Abstract

Background: Severe deficiency of ADAMTS13, the VWF-cleaving protease (<5% of normal) is a specific finding for a thrombotic microangiopathy (TMA) most often labeled clinically as thrombotic thrombocytopenic purpura (TTP). The sensitivity of severe ADAMTS13 deficiency for the clinical diagnosis of idiopathic TTP, however, remains equivocal with an overall sensitivity of about 60% (range 33–100%). This indicates, that other pathogenetic factors may lead to a condition clinically indistinguishable from that seen in severe ADAMTS13 deficiency. Recently, Raife (

Blood
2002
;
99
:
437
–442
) concluded from a small case series including 27 Caucasians with acute TMA, that factor V Leiden (FVL) represented such a risk factor in a subset of TMA patients without severe ADAMTS13 deficiency. The consequence could be a more individualized treatment regimen including anticoagulant drugs complementing plasma exchange therapy in this subset of patients. Therefore, our aim was to estimate the prevalence and risk of FVL carriers in relation to ADAMTS13 activity levels and clinical TMA diagnosis in a large patient group presenting with acute TMA.

Methods: Between January 2001 and July 2003 ADAMTS13 activity was determined in 396 consecutive patients referred to our laboratory for diagnostic purposes. Based on the clinical and patient data provided by the referring clinicians 131 patients were excluded from this study (no clinical information available [n=45]; no acute TMA [50]; no plasma left [26]; non-Caucasians [3] and various reasons [7]). The remaining 265 patients were assigned to three principal clinical categories: idiopathic TMA (n=204, among them 80 patients with the clinical diagnosis of TTP and 124 cases with hemolytic-uremic syndrome [HUS]), secondary TMA (30) and TMA not further specified (31). ADAMTS13 activity was assessed by a quantitative immunoblotting assay. FVL carrier-ship was determined by a commercial aPTT-based APC resistance assay and in cases with prolonged base-line aPTT (>42s), decreased factor V clotting activity (<50%) or equivocal APC sensitivity ratio by genotyping using DNA purified from patient’s plasma.

Results: A severe ADAMTS13 deficiency was found in 22% (59/265) of patients investigated, among them none of the HUS cases but 49 patients diagnosed as having TTP. Twenty-one (7.9%) of all patients were FVL carriers consistent with the FVL prevalence reported for Europe (0.9–14%), especially however, for Germany (4–8.9%) and Switzerland (3–7%), who referred most patients (176 [66.4%] and 52 [19.6%], respectively). Similar allele frequencies were observed among patients diagnosed as TTP (6.3%, 5/80) or HUS (8.9%, 11/124). The difference between the latter two was statistically not significant (p=0.497, chi-square test). FVL was found in 6.8% (4/59) of patients with severe ADAMTS13 deficiency and in 8.3% (17/206) without severe ADAMTS13 deficiency (p=0.712, chi-square test). Data did not change when the cut-off level for severe ADAMTS13 deficiency was raised to an ADAMTS13 activity of 10%.

Conclusions: We conclude, that FVL is not more prevalent in patients with acute TMA without severe ADAMTS13 deficiency than in TMA patinets with severe ADAMTS13 deficiency. Furthermore, there is no difference in the FVL prevalence in patients diagnosed as having HUS or TTP. Based on our results, FVL is not a risk factor for acute TMA and pathogenetically not involved in acute TMA without ADAMTS13 deficiency.

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