Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura

Diagnosis and treatment of these thrombotic microangiopathy syndromes.


Background

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) represent 2 of many diverse thrombotic microangiopathy (TMA) syndromes that have in common clinical and pathological features (Table 1). Systemic conditions, including infections, malignancy, vitamin deficiency, and autoimmune disorders, can manifest similarly to primary TMAs, making diagnosis challenging. Furthermore, primary TMAs may sometimes remain indolent until precipitated by secondary conditions. The triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and end-organ damage dominates all TMA syndromes.

Clinical manifestations

The signs and symptoms of TTP and Shiga toxin mediated-HUS (ST-HUS) are related to the triad: weakness, fatigue, pallor; petechiae, purpuras, and bleeding; and organ damage involving the kidneys, heart, and the gastrointestinal and nervous systems (Table 2).

Although the mechanisms behind the diagnoses of TTP and ST-HUS are different, the term TTP-HUS is sometimes used for patients with severe renal failure for whom plasma exchange is appropriate.

Of the 2 syndromes, TTP rarely causes renal involvement. This is perhaps due to the fact that the pathophysiology in TTP is mostly thrombosis-related, whereas in ST-HUS, direct injury to the renal cells (tubular, mesangial, and podocytes) occurs. Hereditary TTP is far less common than its acquired counterpart and might first manifest at birth or remain indolent until adulthood, when secondary conditions, such as pregnancy, precipitate it (99. Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001;14:437-54. [PMID: 11686108]). It causes recurrent episodes, appearing at intervals of about 3 weeks (1010. Moake J, Chintagumpala M, Turner N, McPherson P, Nolasco L, Steuber C, et al. Solvent/detergent-treated plasma suppresses shear-induced platelet aggregation and prevents episodes of thrombotic thrombocytopenic purpura. Blood. 1994;84:490-7. [PMID: 8025277]).

Acquired TTP has more of a diverse presentation, ranging from mild to severe. It usually occurs as a single episode but can be recurrent in over 30% of patients at irregular intervals (1111. Shumak KH, Rock GA, Nair RC. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Ann Intern Med. 1995;122:569-72. ). Both hereditary and acquired TTP can present with a range of mild to severe neurological symptoms. The classic pentad of MAHA, thrombocytopenia, fever, renal failure, and neurological deficits occurs in only about 5% of patients (1212. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060-9. [PMID: 20686117] doi:10.1182/blood-2010-07-271445).

Adult ST-HUS is more severe than its pediatric counterpart and is associated with higher mortality. ST-HUS has a predominant renal failure presentation. The prodromal phase of severe abdominal pain and diarrhea (usually bloody) starts and resolves before thrombocytopenia and renal failure. HUS without the diarrheal prodrome has been given the term “atypical HUS” or “diarrhea-negative HUS” and is due to hereditary abnormalities in complement regulation, resulting in uncontrolled complement activation (1313. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol. 2008;3:249-77. [PMID: 18215115]). Atypical HUS comprises about 5% to 10% of all HUS cases (1414. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:1035-50. [PMID: 15728781]), and is separate from the conditions addressed in this review. Although neurologic symptoms are more common in TTP and renal failure is more common in ST-HUS, the 2 disorders cannot be distinguished on that basis alone.

Diagnosis

Establishing the diagnosis of TTP or ST-HUS is a 2-step process: verifying the presence of MAHA and thrombocytopenia, and excluding systemic/secondary conditions that would cause MAHA, thrombocytopenia, and/or pancytopenia. Among other causes, disseminated intravascular coagulation may also cause MAHA and thrombocytopenia and can be distinguished by laboratory results (Table 3).

Laboratory investigations for any suspected MAHA should include a complete blood count to evaluate the degree of anemia and thrombocytopenia and serum creatinine to check the degree of renal injury, as well as the indirect fraction of bilirubin (increased), haptoglobin (decreased or absent), and lactate dehydrogenase (increased). Renal manifestations include dark urine resulting from hemoglobinuria and proteinuria. Direct and indirect Coombs testing, as well as coagulation studies, are not typically helpful. The utility of tissue biopsies, namely gingival and cutaneous, is controversial and they are not frequently performed (1515. Bukowski RM, King JW, Hewlett JS. Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura. Blood. 1977;50:413-7. [PMID: 560229], 1616. Goodman A, Ramos R, Petrelli M, Hirsch SA, Bukowski R, Harris JW. Gingival biopsy in thrombotic thrombocytopenic purpura. Ann Intern Med. 1978;89:501-4. , 1717. Kwaan HC, Boggio LN. The clinical spectrum of thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 2005;31:673-80. [PMID: 16388418], 1818. Lian EC. Pathogenesis of thrombotic thrombocytopenic purpura: ADAMTS13 deficiency and beyond. Semin Thromb Hemost. 2005;31:625-32. [PMID: 16388413]).

