Residency · Residency · Hematology Thrombosis

Thrombotic Microangiopathies - TTP and HUS

Introduction

The thrombotic microangiopathies (TMAs) are a group of life-threatening disorders united by a common pathologic triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ damage resulting from microvascular thrombosis. The classical clinical pentad of thrombotic thrombocytopenic purpura, which includes fever, MAHA, thrombocytopenia, renal dysfunction, and neurologic symptoms, is present in fewer than 5% of cases at diagnosis, and clinicians must not wait for the full pentad before initiating treatment. Distinguishing among TTP, hemolytic uremic syndrome (HUS), and the numerous TMA mimics is of paramount importance because the therapeutic approaches differ fundamentally and delay in appropriate treatment carries significant mortality.

Pathophysiology

Thrombotic Thrombocytopenic Purpura (TTP)

The pathophysiology of TTP centers on a severe deficiency of ADAMTS13, a metalloprotease that cleaves ultra-large von Willebrand factor (ULVWF) multimers. When ADAMTS13 activity falls below 10%, ULVWF multimers accumulate on the endothelial surface, where they serve as potent platforms for spontaneous platelet adhesion and aggregation, leading to the formation of platelet-rich microthrombi throughout the arteriolar and capillary microvasculature. These thrombi cause mechanical shearing of red blood cells (producing schistocytes) and consumptive thrombocytopenia while obstructing blood flow to vital organs.

Acquired or immune TTP accounts for approximately 95% of cases and is caused by IgG autoantibodies directed against ADAMTS13. This autoimmune form may be associated with other autoimmune conditions, pregnancy, or certain drugs. Congenital TTP (Upshaw-Schulman syndrome) accounts for the remaining 5% and results from biallelic mutations in the ADAMTS13 gene. Congenital TTP typically presents in childhood but may remain occult until a physiologic trigger such as pregnancy unmasks the disease.

Hemolytic Uremic Syndrome (HUS)

Typical HUS, also known as STEC-HUS, is caused by Shiga toxin-producing Escherichia coli, with serotype O157:H7 being the most commonly implicated. Following enteric infection, Shiga toxin enters the systemic circulation and binds to the Gb3 (globotriaosylceramide) receptor, which is expressed at high density on glomerular endothelial cells. This binding causes direct endothelial injury, triggering a renal-predominant TMA with fibrin deposition, platelet consumption, and acute kidney injury that frequently necessitates dialysis.

Atypical HUS (aHUS) is a complement-mediated TMA resulting from dysregulation of the alternative complement pathway. Genetic mutations in complement regulatory proteins underlie the majority of cases, with complement factor H (CFH) mutations being the most common, accounting for approximately 30% of cases. Other affected genes include CFI, MCP/CD46, C3, complement factor B, thrombomodulin, and DGKE. Anti-complement factor H antibodies are found in 5 to 10% of cases, particularly in children, and are often associated with homozygous deletion of CFHR1 and CFHR3. Importantly, the genetic predisposition demonstrates incomplete penetrance of approximately 50%, meaning that many mutation carriers never manifest clinical disease. Triggering events such as infection, pregnancy, transplantation, or certain drugs are frequently required to unmask the underlying complement dysregulation and precipitate a clinical episode.

<image>A comparative pathophysiology diagram showing three panels side by side: TTP, STEC-HUS, and atypical HUS. For TTP: show ADAMTS13 deficiency (blocked by autoantibody) leading to accumulation of ultra-large VWF multimers on the endothelial surface, platelet adhesion forming microthrombi in arterioles. For STEC-HUS: show Shiga toxin binding to Gb3 receptor on glomerular endothelial cells, causing direct endothelial injury, fibrin deposition, and platelet consumption primarily in renal microcirculation. For aHUS: show the alternative complement pathway with normal regulation (Factor H, Factor I, MCP inhibiting C3 convertase) versus dysregulated complement activation (mutations in Factor H, Factor I, or MCP), leading to C5b-9 MAC formation on endothelial surfaces causing endothelial injury and thrombosis. Include molecular detail at each step. Medical illustration style with clear labels and arrows.</image>

