Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
drug-associated TTP; epidemiology; ADAMTS13
Thrombotic thrombocytopenia purpura (TTP) was first described in 1924 as a “pathologic alteration of the microvasculature, with detachment or swelling of the endothelium, amorphous material in the sub-endothelial space, and luminal platelet aggregation leading to compromise of the microcirculation”. Ticlopidine induced TTP has been highly associated with autoimmune induced reduction in ADAMTS-13 activity. These findings, to a lesser extent, have also been found in clopidogrel induced TTP. We report a case of clopidogrel associated TTP in a patient that presented with acute stroke, renal failure, and non-ST elevation myocardial infarction.
Plavix; Thrombotic thrombocytopenic purpura; Antiplatelet therapy
Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening, multisystem disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological changes, renal failure, and fever. These signs and symptoms are thought to be caused by microthrombi, composed of agglutinated platelets and fibrin, which deposit in the arterioles and capillaries without mediation by an inflammatory process. TTP can occur in the first two weeks of initiation of Clopidogrel therapy. Early signs of TTP may be a skin reaction, which may precede the onset of TTP or it may be other type of purpura or neurological changes. We report the clinical and laboratory findings in a 67 years old female patient in whom TTP developed soon after treatment with 40 mg/day oral Clopidogrel after 8 days. She developed thrombocytopenia (platelets count 12000 /mm3). Her clinical signs and symptoms were fever (39.6C), bleeding from the nose and gum, large skin bruises (purpura and ecchymoses), neurological changes including hallucinations, bizarre behavior, altered mental status (fluctuating), headache, and renal dysfunction. Physicians should be aware of the possibility early onset of this syndrome when initiate Clopidogrel treatment.
Thrombotic Thrombocytopenic Purpura (TTP); Clopidogrel; plasma exchange
The cornerstone in clinical evidence of the relative efficacy of thienopyridines (clopidogrel, ticlopidine) versus aspirin in the secondary prevention of vascular disease is the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events trial. This trial showed a modest benefit in the reduction of vascular events by clopidogrel. The results differed according to qualifying disorder: myocardial infarction, -3.7%; ischaemic stroke, +7.3%; and peripheral arterial disease, +23.8% (P = 0.042). Similar results were found for ticlopidine after brain ischaemia. The safety of clopidogrel appears to be similar to that of aspirin and better than that of ticlopidine. However, the recent report of thrombotic thrombocytopenic purpura in association with clopidogrel causes concern.
aspirin; cerebral ischaemia; clopidogrel; myocardial infarction; peripheral artery disease
Thrombotic thrombocytopenic purpura (TTP) affects 1 in 1600 to 1 in 5000 patients who receive ticlopidine, but little is known about the pathogenesis of this complication.
To investigate whether von Willebrand factor (vWF), which has been associated with idiopathic TTP, is involved in the pathogenesis of ticlopidine-associated TTP.
Three tertiary care, university-affiliated medical centers.
Seven patients who developed TTP 2 to 7 weeks after initiation of ticlopidine therapy. Controls were 7 consecutive patients without thrombocytopenia who had been receiving ticlopidine for 3 to 5 weeks and 10 randomly selected hospitalized patients.
Platelet-bound vWF in patients’ EDTA-anticoagulated whole blood samples; vWF proteinase activity in patients’ plasma samples; inhibitory activity of IgG isolated from patients’ plasma samples against the proteinase from the controls’ plasma samples; and vWF multimeric patterns in patients’ EDTA-anticoagulated plasma samples.
Binding of vWF to single platelets was increased in the three patients tested during the most thrombocytopenic phase of TTP episodes. Initial plasma samples from all seven patients lacked the largest vWF multimers and were severely deficient in vWF metalloproteinase. IgG molecules, isolated from plasma samples of five patients, inhibited metalloproteinase in plasma samples from the controls. In patients examined, these abnormalities resolved upon the remission that accompanied plasma exchange and discontinuation of ticlopidine therapy.
In the patients who developed ticlopidine-associated TTP, autoantibodies to the vWF metalloproteinase were formed; this led to the same type of vWF abnormalities observed in patients with idiopathic acute TTP. The findings suggest that failure to process large and unusually large vWF multimers in vivo caused binding of vWF to platelets, systemic platelet thrombosis, and TTP.
