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
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) 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.
The antiplatelet drug clopidogrel has largely replaced ticlopidine, due to an association between ticlopidine and thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS). Clopidogrel at first was thought to be void of this potentially fatal adverse effect, but recent case reports have called that assumption into question. Even with proper treatment (plasma exchange), TTP-HUS can persist for weeks. Clinicians should be aware of this possible adverse effect because prompt therapy is imperative for patients' survival. Earlier reports of clopidogrel-related TTP-HUS have involved patients who had received at least 72 hours of therapy. We describe a case of TTP-HUS in a patient who had received only a 300-mg loading dose of clopidogrel.
clopidogrel; thrombotic thrombocytopenic purpura; hemolytic uremic syndrome
This study aims to review clinical features, treatments, and prognostic factors of thrombotic thrombocytopenic purpura (TTP) associated with systemic lupus erythematosus patients (sTTP). The case reports of sTTP published in world literature from 1999 to 2011 were collected, and 105 cases were divided into death group and survival group. The epidemiologic characteristics, clinical manifestations, laboratory examinations, treatments, and prognostic factors were analyzed. We found that coexistence of renal and neurological impairments were significantly frequent in the death group (100 %) than in the survival group (56.5 %) (P = 0.002). Type IV was predominant in 57.7 % of renal pathological damage, followed by type V (11.5 %), type II (5.8 %), and thrombotic microangiopathy (TMA) (5.8 %). TMA appeared more frequently (50 %) in the death group than in the survival group (6.25 %) (P = 0.042). End-stage renal disease occurred in nine cases with type IV in five (55.6 %), type TMA in one (11.1 %), and unspecified in three cases (33.3 %). Of 32 cases, 40.6 % showed severe ADAMTS13 deficiency and returned to normal or mildly deficient after remission. The total mortality rate of sTTP was 12.4 % and the mortality rate of patients with infection (27.3 %) was significantly higher than those without infection (8.4 %) (P = 0.028). Plasma exchange and glucocorticoids were administrated in over 80 % of cases with 65.7 % remission rate, while additional cytotoxics or rituximab was mostly used in refractory sTTP and achieved over 90 % of remission rate. Above all, coexistence of renal and neurological impairments, infection, and renal damage with type IV or TMA might denote a poor prognosis of sTTP.
ADAMTS13; Infection; Prognostic factors; Systemic lupus erythematosus; Thrombotic thrombocytopenic purpura
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 frequently associated with renal abnormalities, but there have been few reports about renal abnormalities in patients with hereditary TTP. In particular, little is known about the long-term prognosis of patients with childhood-onset congenital TTP.
We report a Japanese patient with congenital TTP (Upshaw–Schulman syndrome) who was followed for 19 years after initiation of hemodialysis when he was 22 years old. At the age of 6 years, the first episode of purpura, thrombocytopenia, and proteinuria occurred without any precipitating cause. He underwent living-related donor kidney transplantation from his mother, but the graft failed after 5 months due to recurrence of TTP. Even after resection of the transplanted kidney and resumption of regular hemodialysis, TTP became refractory to infusion of fresh frozen plasma (FFP). Therefore, splenectomy was performed and his disease remained in remission for 10 years. However, TTP recurred at the age of 39 years. Plasma activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) was less than 3%, while ADAMTS13 inhibitor was not detected (< 0.5 Bethesda units/mL). The patient died suddenly after hemodialysis at the age of 41 years. Subsequent genetic analysis of this patient and his parents revealed two different heterozygous mutations of ADAMTS13, including a missense mutation in exon 26 (c.T3650C causing p.I1217T) inherited from his father and a missense mutation in exon 21 (c.G2723A causing p.C908Y) inherited from his mother. The former mutation has not been detected before in Japan, while the latter mutation is common in Japan. A retrospective review showed that serum C3 levels were consistently low while C4 levels were normal during follow-up, and C3 decreased much further during each episode of TTP.
Congenital TTP was diagnosed from the clinical, biochemical, and genetic findings. Infusion of FFP controlled each thrombotic episode, but the effect was limited and of short duration. Review of the complement profile in this patient suggested that a persistently low serum C3 level might be associated with refractory TTP and a worse renal prognosis.