For TTP, the workup includes an ADAMTS13 level (a metal-dependent enzyme that cleaves von Willebrand multimers); deficiency is defined as an activity of less than 10%. However, a diagnosis of TTP should not be based solely on the ADAMTS13 level because patients might have alternative diagnoses that are associated with a falsely low level, such as malignancies and infections (1919. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-11; quiz 1662. [PMID: 20032506] doi:10.1182/blood-2009-09-243790); recent transfusions can cause an elevated ADAMTS13 level even in the setting of true TTP; and, most important, results might take several days to come back.

Inhibitor autoantibody is present in acquired TTP and absent in hereditary TTP (hTTP) (2020. Rieger M, Mannucci PM, Kremer Hovinga JA, Herzog A, Gerstenbauer G, Konetschny C, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005;106:1262-7. [PMID: 15890682]). When hTTP is highly suspected, ADAMTS13 level should be rechecked after the acute episode. A diagnosis of hTTP is confirmed through genetic testing for the ADAMTS13 gene mutation, which is provided at no cost through the Hereditary TTP Registry.

For ST-HUS, the workup should include stool studies. Microscopic visualization of white and red blood cells on a stool sample hints to inflammatory and enteroinvasive pathogens, respectively. A history of diarrheal illness should prompt a stool culture to check for enterohemorrhagic Escherichia coli. Testing for E. coli O157:H7 requires tellurite-enriched, sorbitol MacConkey agar.

Culturing stool samples for Shigella should optimally be done at the bedside, as the organism is fastidious. If the sample is to be transported, use of buffered glycerol saline is best. Enzyme-linked immunosorbent assay is used to check for the Shiga toxin in stool. Serology tests include checking for IgM and using anti-lipopolysaccharide antibodies against the most frequent Shiga toxin-producing E. coli serotypes. Polymerase chain reaction (PCR) testing can identify Shiga toxin genes (ST-1 and ST-2) in stool. In one study, PCR detected Shigella in 66.7% of stool samples previously diagnosed with a stool culture (2121. Koziel M, Kiely R, Blake L, O’Callaghan I, Corcoran GD, Lucey B, et al. Improved detection of bacterial pathogens in patients presenting with gastroenteritis by use of the EntericBio real-time Gastro Panel I assay. J Clin Microbiol. 2013;51:2679-85. [PMID: 23761157] doi:10.1128/JCM.00809-13). However, due to the associated cost and labor, PCR is not widely used. Isolation of the Shiga toxin is useful but is only feasible during the acute colitis phase that precedes actual ST-HUS.

For any suspected MAHA, a peripheral blood smear should be viewed by a hematologist or other expert. Schistocytes and helmet cells result from the mechanical shearing of red blood cells in microthrombi-rich vasculature. Reticulocytosis, nucleated red blood cells, and polychromatophilia are also observed. Leukocytosis might be present, with or without band forms. Thrombocytopenia ranges from 10 to 100 × 109/L although lower counts have been reported. Examining the smear is helpful in excluding pseudothrombocytopenia, likely due to clumping. Bone marrow examination, although rarely done, would show an increased number of megakaryocytes.

If MAHA is not evident on the smear, the diagnostic focus shifts to disorders that cause pancytopenia, including paroxysmal-nocturnal hematuria, aplastic anemia, and rheumatologic disorders such as systemic lupus erythematosus. Another differential diagnosis, idiopathic thrombotic purpura, is typically not associated with hemolytic anemia, renal or neurological sequelae, or a deficiency in ADAMTS13.

If there is concern about pneumococcal infection, blood and other tissue cultures may be warranted.

Treatment of TTP

TTP presents a medical emergency that can be fatal. The decision to start therapy should be based on clinical findings and should not wait for ADAMST13 test results.

