The Differential Diagnosis and Treatment of Thrombotic Microangiopathies

Abstract

Background: Thrombotic microangiopathies are rare, life-threatening diseaseswhose care involves physicians from multiple specialties. The past five years haveseen major advances in our understanding of the pathophysiology, classification,and treatment of these conditions. Their timely diagnosis and prompt treatment cansave lives.

Methods: This review is based on pertinent articles published up to 17 December2017 that were retrieved by a selective search of the National Library of Medicine'sPubMed database employing the terms "thrombotic microangiopathy," "thromboticthrombocytopenic purpura," "hemolytic-uremic syndrome," "drug-induced TMA," and"EHEC-HUS."

Results: The classic types of thrombotic microangiopathy are thrombotic thrombo -cytopenic purpura (TTP) and typical hemolytic-uremic syndrome (HUS), also knownas enterohemorrhagic Escherichia coli-associated HUS (EHEC-HUS). There are anumber of further types from which these must be differentiated. The key test,beyond a basic hematological evaluation including a peripheral blood smear, ismeasurement of the blood level of the protease that splits von Willebrand factor,which is designated ADAMTS13 (a disintegrin and metalloprotease with thrombo -spondin type 1 motif, member 13). The quantitative determination of ADAMTS13, ofADAMTS13 activity, and of the ADAMTS13 inhibitor serves to differentiate TTP fromother types of thrombotic microangiopathy. As TTP requires urgent treatment,plasmapheresis should be begun as soon as TTP is suspected on the basis of afinding of hemolysis with schistocytes and thrombocytopenia. The treatment shouldbe altered as indicated once the laboratory findings become available.

Conclusion: Rapid differential diagnosis is needed in order to determine the specifictype of thrombotic microangiopathy that is present, because only patients with TTPand only a very small percentage of those with atypical hemolytic-uremic syndrome(aHUS) can benefit from plasmapheresis. The establishment of a nationwideregistry in Germany with an attached biobank might help reveal yet unknowngenetic predispositions.

Figure 1

Algorithm for diagnosis and therapy of thrombotic microangiopathy (modified according to Brocklebank et al. [7]) ADAMTS13: a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13; aHUS: atypical hemolytic uremic syndrome; G/L: Giga per liter; DIC: disseminated intravascular coagulopathy; GI: gastrointestinal; HELLP: hemolysis, elevated liver enzyme levels, and low platelet levels; HUS: hemolytic uremic syndrome; LDH: lactate dehydrogenase; CNS: central nervous system; SP-HUS: Streptococcus pneumoniae; STEC: Shiga toxin–producing Escherichia coli; Susp.: suspicion of; TMA: thrombotic microangiopathy; TTP: thrombotic-thrombocytopenic purpura

Figure 2

Pathophysiology of thrombotic thrombocytopenic purpura (TTP) a: Normal blood flow in a healthy capillary; b: Circulatory disturbance, with microthrombus and schistocyte formation after endothelial damage in thrombotic microangiopathy. von Willebrand Factor (vWF) is secreted from endothelia as an ultra-large vWF multimer (ULvWF multimer) and binds to the endvascular endothelia by P-selectin. Platelets (thrombocytes) aggregate via GPIIb/IIIa (glycoprotein, GP), and the formation of platelet-rich thrombi is initiated. The ULvWF multimers are physiologically cleaved by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13), which reduces the formation of thrombi (a). Inactivity of ADAMTS13 leads to uncontrolled thrombogenesis with ischemia in dependent end organs; in the classical immune-mediated, acquired thrombotic thrombocytopenic purpura (aTTP) (affecting >90% of all TTP patients), ADAMTS13 is inactivated by antibodies (b). A thrombus can occur in all organs; those less affected are the liver and lungs. The mechanical fragmentation of red blood cells (erythrocytes) in partially occluded blood vessels and the presence of vWF fibrils are believed to be responsible for the formation of schistocytes in vivo

eFigure

The complement system is part of the innate immune system and consists of a series of plasma proteins that activate a cascade of effector proteins. The final step is the formation of the membrane attack complexes (MAC) (c5b–9) with lysis of the target cell. Regulation occurs predominantly via inhibitors, including factor H, factor I, and the membrane cofactor protein (MCP). While more than 80 mutations have now been identified, factor H mutations are the most common. The majority of mutations are heterozygous. Some people who are carriers of a mutation will never get the disease, and there is a high interindividual variability for age of the first manifestation. Defects of one of the above-mentioned proteins leads to uncontrolled complement activation with endothelial damage, resulting in thromboses in terminal vascular beds. The close pathophysiological relationship between the complement system and the coagulation system is already known from studies of patients with paroxysmal nocturnal hemoglobinuria, which is considered to be one of the most serious acquired thrombophilic diatheses