Complement in thrombotic thrombocytopenic purpura

This report describes a patient with recurrent thrombotic thrombocytopenic purpura (TTP) in whom complement activation was observed during the acute episodes. Serum C3, C4, and CH50 were reduced, and there was deposition of C3 on red cells and platelets. These findings returned to normal during clinical remission.     

Permanent neurological complications in patients with thrombotic thrombocytopenic purpura

According to previous clinical studies, the neurological manifestations observed in patients with thrombotic thrombocytopenic purpura (TTP) are considered to be transient. The introduction of plasma therapy in 1977 as major treatment modality for TTP has changed the prognosis of the disease. In a clinical survey of 38 patients with TTP who received plasma therapy, we have observed five patients who developed permanent neurological deficits despite their prompt recovery from TTP. In this study, we describe the new complication of TTP and summarize the neurological manifestations observed in these patients during their first episode of TTP and during the relapses, which occurred in 12 of them.     

Studies of a patient with recurring thrombotic thrombocytopenic purpura

A young woman with recurring bouts of thrombotic thrombocytopenic purpura presented an opportunity to study a single patient serially and in depth. This patient underwent 12 remissions in response to fresh frozen plasma, and as little as 250 ml of plasma or plasma from which cryoprecipitate had been extracted was efficacious. Neither the Lian factor nor alterations in either cold-insoluble globulin or protein C could be demonstrated. Evidence in support of the concept of “exhausted” platelets was generated, in that immediately before a thrombocytopenic relapse, platelet function was altered as manifested by bruising, prolongation of the bleeding time, and decreased platelet aggregation. The in vitro addition of normal plasma to such platelets did not improve aggregation. The antiplatelet agent sulfinpyrazone did not seem to add efficacy. Serial observations support the hypothesis that the progression of pathophysiologic events in this patient is: exhausted platelets, thrombocytopenia, hemolysis, renal perturbations, and central nervous system dysfunction.     

Plasma exchange with solvent/detergent-treated plasma of resistant thrombotic thrombocytopenic purpura

A patient with unremitting thrombotic thrombocytopenic purpura (TTP), with circulating von Willebrand factor (VWF) multimers of unusually high molecular weight, and refractory to standard plasma exchange therapy, was treated with solvent detergent (S/D) plasma. The patient achieved a sustained clinical and haematological remission, with normal VWF multimeric profile. Spontaneous remission of this patient's condition could not be excluded but would appear unlikely. S/D plasma was efficacious and potentially safe for repeated large-volume plasma exchange with respect to viral safety and reduction of anaphylactoid reactions. We have assayed coagulation factors and physiological inhibitors of haemostasis in S/D plasma, which were comparable to normal plasma except in the distribution of VWF multimers.
The use of S/D plasma, previously reported in paediatric chronic relapsing TTP, should be assessed in further cases of adult TTP in the context of a clinical trial.     

Combination chemotherapy with CHOP for recurrent thrombotic thrombocytopenic purpura

We report the case of a 42-year-old woman with chronic recurrent thrombotic thrombocytopenic purpura. Therapy with corticosteroids, high-dose immunoglobulins, plasma exchange and cyclophosphamide only induced short-lasting remissions during a course of almost 3 months. Following a severe relapse on day 90 after the start of symptoms, polychemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone (CHOP) was begun. After two cycles of CHOP the patient has stayed in complete remission, with normal platelet counts for more than 9 months to date.     

Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura

OBJECTIVE: This report describes the experience of a case of atypical thrombotic thrombocytopenic purpura (TTP) whose diagnosis was based on severe deficiency of the von Willebrand factor (vWF) cleaving metalloprotease ADAMTS13. METHODS: The level of ADAMTS13 activity, the titer of the inhibitors of this protease and the size distribution of vWF multimers in plasma samples were analysed in a patient with recurrent episodes of dizziness and blurred vision. RESULTS: In the absence of thrombocytopenia or microangiopathic hemolysis, diagnosis of TTP was established by demonstration of very low ADAMTS13 activity levels and the presence of inhibitors of this protease. After rituximab therapy decreased the inhibitor titer and increased the ADAMTS13 level, the patient has had no relapse of ischemic symptoms in the following 16 months. CONCLUSIONS: Acute neurological deficits may occur in TTP without concurrent thrombocytopenia or microangiopathic hemolysis. The role of rituximab for patients with TTP deserves further exploration.     