Treatment is directed at eliminating unusually large von Willebrand factor (ULvWF) multimers from the plasma and restoring ADAMTS13 activity. With the advent of plasma exchange therapy, survival of the initial episode of TTP has increased from 10-20% to 70-80% (1616. Goodman A, Ramos R, Petrelli M, Hirsch SA, Bukowski R, Harris JW. Gingival biopsy in thrombotic thrombocytopenic purpura. Ann Intern Med. 1978;89:501-4. ). Patients treated with plasma exchange have shown an increase in platelet count compared to those who received plasma infusion (with fresh frozen plasma) for the initial episode (2222. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325:393-7. [PMID: 2062330]). They had lower immediate mortality and superior responses at 6-month follow up. This might be due to the fact that plasma exchange provides a larger volume of plasma than infusion while simultaneously avoiding fluid overload. For the management of acute presentations of TTP, a daily exchange of 1 plasma volume is appropriate (1212. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060-9. [PMID: 20686117] doi:10.1182/blood-2010-07-271445). This is administered via a standard dialysis line placed at the bedside. Treatment is tapered or stopped once the platelet count is 150,000 or more for 2 consecutive days.

Plasma exchange therapy can lead to catheter- and plasma-related complications (2323. Nguyen L, Terrell DR, Duvall D, Vesely SK, George JN. Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. IV. An additional study of 43 consecutive patients, 2005 to 2008 [Letter]. Transfusion. 2009;49:392-4. [PMID: 19389220] doi:10.1111/j.1537-2995.2008.02030.x). Catheter-related complications include pneumothoraces, bleeding, thrombosis, line-related sepsis (both local and systemic), and death (from sepsis or hemorrhage). Plasma-related complications include serum sickness, anaphylaxis, and cardiac arrest with pulseless electrical activity.

For patients who appear to have acquired TTP, steroids are added to the initial management (1212. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060-9. [PMID: 20686117] doi:10.1182/blood-2010-07-271445). The rationale is to suppress the production of anti-ADAMTS13 autoantibodies. Depending on the condition of the patient and the severity of disease, regimen options are oral prednisone (1 mg/kg per day orally) and IV methylprednisolone (125 mg 2 to 4 times daily). Higher doses (1,000 mg of methylprednisolone per day for 3 days) can be used for patients with no or suboptimal response or severe illness.

Rituximab is usually reserved for severe or refractory cases (2424. Scully M, Cohen H, Cavenagh J, Benjamin S, Starke R, Killick S, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol. 2007;136:451-61. [PMID: 17233847], 2525. Scully M, McDonald V, Cavenagh J, Hunt BJ, Longair I, Cohen H, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118:1746-53. [PMID: 21636861] doi:10.1182/blood-2011-03-341131). The typical dose is 375 mg/m2 weekly for 4 weeks. Other treatment modalities for refractory disease are listed in Table 4.

TTP patients are at elevated risk for deep venous thrombosis (DVT), so preventive mechanical or pharmacologic measures should be taken, usually when platelet counts reach 50 × 109/L (3535. Camous L, Veyradier A, Darmon M, Galicier L, Mariotte E, Canet E, et al. Macrovascular thrombosis in critically ill patients with thrombotic micro-angiopathies. Intern Emerg Med. 2014;9:267-72. [PMID: 23054401] doi:10.1007/s11739-012-0851-4). Control of blood pressure is also vital, as arterial hypertension is associated with poor outcomes, namely renal dysfunction (3636. Dierkes F, Andriopoulos N, Sucker C, Kuhr K, Hollenbeck M, Hetzel GR, et al. Indicators of acute and persistent renal damage in adult thrombotic microangiopathy. PLoS One. 2012;7:e30886. [PMID: 22292070] doi:10.1371/journal.pone.0030886). Neurological manifestations are the first to resolve, while renal failure is the last. Anemia recovers more slowly than thrombocytopenia (1212. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060-9. [PMID: 20686117] doi:10.1182/blood-2010-07-271445).

There is contradictory evidence regarding the effects of platelet transfusions in TTP. They are usually required prior to dialysis-line placement. Although most reports of adverse outcomes with platelet transfusions come from case reports/series, a systematic review showed no difference in rates of thrombosis, severe neurological events, and death between TTP patients who received platelet transfusions and those who did not (3737. Swisher KK, Terrell DR, Vesely SK, Kremer Hovinga JA, Lämmle B, George JN. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura. Transfusion. 2009;49:873-87. [PMID: 19210323] doi:10.1111/j.1537-2995.2008.02082.x, 3838. Otrock ZK, Liu C, Grossman BJ. Platelet transfusion in thrombotic thrombocytopenic purpura. Vox Sang. 2015;109:168-72. [PMID: 25900398] doi:10.1111/vox.12274). Most recently, however, increased arterial, but not venous, thrombosis as well as mortality was found in TTP patients who received platelet transfusions (3939. Goel R, Ness PM, Takemoto CM, Krishnamurti L, King KE, Tobian AA. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood. 2015;125:1470-6. [PMID: 25588677] doi:10.1182/blood-2014-10-605493). The use of platelet transfusion is therefore mostly reserved for cases of confirmed bleeding, especially when mechanical approaches have failed to resolve it. “Prophylactic” transfusions should be avoided.

