Thrombocytopenia in hospitalized patients: approach to the patient with thrombotic microangiopathy

Abstract Thrombotic microangiopathies (TMAs), specifically, thrombotic thrombocytopenic purpura (TTP) and complement-mediated hemolytic uremic syndrome (CM-HUS) are acute life-threatening disorders that require prompt consideration, diagnosis, and treatment to improve the high inherent mortality and morbidity. Presentation is with microangiopathic hemolytic anemia and thrombocytopenia (MAHAT) and variable organ symptoms resulting from microvascular thrombi. Neurological and cardiac involvement is most common in TTP and associated with poorer prognosis and primarily renal involvement in CM-HUS. TTP is confirmed by severe ADAMTS13 deficiency (which can be undertaken in real time) and CM-HUS by an abnormality in complement regulators, confirmed by mutational analysis (in 60% to 70% of cases) or the presence of Factor H antibodies (which may not be available for weeks or months). Plasma exchange (PEX) should be started as soon as possible following consideration of these TMAs. Differentiation of the diagnosis requires specific treatment pathways thereafter (immunosuppression primarily for TTP and complement inhibitor therapy for CM-HUS). As the diagnosis is based on MAHAT, there are a number of other medical situations that need to be excluded and these are discussed within the article. Other differentials presenting as TMAs may also be associated with micro- or macrovascular thrombosis, yet are more likely to be due to direct endothelial damage, many of which do not have a clear therapeutic benefit with PEX.

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Complement and the prothrombotic state

Blood ◽

10.1182/blood.2020007206 ◽

2021 ◽

Author(s):

Christoph Q Schmidt ◽

Hubert Schrezenmeier ◽

David Kavanagh

Keyword(s):

Complement Activation ◽

Ex Vivo ◽

Atypical Hemolytic Uremic Syndrome ◽

Protein Losing Enteropathy ◽

Mortality And Morbidity ◽

Life Threatening ◽

Uremic Syndrome ◽

Clinical Conditions ◽

Distinct Features

In 2007 and 2009 the regulatory approval of the first-in-class complement inhibitor Eculizumab has revolutionized the clinical management of two rare, life-threatening clinical conditions: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). While being completely distinct diseases affecting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology and clinical presentation. An imbalance between complement activation and regulation at host surfaces underlies both diseases precipitating in severe thrombotic events that are largely resistant to anti-coagulant and/or anti-platelet therapies. Inhibition of the common terminal complement pathway by Eculizumab prevents the frequently occurring thrombotic events responsible for the high mortality and morbidity observed in patients not treated with anti-complement therapy. While many in vitro and ex vivo studies elaborate numerous different molecular interactions between complement activation products and hemostasis, this review focuses on the clinical evidence that links these two fields in humans. Several non-infectious conditions with known complement involvement are scrutinized for common patterns concerning a prothrombotic statues and the occurrence of certain complement activation levels. Next to PNH and aHUS, germline encoded CD59 or CD55 deficiency (the latter causing the disease Complement Hyperactivation, Angiopathic thrombosis, and Protein-Losing Enteropathy; CHAPLE), autoimmune hemolytic anemia (AIHA), (catastrophic) anti-phospholipid syndrome (APS, CAPS) and C3 glomerulopathy are considered. Parallels and distinct features among these conditions are discussed against the background of thrombosis, complement activation, and potential complement diagnostic and therapeutic avenues.

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None of the above: thrombotic microangiopathy beyond TTP and HUS

Blood ◽

10.1182/blood-2016-11-743104 ◽

2017 ◽

Vol 129 (21) ◽

pp. 2857-2863 ◽

Cited By ~ 32

Author(s):

Camila Masias ◽

Sumithira Vasu ◽

Spero R. Cataland

Keyword(s):

Thrombotic Microangiopathy ◽

Specific Treatment ◽

Underlying Disease ◽

Endothelial Damage ◽

Drug Induced ◽

Inappropriate Treatment ◽

Detailed Medical History ◽

Uremic Syndrome ◽

A Disintegrin And Metalloproteinase

Abstract Acquired thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are appropriately at the top of a clinician’s differential when a patient presents with a clinical picture consistent with an acute thrombotic microangiopathy (TMA). However, there are several additional diagnoses that should be considered in patients presenting with an acute TMA, especially in patients with nondeficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (>10%). An increased awareness of drug-induced TMA is also essential because the key to their diagnosis more often is an appropriately detailed medical history to inquire about potential exposures. Widespread inflammation and endothelial damage are central in the pathogenesis of the TMA, with the treatment directed at the underlying disease if possible. TMA presentations in the critically ill, drug-induced TMA, cancer-associated TMA, and hematopoietic transplant–associated TMA (TA-TMA) and their specific treatment, where applicable, will be discussed in this manuscript. A complete assessment of all the potential etiologies for the TMA findings including acquired TTP will allow for a more accurate diagnosis and prevent prolonged or inappropriate treatment with plasma exchange therapy when it is less likely to be successful.