Clinical Presentation

TTP

The hematologic hallmarks of TTP include severe thrombocytopenia, often with platelet counts below 20,000 per microliter, and MAHA characterized by schistocytes on the peripheral smear, markedly elevated LDH (often exceeding 1,000 U/L), undetectable haptoglobin, elevated indirect bilirubin, and a negative direct antiglobulin test. Neurologic symptoms are present in 60 to 80% of patients and range from headache and confusion to focal neurologic deficits, seizures, and coma. In contrast to HUS, renal involvement in TTP is usually mild, with serum creatinine typically remaining below 2 mg/dL; severe acute kidney injury is unusual and should prompt consideration of alternative diagnoses. Fever, though included in the historical pentad, is less commonly present in the era of early recognition. Cardiac involvement is underappreciated but clinically important, with troponin elevation being common and sudden cardiac death representing a recognized cause of mortality.

HUS (Typical/STEC)

Typical HUS presents with a characteristic prodromal illness of bloody diarrhea occurring 5 to 10 days before the onset of the TMA. The disease predominantly affects young children under 5 years of age. The hallmark is severe acute kidney injury, with oliguria or anuria and markedly elevated serum creatinine; approximately 50 to 60% of patients require dialysis during the acute episode. MAHA and thrombocytopenia are present but are typically less severe than in TTP. Central nervous system involvement occurs in approximately 25% of cases and may manifest as seizures or encephalopathy.

Atypical HUS

Atypical HUS lacks the diarrheal prodrome that characterizes STEC-HUS, although intercurrent infection can serve as a trigger. The clinical presentation is dominated by severe renal failure, which may present as a rapidly progressive glomerulonephritis picture. The disease can occur at any age, and recurrence is common, particularly in patients with complement factor H mutations. Hypertension is often a prominent clinical feature. Atypical HUS may also present during pregnancy or in the postpartum period, creating diagnostic overlap with preeclampsia and HELLP syndrome.

Diagnosis

PLASMIC Score (for predicting ADAMTS13 <10%)

The PLASMIC score is a validated clinical prediction tool for estimating the probability that a patient with suspected TMA has severe ADAMTS13 deficiency consistent with TTP. One point is assigned for each of the following: platelet count below 30,000 per microliter, the presence of a combined hemolysis variable (reticulocyte count above 2.5%, undetectable haptoglobin, or indirect bilirubin above 2 mg/dL), no active cancer, no history of solid organ or stem cell transplant, MCV below 90 fL, INR below 1.5, and creatinine below 2.0 mg/dL. A PLASMIC score of 6 or greater carries a positive predictive value of approximately 90% for severe ADAMTS13 deficiency and should prompt initiation of empiric therapeutic plasma exchange. A score of 4 or below indicates a low probability of TTP (less than 5%) and should direct the workup toward alternative diagnoses.

ADAMTS13 Activity

ADAMTS13 activity measurement is the gold standard for confirming the diagnosis of TTP. An activity level below 10% in the presence of an inhibitor or anti-ADAMTS13 antibodies confirms immune TTP. It is critical to send the ADAMTS13 sample before initiating plasma exchange, as the infusion of donor plasma during the exchange procedure will dilute the sample and may falsely normalize the activity level. However, treatment must never be delayed while awaiting ADAMTS13 results, as the turnaround time at reference laboratories is typically 24 to 72 hours.

Complement and HUS Workup

For suspected STEC-HUS, diagnostic evaluation includes Shiga toxin stool PCR or culture and serology for O157 LPS antibodies. For suspected atypical HUS, a comprehensive complement panel should be obtained including C3, C4, CH50, complement factor H, complement factor I, MCP/CD46 expression on white blood cells by flow cytometry, and anti-complement factor H antibodies, followed by genetic testing with a complement gene panel. Serum C3 is low in approximately 50% of aHUS cases, while C4 remains normal, a pattern that distinguishes complement-mediated TMA from lupus or antiphospholipid syndrome-associated disease.