Treatment of ST-HUS

Management of ST-HUS is supportive (4040. Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM. Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis. 2009;53:259-72. [PMID: 18950913] doi:10.1053/j.ajkd.2008.07.038), including early, aggressive hydration to protect renal function. Some patients will require dialysis. There seems to be a role for plasma therapy in acquired ST-HUS, but more evidence is needed (4141. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al; European Paediatric Study Group for HUS. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome [Editorial]. Pediatr Nephrol. 2009;24:687-96. [PMID: 18800230] doi:10.1007/s00467-008-0964-1). Early treatment with eculizumab, a monoclonal antibody that binds to complement factor C5, blocking complement activation, has been shown to help resolve neurological complications; lifelong treatment may be warranted (4242. Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui HN, Lacraz A, et al. Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant. 2014;29:565-72. [PMID: 24293658] doi:10.1093/ndt/gft470, 4343. Pape L, Hartmann H, Bange FC, Suerbaum S, Bueltmann E, Ahlenstiel-Grunow T. Eculizumab in Typical Hemolytic Uremic Syndrome (HUS) With Neurological Involvement. Medicine (Baltimore). 2015;94:e1000. [PMID: 26091445] doi:10.1097/MD.0000000000001000). Reports on the use of antibiotics in the setting of diarrheal illness have been conflicting, with some showing increased risk of developing ST-HUS (4444. Wong CS, Mooney JC, Brandt JR, Staples AO, Jelacic S, Boster DR, et al. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis. 2012;55:33-41. [PMID: 22431799] doi:10.1093/cid/cis299) and some showing no increased risk (4545. Safdar N, Said A, Gangnon RE, Maki DG. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA. 2002;288:996-1001. [PMID: 12190370]). Generally, antibiotics should be avoided in the setting of acute diarrhea from enterohemorrhagic Escherichia coli, as their use has not been irrefutably shown to improve outcomes.

Prognosis

Risk of relapse in TTP is highest during the first year after recovery and can be as high as 41% at 7.5 years (1919. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-11; quiz 1662. [PMID: 20032506] doi:10.1182/blood-2009-09-243790). Overexpression of HLA-DRB1 and HLA-DRB5 was associated with higher risk of relapse (4646. Edgar CE, Terrell DR, Vesely SK, Wren JD, Dozmorov IM, Niewold TB, et al. Ribosomal and immune transcripts associate with relapse in acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura. PLoS One. 2015;10:e0117614. [PMID: 25671313] doi:10.1371/journal.pone.). Increased rates of cognitive impairment (4747. Kennedy AS, Lewis QF, Scott JG, Kremer Hovinga JA, Lämmle B, Terrell DR, et al. Cognitive deficits after recovery from thrombotic thrombocytopenic purpura. Transfusion. 2009;49:1092-101. [PMID: 19222817] doi:10.1111/j.1537-2995.2009.02101.x) as well as major depression (4848. Han B, Page EE, Stewart LM, Deford CC, Scott JG, Schwartz LH, et al. Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura. Am J Hematol. 2015;90:709-14. [PMID: 25975932] doi:10.1002/ajh.24060) have been described. Patients with TTP seem to be at a higher risk of developing other autoimmune diseases, namely systemic lupus erythematosus (4949. George JN, Vesely SK, James JA. Overlapping features of thrombotic thrombocytopenic purpura and systemic lupus erythematosus. South Med J. 2007;100:512-4. [PMID: 17534089]).

As for ST-HUS, 12% of patients have been found to die or develop end-stage renal disease, and 25% of survivors continued to have renal complications (5050. Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA. 2003;290:1360-70. [PMID: 12966129]). The severity of the acute illness, namely the impact on the central nervous system, as well as the need for initial dialysis, are associated with worse long-term prognosis.

Conclusion

Early recognition of TTP and ST-HUS by hospitalists is crucial as poor outcomes result from delayed diagnosis and treatment. While plasma exchange is the standard of therapy for TTP, treatment of ST-HUS remains supportive. Plasma exchange has markedly improved the outcomes of TTP patients but not their survival. Furthermore, plasma exchange is not without risks. Future studies are needed to better identify approaches to improve outcomes in this patient population.