Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

BACKGROUND: Recurrent thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) during a subsequent pregnancy is an important concern because pregnancy may increase the risk for relapse. STUDY DESIGN AND METHODS: Outcomes of all pregnancies after recovery from TTP-HUS in the Oklahoma TTP-HUS Registry, a cohort of 301 consecutive patients during the period of 1989 through 2003, were assessed and compared to the total published experience. RESULTS: In the Oklahoma Registry, 3 of 7 (43%) women with idiopathic TTP-HUS, 2 of 11 (18%) women who were pregnant/postpartum, and 0 of 1 (0%) woman with a bloody diarrhea prodrome at their initial presentation were diagnosed with TTP-HUS during a subsequent pregnancy; all 5 women recovered. In published reports, 10 of 11 (91%) women with idiopathic TTP-HUS and 11 of 18 (61%) women who were pregnant/postpartum at their initial presentation, and all 11 (100%) women with congenital TTP-HUS were diagnosed with TTP-HUS during a subsequent pregnancy. Rates of recurrence in the Oklahoma Registry may be less because of case report bias for exceptional patients. Recurrent TTP-HUS was difficult to diagnose because other pregnancy-related complications were frequent. CONCLUSIONS: Although pregnancies in these women were often complicated, a future pregnancy may be a safe and appropriate decision for women who have recovered from TTP-HUS.     

Lessons learned from the Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome registry

The Oklahoma TTP-HUS Registry provides a complete community perspective of thrombotic thrombocytopenic purpura (TTP). This is possible because plasma exchange is the essential treatment for TTP and the Oklahoma Blood Institute provides all plasma exchange procedures for a region encompassing most of the State, including 58 of Oklahoma's 77 counties. The Registry is an inception cohort of consecutive patients for whom plasma exchange treatment was requested for a diagnosis of either TTP or hemolytic uremic syndrome (HUS). All 382 patients identified from January 1, 1989 to December 31, 2007 have consented to be enrolled. Complete follow-up is available for 380 of 382 patients. Patients are described both by clinical categories, related to their associated conditions and clinically apparent etiologies, and by the presence of severe ADAMTS13 deficiency. ADAMTS13 activity has been measured on 235 (93%) of 254 patients since 1995. Registry data have provided new perspectives on the definition and diagnoses of these syndromes as well as their outcomes. Long-term follow-up has documented that relapse is common among patients with ADAMTS13 deficiency but rarely occurs in patients without ADAMTS13 deficiency. Long-term follow-up has also documented persistent abnormalities of health-related quality-of-life and cognitive function. In addition to providing new perspectives on the natural history of these syndromes, The Oklahoma TTP-HUS Registry provides a support group for our patients, information about evaluation and management for community physicians, and a resource for research and educational programs.     

The role of ADAMTS13 in the pathogenesis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome

The identification, characterization, and clinical observation of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains) have provided important insights into the pathogenesis of thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is a plasma enzyme essential for postsecretion proteolytic processing of von Willebrand factor (VWF). Absence of ADAMTS13 is associated with the occurrence of abnormally large multimers of VWF and is also associated with the occurrence of TTP. Initial assumptions that absent ADAMTS13 was itself the etiology of TTP have been tempered by subsequent observations that ADAMTS13 activity can be severely deficient without clinical abnormalities and that patients can have characteristic clinical features of TTP without severe ADAMTS13 deficiency. A current interpretation of these observations is that ADAMTS13 deficiency is a major risk factor for the development of TTP, but it is neither always necessary nor sufficient to cause TTP. This interpretation is consistent with other vascular and thrombotic disorders in which multiple risk factors and associated conditions contribute to the etiology of acute events.     

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: outcome with plasma exchange.

A retrospective analysis was made of 14 consecutive adults with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) who were treated with plasma exchange (PE). In six patients the disease was primary, whilst in eight HUS/TTP was considered secondary to an associated condition. Thirteen patients had renal involvement, six had central nervous system symptoms or signs, three had fever, and one had myocardial damage. Twelve patients (86%) recovered. Four of these relapsed, but responded to further treatment. Two patients failed to respond and died. Hematological response occurred rapidly in survivors: thrombocytopenia resolved after a median of four exchanges, and hemolysis after a median of six. Four patients had a complete recovery, seven had residual mild end organ damage, and one had severe renal impairment. PE was an effective treatment for both primary and secondary HUS/TTP. The platelet count proved to be the earliest indicator of clinical outcome. Continuing follow-up of survivors is required because of the risk of relapse and the high incidence of end organ damage.     

