Thrombotic Thrombocytopenic Purpura-hemolytic Uremic Syndrome Research Articles

The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

A total of 290 Japanese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) were analyzed with respect to ADAMTS-13 activity and its inhibitor. Twenty-one patients (17 families) had Upshaw-Schulman syndrome, and 12 patients (six families) had familial HUS of undetermined etiology. The number of patients with acquired HUS and TTP was 44 and 213, respectively. In acquired TTP, patients with severe deficiency of ADAMTS-13 activity secondary to the presence of an inhibitor were high responders to plasma exchange, but others were low responders to plasma exchange. The former patients were associated with “idiopathic” TTP, drugs, and pregnancy, and the latter patients with malignancy and stem cell transplantation. Patients with autoimmune disease-associated TTP fit into both groups.

The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome occurs more commonly in women and among women is commonly associated with pregnancy. Case series of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome from 1964 to 2002 were reviewed (1) to document the reports of occurrence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome during pregnancy and (2) to search for reports of women with congenital or familial thrombotic thrombocytopenic purpura-hemolytic uremic syndrome who were initially diagnosed during their first pregnancy. The time during pregnancy with greatest risk for development of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome is near term and during the postpartum period. This is also the time of greatest risk for thrombotic events and for the occurrence of other pregnancy-related syndromes: preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. These other syndromes may also be associated with thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, and renal insufficiency, making their distinction from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome difficult or impossible. The occurrence of preeclampsia and related syndromes, the hypercoaguable state that occurs in late pregnancy and postpartum, and the progressively decreasing concentration of ADAMTS13 that occurs during late pregnancy may combine to increase the risk for occurrence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

ADAMTS13 activity in thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients

AbstractInitial management of patients with thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. Although severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency may be specific for TTP, the role of ADAMTS13 activity measurements for initial management decisions is unknown. ADAMTS13 was measured before beginning plasma exchange treatment in 142 (88%) of 161 consecutive patients with clinically diagnosed TTP-HUS with assignment to 1 of 4 categories: less than 5% (severe deficiency), 5% to 9%, 10% to 25%, and more than 25%. Eighteen (13%) of 142 patients had severe ADAMTS13 deficiency. Among 6 predefined clinical categories (stem cell transplantation, pregnant/postpartum, drug association, bloody diarrhea, additional/alternative disorder, idiopathic), severe deficiency occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. The presenting features and clinical outcomes of the 16 patients with idiopathic TTP-HUS who had severe ADAMTS13 deficiency were variable and not distinct from the 32 patients with idiopathic TTPHUS who did not have severe ADAMTS13 deficiency. Many patients in all ADAMTS13 activity categories apparently responded to plasma exchange treatment. Therefore, severe ADAMTS13 deficiency does not detect all patients who may be appropriately diagnosed with TTP-HUS and who may respond to plasma exchange treatment. (Blood. 2003;102:60-68)

Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No

Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No

Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes

Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes

Postpartum hemorrhagic shock resulting in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

Postpartum hemorrhagic shock resulting in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

A support group for patients who have recovered from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): The six-year experience of the Oklahoma TTP-HUS Study Group.

A support group for patients who have recovered from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS), named The Oklahoma TTP-HUS Study Group, has been a successful program for 6 years. This group has met 3 times each year with an average attendance of 16 former patients; in addition, an average of 14 family members and friends have attended each meeting. Eighty-four percent of patients who attended a meeting were women as compared to 68% women among those who did not attend (P = 0.016). Twenty-three percent of patients who attended a meeting have relapsed as compared to 8% among those who did not attend (P = 0.006). There was also a difference in the rates of attendance among the different clinical categories of patients (P < 0.001). A survey of former patients, as well as their families and friends, documented that interest in learning more about TTP-HUS and talking with other people who have had TTP-HUS were principal motivations for attending the meetings. The meetings of The Oklahoma TTP-HUS Study Group have been successful not only for support of former patients but also for research. Long-term patient follow-up has been facilitated and the group discussions have revealed previously unreported persistent problems with cognitive ability and endurance. A survey of member centers of the American Association of Blood Banks and America's Blood Centers revealed no similar programs for patients who have recovered from TTP-HUS. The absence of a support group for TTP-HUS in the national survey contrasts to the 274 patient support groups and related wellness/education classes, including some for rare disorders, currently active in the Oklahoma City metropolitan area. The experience of The Oklahoma TTP-HUS Study Group suggests that it serves a previously unmet need.

