytic anemia with or without obvious organ damage.

Key message: ADAMTS13 testing is the most important specific test to classify TMA.

Keywords: Hemolytic uremic syndrome; Thrombotic microangiopathy; Thrombotic thrombocytopenic purpura.

Fig. 1.

Systematic workup for suspected TMA. Rapid exclusion of life-threatening differential diagnosis such as disseminated intravascular coagulation (DIC), severe heparin induced thrombocytopenia type 2 (HIT 2), and pregnancy-related disease is mandatory. ADAMTS13 testing, testing for Shiga toxin needs to be done as soon as possible to diagnose TTP or STEC-HUS. ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ANA, anti-nuclear antibody; ANCA, anti-nuclear cytoplasmic antibody; APS, antiphospholipid antibody syndrome; CAPS, catastrophic APS; DGKE, diacylglycerol kinase epsilon; dsDNA, double-stranded DNA; ENA, extractable nuclear antigen panel; HSCT, hematopoietic stem cell transplant; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MMA, methylmalonic acid; RAAS, renin-angiotension-aldosterone; RF, rheumatoid factor; SLE, systemic lupus erythematosus; STEC, shiga toxin E. coli; TMA, thrombotic microangiopathy; TPE, therapeutic plasma exchange; TTP, thrombotic thrombocytopenic purpura.

Fig. 2.

The complement system is part of the innate immune system and permanently active. cmTMA is caused by uncontrolled activation of the complement system due to inherited mutations or anti-factor H antibodies. This results in severe platelet consumption und hemolysis. Treatment of cmTMA is based on inhibition of the complement pathway by blocking C5 using eculizumab or ravulizumab.