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.     

Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome

BACKGROUND: With the increased frequency of diagnosis and improved survival of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome (TTP-HUS), the morbidity of plasma exchange (PE) treatment has become more important. STUDY DESIGN AND METHODS: Data were prospectively collected on 71 consecutive patients referred to the Oklahoma Blood Institute (OBI) for PE treatment for clinically suspected TTP-HUS from mid-1996 to mid-1999. Complications were defined as major or minor, and distinguished between those related to central venous catheter access or to the plasma. RESULTS: Twenty-one patients (30%) had 27 major complications, which caused two deaths. The major complications included 2 episodes of hemorrhage after subclavian line insertion (1 death), 1 pneumothorax requiring a chest tube, 12 systemic infections (1 death), 7 episodes of catheter thrombosis requiring removal of the central venous catheter, 2 episodes of venous thrombosis requiring anticoagulant treatment, 2 episodes of hypoxemia and hypotension, and 1 episode of serum sickness. Minor complications occurred in 22 additional patients (31%). Twenty-eight patients (39%) had no complications. CONCLUSIONS: The morbidity and mortality of catheter placement and PE are important considerations when PE treatment for clinically suspected TTP-HUS is anticipated.     

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.     

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: Diagnosis and management

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a clinical syndrome defined by the presence of thrombocytopenia and microangiopathic hemolytic anemia without a clinically apparent etiology. Patients may also have multiple other symptoms and signs including neurologic and renal abnormalities and fever. In the era prior to effective therapy with plasma exchange, most patients developed multisystem abnormalities and the syndrome was more easily recognized. Now, since there is urgency to begin treatment, sufficient diagnostic criteria for TTP-HUS are only thrombocytopenia and microangiopathic hemolytic anemia without a clinically apparent cause; patients may have no neurologic symptoms, renal abnormalities, or fever. This has lead to an apparent increased incidence because of both the increased importance of early recognition and the decreased specificity of the diagnostic criteria. Effective treatment has also revealed new aspects of the clinical course of TTP-HUS following the initial response to plasma exchange treatment: prompt exacerbations, which are common when plasma exchange is diminished in frequency or discontinued, and later relapses, which may occur many years after the initial episode. This review describes the evolution of the syndrome of TTP-HUS in the current era of effective treatment, and describes the management and clinical outcomes among patients treated by the Oklahoma Blood Institute. J. Clin. Apheresis 13:120–125, 1998. © 1998 Wiley-Liss, Inc.     

Predictors of response and relapse in a cohort of adults with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a single-institution experience

BACKGROUND: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a diagnosis of exclusion when a patient presents with the sine qua non findings of thrombocytopenia and microangiopathic hemolytic anemia without an identifiable cause. Although most patients respond to therapeutic plasma exchange (TPE), a significant number of patients relapse. The aim was to determine if clinical, laboratory, and/or treatment features could predict response and/or relapse. STUDY DESIGN AND METHODS: This study was a retrospective review of adults with TTP-HUS treated with TPE at our institution from January 1996 to February 2004. RESULTS: The study population consisted of 90 patients (69% female) with mean age of 45 years and mostly obese (65%). The majority of cases were considered idiopathic. Ten patients died (11%) from the disease before achieving a response, whereas 79 percent were considered responders. Obesity and severe anemia at presentation were predictors of response to TPE (p = 0.0126 and p = 0.0071, respectively). Among the responders, 28 percent relapsed in a median of 14 months. Male sex, severe thrombocytopenia (mean +/- SD, 13 x 10(9) +/- 8 x 10(9)/L), and higher lactate dehydrogenase pre-/posttreatment ratio were associated with relapse (p values of 0.0141, 0.0199, and 0.0407, respectively). ADAMTS-13 values were not obtained on enough number of patients to provide important data. CONCLUSION: Although patient and laboratory characteristics associated with response and relapse were identified, there was significant overlap between patient groups. Thus, our findings offer preliminary evidence and do not yet justify short- or long-term changes in the management of patients with TTP-HUS.     