Postpartum hemorrhagic shock resulting in thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

Thrombotic microangiopathies may be initiated by a number of antecedent events. When presented with postpartum hemorrhage and unexplained thrombocytopenia, it is prudent to consider microangiopathic hemolyticanemia in the differential diagnosis. A 25-year-old woman, gravida 2, para 1, had an uncomplicated repeat Cesarean delivery at 38 weeks' gestation. She subsequently had an exploratory laparotomy for hemoperitoneumresulting from a left uterine artery laceration. On postoperative day 3, she developed thrombotic thrombocytopenic purpura–hemolytic uremic syndrome and was treated with plasma exchange therapy anddialysis. It is critical that clinicians consider this potentially fatal disease in the differential diagnosis when hemorrhagic shock is associated with unexplained thrombocytopenia, so that appropriateand early treatment may lead to a favorable outcome.

Vascular Events Associated with Alpha Interferon Therapy

Alpha Interferon (IFN) is a biological agent used for the therapy of an increasing number of diseases, either as an established effective therapeutic tool or in the context of clinical trials. The use of IFN may be complicated by serious adverse reactions. We describe here the clinical course of a variety of vasculopathic complications in association with IFN-therapy in 12 patients with the diagnosis of chronic myeloid leukemia and 1 patient with malignant melanoma treated at our institute. Vascular manifestations in these patients include Raynaud's phenomena, digital ulcerations and gangrene, pulmonary vasculitis, pulmonary hypertension and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). These reactions occurred after 3 months to 3 years of 3-10 million units (MU) daily IFN therapy. Concomitant administration of hydroxyurea (HU) was noted in 5 patients. Discontinuation of IFN and initiation of immunosuppressive therapy brought about a complete resolution or arrested progression of these reactions. IFN-therapy may be complicated by severe vasculopathic/vasospastic complications that usually improve after its discontinuation. Possible underlying mechanisms for these complications are discussed. The early diagnosis of these complications may be vital and IFN should be immediately discontinued when early signs of these complications become evident.

Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies.

Current reimbursement policy of health insurance for therapeutic plasmapheresis requires proof of efficacy using the concept of evidence-based medicine. The aim of this paper is to review the outcome of plasmapheresis used to treat thrombotic microangiopathy (TMA)-associated syndromes in the last decade to provide scientific evidence to back up reimbursement applications. The strength of evidence of each reviewed study was assessed using the five levels of evidence criteria as defined by the American Society of Hematology in 1996 for assessment of the treatment of immune thrombocytopenia. The level Experimental indication was added for situations where only case reports or small series supported by pathophysiological reasoning are available. The definitions of evidence used in this paper are as follows: Level I, randomized clinical trial with low rates of error (p < 0.01); Level II, randomized clinical trial with high rates of error (p < 0.05); Level III, nonrandomized studies with concurrent control group; Level IV, nonrandomized studies with historical control group; Level V, case series without a control group or expert opinion; and Experimental, case reports and pathophysiological reasoning. The results of this analysis based on the published data is summarized as follows: The indication of plasmapheresis is assigned to Level IV evidence for thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS); cancer/chemotherapy-associated TTP/HUS is assigned to Level V evidence; and TTP/HUS refractory to standard plasma exchange and post-bone marrow transplantation TTP/HUS are assigned to Experimental indication. For both subsets, protein A immunoadsorption is reportedly successful. The other TMA-associated syndromes, hemolysis elevated liver enzymes low platelets and HUS in early childhood, are no indication of plasmapheresis. Two randomized clinical trials were performed in order to demonstrate the superiority of plasma exchange/fresh frozen plasma (PEX/FFP) over plasma transfusion in the management of TTP/HUS. The results prove the greater clinical success of the latter type of plasma administration. Standard PEX/FFP has reduced the mortality of TTP/HUS from 94.5% to 13%.

Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes.

Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is thought to be uncommon and to have a good prognosis. To describe the frequency, clinical features, and long-term outcomes of quinine-associated TTP-HUS. Case series. Hospitals in central-western Oklahoma. 225 consecutive patients with TTP-HUS, 1989-2000. Presenting features and clinical outcomes. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was associated with quinine in 17 patients. Four patients died, and 7 survivors currently have chronic renal failure. Since 1 July 1995, 132 patients with clinically suspected TTP-HUS were explicitly asked about drug exposure. Fourteen (11%) had taken quinine, and 7 had taken other drugs associated with TTP-HUS. Neurologic abnormalities were as severe in patients with quinine-associated TTP-HUS as in the 118 patients who had not taken quinine. Quinine is a common cause of drug-associated TTP-HUS and can cause death and chronic renal failure. When the disorder is described as TTP-HUS rather than only as HUS, the severity of neurologic abnormalities and the occasional absence of renal failure are emphasized. If recurrent disease is to be prevented, clinicians must recognize quinine as a possible cause.

Quinine and Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome

Quinine and Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: diagnosis and treatment.

Prompt recognition of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) and initiation of plasma exchange treatment is critical as it substantially decreases mortality. Nevertheless, death and long-term complications remain common. The recent relaxation of diagnostic criteria has dramatically increased the number of patients treated for clinically suspected TTP-HUS.

Report on the workshop: Von Willebrand factor and Thrombotic Thrombocytopenic Purpura.

INTRODUCTION (Dr. P. Ganguly)A workshop on von Willebrand factor (vWf) andThrombotic Thrombocytopenic Purpura (TTP) was orga-nized by the Division of Blood Diseases and Resourcesof the National Heart, Lung, and Blood Institute(NHLBI) and was held on July 31, 2000 at the Lister HillAuditorium on the National Institutes of Health campus.TTP is a difficult disease with a high mortality and treat-ment options are limited to plasma transfusion or ex-change. The objective of the workshop was to review thecurrent understanding of the pathogenesis of TTP and tostimulate new research and clinical advances.The agenda of the workshop was broadly divided intothree parts. The first group of lectures addressed the fun-damental aspects of vWf molecular structure, vWf bio-synthesis, vWf-platelet interactions, classification ofmetalloproteases, and general principles of antibody for-mation.The second group of presentations discussed the dys-function of the vWf-cleaving metalloprotease in TTP pa-tients, the specificity of this observation and correlationwith disease status, assay of the vWf-cleaving metallo-protease, and development of an autoantibody in somepatients with acute idiopathic TTP. The third session fo-cused on the management of patients with TTP and thehemolytic-uremic syndrome (HUS), and the possible roleof vWf in these conditions. In the following text, theWorkshop speakers on each topic are identified.VON WILLEBRAND FACTOR: SYNTHESIS,STRUCTURE AND FUNCTION (Drs. E. Sadler,D. Wagner, and Z. Ruggeri)The vWf gene is located on chromosome 12. The pri-mary translation product includes a large 741 amino acidpropeptide sequence located at the N-terminal end of themolecule.In the endoplasmic reticulum, pro-vWf dimers areformed by disulfide bonding between “cystine knots” atthe C-terminal ends of pro-vWf molecules. The pro-vWfdimers then polymerize (multimerize) by the formationof additional disulfide bonds at the N-terminal ends ofthe pro-vWf dimers. The propeptide may function as adisulfide isomerase to promote this multimerization ofpro-vWf dimers in the acidic environment of the trans-Golgi network. After multimerization, the propeptidesare removed by intra-cellular proteolysis. The multimersof mature vWf subunits are then further modified byglycosylation and sulfation. The largest vWf multimersproduced by this complicated synthetic machinery maycontain more than 40 subunits, and exceed 20 millionDaltons in molecular mass. The completed vWf multi-mers, along with the previously removed propeptide mol-ecules, are either secreted constitutively or stored in theWeibel-Palade bodies of endothelial cells (and thea-granules of megakaryocytes and platelets). It is fromthe Weibel-Palade bodies that the most biologically ac-tive large and unusually large vWf multimers are re-leased when endothelial cells are stimulated.vWf mediates the adhesion of platelets to sites of vas-cular damage and, as the carrier protein for blood clottingfactor VIII, is required for normal factor VIII survival inthe circulation. The binding site for factor VIII on vWfmultimers is located near the N-terminal regions of ma-ture vWf subunits. Each vWf subunit consists of 2,050amino acids organized into separate domains with differ-ent structures and functions. The critical binding site forplatelet glycoprotein(GP) Iba, for example, is containedwithin domain A1. Other domains encode binding sitesfor collagen and a binding site for platelet GP IIb-IIIacomplexes (integrin aIIbb3). This latter binding site con-tains the amino acid sequence Arg-Gly-Asp (a sequencethat also enables fibrinogen and fibronectin to bind GPIIb-lIIa).

Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is an inclusive term describing diverse syndromes of multiple etiologies with the common features of thrombocytopenia and microangiopathic hemolytic anemia. Other organ involvement, including renal failure, neurologic abnormalities, and gastrointestinal symptoms, is common. Adverse reactions to drugs increasingly are reported as a potential cause of TTP-HUS. More than 50 drugs and other substances have been associated with the development of TTP-HUS, but many case reports are difficult to interpret because there is uncertainty regarding the diagnosis of TTP-HUS and because there is uncertainty regarding the relation of drug exposure to the onset of TTP-HUS. A systematic analysis of reports of drug-associated TTP-HUS will be required to better understand the strength of clinical evidence linking drugs to the etiology of TTP-HUS. In this review, five drugs that have been the subject of the most and the most recent reports of drug-associated TTP-HUS are discussed: mitomycin C, cyclosporine, quinine, ticlopidine, and clopidogrel. The clinical features of TTP-HUS associated with these drugs are different, suggesting two principal mechanisms by which drugs may cause TTP-HUS: dose-related toxicity (mitomycin C, cyclosporine), and immune-mediated reaction (quinine, ticlopidine, clopidogrel). The role of plasma exchange is uncertain, but this treatment is appropriate because of the high mortality and morbidity of drug-associated TTP-HUS. Recognition of a drug-associated etiology in a patient with TTP-HUS is critical to avoid re-exposure and recurrent illness.

Extracorporeal Plasma Treatment in Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome: A Review

This review summarizes the state of the art of apheresis in hemolytic uremic syndrome (HUS) and in thrombotic thrombocytopenic purpura (TTP). Both entities are characterized by thrombotic microangiopathy, hemolytic anemia, and thrombocytopenia. While HUS often presents with renal insufficiency, cerebral involvement is more common in TTP. Recently, in TTP, a primary or secondary lack of activity of a von Willebrand factor (vWF) degrading enzyme was made responsible for the presence of unusually large vWF multimers causing platelet aggregation and thrombus formation in the microvasculature. In contrast, in familial HUS, a factor H deficiency with uninhibited complement activation seems to play a role. Therapeutic plasma exchange (TPE) using fresh frozen plasma or cryosupernatant as the substitution fluid is indicated in acute TTP and atypical HUS without antecedent diarrhea. As a rule, it will show good effectiveness, especially in the former entity. HUS in pregnancy should be treated by instant delivery whereas postpartum HUS may resolve using protracted courses of TPE. In contrast, in thrombotic microangiopathy after bone marrow transplantation as well as in HUS due to cancer, mitomycin C, or after renal transplantation, TPE is of questionable value and indicated only as a last resort treatment.