Congenital thrombotic thrombocytopenic purpura; ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13); Chronic hemodialysis; Complement activation; C3; Alternative pathway
Many patients with acquired thrombotic thrombocytopenic purpura (TTP) harbor autoantibodies that may bind and/or inhibit ADAMTS-13 proteolytic activity and accelerate its clearance in vivo.
To test this hypothesis, we determined ADAMTS-13 activity and antigen levels in parallel plasma samples from patients clinically diagnosed with TTP. Collagen binding, GST-VWF73 and FRETS-VWF73 assays were used to determine ADAMTS-13 activity and to detect inhibitory autoantibodies. Enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation plus Western blotting (IP/WB) were used to detect total anti-ADAMTS-13 IgG (inhibitory and non-inhibitory).
Among 40 patients with TTP (21 idiopathic and 19 non-idiopathic), inhibitory autoantibodies were detected (by FRETS-VWF73) in 52% of idiopathic and 0% of non-idiopathic TTP patients. In contrast, non-inhibitory IgG autoantibodies were detected in 29% of idiopathic and 50% of non-idiopathic TTP patients. The concentration of inhibitory IgG autoantibody in idiopathic TTP patients was significantly higher than that of non-inhibitory IgG in either idiopathic or non-idiopathic TTP patients. Idiopathic TTP patients demonstrated significantly reduced ADAMTS-13 activity compared with non-idiopathic patients, but only slightly lower ADAMTS-13 antigen levels. Interestingly, patients with inhibitory autoantibodies exhibited significantly lower ADAMTS-13 antigen levels than those with only non-inhibitory IgG autoantibodies or no autoantibody. Serial plasma exchanges increased levels of ADAMTS-13 activity and antigen concurrently in patients with inhibitory autoantibodies.
The identification of severe ADAMTS-13 deficiency and autoantibodies or inhibitors appears to be assay-dependent; the inhibitory IgG autoantibodies, in addition to binding and inhibiting ADAMTS-13 proteolytic activity, may accelerate ADAMTS-13 clearance in vivo.
a disintegrin and metalloprotease with thrombospondin type 1 repeats; autoimmune disorder; thrombotic microangiopathy; von Willebrand factor
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
Functional assays are commonly used to measure the antibodies of ADAMTS13 found in patients of thrombotic thrombocytopenic purpura (TTP). In this study we used an enzyme-linked immunoassay to analyze the ADAMTS13-binding IgG levels in six groups of individuals: normal, random hospitalized patients, acute TTP,TTP after receiving plasma therapy, TTP in remission, and other types of thrombotic microangiopathy (TMA). The results showed thatADAMTS13-binding IgG levels were elevated in 100% of the acute TTP group, 75% of the TTP group after receiving plasma therapy, and 40% of the remission group. Overall, the ADAMTS13-binding IgG levels correlated with the inhibitory activity levels against ADAMTS13 (r=−0.69,P<0.0001). The assay also detected elevated IgG binding levels in 5% – 15% of the normal, random, and other TMA control groups. Addition of purified ADAMTS13 protein to the plasma samples suppressed the IgG binding in each of the acute TTP patients, but in none of the non-TTP groups. Serial measurement in a patient that had two exacerbations of TTP within the first three weeks revealed that the ADAMTS13 activity levels remained < 0.1 U/ml during this period, and the ADAMTS13-binding IgG remained elevated, suggesting thatADAMTS13 analysis may provide valuable insight to the disease status during the course of therapy. Analysis of ADAMTS13-binding IgG is helpful for the diagnosis and management of TTP.
ADAMTS13; thrombotic thrombocytopenic purpura; antibody
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
Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (TTP-HUS) are related and uncommon disorders with a high fatality and complication rate if untreated. Plasma exchange therapy has been shown to produce high response rates and improve survival in patients with many forms of TTP-HUS. We performed a retrospective cohort study of 178 consecutively treated patients with TTP-HUS and analyzed whether clinical or laboratory characteristics could predict for important short- and long-term outcome measures.
