Thrombotic thrombocytopenic purpura classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Classification
Roughly, there are two forms of TTP: idiopathic and secondary TTP. A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Schulman syndrome.
The differential diagnosis of TTP includes hemolytic-uremic syndrome (HUS; which has neurosymptoms, renal failure, hypertension and fever). Note that ADAMTS13 activity is normal in HUS.
Idiopathic TTP
The idiopathic form of TTP was recently linked to the inhibition of the enzyme ADAMTS13 by antibodies, rendering TTP as an autoimmune disease. von Willebrand factor (vWF) is a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation. ADAMTS13 is a proteinase responsible for the breakdown of VWF; very large VWF molecules are prone to coagulation. Without proper cleavage of VWF by ADAMTS13, these unusually large VWF cause coagulation at a higher rate, especially in the part of the circulatory system where VWF is most active due to high shear stress - in the microvascualture, thereby causing thrombi.
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%). The relationship of reduced ADAMTS13 to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent researchers who published their research in the same issue of the New England Journal of Medicine in 1998.[1][2][3] This theory is seen as insufficient to explain the etiology of TTP, since many patients with a hereditary lack of ADAMTS13 activity do not manifest clinical symptoms of TTP.
Congenital or acquired ADAMTS13 deficiency causes TTP; acute TTP in adults is usually due to an acquired atuoantibody to ADAMTS13. However, as stated before, cases of plasma exchange-responsive acute TTP have been reported in patients who have no evidence of an autoantibody to ADAMTS13 and patients with congenital ADAMTS13 deficiency may not manifest TTP until adulthood. Autoantibodies against ADAMTS13 present in a majority of patients with idiopathic TTP and, additionally, ticlopidine and clopidogrel associated TTP. Severe deficiency of ADAMTS13 activity (<5%) is a specific feature of TTP. Normal levels of ADAMTS13 do NOT rule out the diagnosis of TTP. Normally there is only a slight increase in D-dimers, FDP and thrombin-antithrombin complexes in acute TTP. Secondary DIC may arise due to prolonged tissue ischemia and is an ominous prognostic sign.
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; (TBI is a risk factor).
- Pregnancy; rare.
- Medication use:
- Platelet aggregation inhibitors (ticlopidine and clopidogrel)
- Immunosuppressants (cyclosporine, 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 inhibitors cannot be detected. The probable etiology may involve, at least in some cases, endothelial damage. A small fraction of patients treated for arterial thrombosis with the platelet P2Y12 adenosine diphosphate receptor inhibiting thienopyridine drugs ticopidine (Ticlid) or clopidogrel (Plavix) develop TTP within a few weeks after the initiation of treatment. Autoantibodies that inhibit plasma ADAMTS13 have been demonstrated in a few patients with Ticlid-associated or Plavix-associated TTP, indicating a possible immune dysregulation induced by these similar thienpyridine compounds. Ticlodipine-associated TTP may respond to drug withdrawal and plasma exchange whereas TTP-like syndromes occuring after transplantation (often in associated with cyclosporine or FK506) are less likely to be responsive to plasma exchange treatment.
Upshaw-Schulman syndrome
A hereditary form of TTP is called the Upshaw-Schulman 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-Schulman syndrome.
References
- ↑ Moake JL (1998). "Moschcowitz, multimers, and metalloprotease". N. Engl. J. Med. 339 (22): 1629–31. PMID 9828253.
- ↑ Furlan M, Robles R, Galbusera M; et al. (1998). "von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome". N. Engl. J. Med. 339 (22): 1578–84. PMID 9828245.
- ↑ Tsai HM, Lian EC (1998). "Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura". N. Engl. J. Med. 339 (22): 1585–94. PMID 9828246.