Elevated endothelial microparticles in thrombotic thrombocytopenic purpura: findings from brain and renal microvascular cell culture and patients with active disease

Endothelial injury is believed to be a key initiating event in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), leading to platelet activation and formation of platelet-rich thrombi in microvasculature. However, the nature of endothelial injury in TTP is poorly defined and clinical assays to rapidly and reliably monitor endothelial damage are not readily available. Using flow cytometry, we measured endothelial microparticles (EMPs) generated from cultured renal and brain microvascular endothelial cells (MVECs) during activation and apoptosis, and evaluated the effect of TTP plasma on them. EMPs were measured using positivity for monoclonal antibodies (mAbs) CD31 and CD51, and their procoagulant activity was assessed using a Russell viper venom assay. Both cell lines generated procoagulant EMPs when cultured with inducers of activation (tumour necrosis factor alpha; TNF-alpha) or apoptosis (mitomycin C). TTP plasma induced a five- to sixfold increase of EMP generation and a two- to threefold increase of procoagulant activity in cultured brain and renal MVECs. TTP plasma induced a threefold and 13-fold increase of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, respectively, on renal MVECs. Procoagulant activity tended to parallel EMP numbers. The effect of TTP plasma on cell viability was similar to that of TNF-alpha, implying that it induced activation rather than apoptosis. Control plasma and idiopathic thrombocytopenic purpura (ITP) plasma had little effect. In the clinical study, EMP assay of blood from acute TTP patients showed levels markedly elevated compared with normal controls, but values returned to normal in remission. In conclusion, TTP plasma activated and induced injury to MVECs in culture, judged by production of EMP and expression of activation markers. Released procoagulant EMP may play a role in the pathogenesis of TTP. Assay of EMP may be a useful marker of disease activity and endothelial injury in TTP and possibly other thrombotic disorders.     

Pediatric thrombotic thrombocytopenic purpura

Child‐onset thrombotic thrombocytopenic purpura (TTP) is a rare entity of thrombotic microangiopathy (TMA). The pathophysiology of the disease is based on a severe functional deficiency of ADAMTS13 (activity <10%), the specific von Willebrand factor (VWF)‐cleavage protease. This deficiency may be either acquired (associated anti‐ADAMTS13 autoantibodies) or congenital (resulting from biallelic mutations of ADAMTS13 gene). ADAMTS13 deficiency is responsible for the accumulation of high molecular weight multimers of VWF and the formation of platelet thrombi in the microcirculation. Consequently, microangiopathic hemolytic anemia and consumption thrombocytopenia are associated with organ ischemia. The differential diagnosis with other TMAs, autoimmune cytopenias or hematological malignancies may be challenging. The exploration of ADAMTS13 (activity, antibodies, antigen, ADAMTS13 gene) supports the diagnosis of TTP. The first‐line treatment of the acute phase of TTP is based on plasmatherapy. In congenital TTP, patients with a chronic disease benefit from a prophylactic plasmatherapy. In autoimmune TTP, steroids and B‐cells depleting therapies increasingly are used together with plasma exchange. Long‐term follow‐up including the monitoring of ADAMTS13 activity is mandatory. A severe decrease in ADAMTS13 activity (<10%) may predict relapses and preemptive B‐cell depletion with rituximab can be used to prevent relapses.     