Overall 30-day mortality was 16% (n = 27). 171 patients (96%) received plasma exchange as the principal treatment, with a mean of 8 exchanges and a mean cumulative infused volume of 42 ± 71 L of fresh frozen plasma. The rate of complete response was 65% or 55% depending on whether this was defined by a platelet count of 100,000/μl or 150,000/μl, respectively. The rate of relapse was 18%. The Clinical Severity Score did not predict for 30-day mortality or relapse. The time to complete response did not predict for relapse. Renal insufficiency at presentation was associated with a decreased risk of relapse, with each unit increase in serum creatinine associated with a 40% decreased odds of relapse. 72% of our cohort had an idiopathic TTP-sporadic HUS, while 17% had an underlying cancer, received a solid organ transplant or were treated with a mitomycin-based therapy. The estimated overall 5-year survival was 55% and was significantly better in those without serious underlying conditions.
Plasma exchange therapy produced both high response and survival rates in this large cohort of patients with TTP-HUS. The Clinical Severity Score did not predict for 30-day mortality or relapse, contrary to our previous findings. Interestingly, the presence of renal insufficiency was associated with a decreased risk of relapse. The most important predictor of mortality was the presence or absence of a serious underlying disorder.
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.
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
HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIV-TTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (<5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression.
HIV-TTP; Hemorrhagic stroke; HIV-ITP; HIV-HUS; Microangiopathic hemolytic anemia; Immune thrombocytopenic purpura; Antiretroviral therapy; Plasma exchange
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.
We report a case of a 39-year-old man with expressive aphasia due to occlusion of the temporal stem of the left middle cerebral artery. Laboratory tests showed microangiopathic haemolytic anaemia and thrombocytopenia. A thrombotic thrombocytopenic purpura (TTP) was diagnosed, and thrombolytic therapy (TT) with alteplase followed by therapeutic plasma exchange (TPE) were performed with complete resolution of symptoms. The gold standard TTP treatment is TPE, and its delay can be lethal. The use of TT in TTP is controversial and has potential risks. This case shows a successful TT in a patient with typical TTP presenting as a stroke due to a large cerebral artery occlusion.
Pregnant women with a history of acquired thrombotic thrombocytopenic purpura (TTP) are considered at risk for disease recurrence and might be at risk for miscarriage, similar to other autoimmune disorders. However, the exact entity of these risks and their causes are unknown. The aim of this study was to evaluate risk factors associated with adverse pregnancy outcome, in terms of both gravidic TTP and miscarriage, in women affected by previous acquired TTP.
We conducted a nested case–control study in women with a history of acquired TTP enrolled in the Milan TTP registry from 1994 to October 2012, with strict inclusion criteria to reduce referral and selection bias.
Fifteen out of 254 women with acquired TTP were included, namely four cases with gravidic TTP, five with miscarriage, and six controls with uncomplicated pregnancy. In the cases, ADAMTS13 activity levels in the first trimester were moderately-to-severely reduced (median levels <3% in gravidic TTP and median levels 20% [range 14-40%] in the women with miscarriage) and anti-ADAMTS13 antibodies were invariably present, while in the control group ADAMTS13 activity levels were normal (median 90%, range 40-129%), with absence of detectable anti-ADAMTS13 antibodies. Reduced levels of ADAMTS13 activity (<25%) in the first trimester were associated with an over 2.9-fold increased risk for gravidic TTP and with an over 1.2-fold increased risk for miscarriage (lower boundary of the confidence interval of the odds ratio). In addition, the presence of anti-ADAMTS13 antibodies during pregnancy was associated with an over 6.6-fold increased risk for gravidic TTP and with an over 4.1-fold increased risk for miscarriage.
ADAMTS13 activity evaluation and detection of anti-ADAMTS13 antibody could help to predict the risk of complications in pregnant women with a history of acquired TTP.
ADAMTS13; Anti-ADAMTS13 antibodies; Miscarriage; Pregnancy; Thrombotic thrombocytopenic purpura
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
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
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 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.