We report the case of an African American male with no significant past medical history presenting with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura (TTP) despite aggressive treatment with several lines of treatment. Incidentally, these episodes were associated with severe abdominal pain which eventually developed into acute abdomen and prompted exploratory laparotomy, revealing diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology made a final diagnosis of peritoneal mesothelioma. TTP-like syndrome (TTP-LS) has been described as a paraneoplastic phenomenon in several malignancies but never before in the setting of malignant mesothelioma. Paraneoplastic TTP-like syndrome has historically been associated with a dismal prognosis and particular clinical and laboratory abnormalities described in this paper. It is of utmost importance to make a prompt determination whether TTP is idiopathic or secondary to an underlying condition because of significant differences in their prognosis, treatment, and response. This paper also reviews the current literature regarding this challenging condition.
Clopidogrel has been reported to be safe and effective in reducing vascular events. Nevertheless, there is growing evidence that clopidogrel may cause thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome (TTP/HUS). This association has been debated, since in several cases alternative causes could not be excluded. Two new cases of TTP/HUS associated with clopidogrel are reported here. After discontinuation of clopidogrel and treatment with plasma exchange, both patients had a complete and sustained recovery from TTP/HUS. These cases corroborate previous observations that clopidogrel may indeed be a rare cause of TTP/HUS.
platelet aggregation inhibitors; clopidogrel; thrombotic thrombocytopenic purpura; haemolytic uraemic syndrome; adverse effects
A bisexual male presented with acute thrombotic thrombocytopenic purpura (TTP) in association with established acquired immune deficiency syndrome. The patient had classic clinical and laboratory findings of TTP and responded well to plasmapheresis therapy. Previously reported cases of TTP in association with human immunodeficiency virus (HIV) infection are briefly reviewed. Basic concepts in the pathogenesis of TTP are examined in reference to HIV infection.
Acquired immune deficiency syndrome; Anemia; Human immunodeficiency virus; Thrombocytopenia; Thrombotic microangiopathy; Thrombotic thrombocytopenic purpura
Several rare, potentially fatal types of hematologic dyscrasia, such as agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and thrombotic thrombocytopenic purpura (TTP), have been associated with ticlopidine therapy. The extent to which ticlopidine is the causative factor has not been addressed quantitatively.
We identified 211 published case reports of hematologic dyscrasia associated with ticlopidine therapy from a MEDLINE search. We analyzed the 91 reports that could be evaluated, using the Bayesian Adverse Reaction Diagnostic Instrument to calculate the posterior probability that ticlopidine caused the hematologic dyscrasia based on epidemiologic and clinical trial data (prior odds) and case information (likelihood ratio).
The median posterior probability values (and range) for agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and TTP were 0.95 (0.53–0.98), 0.81 (0.57–0.93), 0.86 (0.75–0.96), 0.78 (0.61–0.89), 0.74 (0–0.92) and 1.0 (0.33–1.00) respectively. The posterior probability was 0.75 or greater in 82 (90%) of the case reports.
This systematic analysis provides stronger evidence to implicate ticlopidine as the causative factor in the various types of hematologic dyscrasia in most published case reports.
Thrombotic thrombocytopenic purpura (TTP) is an uncommon life-threatening disease characterized by microangiopathic hemolytic anemia and thrombocytopenia, commonly associated with infections, malignancy, drugs, and autoimmune diseases. We report a case of 19-year-old previously healthy female that presents with anemia and thrombocytopenia diagnosed with thrombotic thrombocytopenic purpura that was treated successfully with plasmapheresis and corticosteroids. Laboratory findings also revealed antinuclear antibodies and antibodies to double-stranded DNA. Two weeks after presentation developed inflammatory arthritis, fulfilling diagnostic criteria for systemic lupus erythematosus (SLE). Prompt diagnosis and treatment with plasma exchange and corticosteroids should be instituted as soon as the diagnosis of TTP is suspected, even if other diagnoses, including lupus, are possible. When present, the coexistence of these two etiologies can have a higher mortality than either disease alone. An underlying diagnosis of SLE should be considered in all patients presenting TTP and the study of this association may provide a better understanding of their immune-mediated pathophysiology.
Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening complication of gemcitabine treatment. Since the approval of this nucleoside analog for the treatment of pancreatic cancer by the FDA in 1996, reported incidence varies from 0.015 to 1.4%. The classic ‘pentad’ describing the disease process (fever, hemolytic anemia, thrombocytopenia, neurological complications and renal impairment) is not always present to the same extent in every patient. Here, we present a rare case of TTP associated specifically with gemcitabine treatment, and further, we briefly discuss the manifestations, treatment options and outcomes related to the complication. In our opinion, it is important to realize that as the indications for the use of gemcitabine increase and its use becomes more widespread, TTP and other disorders on the spectrum of thrombotic microangiopathies are important considerations to remember in patients with worsening anemia and thrombocytopenia. New onset or exacerbation of underlying hypertension may provide a clue to diagnose the disease entity earlier in this subgroup of patients.
