Thrombotic microangiopathies: Similar presentations, different therapies
ABSTRACT
Thrombotic thrombocytopenic purpura, Shiga toxin hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome are thrombotic microangiopathies that present similarly but arise from different causes. Management depends on distinguishing them promptly and providing targeted therapy.
KEY POINTS
- Thrombotic thrombocytopenic purpura is diagnosed with the ADAMTS13 assay. As soon as it is suspected, it should be treated with daily plasma exchange, steroids (at least until the diagnosis is certain), and, if additional treatment is needed, rituximab.
- Hemolytic uremic syndrome is seen in children who handle farm animals and in children and adults in food outbreaks. It is managed supportively with transfusion of packed red blood cells and dialysis.
- Atypical hemolytic uremic syndrome should be suspected in patients with normal ADAMTS13 and without diarrhea or evidence of Shiga toxin-producing Escherichia coli. It often responds well to eculizumab, a blocker of C5 (the fifth component of complement).
- Antiphospholipid syndrome should be investigated in women who have multiple miscarriages or thrombotic events. Symptomatic disease requires long-term anticoagulation therapy.
ANTIPHOSPHOLIPID SYNDROME
A young woman with a history of thrombosis and miscarriages
A 27-year-old woman presents with arthralgias, low-grade fever, and malaise. She has a history of 3 spontaneous abortions and Raynaud phenomenon. Two years ago, she had deep vein thrombosis of the right calf after a long automobile trip.
She now has swollen metacarpophalangeal and proximal interphalangeal joints, livedo reticularis (a mottled venous pattern of the skin best seen under fluorescent light) of the legs and arms, and ankle edema (2-cm indentation).
Her blood pressure is 152/92 mm Hg. Laboratory values:
- White blood cell count 3.6 × 109/L (reference range 4.5–11.0)
- Hematocrit 24% (36%–47%)
- Platelet count 89 × 109/L (150–450)
- Urinalysis: protein 4+, heme 3+, red blood cells 8–15 per high-power field (< 3), red blood cell casts present
- Blood urea nitrogen 43 mg/dL (10–20)
- Creatinine 2.6 mg/dL (0.5–1.1).
- Prothrombin time 14.6 s (10–14)
- Partial thromboplastin time 85 s (25–35)
- Antinuclear antibody positive at 1:160
- Anti-double-stranded DNA and serum complement normal
- Syphilis serologic screening (VDRL) positive.
The patient has leukopenia, anemia, thrombocytopenia, hematuria, proteinuria, high blood urea nitrogen, and markedly elevated partial thromboplastin time. Although she has a positive antinuclear antibody test and renal dysfunction, her anti-dsDNA and serum complement tests are normal, making the diagnosis of systemic lupus erythematosus unlikely.
Consider antiphospholipid syndrome
In any patient with multiple pregnancy losses, lupus, or a history of thrombosis, antiphospholipid syndrome should be considered.
In a series of patients with antiphospholipid antibody who underwent kidney biopsy, more than half were men, indicating that, unlike lupus, this is not primarily a disease of young women.
Diagnosis based on specific criteria
Clinical criteria require at least one of the following in the patient’s history23:
- One or more episodes of arterial, venous, or small-vessel thrombosis
- Unexplained pregnancy morbidity (death of a fetus or neonate with normal morphology or 3 or more spontaneous abortions).
Serologic criteria for any of the following antiphospholipid antibodies require that at least one of the following tests be positive at least twice and at least 12 weeks apart:
- Anticardiolipin antibodies—high-titer immunoglobulin (Ig) G or IgM
- Autoantibodies for beta 2-glycoprotein
- Lupus anticoagulant—autoantibodies that increase clotting time in vitro and target beta 2-glycoprotein I and prothrombin (despite its name and actions in vitro, lupus anticoagulant functions as a coagulant).
As with the other thrombotic microangiopathies, patients with anticardiolipin syndrome have microthrombi in the glomeruli and blood vessels that are evident on kidney biopsy.
Suspect condition in likely groups
Antiphospholipid syndrome is surprisingly common.24 In a case-control study, de Groot et al25 found that 3.1% of patients under age 70 with a first episode of venous thrombosis and no known cancer were positive for lupus anticoagulant vs 0.9% of controls. In another case-control study, Urbanus et al26 found that 17% of women under age 50 with a stroke tested positive for lupus anticoagulant compared with less than 1% of controls. Because of such studies, it has become routine to test for anticardiolipin and lupus anticoagulant in young patients presenting with a stroke.
