Is There a Shared Pathophysiology for Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome?
Karl Desch* and
David Motto
Department of Pediatrics, University of Michigan, Life Sciences Institute, Ann Arbor, Michigan; and Departments of Internal Medicine and Pediatrics, University of Iowa, Iowa City, Iowa
Correspondence: Dr. David Motto, Departments of Internal Medicine and Pediatrics, University of Iowa, 3269C Carver Biomedical Research Building, Iowa City, IA 52242. Phone: 319-353-5630; Fax: 319-353-8383; E-mail: david-motto{at}uiowa.edu
Thrombotic microangiopathy is characterized by microvascularthrombosis coupled with thrombocytopenia, hemolytic anemia,and red blood cell fragmentation. Familiar to nephrologistsand hematologists alike, classically associated with thromboticmicroangiopathy are the hemolytic-uremic syndrome (HUS) andthrombotic thrombocytopenic purpura (TTP), the histories andpresentations of which are closely intertwined. Not surprising,these two disorders are considered by many to be manifestationsof the same disease process, whereas others consider HUS andTTP to be distinct clinical and pathologic entities. Hereinare reviewed HUS and TTP along with recent progress sheddingnew light on possible shared pathophysiologic mechanisms forthese two intriguing disorders.
Since its first description in 1925, thrombocytopenic purpura(TTP) has been considered to be a systemic hematologic disease.TTP typically presents abruptly with fever, thrombocytopenia,microangiopathic hemolytic anemia, and varying degrees of neurologicand renal dysfunction, although the clinical picture can bevariable.1 These findings occur secondary to the widespreaddeposition of platelet-rich thrombi in the microvasculatureof various organs, most notably the heart, brain, and kidneys.Historically referred to as "hyaline thrombi," these lesionsare thought to underlie the thrombocytopenic purpura (TMA) findingsof thrombocytopenia (secondary to platelet consumption) andmicroangiopathic hemolytic anemia (resulting from abnormallyhigh levels of shear stress in the microcirculation).1,2 Althoughsome degree of renal impairment with proteinuria and/or hematuriais common, hypertension and acute renal failure that requiresdialysis are rare in TTP.2 In a manner not soon forgotten, TTPcan progress rapidly with a shock-like clinical picture to comaand death, with untreated mortality >90%. However, even withmodern intensive care including plasma exchange (the currentstandard of care), mortality in recent series is still reportedin the 10 to 20% range.3
Initially described in 1955 as a syndrome comprising renal failure,hemolytic anemia, and thrombocytopenia, hemolytic-uremic syndrome(HUS) is often considered to be a renal disease with systemiccomplications. Widespread deposition of microthrombi throughoutthe kidneys is thought to cause thrombocytopenia and microangiopathichemolytic anemia in a manner analogous to TTP, although renaldamage typically is more severe in HUS and systemic thrombosismay not be as widespread.1,2,4 Nonetheless, neurologic findingsare common and, when present, greatly complicate the distinctionfrom TTP.
Although both disorders share a strong clinical and historicalrelationship, much recent investigation into HUS and TTP hasfollowed independent and seemingly unrelated directions. TTPresearch has focused on regulation of the blood coagulationprotein von Willebrand factor (VWF), whereas much HUS efforthas been concentrated on understanding the mechanisms of injuryto the renal endothelium.
