THROMBOTIC
MICROANGIOPATHY
The thrombotic microangiopathies are a group of
disorders that share common clinical and histopathologic features. Two major
types are known as thrombotic thrombocytopenic purpura (TTP) and hemolyticuremic
syndrome (HUS). TTP is characterized by systemic formation of occlusive
microvascular thrombi composed primarily of platelets, which cause organ
ischemia that is rapidly fatal if untreated. In HUS the microvascular thrombi
are primarily localized to the kidney, with acute kidney injury being the
principal clinical feature.
The major laboratory findings of
both TTP and HUS include thrombocytopenia, resulting from plate- let
consumption, and microangiopathic hemolytic anemia (MAHA), resulting from the
mechanical stress on erythrocytes as they pass through the narrow, thrombosed
vessels.
The distinction between TTP and HUS
is often made based on the organ system most affected. As stated previously,
HUS is said to feature prominent renal dysfunction, whereas TTP is said to
feature more systemic abnormalities, including neurologic findings. In some
cases, however, both disease processes can be associated with both renal and
neurologic symptoms. Thus a simple classification scheme based on symptoms is
often unreliable. Recent research, however, has helped elucidate the actual mechanisms
that underlie HUS and TTP, which may eventually permit rapid differentiation
and focused treatment irrespective of the presenting symptoms.
PATHOPHYSIOLOGY
Hemolytic Uremic Syndrome. HUS may occur in multiple settings, but more than 90% of cases (termed
“typical HUS”) are related to infection with bacteria that produce Shiga-like
toxins (Stx). In a small number of patients infected with such bacteria, Stx
enters the general circulation and binds to receptors on glomerular endothelial
cells. The toxin causes extensive endothelial damage and promotes increased
expression of cytokines, chemokines, and cell adhesion molecules. The resulting
inflammation triggers platelet activation and diffuse thrombosis of
the renal microvasculature. Bacteremia is neither necessary for this process
nor commonly observed.
The incidence is highest in
children under 5 years of age, among whom there are 6.1 cases per 100,000
persons per year. The major pathogen is Stx-producing E.
coli O157:H7, but other E.
coli serotypes may also be responsible. Infection with these pathogens
results from ingestion of contaminated food (usually under-cooked ground beef
or dairy) or water. Because these pathogens also cause diarrhea in a majority
of cases, typical HUS is also known as diarrhea-associated (D+) HUS. The distinct age-related incidence of this condition could be
explained by a greater affinity of glomerular endothelial cells for Stx
in young children.
Atypical HUS (also called D-HUS because it lacks a diarrhea prodrome), in contrast, may occur for
numerous reasons. In some patients, it appears to reflect dysregulated
activation of the complement system, which leads to endothelial damage and
platelet aggregation. Affected individuals have been found to possess mutations
in genes encoding inhibitors of the alternative, C3b-mediated complement
pathway. These inhibitors include factor H, factor C, factor I, factor B, and
membrane cofactor protein (MCP). If severe enough, these mutations cause
spontaneous and recurrent activation of the complement system starting in
childhood.
The reason for the particular
susceptibility of the renal circulation is not clear; however, it has been
postulated that the presence of endothelial fenestrations in the glomerulus
increases exposure of the circulating factors to subendothelial proteins, which
may serve as a focus for complement activation. Patients with such mutations
often have a family history of similar events and are the
refore said to have a “familial” form of atypical HUS.
The remaining patients with
atypical HUS have a “sporadic” form that is either idiopathic or related to
triggers, such as pregnancy, infection (e.g., Streptococcus pneumoniae),
and certain drugs (e.g., quinine, cyclosporine, tacrolimus). The mechanisms are
probably diverse. Quinine, for example, appears to modify an epitope on
platelets, leading to binding of antibodies. S. pneumoniae is believed
to produce an enzyme that can expose a cryptic antigen on erythrocytes,
platelets, and glomeruli endothelial cells, leading to an autoimmune response.
Finally, it is possible that some patients have complement mutations that do
not cause thrombosis under normal physiologic conditions, but which lead to
thrombosis in response to the endothelial damage associated with certain
triggers.
Thrombotic Thrombocytopenic
Purpura. TTP generally
involves more diffuse thrombus formation than HUS. It also occurs in both
familial and sporadic forms. The main pathogenetic factor appears to be a
deficiency of a normal plasma enzyme, ADAMTS13 (A Disintegrin and
Metalloprotease with ThromboSpondin type 1 domains, member 13), that is
required for processing of von Willebrand factor (vWF) multimers. In normal
conditions, endothelial cells constitutively secrete a range of vWF multimers,
including unusually large multimers (ULvWF). These unusually large vWF
multimers have a much higher platelet binding affinity than the smaller
multimers, but under normal conditions they undergo cleavage by ADAMTS13
immediately after release. In TTP, ADAMTS13 may be absent or dysfunctional, and
the resulting circulation of ULvWF can cause formation of platelet-rich
thrombi.