Differential Diagnosis of TMA

The differential diagnosis of TMA is broad and includes TTP (defined by ADAMTS13 below 10%), STEC-HUS (defined by positive Shiga toxin testing), atypical HUS (complement-mediated), disseminated intravascular coagulation (distinguished by prolonged PT/PTT and low fibrinogen, which are characteristically normal in TTP and HUS), HELLP syndrome and preeclampsia, malignant hypertension, scleroderma renal crisis, catastrophic antiphospholipid syndrome (CAPS), drug-induced TMA (caused by agents such as quinine, calcineurin inhibitors, gemcitabine, bevacizumab, and other VEGF pathway inhibitors), and transplant-associated TMA. Careful clinical and laboratory assessment is required to distinguish among these entities, as each requires a different therapeutic approach.

Treatment of TTP

Acute Management

Therapeutic plasma exchange (TPE) remains the cornerstone of acute TTP management. The mechanism of TPE in TTP is twofold: it removes the pathogenic ADAMTS13 autoantibodies and ULVWF multimers from the patient's plasma while simultaneously replacing the deficient ADAMTS13 enzyme through the fresh frozen plasma or cryoprecipitate-poor plasma used as replacement fluid. Exchanges are performed daily, processing 1 to 1.5 plasma volumes per session, and are continued until the platelet count exceeds 150,000 per microliter for two consecutive days, LDH is normalizing, and clinical improvement is evident. The exchange is then tapered with every-other-day sessions for 2 to 3 treatments before discontinuation.

Corticosteroids are administered concurrently, typically as pulse methylprednisolone at 1 g intravenously daily for 3 days followed by prednisone at 1 mg/kg/day. Caplacizumab (Cablivi), an anti-VWF nanobody that blocks the interaction between VWF and the platelet GPIb receptor, has transformed acute TTP management. In the pivotal HERCULES trial, caplacizumab achieved faster platelet normalization and a 74% reduction in the composite endpoint of TTP-related death, recurrence, and thromboembolic events. Caplacizumab is administered as an 11 mg intravenous bolus before the first TPE, followed by 11 mg subcutaneously daily during the TPE course and for 30 days after the last exchange. The drug increases the risk of bleeding, and VWF activity and ADAMTS13 levels should be monitored to guide the duration of therapy. Caplacizumab should be continued until ADAMTS13 activity exceeds 10% to prevent relapse after discontinuation.

Rituximab at 375 mg/m2 weekly for 4 doses is indicated for refractory TTP (failure to respond to TPE and steroids), relapsing TTP, and persistent ADAMTS13 deficiency below 10%. Rituximab is increasingly used upfront in combination with TPE, steroids, and caplacizumab. Preemptive rituximab, administered when monitoring reveals a declining ADAMTS13 level during remission, has been shown to prevent clinical relapse.

DO NOT Transfuse Platelets

Platelet transfusion in TTP is classically described as "fuel on the fire" because providing additional platelets to a patient whose microvasculature is already laden with platelet-rich thrombi can precipitate worsening thrombosis and organ damage. Platelet transfusion should be avoided except in the setting of life-threatening hemorrhage or when necessary to facilitate central venous catheter placement in a patient with a platelet count below 10,000 per microliter.

Monitoring During and After Treatment

During the acute phase, a daily CBC, LDH, and haptoglobin should be monitored to track the response to therapy. ADAMTS13 activity should be measured at diagnosis, at the time of clinical remission, and then every 1 to 3 months during the first year of follow-up. The relapse risk is 30 to 50% in patients who do not receive rituximab. An ADAMTS13 activity below 10% detected during remission monitoring should trigger preemptive rituximab administration to avert clinical relapse.