The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency

BACKGROUND: Accurate estimates of the incidence of thrombotic thrombocytopenic purpura (TTP) are important to assess the resources required for current treatments as well as to anticipate the need to develop new treatments. Previous estimates have been indirect and have not reported data on patients with ADAMTS-13 deficiency. OBJECTIVE: To determine the incidence of patients with TTP-hemolytic uremic syndrome (HUS) in three categories: all patients with clinically suspected TTP-HUS, patients with idiopathic TTP-HUS, and patients with severe ADAMTS-13 deficiency. METHODS: Incidence rates were estimated from the Oklahoma TTP-HUS Registry, analyzing all 206 consecutive patients from January 1, 1996 to June 30, 2004 who were treated with plasma exchange for their initial episode of clinically suspected TTP-HUS. ADAMTS-13 activity was measured in 186 (90%) of the 206 patients. RESULTS: The age-sex-race standardized annual incidence rates were 11.29 x 10(6) (95% CI: 9.70-12.88) for all patients with clinically suspected TTP-HUS; 4.46 x 10(6) (95% CI: 3.43-5.50) for patients with idiopathic TTP-HUS; and 1.74 x 10(6) (95% CI: 1.06-2.41) for patients with severe ADAMTS-13 deficiency (<5% activity). In all three categories, the incidence rates were greater for women and for blacks. For patients with severe ADAMTS-13 deficiency, the age-sex standardized incidence rate ratio of blacks to non-blacks was 9.29 (95% CI: 4.33-19.93). CONCLUSIONS: Accurate incidence rate estimates for all patients with clinically suspected TTP-HUS, idiopathic TTP-HUS, and TTP associated with severe ADAMTS-13 deficiency have been determined. The greater incidence among women and blacks is comparable with their increased risk for other autoimmune disorders.     

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma

BACKGROUND: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has been described as a specific sequela of allogeneic HPC transplantation (HPCT). Nevertheless, because multiple transplant-related sequela can cause the characteristic clinical features of TTP-HUS, the diagnosis is difficult. STUDY DESIGN AND METHODS: All English-language articles describing patients with TTP-HUS following HPCT were identified. Articles reporting five or more total patients, including at least one patient diagnosed with TTP-HUS following allogeneic HPCT, were reviewed. All articles describing autopsies of patients diagnosed with TTP-HUS following allogeneic HPCT were also reviewed. RESULTS: Thirty-five articles reporting 5 or more total patients described 447 patients diagnosed with TTP-HUS following allogeneic HPCT. The frequency of diagnosis of TTP-HUS following allogeneic HPCT varied by 125-fold (0.5%-63.6%). Twenty-eight different sets of diagnostic criteria were described in the 35 articles; 25 articles included both RBC fragmentation and increased serum LDH. Many risk factors described as correlating with the diagnosis of TTP-HUS also predict greater risk for multiple transplant-related complications. Benefit of plasma exchange treatment could not be documented. Survival information was reported for 379 patients, 232 (61%) died, and reported mortality rates varied from 0 to 100 percent. Autopsies have been reported for 35 patients who were diagnosed with TTP-HUS following allogeneic HPCT; none had systemic thrombotic microangiopathy, the diagnostic abnormality of TTP-HUS; and infection (19 patients) was the most commonly reported cause of death. CONCLUSIONS: The clinical features of TTP-HUS following allogeneic HPCT may be caused by common transplant-related complications; the benefit from plasma exchange treatment is uncertain.     

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.     

