The Study of Clinical Chracteristics and Pathogenesis of Thrombotic Thrombocytopenic Purpura
|Keywords||thrombotic thrombocytopenic purpura ADAMTS13 treatment gene mutation|
ObjectiveThrombotic Thrombocytopenic Purpura (TTP) is a form of thrombotic microangiopathy, once was a lethally disease with 90% mortality before the introduction of plasma exchange therapy. We analysed 30 cases with TTP from The First Affiliated Hospital of Soochow University and 100th Hospital of PLA from Jan.2007 to Mar. 2011. We aimed to conclude the clinical characteristics, laboratorial features, therapy and prognosis of TTP, based on this group patients and explore effective method of diagnosis and treatment. At the sametime, we analysed ADAMTS13 gene of highly suspected hereditary TTP to explore the relation between mutation of ADAMTS13 gene and the episodes of TTP.MethodsWe retrospectively reviewed clinical, laboratory, treatment and outcome data of 30 TTP patients who confirmed and received treatment in The First Affiliated Hospital of Soochow University and 100th Hospital of PLA from Jan.2007 to Mar. 2011. We extracted genomic DNA from the peripheral blood of highly suspected hereditary TTP patients, amplified 29 exons, intron boundaries of ADAMTS13 by PCR. The PCR products were subjected to agarose gel electrophoresis, and then screened by direct sequencing.Results1. We found:①the male-to-female ratio was approximately 1:4, the median age was 40, the maximal age was 90, the minimal age was 13 ; mortality rate was 10% (2 died after first plasma exchange, 1 died without plasma exchange); the relapse rate was 22%, 6 patients relapsed within 1 month( 2 hereditary TTP patients relapsed about every 2 weeks and others relapsed only once up to now.②When admission to hospital, 11 patients (37%) had typical pentalogy of TTP, 11 patients (37%) had 4 symptoms,3 patients (10%) had 3 symptoms, 4 patients (13%) had 2 symptoms of typical pentalogy of TTP, and 1 patient (3%) only represented fever. From other side, 90% patients had microangiopathic hemolytic anemia, 90% patients had neurologic abnormalities, 73% had renal abnormalities, 70% had thrombocytopenia and 67% had fever ( the median was 38℃) .℃7 6% patients had haemoglobin≤90g/L; 76% patients had platelet count <30×109/L; 70.83% patients had LDH >1000 U/L ; 76.5% ( 15/17 ) patients’ADAMTS13 activity <10%; 72% could find schistocyte on the blood film(≥1%); 66.7% patients had plasma free hemoglobin .④71%(15/21) patients had impairment of myocardial or other muscle.⑤Compared to patients who had bad prognosis ( include died or gave up treatment) , patients who achieved a complete response have distinctly lower value of total bilirubin (T-BIL) and lactic dehydrogenase (LDH) (95% confidence interval p=0.026, p=0.048 respectively).2. We investigate a patient highly suspected hereditary TTP, two kind mutation in the first CUB domain of ADAMTS13 were found by genetic analysis: in the 26th exon, there was a C base deletion during 3676-3680, which results in the frameshift mutation, in the 27th exon, in addition to point mutation ( 3776C→A; Asn 1259 Ala), there was 15 bases base deletion, which results in the loss of 5 corresponding animo acids(Met1260-Ser1264). Abnormal of the translation of ADAMMTS13 results in abnormal of the animo acids sequence and space structure of ADAMTS13, so the activity of ADAMTS13 will decrease.Conclusion1. Althrough the mortality rate of TTP has decreased to 10% after the introduction of plasma exchange therapy, there was 20% patients giving up treatment for no response to plasma exchange. So the remission rate was still low, two main reasons: early diagnosis was hardly determinated and treatment was delayed. We found that 90% patients had microangiopathic hemolytic anemia or neurologic abnormalities, recommend we should highly suspect TTP when thrombocytopenia accompanied with microangiopathic hemolytic anemia or neurologic abnormalities and administer plasma exchange therapy immediately. Higher T-BIL and LDH when admission may suggest poor prognosis. Most TTP patients had impairment of myocardial or other muscle, we should pay attention to prevention of cardiac insufficiency during treatment.2.Two kind mutation in the first CUB domain of ADAMTS13 we found may lead to impairment in ADAMTS13’s synthesis or secretion or interaction between ADAMTS13 and VWF, which impaire ADAMTS13 activity.