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C H A P T E R 134

THROMBOTIC THROMBOCYTOPENIC PURPURA AND THE

HEMOLYTIC UREMIC SYNDROMES

Robert Schneidewend, Narendranath Epperla, and Kenneth D. Friedman

In 1924 Moschowitz reported a case of a 16-year-old girl who died eclampsia, HELLP syndrome [an acronym for hemolysis, elevated
of a previously undescribed illness characterized by microangiopathic liver function tests, and low platelet counts]), cryoglobulinemia,
hemolytic anemia (MAHA), petechiae, hemiparesis, and fever. or infection with rickettsial or, more rarely, hemorrhage-inducing
Postmortem examination revealed numerous hyaline thrombi, most viral organisms, may all mimic TMAs. Occasionally, patients with
prevalent in the terminal arterioles and capillaries of the heart and disseminated intravascular coagulation secondary to malignancy
kidneys. In 1936 four similar cases were reported by Baehr and or sepsis present with microangiopathy of sufficient severity to be
colleagues, who proposed that the hyaline thrombi were secondary to confused with primary TMAs (see Chapter 139). In the setting of
agglutinated platelets. In 1947 Singer suggested that the term throm- renal transplantation, a biopsy may be required to distinguish TMAs
botic thrombocytopenic purpura (TTP) be used to describe this disorder. from allograft rejection or recurrence of a preexisting renal vascular
In 1955 Gasser used the term hemolytic uremic syndrome (HUS) to disorder. Occasional patients present with acute pancreatitis, acute
describe a related syndrome consisting of Coombs-negative hemolytic respiratory distress syndrome, memory and personality changes, or
anemia, thrombocytopenia, and renal failure. The clinical features of other poorly defined neurologic symptoms, which have a broad dif-
Shiga toxin–associated HUS (ST-HUS) were described in six young ferential diagnosis.
children who presented with renal failure following a diarrheal illness Clues suggesting STEC-HUS include age at the time of presenta-
in 1962. An association to Shigella was recognized in 1975 and the tion, ingestion of undercooked ground beef or other food that might
linkage to Shiga toxin–producing E. coli (STEC) was made in 1983. have become contaminated by cattle, contact with farm animals, or
These disorders are now referred to as thrombotic microangiopathies concurrent HUS in another family member. History of asynchronous
(TMAs), based on their shared features of MAHA, thrombocyto- presentation in a sibling would suggest inherited TTP or aHUS.
penia, and microvascular thrombotic lesions with resultant organ Historical approaches to the distinction of TTP from aHUS have
dysfunction. relied heavily upon the age of presentation and distribution of
By definition, MAHA and thrombocytopenia are cardinal signs/ symptoms. However, as demonstrated by the recent trials showing
features of all TMA syndromes, leading to overlapping clinical and the utility of eculizumab, aHUS is not uncommonly diagnosed in
pathologic features. However, a multitude of different pathogenic adults. Similarly, there is significant end-organ dysfunction overlap
pathways lead to vascular endothelial injury in these conditions. The between these two disorders. While the kidney remains a major target
vast majority of cases of TTP appear to be caused by deficiency of organ in aHUS, renal injury of sufficient severity to require dialysis
ADAMTS13 (a disintegrin-like and metalloprotease with thrombos- may occur in up to 10% of patients with TTP. Neurologic symptoms
pondin type1 motif, family member 13), resulting in failure to are reported in 25% to 79% of patients diagnosed with TTP but may
control the interaction of von Willebrand factor (vWF) with platelets also be seen in 10% to 30% of patients with aHUS.
and subsequent organ dysfunction as a consequence of platelet-rich Choosing the appropriate therapy depends on an accurate diag-
thrombi formation in the microcirculation (and occasionally in large nosis. While symptoms may not support distinctions, several groups
vessels). Recent studies indicate that “atypical” hemolytic uremic have reported that platelet counts and creatinine levels are signifi-
syndrome (aHUS) is mainly attributable to a defect in the regulation cantly lower in patients with severe ADAMTS13 deficient TTP; it
of the complement mechanism and unregulated deposition of comple- has been suggested that a platelet count under 30,000/µL or a creati-
ment factor C3b on cellular surfaces. A rare autosomal recessively nine under 2.3 mg/dL favors a diagnosis of TTP. An ADAMTS13
inherited form of aHUS occurs in patients with defects in the gene level below 10% in the appropriate clinical context provides strong
encoding for diacylglycerol kinase epsilon (DGKE), which results in evidence for a diagnosis of TTP, although TTP should not be excluded
a shift of endothelial cells to a prothrombotic phenotype. Finally, in in patients with characteristic/prototypic presentation whose levels of
STEC-HUS, endothelial injury is caused by Shiga toxin and inflam- ADAMTS13 are not severely reduced. STEC infection should be
matory cytokines, perhaps inciting disease with increased frequency ruled out as soon as possible when infectious HUS is possible utilizing
in individuals with specific genetic predispositions. With improved appropriate microbiologic studies (stool culture, immunoassay for
understanding of the pathogenesis of TMAs and the availability of Shiga toxin or fecal polymerase chain reaction). Children may also
specific therapy that targets that pathogenesis, distinction of the merit testing for a cobalamin C defect, as defects of cobalamin
various TMA syndromes is clinically important. Several pathogenesis- metabolism may present with a similar hematologic picture (includ-
based classification schemes for TMAs have been developed; one ing thrombocytopenia, presence of bizarre microcytic red cells on the
example is illustrated in Fig. 134.1. peripheral blood film, and elevations of lactate dehydrogenase [LDH]
and bilirubin)
DIFFERENTIAL DIAGNOSIS
THROMBOTIC THROMBOCYTOPENIC PURPURA
The differential diagnosis of MAHA and thrombocytopenia is exten-
sive. An example of a decision tree is shown in Fig. 134.2. Vascular Clinical Manifestation
damage secondary to severe sepsis, autoimmune disorders (i.e., sys-
temic lupus erythematosus, scleroderma, antiphospholipid antibody The classic pentad of signs and symptoms that compose the TTP
syndrome, see Chapter 141), septic or tumor emboli, immune syndrome include MAHA, thrombocytopenia, neurologic impair-
complex-mediated vasculitis (e.g., infective endocarditis), malignant ment, fever, and renal dysfunction. More recent data have shown
hypertension, complications of pregnancy (severe preeclampsia, that the majority of TTP cases, which are caused by an acquired

1984