Thrombotic thrombocytopenic purpura; Gemcitabine Non-small cell lung cancer
Clopidogrel, in combination with aspirin, is commonly used for the prevention of thrombosis in patients who have received coronary artery stents. As a rare but critical complication, clopidogrel associated thrombotic thrombocytopenic purpura (TTP) has previously been described. A 78 year old man presented with unstable angina and filiform subtotal stenosis of the left anterior descending artery. He was treated with balloon angioplasty and stent implantation. After four days the patient again had angina caused by stent thrombosis, which was treated with balloon angioplasty. During hospital stay the typical course of clopidogrel associated TTP was observed with thrombocytopenia and petechial purpura occurring 14 days after drug initiation and prompt response to therapeutic plasma exchanges. These findings strongly suggest that clopidogrel may have increased platelet activation and aggregation in this immunologically susceptible patient, ultimately leading to a stent thrombosis.
clopidogrel; stent; thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenia purpura (TTP) caused by a deficiency in ADAMTS-13 activity is considered to involve a subset of thrombotic microangiopathy (TMA). Although concept of TTP is included under the umbrella of TMA, discrimination of TTP from TMA is occasionally difficult in an autoimmune disorder. Herein, we report a case with TTP associated with systemic lupus erythematosus (SLE). In this case, it was difficult to discriminate TTP from TMA and the measurement of ADAMTS-13 activity was useful for obtaining an accurate diagnosis. SLE patients having thrombocytopenia in complication with anemia should be considered a monitoring of ADAMTS-13 activity even though the patients lacked symptoms of TTP related to the microvascular coagulation.
Thrombotic thrombocytopenic purpura (TTP) is a rare condition but associated with 90% mortality if left untreated. The diagnosis is usually made when there is thrombocytopenia and microangiopathic haemolytic anaemia, although the full pentad also includes fever, renal impairment, and neurological dysfunction. A variety of underlying causes have been implicated in acquired TTP including bacterial and viral infections, bone marrow and organ transplantation, pregnancy, immune disorders, and certain drugs. To date there is just one case report of TTP associated with statin treatment. The clinical course of a patient who presented with TTP after being started on simvastatin, a HMG-CoA inhibitor, is described.
Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent multiple disorders with diverse etiologies. We compared the gender and race of 335 patients enrolled in the Oklahoma TTP-HUS Registry across 21 years for their first episode of TTP or HUS to appropriate control groups. The relative frequency of women and white race among patients with TTP-HUS associated with a bloody diarrhea prodrome and the relative frequency of women with quinine-associated TTP-HUS were significantly greater than their control populations. The relative frequency of women and black race among patients with idiopathic TTP and TTP associated with severe ADAMTS13 deficiency was significantly greater than their control populations. The relative frequency of black race among patients who had systemic lupus erythematosus (SLE) preceding TTP was significantly greater than among a population of patients with SLE, and the relative frequency of black race among patients with other autoimmune disorders preceding TTP was significantly greater than their control population. No significant gender or race disparities were present among patients with hematopoietic stem cell transplantation-associated thrombotic microangiopathy, TTP associated with pregnancy, or TTP associated with drugs other than quinine. The validity of these observations is supported by the enrollment of all consecutive patients across 21 years from a defined geographic region, without selection or referral bias. These observations of different gender and race disparities among the TTP-HUS syndromes suggest the presence of different risk factors and may serve as starting points for novel investigations of pathogenesis.
Thrombotic thrombocytopenic purpura; hemolytic uremic syndrome; ADAMTS13; quinine; race disparities; gender disparities
Thrombotic thrombocytopenic purpura (TTP) is a rare clinical disorder which was associated with poor prognosis for a long time. The outcome has been improved by the consistent introduction of thera-peutic plasma exchange (TPE) as standard treatment of TTP.
Patients and Methods
We describe our experience in the use of solvent/detergent-treated plasma (SDP) for TPE in TTP. We retrospectively analyzed acute TTP epi-sodes in 8 patients (mean age = 27 years, range 18–44 years) treated with TPE using SDP with regard to tolerability and efficacy.
All 8 patients were positive for anti-ADAMTS-13 antibody. Seven out of 8 had a se-vere ADAMTS-13 deficiency. All patients responded rapidly to SDP TPE with an increase in platelet count to above 150 × 109/l. Hemolytic anemia disappeared over the treatment period. Approximately 2,000 l SDP were used for more than 500 treatments. Treatment with SDP was well tolerated; none of the patients experienced an adverse drug reaction after exposure to SDP. No major complications occurred even after multiple TPE.