Therapeutic plasma exchange in patients with thrombotic thrombocytopenic purpura: A retrospective multicenter study

Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy typically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological abnormalities, and renal dysfunction. TTP requires a rapid diagnosis and an adapted management in emergency. Daily sessions of therapeutic plasma exchange (TPE) remain the basis of management of TTP. Also, TTP is a rare disease that is fatal if it is not treated. TPE has resulted in excellent remission and survival rates in TTP patients.AimWe aimed to present our experience in 163 patients with TTP treated with TPE during the past 5 years from 10 centers of Turkey.Patients and methodsOne hundered and sixty-three patients with TTP treated with TPE during the past 5 years from 10 centers of Turkey were retrospectively evaluated. TPE was carried out 1–1.5 times plasma volume. Fresh frozen plasma (FFP) was used as the replacement fluid. TPE was performed daily until normalization of serum lactate dehydrogenase (LDH) and recovery of the platelet count to >150 × 10⁹/dL. TPE was then slowly tapered. Clinical data, the number of TPE, other given therapy modalities, treatment outcomes, and TPE complications were recorded.ResultsFifty-eight percent (95/163) of the patients were females. The median age of the patients was 42 years (range; 16–82). The median age of male patients was significantly higher than female (53 vs. 34 years; p < 0.001). All patients had thrombocytopenia and microangiopathic hemolytic anemia. At the same time, 82.8% (135/163) of patients had neurological abnormalities, 78.5% (128/163) of patients had renal dysfunction, and 89% (145/163) of patients had fever. Also, 10.4% (17/163) of patients had three of the five criteria, 10.4% (17/163) of patients had four of the five criteria, and 6.1% (10/163) of patients had all of the five criteria. Primary TTP comprised of 85.9% (140/163) of the patients and secondary TTP comprised of 14.1% (23/163) of the patients. Malignancy was the most common cause in secondary TTP. The median number of TPE was 13 (range; 1–80). The number of TPE was significantly higher in complete response (CR) patients (median 15.0 vs. 3.5; p < 0.001). CR was achieved in 85.3% (139/163) of the patients. Similar results were achieved with TPE in both primary and secondary TTP (85% vs. 87%, respectively; p = 0.806). There was no advantage of TPE + prednisolone compared to TPE alone in terms of CR rates (82.1% vs. 76.7%; p = 0.746). CR was not achieved in 14.7% (24/163) of the patients and these patients died of TTP related causes. There were no statistical differences in terms of mortality rate between patients with secondary and primary TTP [15% (21/140) vs. 13% (3/23); p = 0.806]. But, we obtained significant statistical differences in terms of mortality rate between patients on TPE alone and TPE + prednisolone [14% (12/86) vs. 3% (2/67), p < 0.001].ConclusionsTPE is an effective treatment for TTP and is associated with high CR rate in both primary and secondary TTP. Thrombocytopenia together with microangiopathic hemolytic anemia is mandatory for the diagnosis of TTP and if these two criteria met in a patient, TPE should be performed immediately.     

溶血性尿毒症综合征误诊为血小板减少性紫癜

【病例】　女 ,7岁。因呕吐、腹泻 5天 ,皮疹 1天入院。患儿于 5天前无明显诱因出现呕吐 ,非喷射性 ,每日 5 6次 ,同时排黄色稀水便 ,每日 78次 ,外院按“急性胃肠炎”治疗 ,症状稍有减轻。 1天前出现全身皮疹 ,伴有精神、食欲差 ,乏力 ,收入我院。查体 :体温 3 7 4℃ ,脉搏 118/min ,呼吸 3 8/min ,血压 13 5 /98mmHg ,体重 2 4kg。精神差 ,面色苍白 ,全身皮肤粘膜无黄染 ,躯干、四肢皮肤可见散在针尖大小出血点 ,浅表淋巴结未触及肿大 ,心、肺、腹部及神经系统检查未见异常。血常规 :血红蛋白 60g/L ,白细胞 19 3× 10 9/L ,中性粒细胞0…     

Pathophysiology of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Summary

Thrombotic microangiopathies are rare disorders characterized by the concomitant occurrence of severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic end‐organ damage. The latter particularly affects the brain, the heart, and the kidneys. The primary forms, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), although their clinical presentations often overlap, have distinctive pathophysiologies. TTP is the consequence of a severe ADAMTS‐13 deficiency, either immune‐mediated as a result of circulating autoantibodies, or caused by mutations in ADAMTS‐13. HUS develops following an infection with Shiga‐toxin producing bacteria, or as the result of excessive activation of the alternative pathway of the complement system because of mutations in genes encoding complement system proteins.