Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP or Moschcowitz disease) is a rare disorder of the blood coagulation system that in most cases arises from the deficiency or inhibition of the enzyme ADAMTS13, which is responsible for cleaving large multimers of von Willebrand factor. It is a serious condition that leads to hemolysis and end-organ damage, and may require plasmapheresis therapy.

Signs and symptoms

Classically, the following five symptoms are indicative of this elusive disease:

Fluctuating neurological symptoms, such as bizarre behavior, altered mental status, stroke or headaches (65%)
Kidney failure (46%)
Fever (33%)
Thrombocytopenia (low platelet count), leading to bruising or frank purpura;
Microangiopathic haemolytic anaemia (anemia and a characteristic blood film)

Diagnosis

The combination of the symptoms and a routine blood film often lead to the detection of schistocytes (fragmented red cells) and "helmet cells" on the blood film. This is indicative of breakdown of red blood cells through factors in the small blood vessels.

Other tests to be performed are reticulocyte counts, lactate dehydrogenase, direct antiglobulin test (DAT/Coombs' test), renal function (creatinine), electrolytes and liver enzymes. Very high LDH levels may be present; these mainly originate from the poorly perfused tissues, and not so much from the hemolysis.

The above symptoms and findings are the main criteria for diagnosis, although the fever, renal and neurological symptoms can be absent. Increased lactate dehydrogenase levels and a negative direct antiglobulin test (DAT, Coombs' test) in the context of microangiopathic haemolytic anaemia (MAHA) are indicative of TTP.

The main differential diagnosis is between TTP and hemolytic uremic syndrome (HUS). The syndromes show a remarkable overlap in symptoms, and researchers have argued in the past that the two diseases are part of a continuum. Generally, HUS leads mainly to renal symptoms, while neurological abnormalities tend to be rare in HUS. Also, many HUS cases are preceded by an episode of bloody diarrhea due to infection with a verotoxin-positive H7 (enterohemorrhagic strain).

Although its utility in clinical settings is still under discussion, measurement of the von Willebrand factor-cleaving metalloproteinase ADAMTS13 (see below) and IgG inhibitors to this enzyme have been shown to aid in the diagnosis of TTP. In the series reported by Zheng et al (2004), low ADAMTS13 activity and detection of an inhibitor predicted response to therapy, and high titres of the inhibitor predicted the necessity of additional therapy.

The inhibitor is measured by inactivating innate ADAMTS13 in the patient's plasma by heating it, and then diluting it (1:1, 1:2, 1:4 etc) in saline by titration. These dilutions are then mixed with normal plasma. If ADAMTS13 activity can be detected in all dilutions, then no inhibitor is detectable. If decreased activity is limited to low dilutions, there are low inhibitor concentrations (low titers), while decreased activity in all or most dilutions shows high inhibitor levels.

Causes

TTP (as with other MAHAs) is caused by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the coagulation process, and the fibrin mesh quite literally "tears apart" red blood cells, leading to hemolysis.

Roughly, there are two forms of TTP: idiopathic and secondary TTP. A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Shulman syndrome.

Idiopathic TTP

The idiopathic (literally: of unknown cause) form of TTP was recently linked to the inhibition of the enzyme ADAMTS13 by antibodies, rendering TTP an autoimmune disease. ADAMTS13 is a metalloproteinase responsible for the breakdown of the so-called von Willebrand factor (vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation. Very large vWF molecules are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the part of the blood vessel system where vWF is most active due to high shear stress: in the microvasculature.

In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44-56%).

Secondary TTP

Secondary TTP is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:

Cancer
Bone marrow transplantation
Pregnancy
Medication use:
- Platelet aggregation inhibitors (ticlopidine and clopidogrel)
- Immunosuppressants (ciclosporin, mitomycin, tacrolimus/FK506, interferon-α)
HIV-1 infection

The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inihibitors cannot be detected.

Upshaw-Shulman syndrome

A hereditary form of TTP is called the Upshaw-Shulman syndrome; this is generally due to inherited deficiency of ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factor levels, e.g. infection. Reportedly, 5-10% of all TTP cases are due to Upshaw-Shulman syndrome.

Treatment

Since the early 1990s, plasmapheresis has become the treatment of choice for TTP. This is the removal of the patient's blood plasma through apheresis and replacement with donor's plasma (fresh frozen plasma or cryosupernatant); the procedure has to be repeated daily to eliminate the inhibitor and ablate the symptoms. Lactate dehydrogenase levels are generally used to monitor disease activity.

Many TTP patients need additional immunosuppressive therapy, with steroids (prednisone), vincristine, cyclophosphamide, splenectomy or a combination of the above. Rituximab, a monoclonal antibody targeting B cells, has been successfully been used to treat patients with refractory disease.

Children with Upshaw-Shulman syndrome receive plasma every three weeks prophylactically; this maintains adequate levels of functioning ADAMTS13.

Epidemiology

The incidence of TTP is about 3-6 per million people per year. As with most other autoimmune disorders, idiopathic TTP occurs more often in women and blacks, while the secondary forms do not show this distribution.

Prognosis

The mortality rate is approximately 95% for untreated cases, but the prognosis is reasonably favorable (80-90%) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.

Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.

Secondary TTP still has a dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.

History

TTP was initially described in a 16-year old girl by a Dr Eli Moschcowitz of New York City in 1924. Moschcowitz ascribed the disease (incorrectly) to a toxic cause.

References

Moake JL. Thrombotic microangiopathies. N Engl J Med 2003;347:589-600. PMID 12192020.
Moake JL. Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Semin Hematol 2004;41:4-14. PMID 14727254.
Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc NY Pathol Soc 1924;24:21-4. Reprinted in: Mt Sinai J Med 2003;70:352-5. PMID 14631522.
Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004;103:4043-9. PMID 14982878.

External links

Autoimmune diseases | Hematology | Rare diseases

Thrombotisch-thrombozytopenische Purpura | Purpura thrombotique thrombocytopénique | 血栓性血小板減少性紫斑病

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