The familial form of TTP, known as
Upshaw-Schul-man syndrome, accounts for a very small fraction of cases. In this
case, there is near total absence of the ADAMTS13 protein. The disease often
appears shortly after birth, with subsequent relapses occurring in the setting
of infection, pregnancy, or other physiologic stressors, presumably because of
increased ULvWF multimer production. In some cases, however, the first episode
may not occur until these stressors are experienced in adulthood. Inheritance
follows an autosomal recessive pattern.
A sporadic, acquired form of TTP
accounts for a majority of cases and typically affects adults. Most cases
appear to reflect abnormal production of anti-ADAMTS13 IgG autoantibodies, which
either promote clearance of ADAMTS13 or neutralize its binding site. It is not
known why certain individuals develop these antibodies, which often disappear
after symptoms resolve.
Secondary TTP may occur in
susceptible individuals, such as in the setting of pregnancy. It is not clear
why certain triggers cause systemic platelet thrombosis; however, it is
possible that ongoing endothelial stress leads to an overwhelming increase in
ULvWF secretion.
PRESENTATION AND DIAGNOSIS
Patients with either TTP or HUS can
have acute kidney injury, manifesting as oliguria,
fatigue, nausea, and
vomiting; fluctuating neurologic symptoms, such as seizures, focal deficits, or
even coma; or both. In addition, patients may have fever and purpura, although
overt bleeding is unusual. These symptoms are often sudden, but in up to one
fourth of patients they can be present for weeks before presentation.
On further investigation, patients
are found to have thrombocytopenia, with platelet counts often below 20,000/µL; MAHA, evidenced as
numerous schistocytes on a peripheral blood smear; and
elevated lactate dehydrogenase (LDH). Serum creatinine concentration is
elevated if there is renal involvement, and urinalysis may be normal or reveal
RBCs and mild proteinuria. Prothrombin and partial thromboplastin times, as
well as levels of individual clotting factors, should be normal in both TTP and
HUS and can help facilitate the distinction from disseminated intravascular
coagultion (DIC).
The laboratory findings of thrombocytopenia,
elevated LDH, and schistocytosis in the absence of another apparent cause (such
as DIC, malignant hypertension, or recent stem cell transplantation) are
sufficient to make the diagnosis of TTP or HUS.
TREATMENT
The definitive distinction between
TTP and HUS is neither possible nor necessary in the acute setting. In all
patients, the drug regimen should be examined and potential precipitants
stopped. Supportive care should focus on managing fluid and electrolyte status,
treating hypertension, and offering dialysis, packed RBC transfusions, or
antiepileptic drugs as needed. The indications for dialysis in TTP and HUS are
the same as in other settings. Platelet transfusion should not be performed
unless there is overt bleeding or an invasive procedure is required because it
may precipitate the formation of additional thrombi.
Further management depends on
patient characteristics and clinical findings. Infants and young children
with a recent history of bloody diarrhea, for example, likely have typical HUS
and usually recover completely with supportive therapy alone. Plasma
exchange/infusion and Shiga-toxin binding agents do not appear to improve
outcomes. Antimotility agents and antibiotics may actually worsen the toxinmediated
damage. In most patients, hematologic markers will return to normal within 1 to
2 weeks. Infants and young children without a recent history of bloody diarrhea
could have typical HUS, atypical HUS, or Upshaw-Schulman syndrome. In this
case, patients typically receive plasma infusions, which replace the missing
factors in the hereditary conditions. Genetic testing should be
performed to guide further management.
Older children and adults could
have any form of TTP or HUS, and the distinction is often unclear at initial
presentation. For example, adults with a recent history of bloody diarrhea
could have typical HUS caused by E. coli 0157:H7 infection or TTP with
mesenteric ischemia. Likewise, the presence of a potential trigger for either
secondary TTP or atypical HUS does not exclude the possibility of idiopathic
TTP.
Thus plasma exchange should be
offered to all older children and adults to remove possible ADAMTS13
autoantibodies. After the initiation of plasma exchange, symptoms and
laboratory markers should improve within 1 to 3 days. If there is a lack of
response, patients may be candidates for pharmacologic immunosuppression, which
reduces the production of autoantibodies.
PROGNOSIS
In children, the prognosis of
typical HUS is excellent if appropriate supportive care is given, with
most recovering normal renal function. All patients should undergo annual
monitoring for late complications such as hypertension and mild proteinuria.
Relapses are very rare. In familial D-HUS, the prognosis depends on the
responsible mutation. For example, patients with complement factor H mutations
may become dependent on plasma exchange. The possible role of complement
cascade inhibitors such as eculizumab, an anti-C5 monoclonal antibody, is
currently under investigation.
In adults, the prognosis of
untreated TTP or HUS is extremely poor, with survival rates of only 10%. With
plasma exchange, however, survival rates have improved to 80%, although
relapses occur in one third of patients with TTP associated with ADAMTS13
autoantibodies. Chronic kidney disease generally does not occur in patients
with ADAMTS13 autoantibodies; however, patients may report persistence of minor
cognitive symptoms, such as poor concentration or memory.
