Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Thrombotic thrombocytopenic microangiopathies are a group of disorders characterized by

thrombocytopenia, 
a microangiopathic hemolytic anemia evident by fragmented RBCs and 
laboratory evidence of hemolysis, and microvascular thrombosis. 

This includes thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), as well as syndromes complicating bone marrow transplantation, certain medications and infections, pregnancy, and vasculitis. In DIC, while thrombocytopenia and microangiopathy are seen, a coagulopathy predominates, with consumption of clotting factors and fibrinogen resulting in an elevated prothrombin time (PT) and often activated partial thromboplastin time (aPTT). The PT and aPTT are characteristically normal in TTP or HUS.




Thrombotic Thrombocytopenic Purpura


TTP and HUS were previously considered overlap syndromes. However, in the past few years the pathophysiology of inherited and idiopathic TTP has become better understood and clearly differs from HUS. TTP was first described in 1924 by Eli Moschcowitz and characterized by a pentad of findings that include microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic findings, and fever. The full-blown syndrome is less commonly seen now, probably due to earlier diagnosis. The introduction of treatment with plasma exchange markedly improved the prognosis in patients, with a decrease in mortality from 85–100% to 10–30%.

The pathogenesis of inherited (Upshaw-Schulman syndrome) and idiopathic TTP is related to a deficiency of, or antibodies to, a metalloprotease that cleaves vWF and ADAMTS13, respectively.

vWF is normally secreted as ultra-large multimers, which are then cleaved by ADAMTS13. The persistence of ultra-large vWF molecules are thought to contribute to pathogenic platelet adhesion and aggregation . This defect alone, however, is not sufficient to result in TTP as individuals with a congenital absence of ADAMTS13 develop TTP only episodically. Additional provocative factors have not been defined. The level of ADAMTS13 activity, as well as antibodies, can now be detected by laboratory assays. However, assays with sufficient sensitivity and specificity to direct clinical management have yet to be defined.

Figure



Pathogenesis of thrombotic thrombocytopenic purpura (TTP).

 Normally the ultra-high molecular-weight multimers of von Willebrand factor (vWF) produced by the endothelial cells are processed into smaller multimers by a plasma metalloproteinase called ADAMTS13. In TTP the activity of the protease is inhibited, and the ultra-high molecular-weight multimers of vWF initiate platelet aggregation and thrombosis.

Idiopathic TTP appears to be more common in women than in men. No geographic or racial distribution has been defined. TTP is more common in patients with HIV infection and in pregnant women.

 Medication-related TTP may be secondary to antibody formation (ticlopidine and possibly clopidogrel) or direct endothelial toxicity (cyclosporine, mitomycin C, tacrolimus, quinine), although this is not always so clear, and fear of withholding treatment, as well as lack of other treatment alternatives, results in broad application of plasma exchange. However, withdrawal, or reduction in dose, of endothelial toxic agents may decrease the microangiopathy.

Thrombotic Thrombocytopenic Purpura: Treatment

TTP is a devastating disease if not diagnosed and treated promptly. In patients presenting with new thrombocytopenia, with or without evidence of renal insufficiency and other elements of classic TTP, laboratory data should be obtained to rule out DIC and to evaluate for evidence of microangiopathic hemolytic anemia.

 Findings to support the TTP diagnosis include an
increased lactate dehydrogenase
 indirect bilirubin,
 decreased haptoglobin, 
increased reticulocyte count
negative direct antiglobulin test.

The peripheral smear should be examined for evidence of schistocytes (Fig. 109-1D). Polychromasia is usually also present due to the increased number of young red blood cells, and nucleated RBCs are often present, which is thought to be due to infarction in the microcirculatory system of the bone marrow.


Plasma exchange remains the mainstay of treatment of ITP. ADAMTS13 antibody–mediated TTP (idiopathic TTP) appears to respond best to plasma exchange. Plasma exchange is continued until the platelet count is normal and signs of hemolysis are resolved for at least 2 days. While never evaluated in clinical trial, the use of glucocorticoids seems a reasonable approach, but they should only be used as an adjunct to plasma exchange. Additionally, other immunomodulatory therapies have been reported to be successful in refractory or relapsing TTP, including rituximab, vincristine, cyclophosphamide, and splenectomy. The role of rituximab in the treatment of this disorder needs to be defined. A significant relapse rate is noted: 25–45% within 30 days of initial "remission" and 12–40% with late relapses. Relapses may be more frequent in patients with severe ADAMTS13 deficiency at presentation.

Hemolytic Uremic Syndrome


HUS is a syndrome characterized by acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. It is seen predominantly in children and in most cases is preceded by an episode of diarrhea, often hemorrhagic in nature. Escherichia coli O157:H7 is the most frequent, although not only, etiologic serotype. HUS not associated with diarrhea (termed D-HUS) is more heterogeneous in presentation and course. Some children who develop D-HUS have been found to have mutations in genes encoding Factor H, a soluble complement regulator, and membrane cofactor protein that is mainly expressed in the kidney.

Hemolytic Uremic Syndrome: Treatment


Treatment of HUS is primarily supportive. In D+HUS, many (~40%) children require at least some period of support with dialysis; however, the overall mortality is <5%. In D–HUS the mortality is higher, approximately 26%. Plasma infusion or plasma exchange has not been shown to alter the overall course. ADAMTS13 levels are generally reported to be normal in HUS, although occasionally they have been reported to be decreased. As ADAMTS13 assays improve, they may help in defining a subset that better fits a TTP diagnosis and may respond to plasma exchange.