Thrombotic thrombocytopenic purpura: Meaning (information, definition, explanation, facts)

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of the blood coagulation system that arises from the deficiency or inhibition of the enzyme responsible for cleaving von Willebrand factor.

Signs and symptoms

• Fluctuating neurological symptoms, such as bizarre behavior, altered mental status, stroke or headaches (65%)
• Kidney failure (46%)
• Fever (33%)

Examination of the blood film, which is essential for the diagnosis, shows:

• Low platelet count;
• Microangiopathic haemolytic anaemia - red blood cells break down through factors in the small blood vessels; this shows as schistocytes (fragmented red cells) and "helmet cells" on the blood film.

Other tests to be performed are reticulocyte counts, lactate dehydrogenase, direct antiglobulin test (DAT/Coombs' test), renal function (creatinine), electrolytes and liver enzymes.

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 (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. These dilutions are then mixed with normal plasma. If ADAMTS13 activity can be detected in all dillutions, then no inhibitor is detectable. If decreased acitivity is limited to low dilutions, there are low inhibitor concentrations, while decreased activity in all or most dillutions shows high inhibitor levels.

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 Shulman-Upshaw 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 (cyclosporine A, 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.

Shulman-Upshaw syndrome

A hereditary form of TTP is called the Shulman-Upshaw 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 Shulman-Upshaw syndrome.

Since the early 1990s, plasmapheresis has become the treatment of choice for TTP. This is the removal of the patient's blood plasma 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 treatment and the rate of hemolysis.

Many TTP patients need additional immunosuppressive therapy, with steroids (prednisone), vincristine, cyclophosphamide, splenectomy or a combination of the above.

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

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.

The mortality rate is approximately 95% for untreated cases, but the prognosis is reasonably high (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 an dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.

• Moake JL. Thrombotic microangiopathies. N Engl J Med 2003;347:589-600.
• 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.
• eMedicine - Thrombocytopenic purpura