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2260 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2261

TABLE 132–2. Complement Defects in Atypical Hemolytic of aHUS may be approximately 50 percent for mutations in any of the
predisposing genes.
138,139
Uremic Syndrome
Progression CLINICAL FEATURES
Gene or Prevalence to End-Stage
Subgroup in aHUS Low C3 Renal Disease Death Approximately 20 percent of patients have a subacute or chronic course
CFH 25–30% 50–60% 50–60% 5–20% of mild anemia, variable thrombocytopenia and relatively normal renal
function. However, patients usually present acutely with thrombotic
CFI 4–10% 20–50% ~60% 0–10% microangiopathy and renal failure, sometimes with progressive hyper-
MCP 7–10% 6–30% 6–35% 0% tension. Most patients report a possible triggering event such as a viral
or bacterial upper respiratory infection, gastroenteritis, or pregnancy.
CFB <1.5% ≤100% ~50% 0%
aHUS is not classically preceded by bloody or painful diarrhea. 138,139
C3 4–8% 70–80% 55–70% 0% Women with pregnancy-associated aHUS usually present postpar-
THBD (TM)* <5% ~50% ~50% ~30% tum. Most of the rest develop symptoms in the third trimester, some-
times complicated by fetal loss and preeclampsia. 142
Anti– 3–7% ~40% 30–60% 0%
complement Extrarenal symptoms occur in 10 to 20 percent of patients. Central
factor H nervous system involvement is most common. Myocardial infarction,
antibody pancreatitis, and necrosis of skin or digits have been reported. Extrare-
nal involvement is relatively uncommon for aHUS caused by MCP
No mutation 30–50% ~20% ~40% 3–7%
mutations. 138,139
Based on outcomes after 5 years from the International Registry of
Recurrent and Familial HUS/TTP and after 3 years from the French LABORATORY FEATURES
138
Study Group for aHUS. 139
*THBD is the gene for thrombomodulin. Patients have the laboratory findings characteristic of microangiopathic
hemolysis, as observed for TTP and STEC-HUS. The mean platelet
count in aHUS is 40 × 10 /L, typically higher than in TTP. Serum crea-
9
cofactor protein (MCP, CD46). These cofactors are structurally and
functionally similar, but factor H is a plasma protein whereas MCP tinine can be markedly elevated, with microhematuria and proteinuria
is a transmembrane protein found on the surface of almost all cells. if the patient is not anuric.
If not restrained by these inhibitors, C3b interacts with factor B to Complement C4 is usually normal and C3 may be low, consistent
form a potent C3 convertase that amplifies the deposition of C3b, with activation of the alternative complement pathway, but the likeli-
which attracts phagocytes and promotes membrane attack complex hood of a low C3 level varies considerably and depends on the involved
formation on renal glomerular and arteriolar endothelium and base- locus (see Table 132–2). Approximately 3 to 7 percent of patients have
ment membrane. The resultant vascular damage causes thrombotic autoantibodies against CFH that can be detected by ELISA. In favor-
microangiopathy. able cases, flow cytometry on peripheral blood leukocytes can identify
Heterozygous mutations in alternative complement pathway pro- cell-surface MCP deficiency for patients with MCP mutations. Assays of
teins have been identified in 60 to 70 percent of patients with aHUS CFH and CFI may be useful to identify specific deficiencies, but patients
(Table 132–2). These include loss-of-function mutations in factor H, are usually heterozygous and mutations at these loci may not clearly
138,139
MCP, factor I, complement factor H-related proteins 1 and 3 (CFHR1, decrease the factor levels.
CFHR3), and thrombomodulin (TM); and gain-of-function mutations DNA sequencing should be considered to detect mutations in
in factor B and C3. In addition, autoantibodies to factor H have been CFH, CFI, MCP, C3, CFB and TM before renal transplantation because
identified in some patients with aHUS, often in association with muta- the risk of relapse and need for subsequent prophylaxis depends on the
tions in CFHR1 and CFHR3. Patients sometimes have mutations at affected locus. Candidate mutations in one of these loci or antibodies to
more than one locus, or a combination of autoantibodies to CFH and CFH can be found in approximately 70 percent of patients with aHUS.
mutations. 138,139 Sequencing of DGKE should be considered for patients presenting
Homozygous or compound heterozygous mutations in diacylglyc- before age 1 year.
erol kinase ε (DGKE) cause aHUS with high penetrance that presents As in STEC-HUS, renal lesions in aHUS are rich in fibrin but poor
before 1 year of age with hypertension, hematuria, and proteinuria. in platelets or VWF.
How DGKE mutations cause aHUS is not established. DGKE mutations
may account for a few percent of aHUS. 140 DIFFERENTIAL DIAGNOSIS
Signs and symptoms consistent with aHUS may occur in TTP or STEC-
HUS, and distinguishing among these entities is important because they
EPIDEMIOLOGY are treated differently. Correct diagnosis is not always straightforward.
Atypical HUS affects approximately 5 percent as many children as develop For example, MCP mutations may cause thrombotic microangiopathy
STEC-HUS, with an estimated incidence of two per million population without renal insufficiency that resolves coincidentally during a course
per year. Approximately one-half of patients are younger than age of plasma exchange and therefore resembles TTP except for normal
141
18 years. Approximately 60 percent of affected children have their first ADAMTS13 activity. Infection with STEC may be difficult to doc-
143
episode of aHUS before age 2 years, and 25 percent before age 6 months. ument, and some patients with STEC-HUS do not have a diarrheal
In contrast, STEC-HUS is rare before age 6 months. Most adults have prodrome. 121
their first episode of aHUS between ages 20 and 40 years. Childhood Secondary causes of thrombotic microangiopathy should be con-
aHUS affects males and females equally, whereas onset in adults dis- sidered (see Table 132–1). For children, conditions that usually present
proportionately affects females mainly because of disease triggered by in that age group deserve special attention such as Streptococcus pneu-
pregnancy. Analysis of relatives of probands shows that the penetrance moniae infections and inherited cobalamin defects.

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