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Hemolytic uremic syndrome: how do factor H mutants mediate endothelial damage?

Trends in Immunology ◽

10.1016/s1471-4906(01)01972-x ◽

2001 ◽

Vol 22 (7) ◽

pp. 345-348 ◽

Cited By ~ 39

Author(s):

Peter F Zipfel

Keyword(s):

Hemolytic Uremic Syndrome ◽

Endothelial Damage ◽

Factor H ◽

Uremic Syndrome

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Pediatric Atypical Hemolytic Uremic Syndrome Advances

Cells ◽

10.3390/cells10123580 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3580

Author(s):

Rupesh Raina ◽

Nina Vijayvargiya ◽

Amrit Khooblall ◽

Manasa Melachuri ◽

Shweta Deshpande ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Regulatory Proteins ◽

High Rate ◽

Complement Factor ◽

Mortality And Morbidity ◽

Complement Regulatory Proteins ◽

Alternate Pathway ◽

Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

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Eculizumab Is an Effective Treatment for Atypical Hemolytic Uremic Syndrome in Patients with or without Identified Genetic Complement Mutations or Complement Factor H Auto-Antibodies.

Blood ◽

10.1182/blood.v120.21.2085.2085 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2085-2085

Author(s):

Samhar I. Al-Akash ◽

Timothy H. J. Goodship ◽

Richard J. H. Smith ◽

Christophe M. Legendre ◽

Christoph Licht ◽

...

Keyword(s):

Genetic Testing ◽

Complement Activation ◽

Research Funding ◽

Atypical Hemolytic Uremic Syndrome ◽

Genetic Mutation ◽

Factor H ◽

Complement Factor ◽

Life Threatening ◽

Uremic Syndrome ◽

Terminal Complement

Abstract Abstract 2085 Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare chronic disorder characterized by persistent uncontrolled complement activation that results in life-threatening systemic thrombotic microangiopathy (TMA). In an estimated 50%–70% of patients (pts) with aHUS, uncontrolled complement activation can be attributed to identified genetic mutation(s) in complement regulatory factors and/or the presence of complement factor H auto-antibodies (CFH auto-Abs); newly identified complement mutations continue to be reported in the medical literature. For the 30%–50% of pts who currently have no identified genetic mutation/CFH auto-Abs, the overall risk of end-stage renal disease or death is high and similar to that observed in pts with known genetic mutation(s)/CFH auto-Abs, supporting the need for immediate management of disease in all aHUS pts regardless of mutation/CFH auto-Ab status. Eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, is the only approved treatment for aHUS. Chronic eculizumab treatment has been proven to inhibit systemic TMA via terminal complement inhibition, improve renal function, and reduce or eliminate the need for plasma exchange/infusion (PE/PI) and dialysis. Furthermore, earlier eculizumab treatment has been associated with greater clinical improvement. The purpose of this analysis was to evaluate the relative efficacy of eculizumab in aHUS pts with or without identified genetic complement mutation(s)/CFH auto-Abs based on data from 3 clinical studies. Methods: This report summarizes a subgroup analysis of efficacy outcomes based on the presence or absence of identified genetic mutation(s)/CFH auto-Abs in 3 aHUS studies: 2 controlled, prospective studies (pts aged ≥12 y), and 1 retrospective study (pts aged <18 y). Results: Across the 3 studies, 24%–41% of pts had no identified genetic complement mutation or detectable CFH auto-Abs. The efficacy of eculizumab was similar regardless of mutation/CFH auto-Ab status (Table). Conclusions: Across 3 studies investigating the efficacy of eculizumab treatment in aHUS pts, our analysis shows that improvements in hematologic, renal, and supportive care interventions (PE/PI, dialysis) outcomes were similar in pts with or without identified genetic complement mutation(s)/CFH auto-Abs. Given that (1) genetic testing often requires several months to complete, (2) uncontrolled complement activation places aHUS pts at risk of life-threatening systemic TMA events and organ damage, and (3) earlier intervention with eculizumab is associated with greater clinical improvement, we conclude that the results of this analysis provide a rationale for initiating eculizumab as first-line therapy at the time of clinical diagnosis of aHUS, without the availability of genetic testing results Disclosures: Goodship: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Licht:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Muus:Alexion Pharmaceuticals.: Sat on advisory board of Alexion Pharmaceuticals. Other. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.

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