Thrombotic Microangiopathies - Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Medical Experts

Contributor

Couturier

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Microbiology and Immunology; Medical Director, Emerging Public Health Crises, Parasitology/Fecal Testing, and Infectious Disease Antigen Testing, ARUP Laboratories

Contributor

Moser

Karen A. Moser, MD

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

Contributor

Smock

Kristi J. Smock, MD

Professor of Pathology (Clinical), University of Utah

Chief Medical Director, ARUP Institute for Clinical and Experimental Pathology

Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

Thrombotic microangiopathies (TMAs) are a group of potentially life-threatening conditions characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombi. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are distinct TMAs, the causes of which include infection, autoimmunity, genetic variation, and a range of medical factors and conditions.^,^,

Diagnosis of TMAs is complicated by a lack of specific clinical features among the different entities. Although a provisional diagnosis can be made based on clinical picture and initial laboratory studies (refer to the Hemolytic Anemias topic for more information), specialized laboratory testing is necessary to confirm a diagnosis and ensure appropriate treatment and monitoring according to etiology.^, Because of the severity of TMAs and potential for permanent organ damage, a variety of initial tests should be performed to narrow down the differential diagnosis as promptly as possible.

Quick Answers for Clinicians

How can thrombotic thrombocytopenic purpura and hemolytic uremic syndrome be distinguished from disseminated intravascular coagulation or preeclampsia with HELLP syndrome?

Both disseminated intravascular coagulation (DIC) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome share findings in common with thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS): namely, thrombocytopenia and microangiopathic hemolytic anemia.^, Laboratory testing is important to ensure accurate diagnosis and appropriate treatment.

Investigations to differentiate thrombotic microangiopathies (TMAs) and DIC include coagulation (clotting times, fibrinogen) and D-dimer tests, the results of which are often normal or near normal in patients with TMAs. However, fulminant TMA presentations can sometimes demonstrate significant coagulopathies. For additional information about evaluation for DIC, refer to the ARUP Consult Disseminated Intravascular Coagulation - DIC topic.

In obstetric patients with microangiopathic hemolytic anemia and thrombocytopenia, in addition to the recommended testing for thrombotic microangiopathies and HELLP syndrome (which may occasionally co-occur), soluble fms-like tyrosine kinase 1 and placental growth factor (sFlt-1:PlGF) ratio testing and other tests for preeclampsia may inform clinical management. For more details on the evaluation for preeclampsia, refer to the ARUP Consult Preeclampsia Testing topic.

What is the role of clinical scoring systems in thrombotic thrombocytopenic purpura?

Currently, two scoring systems exist to assess the pretest probability of thrombotic thrombocytopenic purpura (TTP) and inform acute intervention: the PLASMIC score and the French score. However, according to the International Society on Thrombosis and Haemostasis (ISTH), ADAMTS13 activity testing should be performed in all patients with possible TTP (ie, with unexplained microangiopathic anemia and thrombocytopenia). The British Society for Haematology (BSH) also recommends early ADAMTS13 activity testing in any patient in whom TTP is clinically suspected. If a scoring system is used to determine the pretest probability of TTP, results should be interpreted carefully in children, older adults, and individuals with comorbidities, as the PLASMIC and French scoring systems were designed for use in adult patients with no comorbidities.^,

Indications for Testing

Testing for TMAs should be performed in patients with a compatible clinical picture. Thrombocytopenia and microangiopathic hemolytic anemia are sufficient to prompt testing. Organ dysfunction and fever may also be present.^,

Treatment for possible TTP (eg, plasma exchange) should not be delayed pending results. Collection of a plasma sample for ADAMTS13 activity testing should occur before initiation of plasma exchange to avoid false-negative results.^,

Initial Testing

Although certain clinical findings and patient factors are commonly associated with specific TMAs, manifestations may vary among individuals. For example, renal injury is traditionally associated with HUS; however, it is likewise seen in cases of TTP, and HUS may also present with extrarenal manifestations. Similarly, although HUS induced by Shiga toxin-producing Escherichia coli (STEC) is often associated with a prodrome of bloody diarrhea, approximately 10% of cases vary in presentation. Because clinical presentation and preliminary findings can significantly overlap among TMAs, testing is required to confirm or rule out a specific diagnosis.

