Case Discussion < Brief History >      A 36-year-old woman who denied any systemic disease developed fever 6 days prior to admission. She had been quiet well-being before this admission and no abnormality was detected in previous annual health examinations. In additional to the fever, she also found that many purpura lesions involving the extremities and trunk. The size was around 1 to 2 cm in diameter with irregular shape. Besides, pale face was also noted by her family. There was no history of trauma, headache, blurred vision, epistaxis or focal neurologic symptoms. One day before admission, she was found to have intermittent confusion and lethargy. Progressive dyspnea was also noted. Because of the altered consciousness, she was brought to our Emergency Service subsequently. On arrival, the Glasgow Coma Score was E4V5M6. Physical examination showed a woman of 159 cm in height and 65 kg in weight. Her body temperature was 37.8 oC, blood pressure 152/86 mmHg, and pulse rate was 122 beats per minute. No focal neurologic deficit was detected but mild confusion was noted. Her conjunctiva was remarkably pale, and some scattered painless purpura were found on the trunk. According to her family's statement, she was not a vegetarian. She had no recent history of taking medicines or travel. Because of severe anemia, she was transfused with I unit of packed RBC at the Emergency Service after the lab data were available. < Laboratory and Image Study > 1. CBC: Day after admission WBC K/μL Hgb g/dL Hct % MCV fL Plt K/μL ER 9.51 7.3 21.9 104 65 2nd 9.54 7.9 23 104 50 3rd 8.98 8.7 25.3 102 48 5th 9.03 9.3 28.8 102 45 7th 10.3 8.9 25.0 101 54 10th 12.1 9.2 28.6 102 55 15th 10.4 9.3 28.0 100 78 25th 9.6 10.4 30.4 98 150 2. Biochemistry: Day after admission BUN mg/dl Cre mg/dl Na mmol/l K mmol/l GOT U/l LDH U/l T-Bil mg/dl I-Bil mg/dl ER 29.3 2.9 141 4.8 104 1288 1.6 1.2 2nd 48 3.3 138 4.6 123 1250 1.6 1.2 3rd 54 4.8 136 4.4 158 1365     5th 76 5.9 135 4.5 204 1402 1.4 1.0 7th 95 8.1 133 4.9 356 1532     10th 93 8.2 136 4.5 365 1280 1.4 1.1 15th 67 7.2 137 4.3 254 767     25th 34 2.5 137 4.2 45 150 1.0 0.4 3. Urine analysis: Day after admission Appearance Sp. gr pH Protein mg/dL Glu g/dL Ketones O.B Urobil EU/dL Bil  ER R;Cloudy 1.02 6.5 >300 － － +  0.1 － 5th R;Cloudy 1.02 6.5 >300 － － + 0.1 － 25th Y;C 1.01 7.0  Trace － － － 0.1 － Day after admission Nitrite WBC RBC /HPF WBC /HPF EpithCell /HPF Cast /LPF Crystal Bact ER － － 10-15 0-1 0-3 － － － 5th － － 10-15 0 3-5 － － － 25th － － 3-5 0 0 － － －   PT & aPTT: Both were within normal range 4. Renal sonography: Size R't 10.5 cm ; L't 10.9 cm Shape Bilaterally normal Cortical thinkness R't: 10 mm; L't: 9 mm (within normal limit) Central sinus No hydronephrosis Solid or cystic lesion Nil 5. CXR: Normal heart size and clear lung fields. 6. Coombs' Test: Negative  < Course and Treatment >      After admission, antibiotics were prescribed for presumed sepsis. Because of the fever, profound renal failure, highly elevated LDH, low platelets, skin purpura and fluctuating neuroloic symptoms, TTP was highly suspected. Because of the bleeding tendency, renal biopsy was postponed, and plasmapheresis was instituted immediately 5 days after admission. She also underwent packed RBC transfusion for severe anemia. Ten days after the initiation of plasmapheresis, her platelet number and LDH improved gradually. After the platelet levels and LDH were normal, plamapheresis was suspended. Because urine out was adequate, no hemodialysis was needed. She still had impairment of renal function 30 days after admission. Two months after discharge, the hemogram and renal function were normalized. < Analysis >      Thrombotic thrombocytopenic purpura (TTP) is more common in women than in men, with a female-to-male ratio of 3:2. TTP is most common in adults, and the peak age occurs in the fourth decade of life, with a median age at diagnosis of 35 years. TTP can be divided into idiopathic and acquired forms. Some drugs like quinine, mitomycin-C, calcineurin inhibitors, and ticlopidine are the most common. And antibodies against vWF cleaving protein have ever been reported. Cancers and infection (mostly HIV infection) have also been reported to be associated with TTP. Pregnancy and the postpartum state also account for 10-25% of the cases of TTP. However, for many patients with acquired TTP, no underlying cause can be established. It belongs to thrombotic microangiopathies, a group of diverse disorders that are classified based on common morphologic