Our investigations suggest that TPE using SDP as replacement fluid is an effective treatment for TTP. The data described also indicate that SDP might offer the benefit of reducing adverse drug reactions.
Thrombotic thrombocytopenic purpura; TTP; Therapeutic plasma exchange; TPE; Solvent/detergent-treated plasma; SDP; ADAMTS-13
Thrombotic thrombocytopenic purpura (TTP) is a multisystemic microvascular disorder that may be caused by an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. In acquired TTP, especially in secondary TTP with various underlying diseases, the diagnosis is difficult because there are many cases that do not exhibit severe deficiency of ADAMTS13 or raised levels of ADAMST13 inhibitors. It is well known that collagen disease, malignancy, and hematopoietic stem cell transplantation can be underlying conditions that induce TTP. However, TTP induced by acute pancreatitis, as experienced by our patient, has rarely been reported. Our patient completely recovered with treatments using steroids and plasma exchange (PE) only. In cases where patients develop acute pancreatitis with no apparent causes for hemolytic anemia and thrombocytopenia, the possibility of TTP should be considered. Treatments for TTP including PE should be evaluated as soon as a diagnosis is made.
thrombotic thrombocytopenic purpura; ADAMTS13; acute pancreatitis; plasma exchange
Background Thrombotic thrombocytopenic purpura (TTP) can present with many laboratory features of preeclampsia, which can make an accurate diagnosis difficult in late pregnancy. Because the treatments of TTP and preeclampsia are different and the clinical sequelae of delayed therapy potentially lethal, a rapid and accurate diagnosis is important.
Case Report We present a case of an acute episode of TTP secondary to acquired autoantibodies complicated by severe preeclampsia with headache and treated with corticosteroids, plasma exchange therapy, magnesium sulfate, and delivery. The postpartum course was complicated and resulted in a prolonged hospital stay. A multidisciplinary team was recruited as consultants.
Conclusion Concurrent TTP and severe preeclampsia can result in life-threatening complications. To ensure the best possible clinical outcome, an awareness of the medical systems' resources is required.
TTP; severe preeclampsia; multidisciplinary team; autoantibodies
Thrombotic thrombocytopenic purpura (TTP) is a multisystemic disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia, which may be accompanied by fever, renal, or neurologic abnormalities. Cases are divided into acute idiopathic TTP and secondary TTP. Autoimmune diseases, especially systemic lupus erythematosus, in association with TTP have been described so far in many patients. In contrast, TTP occurring in a patient with mixed connected tissue disease (MCTD) is extremely rare and has only been described in nine patients. We describe the case of a 42-year-old female with MCTD who developed thrombocytopenia, microangiopathic hemolytic anemia, fever, and neurological symptoms. The patient had a good clinical evolution with infusion of high volume of fresh frozen plasma, steroid therapy, and support in an intensive care unit. Although the occurrence of TTP is rare in MCTD patients, it is important to recognize TTP as a cause of thrombocytopenia and hemolytic anemia in any patient with autoimmune diseases. Prompt institution of treatment remains the cornerstone of treatment of TTP even if plasma exchange is not available like what frequently happens in developing countries.
Several reports have been published regarding the use of cyclosporine (CSA) in the treatment of idiopathic thrombotic thrombocytopenic purpura (TTP). We hypothesized that prophylactic CSA therapy may prevent recurrences in patients with a history of multiple relapses of TTP. Nineteen patients with idiopathic TTP were enrolled on prospective studies at Ohio State University between September 2003 and May 2007. Patients achieving remission remained on CSA therapy for 6 months, allowing us to evaluate the efficacy of CSA as prophylactic therapy. CSA was administered orally at a dose of 2–3 mg/kg in a twice a day divided dose in all patients and continued for a total of 6 months. Long-term clinical follow-up with serial analysis of ADAMTS13 biomarkers during and after CSA therapy were performed to evaluate the efficacy of CSA as a prophylactic therapy. 17/19(89%) patients completed 6 months of CSA therapy in a continuous remission. Two patients relapsed during therapy with CSA and 7 patients relapsed after discontinuing CSA therapy. Ten patients have maintained a continuous remission a median of 21 months (range, 5 to 46) after discontinuing CSA. The ADAMTS13 data suggest that CSA resulted in a significant increase in the ADAMTS13 activity during therapy with CSA. 8/9(89%) relapsing patients had severely deficient ADAMTS13 activity (< 5%) suggesting this is a significant risk factor for relapse of TTP. These data support the hypothesis that prophylactic CSA improves the ADAMTS13 activity and may be effective at preventing relapses in patients at risk for recurrences of TTP.
thrombotic thrombocytopenic purpura; ADAMTS13; cyclosporine; relapse; prophylactic therapy
Plasma exchange is first-line therapy for patients with thrombotic thrombocytopenic purpura (TTP). Splenectomy is often indicated for patients with relapsing or refractory disease. Concerns exist about its efficacy and safety in these patients. We describe a series of patients whose TTP was treated with laparoscopic splenectomy. We also reviewed the literature in order to describe the use and safety of splenectomy for refractory or relapsing TTP.