Evaluation of women with clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome during pregnancy.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is more common in women, and commonly occurs during pregnancy and the immediate postpartum period. An important clinical issue is the distinction of TTP-HUS from the more common obstetric complications, preeclampsia and HELLP syndrome (hemolysis, elevated liver function tests, low platelets). Clinical suspicion of TTP-HUS requires urgent intervention with plasma exchange treatment, a procedure with substantial risk, while preeclampsia and HELLP syndrome typically resolve spontaneously following delivery. Since clinical features of these syndromes can be similar, especially if preeclampsia becomes severe or if seizures (defining eclampsia) occur, the differential diagnosis may be arbitrary. This review addresses the evaluation and management of these syndromes and describes a clinical approach for determining when plasma exchange is appropriate.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS): the new thinking.

TTP and HUS are two disorders with many similarities. Though their first descriptions appeared at different time in history, there has been a trend among physicians to consider them as the same clinical entity. However, in recent years new research findings on the pathophysiology of TTP and HUS have revealed some differences between the two disorders. In this paper, we will review the current approaches to the clinical and laboratory diagnosis of TTP and HUS, as well as therapeutic strategies. We will also summarize the recent advances in three areas in the study of the pathophysiology of TTP and HUS, namely the newly discovered von Willebrand factor multimer-cleaving protease, endothelial cell apoptosis induced by serum from patients with TTP and atypical HUS and the activation of complement system. Since distinguishing and differentiating between TTP and HUS may help to develop more effective therapies targeted at key steps of the disease development, we will discuss possible ways of reclassifying the TTP-HUS disorders. In the end, we also present our views on possible future development.

How I treat patients with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are, in adults, clinically and pathologically indistinguishable except for the severity of renal failure. They are best described as a single disorder, TTP-HUS, because the diagnostic evaluation and initial management are the same. Treatment with plasma exchange, available for more than 20 years, has dramatically altered the course of disease in adults with TTP-HUS. Plasma exchange has improved survival rates from 10% to between 75% and 92%, creating urgency for the initiation of treatment. This has resulted in decreased stringency of diagnostic criteria, which in turn has resulted in a broader spectrum of disorders for which the diagnosis of TTP-HUS is considered. Long-term follow-up has revealed increasing frequencies of relapse and of chronic renal failure. Although the increased survival rate is dramatic and recent advances in understanding the pathogenesis of these syndromes are remarkable, clinical decisions remain empirical. Therefore, the management decisions for patients with suspected TTP-HUS rely on individual experience and opinion, resulting in many different practice patterns. Multipractice clinical trials are required to define optimal management.

How I treat patients with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

AbstractThrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are, in adults, clinically and pathologically indistinguishable except for the severity of renal failure. They are best described as a single disorder, TTP-HUS, because the diagnostic evaluation and initial management are the same. Treatment with plasma exchange, available for more than 20 years, has dramatically altered the course of disease in adults with TTP-HUS. Plasma exchange has improved survival rates from 10% to between 75% and 92%, creating urgency for the initiation of treatment. This has resulted in decreased stringency of diagnostic criteria, which in turn has resulted in a broader spectrum of disorders for which the diagnosis of TTP-HUS is considered. Long-term follow-up has revealed increasing frequencies of relapse and of chronic renal failure. Although the increased survival rate is dramatic and recent advances in understanding the pathogenesis of these syndromes are remarkable, clinical decisions remain empirical. Therefore, the management decisions for patients with suspected TTP-HUS rely on individual experience and opinion, resulting in many different practice patterns. Multipractice clinical trials are required to define optimal management.