Thrombotic Microangiopathies

This issue of Seminars in Thrombosis and Hemostasis reviews certain aspects of thrombotic microangiopathies, a term used to describe several different thrombotic/hemolytic disorders. Most of these diseases are associated with a high mortality. In the last few years considerable progress has been made in elucidating the underlying pathophysiology of some of the disorders. These discoveries have opened new avenues for a potentially improved and targeted management of these patients.

This issue focuses primarily on the hemolytic uremic syndrome (HUS), although a few articles discuss thrombotic thrombocytopenic purpura (TTP), the most commonly encountered thrombotic microangiopathy. These contributions reiterate what was already reviewed extensively in a previous issue (volume 31, number 6, 2005) of the journal.

In the first article, Galbusera and coworkers review the most commonly encountered microangiopathy, TTP in children. The clinical presentation of TTP, its pathophysiology, and the differential diagnosis, especially compared with HUS, are reviewed expertly and comprehensively.

Loirat et al review the pathophysiology of TTP with particular emphasis on the role of ADAMTS13, the von Willebrand factor-cleaving protease, in this disorder. Most children have the inherited form of TTP (Upshaw-Schulman syndrome) that is an autosomal-recessive defect in ADAMTS13. This defect can be in the form of a deficiency or in the form of a genetically altered and defective molecule. The onset of the disease may be soon after birth, but most commonly before the age of 10 years. Recurrences of the disorder frequently are encountered every 3 to 4 weeks, or occasionally every few months. Neurological sequelae and renal impairment due to hemoglobinuria and microvascular thromboses are common. Treatment traditionally is with fresh frozen plasma, but newer modalities are under investigation.

In the next article, Kentouche and coworkers describe their investigations of ADAMTS13 levels in patients undergoing stem cell transplantation. In these patients transplantation can be complicated by a microangiopathy that resembles in many aspects TTP or other similar disorders. These patients also frequently have ultralarge von Willebrand factor multimers circulating in their plasma, suggesting that there could be a potential problem with the cleavage of von Willebrand factor by ADAMTS13. Most transplantation patients had decreased levels of ADAMTS13 in the posttransplant phase, but these levels did not correlate with the encountered thrombotic microangiopathy crises. Plasma exchange also did not benefit these patients.

Karch and coworkers next review new insights into the pathogenesis of the enteropathic HUS. In addition to the enteropathic form, there is HUS unrelated to Shiga toxin (Stx) -producing Escherichia coli. This form is named atypical HUS. The clinical outcome of enteropathic HUS appears to depend on the genotype of the Stx. Some of these cause severe disease, whereas others have a milder outcome and a better prognosis. In addition, the level of Stx production seems to play a role in the pathogenesis of HUS. The authors review extensively the types of Stx and correlate them with the clinical presentation of HUS.

Zimmerhackl and coworkers describe the preliminary results of the European Study Group for Hemolytic Uraemic Syndrome. The group defined HUS, atypical HUS, and recurrence of HUS, and then established a registry that presently contains information on 167 children from 11 countries who all had atypical HUS. A prevalence of 3.3 children/million was calculated, although this number may be lower than in reality because participation in the registry was voluntary. Clinical course, symptomatology, and treatment options are reviewed. Although in general, the disease is rare, it is severe in nature and associated with a high mortality. New treatment modalities are needed urgently to improve the prognosis of these children.

Prüfer and associates describe the role of the complement system in atypical/recurrent HUS. They measured terminal complement complexes (TCCs) in 42 patients from five European countries. Measurement of TCCs is better than the determination of individual components of the complement system because TCCs form membrane attack complexes that cause the lytic effects of the complement system. Children with atypical HUS had significantly higher TCC levels, suggesting an activated complement system that may mediate cell toxicity and ultimately be responsible for the poor outcome of this disease.

Karpmann and coworkers review extensively the role of platelet activation in microvascular thrombotic syndromes in general and HUS in particular. Because these diseases are characterized by endothelial damage, platelets play a major role in the formation of the microthrombi. Several mechanisms of activation, such as interaction with damaged endothelium, interaction with leukocytes, chemokine release, complement activation, and antimicrobial defense, are discussed by the authors. Platelets are involved in thrombus formation and in tissue injury. This extensive review provides the reader with a wealth of information.

Zipfel and colleagues examine the role of the complement system in atypical HUS. Defective complement activation and defective control of the system are the major contributing factors that cause HUS. Several gene mutations of critical components of the complement system have been identified. In addition, autoantibodies to factor H have been identified. These disturbances all influence the critical enzyme of the alternate pathway, C3bBb convertase. Uncontrolled activity of this enzyme leads to endothelial cell damage that is typical of HUS.

Kavanagh and Goodship review the role of the membrane cofactor protein, factor H, and factor I in atypical HUS. Gene mutations of factor H, membrane cofactor protein, and FI have been identified in several patients with this disease. These mutations lead to disturbances in secretion, expression, and regulatory function of the complement system. Almost all patients develop end-stage renal failure and require transplantation that has a poor outcome in most patients with factor H and factor I mutations. It is hoped that future use of targeted complement inhibitors will yield better therapeutic outcomes for these patients.

The final article by Saunders and Perkins serves as a guide for use of an interactive web database for factor H-associated atypical HUS. This database allows easier access to the many genetic defects that have so far been described in the literature for factor H. This database integrates genotype, phenotype, and structural information for factor H mutations and makes interpretation of the reported data easier. It also can serve as a provider for predictions and analyses of new mutations.

Thanks and appreciation are expressed to all authors for their expert contributions that the readers will find most informative. Special thanks go to Karim Kentouche and his co-guest editors for assembling this interesting issue.