We reviewed the charts of consecutive patients with TTP referred for splenectomy and searched MEDLINE for studies describing outcomes following splenectomy for relapsing or refractory TTP.
In all, 5 patients were referred for relapsing TTP and underwent uneventful laparoscopic splenectomy. All 5 were in remission after more than 40 months of follow-up. We found 18 studies (87 patients) reporting the results of splenectomy for relapsing TTP and 15 studies (74 patients) involving patients who underwent splenectomy for refractory TTP. The aggregate complication (6% v. 10%) and mortality rates (1.2% v. 5%) were lower for patients who received treatment for relapsing versus refractory TTP. The rate of postsplenectomy relapse among patients with relapsing disease was 17%, whereas the nonresponse rate was 8% for patients with refractory TTP. There were no complications among the 22 laparoscopic cases reported.
Although the data supporting splenectomy for treatment of TTP are limited to case series with no control groups, they suggest that splenectomy is an option for patients with refractory or relapsing disease. When performed laparoscopically in patients with relapsing disease, splenectomy is associated with minimal morbidity and mortality.
The absence of specific diagnostic criteria, the urgency to begin plasma exchange treatment, and the risk for complications from plasma exchange make the initial evaluation of patients with suspected thrombotic thrombocytopenic purpura (TTP) difficult. Systemic infections may mimic the presenting clinical features of TTP. In the Oklahoma TTP-HUS (hemolytic-uremic syndrome) Registry, 1989–2010, 415 consecutive patients have been clinically diagnosed with their first episode of TTP; in 31 (7%) the presenting clinical features were subsequently attributed to a systemic infection. All 31 patients had diagnostic criteria for TTP; 16 (52%) had the complete “pentad” of microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, renal failure and fever. Four (16%) of 25 patients who had ADAMTS13 measurements had <10% activity; three patients had a demonstrable ADAMTS13 inhibitor. Compared to 62 patients with severe ADAMTS13 deficiency (<10%) who had no recognized alternative disorders, patients with systemic infections had more frequent fever, coma, renal failure, and the complete “pentad” of clinical features. Seventeen different infectious etiologies were documented. A systematic literature review identified 67 additional patients with a diagnosis of TTP or HUS and also a systemic infection. Among all 98 patients, infections with 41 different bacteria, viruses, and fungi were documented, suggesting that many different systemic infections may mimic the presenting clinical features of TTP. Initial plasma exchange treatment is appropriate in critically ill patients with diagnostic features of TTP, even if a systemic infection is suspected. Continuing evaluation to document a systemic infection is essential to determine the appropriateness of continued plasma exchange.
infection; thrombotic thrombocytopenic purpura; TTP; hemolytic uremic syndrome; HUS; ADAMTS13
Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 has been demonstrated to be the proximate cause of a subset of thrombotic microangiopathic haemolytic anaemias (MAHA) typical for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 gene mutations cause the hereditary form; acquired deficiency has been attributed to presence of an autoantibody, which may represent a specific subset of MAHA best termed ‘autoimmune thrombotic thrombocytopenic purpura’. We describe a patient with relapsing TTP because of ADAMTS13 inhibitors, who failed to achieve sustained remission despite therapies with plasma exchange, steroids, vincristine, staphylococcal protein A and splenectomy. The ADAMTS13 inhibitor titre remained elevated and clinical stability was only maintained by plasma exchange every 2–3 d over a period of 268 d. The patient then received rituximab therapy (eight doses of 375 mg/m2 weekly), during which she required five plasma exchanges in the first 10 d, two exchanges in the next 3 weeks, and none thereafter for 450 d and ongoing. The ADAMTS13 inhibitor titre decreased and enzyme activity increased. We compared this case with that of seven previously reported TTP cases also treated with rituximab; experience suggests that rituximab therapy deserves further investigation for patients with either refractory or relapsing TTP caused by ADAMTS13 inhibitors.
thrombotic thrombocytopenic purpura; rituximab; plasma exchange