Thrombotic Thrombocytopenic Purpura and Hemolytic- Uremic Syndrome

GENERAL PRINCIPLES

Definition

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are thrombotic microangiopathies (TMAs) caused by platelet-vWF aggregates and platelet-fibrin aggregates, respectively, resulting in thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and organ ischemia.

Epidemiology

Acquired TTP has an incidence of approximately 11.3 cases per 10⁶ persons, occurring more frequently in women and African Americans.¹² Typical HUS usually occurs in gastroenteritis outbreaks affecting children. Adults may present with both typical and atypical (non-gastroenteritis-associated) variants of HUS.

Etiology

• Autoantibody-mediated removal of plasma vWF-cleaving protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), leading to elevated levels of abnormally large vWF multimers, causes acquired TTP.¹³ The abnormal vWF multimers spontaneously adhere to platelets and may produce occlusive vWF-platelet aggregates in the microcirculation and subsequent microangiopathy. Second-hit events may involve endothelial dysfunction or injury.

• Typical or enteropathic HUS has an association with Escherichia coli (O157:H7) production of Shiga-like toxins in Shiga toxigenic E. coli HUS (STEC-HUS).

• HUS can also be associated with transplant, endothelial-damaging drugs, and pregnancy.¹⁴

• Inherited or acquired defects in regulation of the alternative complement pathway are present in 30%- 50% of atypical HUS cases.¹⁴

DIAGNOSIS

Clinical Presentation

• The complete clinical pentad of TTP, present in lt;30% of cases, includes consumptive thrombocytopenia, MAHA, fever, renal dysfunction, and fluctuating neurologic deficits.

• The findings of thrombocytopenia and MAHA should raise suspicion for TTP-HUS in the absence of other identifiable causes.

• Patients with autosomal recessive inherited ADAMTS13 deficiencies have relapsing TTP (Upshaw- Schulman syndrome).

• Diarrhea, usually bloody, and abdominal pain often precede STEC-HUS.

• Marked renal dysfunction usually occurs in atypical HUS.

Diagnostic Testing

• TMAs produce schistocytes (fragmented red cells) and thrombocytopenia on blood smears. The findings of anemia, elevated reticulocyte count, low or undetectable haptoglobin, and elevated lactate dehydrogenase (LDH) support the presence of hemolysis.

• Acquired TTP has TMA findings, normal PT/aPTT, very low or undetectable ADAMTS13 enzyme activity, and detectable ADAMTS13 inhibitory antibody.

• The PLASMIC score quantifies the pretest probability of acquired TTP. Each finding contributes one point: platelet lt; 30 ? 10⁹#8725;L, laboratory evidence of hemolysis, no cancer, no transplant, MCV lt; 90 fL, INR lt; 1.5, Creatinine lt; 2.0 mg#8725;dL. Patients with 0-4 points have a low probability of acquired TTP whereas those with 6-7 points have a high probability.¹⁵

• Typical HUS has TMA and acute renal failure. E. coli O157 stool culture has a higher sensitivity than Shiga toxin assays.

• In the absence of precipitating risk factors, testing for atypical HUS should include molecular and serologic tests for complement regulator factor H and I mutations or autoantibodies through reference laboratories.

TREATMENT

• The mainstay of therapy for TTP consists of rapid treatment with plasma exchange (PEX) of 1.0-1.5 plasma volumes daily. PEX is continued for several days after normalization of platelet count and LDH.¹⁶

î If PEX is unavailable or will be delayed, infuse fresh frozen plasma (FFP) immediately to replace ADAMTS13.

• Common practice includes the administration of glucocorticoids: prednisone 1 mg/kg orally per day.

• In observational studies, rituximab (375 mg#8725;m² IV) reduces the risk of relapse in patients with acquired TTP when added to initial therapy with PEX. Comparative studies are needed to determine if low-dose rituximab (e.g., 100 mg#8725;m² may induce a long-term response).^18,19

• Caplacizumab, a humanized monoclonal antibody fragment that binds to vWF and blocks vWF-platelet glycoprotein Ib-IX-V interactions, reduces formation of microthrombi. It is approved for the initial treatment of acquired TTP in combination with PEX and immunosuppressive agents. In the phase III HERCULES trial, caplacizumab reduced mortality, normalized platelet count faster, resulting in fewer PEX days, and was associated with a decrease in relapse events within 30 days.²⁰

• Avoid platelet transfusion in the absence of severe bleeding or an invasive procedure because of the potentially increased risk of additional microvascular occlusions in TTP.

• Ninety percent of treated patients have a remission; however, relapses may occur days to years later.

• Immunosuppression with cyclophosphamide, azathioprine, or vincristine and splenectomy may have

success in the treatment of refractory or relapsing TTP.

• STEC-HUS does not usually improve with PEX, and treatment remains supportive. Antibiotic therapy does not hasten recovery or minimize toxicity for STEC-HUS.

• TMA associated with calcineurin inhibitors (cyclosporine, tacrolimus) usually responds to drug dose reduction or discontinuation of the offending agent.

• Atypical HUS often leads to chronic renal failure necessitating dialysis.

• Eculizumab is a humanized monoclonal antibody used to treat atypical HUS that binds to complement protein C5, which blocks its cleavage into C5a and the cytotoxic membrane attack complex C5b-9, thus inhibiting complement activation.²¹

î Vaccinate for Neisseria meningitides 2 weeks before starting eculizumab; however, if not possible, administer prophylactic antibiotics against N. meningitides for 2 weeks after vaccination.