Background-Thrombotic thrombocytopenic purpura is a potentially fatal disease characterized by widespread platelet thrombi in the microcirculation. In the normal circulation, von Willebrand factor is cleaved by a plasma protease. We explored the hypothesis that a deficiency of this protease predisposes patients with thrombotic thrombocytopenic purpura to platelet thrombosis.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Thrombotic thrombocytopenic purpura (TTP) is characterized by the systemic deposition of platelet thrombi with abundance of von Willebrand factor (vWF) in the arterioles and capillaries. Recently, vWF protease (ADAMTS13) activity was found to be severely deficient in hereditary TTP as well as acquired idiopathic TTP. Homozygous or compound heterozygous mutations of ADAMTS13 gene were demonstrated in hereditary TTP. Autoantibodies against ADAMTS13 were present in majority of patients with idiopathic TTP and ticlopidine- and clopidogrel-associated TTP. The deficiency of ADAMTS13 leaves unchecked the hyperadhesive vWF unfolded under high shear stress in the microvessels, resulting in the formation of platelet thrombi, which in turn causes TTP. ADAMTS13 activity is usually normal in hemolytic uremic syndrome. Approximately 0 to 67% of idiopathic TTP patients reported may not be severely deficient of ADAMTS13. Therefore, acquired TTP is not caused by ADAMTS13 deficiency alone and may be triggered by certain stimuli that possibly cause autoimmune reactivity to ADAMTS13, and also induce platelet aggregation either dependent on or independent of vWF, and/or vascular injury, to account for variable clinical and laboratory presentations. Plasma samples from TTP patients have been shown to induce endothelial cell apoptosis and activation. Platelet aggregating factors independent of vWF purified from the plasma of a subset of TTP patients have been reported and shown to be inhibited by normal plasma and immunoglobulin G purified from normal plasma. Defective fibrinolysis and abnormal natural coagulation inhibitors may enhance the thrombi formation in the microcirculation.

A 21-year-old primigravida in her 20th week of pregnancy developed TTP. She was managed with weekly or semiweekly plasma infusions and delivered a healthy 1.6 kg baby 2 weeks prior to the expected date of delivery. After delivery she continued to have active TTP with thrombocytopenia which responded repeatedly to plasma infusion though their frequency gradually decreased to about one unit every 3-4 weeks. Three years after the birth of the first child she conceived again and was easily managed with repeated plasma infusions although the frequency and amount of plasma required to prevent thrombocytopenia were increased. She delivered a normal 3.4 kg term baby after which she again had a decreased plasma requirement. This is the first report of a woman with 5 years of active TTP managed with plasma alone. She experienced two pregnancies in which both mother and infant survived. We believe that the use of plasma in the management of TTP during pregnancy will improve the survival rate of both mother and infant. At the time of second birth, the platelet count was low in the mother but normal in the baby. This suggests that the platelet depressing factor of this patient does not cross the placental barrier.

SummaryThe acidic mucopolysaccharide extracted from sea cucumber (Stichopus japonicus Selenka) (SJAMP) has been shown to cause platelets to aggregate. Using citrated platelet-rich plasma (PRP), washed platelets and formaldehyde-fixed platelets from humans, we investigated the effects of platelet inhibitors and various plasmas and their fractions on SJAMP-induced platelet aggregation. It was found that the lowest concentration of SJAMP required for the aggregation of human platelets was about 0.4 μg/ ml and the magnitude of aggregation induced by SJAMP was concentration dependent. The platelets were aggregated by SJAMP at 10 μg/ml in 25 out of 28 (89%) normal subjects tested. Platelet inhibitors such as PGE1, aspirin, indomethacin, apyrase, antimycin, 2-deoxy-D-glucose and EDTA inhibited by 70 to 100% the aggregation induced by SJAMP. Washed platelets alone were not aggregated by SJAMP. In the presence of fibrinogetr, washed platelets were aggregated by SJAMP, but formaldehyde-fixed platelets were not. These data indicate that the SJAMP-induced human platelet aggregation requires extracellular calcium, fibrinogen, and energy metabolism. The second phase of aggregation is dependent upon the release of ADP, and cyclooxygenase pathway.

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.

Combined deficiencies of Factor VIII and Factor XI associated with moderate degree of bleeding symptoms were found in 3 brothers. Examination of Factor VIII activity and Factor VIII-related antigen revealed that the Factor VIII activity/Factor VIII-related antigen ratio was significantly decreased in their mother and maternal grandmother consistent with the carrier state of hemophilia. Factor XI deficiency was found in 2 siblings, the father, and 2 of his sisters. The paternal grandmother was thought to carry the abnormal Factor X I gene, although her Factor XI level was normal, because of a significant bleeding history. It was concluded that the combined Factor VIII and XI deficiencies in the 3 brothers represent the coincidental inheritance of 2 separate and independent abnormal genes.

Thrombotic thrombocytopenia purpura (TTP) is a severe multisystem disorder characterized by fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, and impaired renal function. Platelet counts are usually diminished, whereas the bone marrow shows a large number of megakaryocytes indicating peripheral destruction and consumption of platelets. Coagulation studies in patients with TTP are normal or slightly elevated, which helps differentiate this entity from disseminated intravascular coagulation. The peripheral smear shows an abundance of schistocytes, reticulocytes, and, at times, nucleated red blood cells. Serum lactate dehydrogenase and indirect bilirubin are elevated as a result of mechanical destruction of red blood cells. Legionella pneumophila has been identified as a relatively common cause of both community-acquired and hospital-acquired pneumonia. An association between Legionella and TTP has only been cited once in the literature. Here we present a case of severe TTP with concurrent Legionella infection. Our patient presented with the classic clinical findings of TTP and an ADAMTS13 level of less than 5% associated with an inhibitor. After a 3-week treatment course with plasma exchange, steroids, and antibiotics, he had complete clinical recovery and his ADAMTS13 level increased to greater than 75%.