Considerable recent evidence demonstrates TTP to be a disorderof VWF regulation.1–3 VWF synthesized by endothelial cellseither is constitutively secreted in the form of low molecularweight multimers or is stored in specialized granules termedWeibel-Palade bodies.3 In response to vascular injury, storedVWF is released as ultralarge multimers (UL-VWF).3 However,some UL-VWF remains associated with the endothelial surface,providing binding sites for platelets and possibly other bloodcomponents such as leukocytes.5 The presence of UL-VWF may leadto spontaneous platelet aggregation in the circulation or onthe endothelial surface if not processed by the metalloproteaseADAMTS13.5 Lack of UL-VWF cleavage by ADAMTS13 is thought tobe the primary defect underlying TTP pathogenesis. Deficiencyof ADAMTS13 can be genetic (the rare Upshaw-Schulman syndrome)or more common, acquired, resulting from autoimmune productionof inhibitory anti-ADAMTS13 antibodies.1–3
In contrast to TTP, for which efforts have focused on VWF andADAMTS13, much of the latest work in HUS has been directed towardunderstanding mechanisms of damage to the renal endothelium.In the case of diarrhea-associated HUS (D+HUS), renal endothelialdamage is mediated (at least in large part) by the bacterialagent Shigatoxin (Stx), which is actually a family of toxinselaborated by certain strains of Escherichia coli and Shigelladysenteriae (in North America principally shiga-toxigenic E.coli [STEC] strain O157:H7).6–8 STEC infection localizesto the gastrointestinal mucosa and is followed by release ofStx and its subsequent translocation through the epitheliumand into the circulation.6–8 Likely bound to neutrophils,Stx then circulates throughout the body but may preferentiallylocalize to the kidney as a result of the high concentrationof its receptor, globotriaosylceramide, on the renal endothelium.6–8After receptor-mediated endocytosis, Stx inactivates the 28Sribosomal RNA, shutting down protein synthesis and leading eitherto cellular necrosis or to apoptosis.6–8
Although the subsequent events are less well understood, itis becoming clear that the mechanisms by which Stx induces thethrombotic state of HUS involve more than the direct toxic effectsdescribed. For example, Stx induces expression of proinflammatorygenes in endothelial cells and leukocytes, upregulates expressionof adhesion molecules, and can directly activate platelets.8,9In addition, after STEC infection, prothrombotic coagulationabnormalities that precede clinical evidence of renal damagecan be detected.10 The end result of these and, undoubtedly,other mechanisms is a shift in the hemostatic balance of therenal circulation toward thrombosis and TMA and the subsequentdevelopment of renal injury and clinical HUS.
Although approximately 90% of HUS cases result from infectionwith STEC, much insight into the pathogenesis of HUS has beengained from investigations into diarrhea-negative, or "atypical,"HUS (aHUS), which accounts for approximately 5% of HUS cases.8Insight into the pathogenesis of this disorder stemmed fromobservations that occasional patients demonstrated severelyreduced serum levels of complement factor C3, suggesting systemiccomplement activation.8 It is now known that approximately 50%of patients with aHUS carry a heterozygous mutation in one offour genes encoding complement factor H, complement factor I,complement factor B, or membrane co-factor protein.8,11,12 Theseproteins function to control complement activation on cellularsurfaces and therefore to limit complement-mediated damage tohost tissues. Thus, a decrease in their activity results inthe loss of ability to suppress complement activation throughoutthe body. However, for reasons that are only partially understood,the glomerular endothelium is especially sensitive to loss ofcomplement regulation, and microvascular damage in aHUS principallyis restricted to the renal circulation.
