CHAPTER 91: TTP, HUS, and Other Thrombotic Microangiopathies

KEY POINTS

• Thrombotic microangiopathy (TMA), a pathologic term, describes a syndrome of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia with various degrees of organ dysfunction.

• TMA includes thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndromes (HUS), as well as other related syndromes.

• TTP is primarily caused by hereditary or acquired deficiency of plasma ADAMTS13, whereas HUS is mainly caused by Shiga toxin–producing E coli and/or abnormalities of complement activation and regulation.

• TTP should be differentiated from HUS, disseminated intravascular coagulation (DIC), collagen vascular disease with vasculitis, and Hemolytic anemia, Elevated Liver enzymes, and Low Platelets) (HELLP) syndrome, etc.

• Plasma therapy remains the mainstay of therapy for TTP and atypical HUS (aHUS). However, the treatment for aHUS has been less satisfactory. Adjunctive therapies such as corticosteroids, immunosuppressive agents, and anti-CD20 monoclonal antibodies such as rituximab or anti-C5 monoclonal antibodies such as eculizumab may be considered for refractory TTP or HUS cases.

INTRODUCTION

Thrombotic thrombocytopenic purpura (TTP) was first described by Eli Moschcowitz in 1924.¹ He reported a previously unrecognized case of a 16-year-old girl presenting with a constellation of findings including palor, petechiae, fever, and hemiparesis which ultimately was fatal. Postmortem examination revealed numerous hyaline thrombi in the terminal arterioles and capillaries.¹ After reviewing 271 cases, Amorosi and Ultmann in 1966² established a diagnostic pentad for TTP: thrombocytopenia, MAHA, neurologic symptoms, renal failure, and fever without origin. Later, Schulman et al (1960) reported a patient with this syndrome whose symptoms were dramatically improved with infusions of fresh human plasma (FFP).³ Again, Upshaw (1978)⁴ reported a case of 29-year-old female who had repeated thrombocytopenia and MAHA since her childhood. However, her conditions were improved sometime either spontaneously or after infusion of fresh frozen plasma. Upshaw and Schulman hypothesized that a plasma factor that is required for platelet production³ or platelet and red blood cell survival was missing.⁴ However, the mechanism of TTP remained a mystery until 2001 when a plasma metalloprotease that cleaves von Willebrand factor (VWF) was identified^5,6 and cloned.^7,8

Hemolytic uremic syndrome (HUS), a similar syndrome, was first described by Gasser et al in 1955.⁹ Five children, aged 2 months to 7 years, presented with acquired hemolytic anemia, bizarre poikilocytes, and renal insufficiency. Three had thrombocytopenia and all patients died. Later, Kaplan et al (1975)¹⁰ reported 83 siblings from 41 families with HUS and suggested that both genetic and environmental factors might have contributed to the occurrence of familial cases of HUS. Since then, numerous HUS cases were reported.^11-14 HUS is used to describe a syndrome with MAHA, thrombocytopenia, and predominant renal failure in the presence or absence of diarrheal prodrome.

While the clinical signs and symptoms of HUS appear to be indistinguishable from TTP, the underlying etiologies and the molecular mechanisms of the disease may be quite ...