About 1% of women trying to have children have recurrent miscarriages, and of these, 10% to 15% have antiphospholipid antibody present.27–30
Pathogenesis
Patients with antiphospholipid syndrome have a much higher proportion of plasma beta 2-glycoprotein in the oxidized form than do healthy controls. The level is also higher than in patients with a different autoimmune disease whether or not they have antibodies against beta 2-glycoprotein 1. Although about 40% of patients with lupus have an anticardiolipin antibody, only a small percentage develop antiphospholipid syndrome with clotting.
It is thought that antiphospholipid syndrome involves initial injury to the endothelium, then potentiation of thrombus formation. Oxidized beta 2-glycoprotein complexes may bind to the endothelial cell surface, causing it to become the target of antibodies. The exact relationships between the factors are not yet understood.
The risk of a thrombotic event in an asymptomatic patient positive for all 3 factors—lupus anticoagulant, anticardiolipin antibody, and anti-beta 2-glycoprotein I antibody—is more than 5% per year.31
Manage thrombosis with anticoagulation
Khamashta et al,32 in a 1995 study, retrospectively studied patients with antiphospholipid antibodies and a history of thrombosis. Of 147 patients, 66 had idiopathic primary disease, 62 had systemic lupus, and 19 had “lupus-like” disease. Almost 70% (101 patients) had a recurrence of thrombosis, totaling 186 events. The mean time to recurrence was 12 months (range 2 weeks to 12 years). Recurrence rates were 0.01 events per patient per year with high-dose warfarin, 0.23 with low-dose warfarin, and 0.18 with aspirin. But the highest bleeding rates were in the 6 months after warfarin withdrawal; 29 patients had bleeding events, one-fourth of which were severe.
Standard therapy has become anticoagulation, starting with heparin or enoxaparin, then warfarin. There is inadequate evidence for the role of newer oral anticoagulant therapy.
A very high INR is not generally better than a moderately elevated level
For a time, it was thought that the international normalized ratio (INR) should be kept on the very high side to prevent thrombosis.
Crowther et al33 conducted a randomized, double-blind trial comparing moderate warfarin therapy (INR 2.0–3.0) and high-intensity warfarin therapy (INR 3.1–4.0) in antiphospholipid syndrome. Thrombosis actually recurred more frequently in the high-intensity therapy group (10.7% vs 3.4%), with no significant difference in major bleeding events.
A reasonable strategy is to keep the INR between 2.5 and 3.0, keeping in mind that values fluctuate in any individual patient. A higher goal often leads to excessive anticoagulation and bleeding. If the goal is too low, recurrent thrombosis becomes more likely. There are fewer data on the newer oral anticoagulants, but their role is likely to increase as reversal agents are developed.
Recommendations published in 2003 for treating antiphospholipid syndrome include34:
- Warfarin (INR 2.0–3.0) after the first thrombotic event
- Warfarin (INR 3.0–4.0) if a clot develops despite warfarin
- Warfarin (INR > 3.0) for an arterial event.
For the rare but catastrophic antiphospholipid syndrome in which thrombosis occurs in multiple organs, recommendations are for heparin plus steroids, with or without intravenous immunoglobulin and plasmapheresis. This approach has not always been successful, and the mortality rate is high.
Treatment of asymptomatic carriers is uncertain
Treatment of asymptomatic carriers of the antiphospholipid antibody is controversial. Evidence for management is scarce; some experts recommend aspirin therapy, but benefit has yet to be proven in clinical trials.
Canaud et al35 documented the role of activation of the kinase mammalian target of rapamycin (mTOR) in the vascular changes characteristic of antiphospholipid nephropathy. Postkidney transplant surveillance biopsies of patients with antiphospholipid antibodies showed vascular damage occurring over time (despite patients being asymptomatic) compared with other renal transplant patients. Patients with antiphospholipid antibodies who were treated with the immunosuppressive drug sirolimus were protected from developing these changes. Twelve years after transplant, 70% of patients with antiphospholipid antibodies taking sirolimus still had a functioning graft compared with 11% of untreated patients.