features. The most common types are TTP and hemolytic uremic syndrome (HUS). TTP and HUS have several similar presentations, but they are different somehow in the involvement of end organs. Besides, the pathogenesis underlying these two diseases is actually distinct. TTP is characterized by diminished activity of von Willebrand factor (vWF) cleaving protein, whereas HUS has defective vWF cleaving protein. When there is a defect or deficiency of vWF cleaving protein resulting in unusual large vWF which binds to extracellular matrix and platelets, it will induce platelets aggregation and activation, which leads to platelets consumption, thrombi formation, organ ischemia and erythrocyte fragmentation (ie, schistocytes). The vWF cleaving protein is a member of a family of zince metalloproteinases named “a disintegrin and metalloprotease with thrombospondin type 1 repeat” (ADAMTS). Mutations of ADAMTS-13 were observed in patients with familial and recurrent TTP. Based on the pathogenesis, some clinical symptoms can be expected.      There is a clinical pentad of TTP: renal failure (88%), fever (60%), fluctuating central nervous system symptoms (36%), thrombocytopenic purpura and microangiopathic hemolytic anemia (MAHA). The thrombocytopenic purpura and MAHA are always present, but the other three are not. Other non-specific symptoms like fatigue/generalized malaise and arthralgias may be present. TTP is a clinical diagnosis with no pathognomonic laboratory test findings. Current clinical practical diagnostic criteria of TTP include thrombocytopenia, schistocytosis, and significant elevations in serum LDH levels. Measuring protease activity as a single test to distinguish TTP from HUS is not practical at this time. The absence of in vitro tests capable of detecting abnormalities in all the molecular interactions required for the cleavage of unusual large vWF multimers by ADAMTS-13 in vivo is a limitation. Typical abnormal lab results are thrombocytopenia, severe anemia, elevated LDH, impaired renal function, microscopic hematuria and proteinuria but normal PT/aPTT tests.      Because the underlying pathogenesis of TTP is ongoing in patients with active status, it's never too early to treat them with fresh frozen plasma (FFP) infusion or plasmapheresis. FFP infusion is the mainstay of therapy to provide deficit vWF cleaving enzyme. Plasmapheresis or plasma exchange may provide synergism by removing any circulating vWF cleaving protein inhibitor and by facilitating the infusion of large amount of FFP. Steroids might be useful sometimes. Supportive dialysis might also be needed when uremic status is present. Platelet infusions and aspirin are contradicted even though patients have thrombocytopenia and microthrombi, because the platelet aggregation worsens with platelet transfusions which is associated with rapid deterioration and bleeding tendency. In some studies, extensive platelet aggregates were found throughout the CNS on postmortem examination. Desmopressin (DDAVP) is contraindicated because it acts by releasing ULVWF from the endothelium into the circulating blood. The response of the therapy is monitored by platelet and LDH levels. Treatment of refractory or relapsing TTP includes vincristine, a second-line therapy with an unknown mechanism of action. < Reference > Harrison's principles of internal medicine 15 edition Comprehensive Clinical Nephrology 2nd edition eMedicine, Thrombotic Thrombocytopenic Purpura. Last Updated: Nov 30, 2005 繼續教育考題 1. (E) 會造成TTP的原因如下，何者正確？ A  Idiopathic B  Genetic mutation C  Cancer-induced D  Drug-induced E  All of above 2. (B) 有關TTP的描述，何者錯誤？ A  Mainly in female B  Related to enhanced function of von Willebrand factor cleaving protein C  Diagnosed clinically D  Renal failure is not usually present E  All of above 3. (C) TTP相關的clinical pentad 何者錯誤？ A  Renal impairment B  Fluctuating CNS symptoms C  Hepatic failure D  Thrombocytopenia E  Non of above 4. (A) 對TTP診斷的描述何者錯誤？ A  Based on clinical diagnosis B  Normal PT/aPTT C  Microangiopathic hemolytic anemia and thrombocytopenia are essentials D  Elevated LDH or GOT means decompensated liver function E  Non of above 5. (C) 何者是TTP最佳治療方式？ A  Hemodialysis B  Cryoprecipitate infusion C  Plasmapheresis D  FFP infusion alone E  Platelet infusion 6. (B) 對於 TTP和HUS的差別何者錯誤？ A  Both belong to a group of diverse disorders B  Kidney is the main target of TTP C  Both relate to impaired vWF cleaving protein D  TTP and HUS have similar clinical presentations E  None of above