Recommended initial investigations include^,^,^,:

ADAMTS13 quantitative activity assay (plasma specimen)
ADAMTS13 immunoglobulin G (IgG) or inhibitor antibody testing (collect plasma for testing in case of low ADAMTS13 activity or use a reflexive panel)
O157 STEC culture (stool specimen)
Shiga toxin by polymerase chain reaction (PCR) or antigen detection (immunoassay) (specimen derived from stool culture)

Specimens should be collected before treatment; however, treatment for possible TTP (eg, plasma exchange) should not be delayed pending results.

Additional testing, as described below, should follow as needed according to preliminary results.

Testing Considerations: Thrombotic Thrombocytopenia

An ADAMTS13 activity result below 10% of normal is highly sensitive and specific for TTP and confirms the diagnosis. In addition, a positive result for ADAMTS13 neutralizing antibodies or anti-ADAMTS13 IgG points to immune-mediated TTP (iTTP), whereas a lack of ADAMTS13 antibodies and detection of an ADAMTS13 genetic variant confirms congenital TTP (cTTP).^, Because the antibodies are often low titer or highly protein bound, false-negative inhibitor and antibody testing can occur. Normalization of ADAMTS13 activity during disease remission is also consistent with iTTP.

Clinical judgment is necessary in the interpretation and follow-up of equivocal ADAMTS13 activity results (ie, activity at 10-20% of normal). When ADAMTS13 activity results are above 20%, HUS and other compatible diagnoses should be investigated. Preanalytic variables that could affect ADAMTS13 activity (ie, receipt of plasma) should also be considered.

Because TTP may be precipitated by other treatable etiologies (eg, cancer, HIV, hepatitis, etc.), testing for such conditions should be considered, and these causes may respond differently to TTP therapy. Following diagnosis, ADAMTS13 activity testing is recommended to monitor patient status and guide treatment. Siblings of individuals with confirmed cTTP should be screened using ADAMTS13 activity and genetic testing.

Testing Considerations: Hemolytic Uremic Syndrome

Consensus on a formal algorithmic workup for HUS is currently lacking, and numerous etiologies have been associated with HUS. Examples include infection, medication, autoimmunity, malignant hypertension, systemic disease, transplantation, pregnancy, metabolic disorder, malignancy, and complement dysregulation.^,

STEC-HUS (infectious or typical HUS) is the most common form of HUS. The CDC recommends that all individuals with possible HUS be tested for STEC infection as early as possible. Ideally, testing for STEC would be performed within the first week of diarrheal illness to avoid contraindicated treatments (eg, antibiotics and antidiarrheals^,) and optimize the sensitivity and specificity of testing. Testing for STEC includes stool culture for O157 STEC specifically and Shiga toxin detection by immunoassay or PCR. In the absence of positive culture and toxin results, serology may be considered to assess for previous STEC infection.

Atypical HUS (aHUS, a condition caused by complement dysregulation) and secondary nongenetic HUS (caused by one of many possible coexisting conditions) should be investigated in patients negative for STEC. Evaluation for secondary HUS should be guided by clinical suspicion based on findings and patient factors.^, Assessment for aHUS includes testing for complement dysregulation, in particular focusing on the loss of function of factor H, factor I, and membrane cofactor protein, and the gain of function of C3 and factor B.^, Molecular testing for aHUS that includes the following genes should also be performed: C3, CD46 (MCP), CFB, CFH, CFHR1, CFHR3, CFHR4, CFHR5, CFI, DGKE, THBD, and VTN. Treatment should not be withheld due to pending or negative results. Because aHUS may be precipitated by other treatable etiologies, testing for such conditions should be considered.

For additional considerations in pediatric patients, refer to the following article: An International Consensus Approach to Management of Atypical Hemolytic Uremic Syndrome in Children.