Similar to Stx-mediated endothelial damage and the developmentof TMA, the mechanisms following complement activation thatlead to TMA and aHUS are not yet well understood and are thesubject of considerable research effort. However, complementactivation on the glomerular endothelium likely recruits inflammatorycells, resulting in endothelial injury, platelet aggregation,and activation of the coagulation cascade and the subsequentdevelopment of TMA and clinical aHUS.8
Most relevant to the distinction of TTP from HUS are cases ofaHUS, because D+HUS is predominantly a disease of childhood(or sporadic STEC outbreaks), and patients typically exhibitdiarrhea before the onset of renal failure.6,7 It is interestingthat recent evidence demonstrates that neither deficiency ofADAMTS13 nor deficiency of complement regulation is sufficientfor the development of TTP or aHUS, respectively.2,11 In eachcase, disease pathogenesis is thought to involve additionalunknown genetic modifying factors and/or environmental triggers.Not surprising, a similar wide range of potential precipitatingfactors has been reported for both TTP and HUS, including butnot limited to infections, pregnancy, malignancy, collagen vasculardisease, and various medications.2,8,11
In addition to similar precipitating factors, several new andintriguing findings indicate that HUS and TTP may also sharemore of a common mechanistic link than suggested by the independentand seemingly unrelated research directions discussed thus far.Although it has become clear that ADAMTS13 deficiency and UL-VWFplay a major role in TTP pathogenesis, their role in HUS wasmore uncertain. Recently, however, it was demonstrated thatnanomolar concentrations of Stx stimulated the release of storedUL-VWF from cultured human endothelial cells and impaired itscleavage by ADAMTS13, revealing additional possible mechanismsof action for Stx in HUS.13 Subsequently, this finding was extendedin vivo, when it was demonstrated that Stx is able to inducea TTP-like syndrome in ADAMTS13-deficient mice, suggesting arole for this toxin (and perhaps other sources of endothelialinjury) as potential triggers for TTP.14
If Stx can function to stimulate TTP pathogenesis in the settingof ADAMTS13 deficiency, then what about other HUS-related sourcesof endothelial injury, such as complement dysregulation? Itis interesting that a recent report of two sisters with familialADAMTS13 deficiency and TTP may shed some light on this matter.15One of the two siblings experienced a clinical course typicalof familial TTP with primarily neurologic disease and remainsin relatively good health with plasma therapy. However, theother sibling demonstrated a much more severe course, with progressiverenal deterioration and severe neurologic findings that culminatedin her death from a cerebrovascular event at age 55. In additionto ADAMTS13 deficiency, this patient was found to have a heterozygousmutation in the complement factor H gene, which, interestingly,did not cause clinical disease in four other siblings. Thus,ADAMTS13 deficiency and complement dysregulation may have combinedto produce a more serious phenotype than expected from eitheralone.
Although requiring additional human and animal studies for confirmation,these new findings provide more support for the intriguing possibilitythat similar factors may trigger both TTP and HUS and that thesetwo disorders may share some degree of overlapping pathophysiology(Figure 1). It is interesting to speculate that factors affectingADAMTS13 and VWF activity may function to potentiate the endothelialinjury seen in HUS and, conversely, that endothelial injurytriggered by factors typically associated with HUS may be prerequisitesfor the TMA that is thought to result from ADAMTS13 and VWFdysfunction. At a minimum, it seems prudent to extend betterthe current TTP investigation to include mechanisms of endothelialinjury and likewise to expand HUS research to reconsider ADAMTS13and VWF as potential mediators of endothelial injury leadingto TMA. It is likely that future research into these potentialcommon mechanisms of disease will eventually explain the sharedclinical findings of TTP and HUS with which we are strugglingtoday.
Figure 1. Hypothetical model for shared pathophysiology between HUS and TTP. In this proposed model, the inciting event for both HUS and TTP is a similar endothelial insult brought about by any of a variety of sources (or combination of sources) that results in widespread endothelial activation, inflammation, and damage, including the release of VWF and other contents of the Weibel-Palade bodies. The subsequent events may be determined in part by the level of systemic ADAMTS13 activity. In the case of systemic ADAMTS13 deficiency (top), ADAMTS13 is not available to process the newly released VWF, resulting in the widespread formation of VWF and platelet thrombi throughout the arteriolar circulation and the clinical picture of TTP. Conversely, in the case of systemic ADAMTS13 sufficiency (bottom), TTP is avoided by ADAMTS13-mediated release of platelet/VWF thrombi throughout the arteriolar circulation. For reasons that are not understood, circulating ADAMTS13 is not able to cleave efficiently VWF that is released in the glomerular microcapillary circulation, resulting in thrombus formation, increased inflammation, glomerular damage, and the clinical picture of HUS. Potential reasons for the inability of ADAMTS13 to cleave VWF in the glomerular circulation may include unfavorable shear stress not permissive for the proper unfolding of VWF (decreasing access of ADAMTS13 to the sessile bond within the folded VWF A2 domain) and the local presence of molecules that may interfere with ADAMTS13 activity or with its interaction with VWF.
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Abstract
Introduction