Treatment of STEC-HUS

The management of typical STEC-HUS is primarily supportive, consisting of careful fluid management, renal replacement therapy (dialysis) for acute kidney injury, and transfusion support as needed. Antibiotics are contraindicated in STEC-HUS because they may increase Shiga toxin release from dying bacteria and have been associated with worse outcomes in observational studies. Antimotility agents should also be avoided for similar reasons. Therapeutic plasma exchange has no established role in typical HUS. Eculizumab is not considered standard therapy for STEC-HUS, though anecdotal reports of its use exist in patients with severe neurologic involvement.

Treatment of Atypical HUS

Complement Inhibition

The introduction of complement inhibitor therapy has revolutionized the management of atypical HUS. Eculizumab (Soliris), a humanized monoclonal antibody directed against complement component C5, blocks the formation of the terminal complement complex (C5b-9, or the membrane attack complex). In clinical studies, eculizumab has achieved renal recovery in 60 to 80% of patients with aHUS and has dramatically improved dialysis-free survival compared to the pre-eculizumab era. The dosing schedule consists of 900 mg intravenously weekly for 4 weeks, followed by 1200 mg every 2 weeks as maintenance. Because eculizumab blocks terminal complement activation, patients are at markedly increased risk for meningococcal infection and must receive meningococcal vaccination (both MenACWY and MenB) at least 2 weeks before the first dose. If treatment is urgent, prophylactic antibiotics (penicillin or ciprofloxacin) should be administered until vaccination takes effect. The duration of therapy has historically been lifelong, although recent data support attempted discontinuation in selected patients, particularly those with MCP mutations, under close laboratory and clinical monitoring.

Ravulizumab (Ultomiris), a long-acting anti-C5 antibody engineered for an extended half-life, has received FDA approval for aHUS. It offers the convenience of every-8-week dosing after an initial loading period and has demonstrated non-inferior efficacy to eculizumab. Iptacopan, an oral complement factor B inhibitor that has been approved for paroxysmal nocturnal hemoglobinuria, is under investigation for aHUS and represents the potential for an oral complement-targeted therapy in this disease.

<image>A treatment algorithm for thrombotic microangiopathies presented as a decision tree. Start with "MAHA + thrombocytopenia + organ damage (suspected TMA)." First step: calculate PLASMIC score and send ADAMTS13. If PLASMIC ≥5: initiate empiric TPE + steroids + caplacizumab for presumed TTP. Branch based on ADAMTS13 result: if <10% with inhibitor → confirmed TTP → add rituximab, continue TPE until response. If ADAMTS13 >10%: reconsider diagnosis → check for DIC (coagulation studies), STEC (stool studies), complement studies for aHUS, pregnancy-related causes, drug-induced TMA. For STEC-HUS: supportive care, dialysis, NO antibiotics. For aHUS: eculizumab/ravulizumab + meningococcal prophylaxis. Include response criteria and monitoring schedules for each pathway. Clean clinical algorithm with decision diamonds and color-coded treatment boxes.</image>

Key Clinical Pearls

• Do NOT wait for the classic pentad to initiate treatment for TTP; MAHA + thrombocytopenia with no alternative explanation should trigger empiric TPE
• PLASMIC score >=6 with MAHA + thrombocytopenia → start TPE empirically while awaiting ADAMTS13; send ADAMTS13 BEFORE first plasma exchange
• Caplacizumab has changed the acute management of TTP; in combination with TPE and immunosuppression, it reduces time to platelet normalization and TTP-related death/recurrence
• Platelet count <30,000 + creatinine <2.0 mg/dL strongly favors TTP over HUS
• Antibiotics should NOT be given for STEC-HUS (may worsen Shiga toxin release)
• aHUS patients on eculizumab/ravulizumab have lifelong meningococcal infection risk; vaccination and awareness are critical
• ADAMTS13 monitoring in remission is essential: a falling level predicts relapse and should trigger preemptive rituximab

References

1. Joly BS, et al. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846.
2. Scully M, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura (HERCULES). N Engl J Med. 2019;380(4):335-346.
3. Bendapudi PK, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies. Lancet Haematol. 2017;4(4):e157-e164.
4. Legendre CM, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169-2181.
5. Tarr PI, et al. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365(9464):1073-1086.

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