Isolation and characterization of cysteine proteinase in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder characterized by thrombocytopenia, schistocytic haemolytic anaemia, fever, neurologic lesions, and renal failure. A platelet aggregating factor has been postulated to be responsible for this disorder, but its precise identity remains debated. Two different groups of investigators have provided evidence that the platelet aggregating factor is a cysteine proteinase. We have suggested that it was calpain, whereas others have suggested that it was cathepsin L. To help resolve this issue, we have studied the platelet activating activity found in the acute serum samples from 10 different TTP patients as well as purified calpain and cathepsin L. The TTP activity was measured functionally (platelet serotonin release assay and casein lysis assay) and antigenically (immunodepletion using anti-calpain and anti-cathepsin L antibodies and antigenic analysis using SDS PAGE). The TTP serum parallelled the activity of the purified calpain and had optimal pH activity of 7.5. The purified cathepsin L activity had optimal activity at low pH (5.5) and activity was no longer measurable at pH 7.5. Similarly, a specific cathepsin L inhibitor (Z-Phe-Phe-CHN₂) had no effect on the activity of the TTP samples nor on purified calpain, but it did abolish the activity of purified cathepsin L. The platelet activating activity of the TTP samples was detectable in the microparticle pellet following ultracentrifugation of TTP serum, and could be immunodepleted using antibodies to calpain but not to cathepsin L.
These studies indicate that the microparticle-associated platelet activating factor in TTP corresponds to calpain.     

Laboratory abnormalities in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is an uncommon disorder that requires prompt recognition and intervention to prevent death. To date, information regarding the classic laboratory abnormalities in the disease has been derived from small numbers of patients whose laboratory tests have been done at many different sites. We report the laboratory findings in 135 patients who presented with thrombotic thrombocytopenic purpura to 17 Canadian centres. 50 men and 85 women had a mean platelet count of 25.3 ± 19.4 × 10⁹/l. The initial platelet count correlated with mortality; 32% of patients with a platelet count of 20 × 10⁹/l or less died compared with 18% of patients with a platelet count >20 × 10⁹/l ( P  = 0.058). The platelet-associated IgG was elevated in 88% at presentation whereas the indirect platelet suspension immunofluorescence test was positive in only 18%. 93% of the sera showed reactivity against platelets following protein blotting. All sera tested also showed reactivity against endothelial cells. Immune complexes were seen in all patients, whereas the platelet aggregating factor was detected in 59%. Although the von Willebrand factor was elevated in the majority of patients at entry, the multimer pattern was variable and showed no predictive pattern. Renal dysfunction was common (18%).     

Splenectomy for the treatment of thrombotic thrombocytopenic purpura

Plasma exchange is the treatment of choice for patients with thrombotic thrombocytopenic purpura (TTP) and results in remission in >80% of the cases. Treatment of patients who are refractory to plasma therapy or have relapsing disease is difficult. Splenectomy has been a therapeutic option in these conditions but its value remains controversial. We report on a series of 33 patients with TTP who were splenectomised because they were plasma refractory (n = 9) or for relapsed disease (n = 24). Splenectomy generated prompt and unmaintained remissions in all except five patients, in whom remission was delayed (n = 4) or who died with progressive disease (n = 1). Four postoperative complications occurred: one pulmonary embolism and three surgical complications. Median follow-up after splenectomy was 109 months (range 28-230 months). The overall postsplenectomy relapse rate was 0.09 relapses/patient-year and the 10-year relapse-free survival (RFS) was 70% (95% CI 50-83%). In the patients with relapsing TTP, relapse rate fell from 0.74 relapses/patient-year before splenectomy to 0.10 after splenectomy (P < 0.00001). Two patients died from first postsplenectomy relapse. Although these results are based on retrospective data and that the relapse rate may spontaneously decrease with time, we conclude that splenectomy, when performed during stable disease, has an acceptable safety profile and should be considered in cases of plasma refractoriness or relapsing TTP to reach durable remissions and to reduce or prevent future relapses.     

Mycophenolate mofetil in a case of relapsed, refractory thrombotic thrombocytopenic purpura

A case of relapsing and refractory thrombotic thrombocytopenic purpura received mycophenolate mofetil (MMF) to attempt to maintain remission. The possible use of MMF in thrombotic thrombocytopenic purpura is discussed.