It has been postulated that blood group O subjects may be partially protected against thrombotic thrombocytopenic purpura (TTP) because they have lower plasma levels of von Willebrand factor (VWF).
The Oklahoma TTP Registry enrolled 301 consecutive patients from November 13, 1995 (when systematic ADAMTS13 measurements began) through 2009; 281 (93%) patients had ADAMTS13 measurements. Patients were designated as having severe ADAMTS13 deficiency when the activity measurement by either method was <10%. ABO blood group was determined in all 281 patients. The observed frequency of blood group O was compared to the expected frequency. The association between severe ADAMTS13 deficiency and blood group, race, gender, and age were analyzed by logistic regression.
The frequency of blood group O was unexpectedly and significantly greater than the race-ethnicity-adjusted expected frequency in 65 patients with severe ADAMTS13 deficiency (60.0% vs. 47.4%, P = 0.042) but not in 216 patients without severe ADAMTS13 deficiency (44.9% vs. 46.5%, P = 0.639). Blood group O and race-ethnicity were independently associated with severe ADAMTS13 deficiency among patients with TTP. The probability for severe ADAMTS13 deficiency was 45.8% with O and 32.1% with non-O blood groups for black patients and 24.1% with O and 15.1% with non-O blood groups for white patients.
Among patients with TTP and severe ADAMTS13 deficiency the relative frequency of patients with blood group O was greater than expected, suggesting that blood group O may be a risk factor for TTP associated with severe ADAMTS13 deficiency.
The outcomes of the treatment of thrombotic thrombocytopenic purpura (TTP) have been shown to be improved by the administration of plasma exchange. However, treatment options are currently limited for cases refractory to plasma exchange. The autoantibodies that block the activity of ADAMTS13 have been demonstrated to play a role in the pathogenesis of TTP; therefore, high-dose immunoglobulin, which can neutralize these autoantibodies, may be useful for refractory TTP. However, successful treatment with high-dose immunoglobulin for TTP refractory to plasma exchange and corticosteroids has yet to be reported in Korea. Herein, we describe a refractory case which was treated successfully with high-dose immunoglobulin. A 29-year-old male diagnosed with TTP failed to improve after plasma exchange coupled with additional high-dose corticosteroid therapy. As a salvage treatment, we initiated a 7-day regimen of high-dose immunoglobulin (400 mg/kg) infusions, which resulted in a complete remission, lasting up to the last follow-up at 18 months. High-dose immunoglobulin may prove to be a useful treatment for patients refractory to plasma exchange; it may also facilitate recovery and reduce the need for plasma exchange.
Thrombotic Thrombocytopenic Purpura; Plasma Exchange; Glucocorticoids; Immunoglobulin
Thrombotic microangiopathies (TMAs) represent a heterogeneous group of diseases characterized by a microangiopathic hemolytic anemia, peripheral thrombocytopenia, and organ failure of variable severity. TMAs encompass thrombotic thrombocytopenic purpura (TTP), typically characterized by fever, central nervous system manifestations and hemolytic uremic syndrome (HUS), in which renal failure is the prominent abnormality. In patients with cancer TMAs may be related to various antineoplastic drugs or to the malignant disease itself. The reported series of patients with TMAs directly related to cancer are usually heterogeneous, retrospective, and encompass patients with hematologic malignancies with solid tumors or receiving chemotherapy, each of which may have distinct presentations and pathophysiological mechanisms. Patients with disseminated malignancy who present with microangiopathic hemolytic anemia and thrombocytopenia may be misdiagnosed as thrombotic thrombocytopenic purpura (TTP) Only a few cases of TTP secondary to metastatic adenocarcinoma are known in the literature. We present a case of a 34-year-old man with TTP syndrome secondary to metastatic small-bowel adenocarcinoma. Patients with disseminated malignancy had a longer duration of symptoms, more frequent presence of respiratory symptoms, higher lactate dehydrogenase levels, and more often failed to respond to plasma exchange treatment. A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients with TTP have atypical clinical features or fail to respond to plasma exchange.
metastatic cancer; microangiopathic hemolysis; thrombocytopenia; thrombotic thrombocytopenic purpura; ADAMTS13.