Thrombotic Microangiopathy

Essentials of Diagnosis

• Microangiopathic hemolytic anemia and thrombocytopenia, in the absence of another plausible explanation, are sufficient for a presumptive diagnosis

• Fever, neurologic impairment, and kidney disease may occur concurrently but are not required for diagnosis

• Kidney injury is more common and more severe in hemolytic-uremic syndrome (HUS)

General Considerations

• The thrombotic microangiopathies (TMAs) include but are not limited to

  • Thrombotic thrombocytopenic purpura (TTP)

  • HUS

• These disorders are characterized by

  • Thrombocytopenia, due to the incorporation of platelets into fibrin thrombi in the microvasculature

  • Microangiopathic hemolytic anemia, which results from shearing of erythrocytes in fibrin networks in the microcirculation

  • Mutations in complement genes (such as factor H, a complement regulator) account for the uncontrolled activation of complement

• In idiopathic TTP, autoantibodies against the ADAMTS-13 (A disintegrin and metalloproteinase with thrombospondin type 1 repeat, member 13), also known as the von Willebrand factor cleaving protease, leads to accumulation of ultra-large von Willebrand factor (vWF) multimers

  • These multimers bridge and aggregate platelets in the absence of hemostatic triggers

  • This bridging and aggregation in turn leads to the vessel obstruction and various organ dysfunctions seen in TTP

• In some cases of pregnancy-associated TMA, an antibody to ADAMTS-13 is present

• In contrast, the activity of the ADAMTS-13 in congenital TTP is decreased due to a mutation in the gene encoding for the molecule

• Damage to endothelial cells may also lead to TMA

• Certain drugs are associated with the development of TMA

  • Cyclosporine

  • Quinine

  • Ticlopidine

  • Clopidogrel

  • Mitomycin C

  • Bleomycin

Symptoms and Signs

• Microangiopathic hemolytic anemia and thrombocytopenia are presenting signs in all patients with TTP and most patients with HUS

• In a subset of patients with HUS, the platelet count remains in the normal range

• Only approximately 25% of patients with TMA manifest all components of the original pentad of findings (Table 14–4)

  • Microangiopathic hemolytic anemia

  • Thrombocytopenia

  • Fever

  • Kidney disease

  • Neurologic abnormalities

• Most patients (especially children) with HUS have a recent or current diarrheal illness, often bloody

• Neurologic manifestations may result from deposition of microthrombi in the cerebral vasculature

  • Headache

  • Somnolence

  • Delirium

  • Seizures

  • Paresis

  • Coma

Laboratory Tests

• Features of TMA include those associated with microangiopathic hemolytic anemia

  • Anemia

  • Elevated serum lactate dehydrogenase (LD), indirect bilirubin

  • Decreased serum haptoglobin

  • Elevated reticulocyte count

  • Schistocytes on the blood smear

  • Negative direct antiglobulin test

• Thrombocytopenia

• Elevated serum creatinine

• Positive stool culture for E coli O157:H7 or stool assays for Shiga-toxin

• Reductions in ADAMTS-13 activity

• Mutations of genes encoding complement proteins (atypical HUS; specialized laboratory assessment)

• Routine coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen) are within normal range in most patients with TMA

• Immediate plasma exchange is essential

  • Usually performed once daily until the platelet count and LD have returned to normal for at least 2 days, after which the frequency of treatments may be tapered slowly while the platelet count and LD are monitored for relapse

  • In cases of insufficient response to once-daily plasma exchange, twice-daily exchanges should be considered

• Fresh frozen plasma may be administered if immediate access to plasma exchange is not available or in cases of familial TMA

• Platelet transfusions are contraindicated in the treatment of TMAs due to reports of worsening TMA, possibly due to propagation of platelet-rich microthrombi

• In cases of documented life-threatening bleeding, however, platelet transfusions may be given slowly and only after plasma exchange is underway

• Red blood cell transfusions may be administered in cases of clinically significant anemia

• Hemodialysis should be considered for patients with significant kidney injury

• Caplacizumab

  • A bi-specific antibody that targets the A1 domain of von Willebrand factor that prevents vWF interaction with the platelet glycoprotein Ib-IX-V receptor

  • Can reduce the time to platelet count normalization and 30-day mortality

• In cases of TTP relapse following initial treatment, plasma exchange should be reinstituted

• If ineffective, or in cases of primary refractoriness, second-line treatments should be used

  • Rituximab

  • Corticosteroids

  • IVIG

  • Vincristine

  • Cyclophosphamide

  • Splenectomy

• Complement-mediated HUS

  • May respond to plasma infusion initially

  • Serial infusions of the anti-complement C5 antibody, eculizumab, have produced sustained remissions in some patients

  • If irreversible kidney disease has occurred, hemodialysis or kidney transplantation may be necessary

Prognosis

• Mortality rate of > 95% without treatment

When to Refer

• Consultation by a hematologist or transfusion medicine specialist familiar with plasma exchange is required at the time of presentation

• Patients with TMA require ongoing care by a hematologist

When to Admit

• All patients