Predictors of In-hospital Mortality and Acute Myocardial Infarction in Thrombotic Thrombocytopenic Purpura

Background

Despite the widespread availability of plasmapheresis as a therapy, thrombotic thrombocytopenic purpura is associated with significant morbidity and mortality. There is a paucity of data on the predictors of poor clinical outcome in this population. Acute myocardial infarction is a recognized complication of thrombotic thrombocytopenic purpura. Little is known about the magnitude of this problem, its risk factors, and its influence on mortality in patients hospitalized with thrombotic thrombocytopenic purpura.

Methods

We used the 2001-2010 Nationwide Inpatient Sample database to identify patients aged ≥18 years with the diagnosis of thrombotic thrombocytopenic purpura (International Classification of Diseases, 9^th Revision, Clinical Modification [ICD-9-CM] code 446.6) who also received therapeutic plasmapheresis (ICD-9-CM code 99.71) during the hospitalization. Patients with acute myocardial infarction were identified using the Healthcare Cost and Utilization Project Clinical Classification Software code 100. Stepwise logistic regression was used to determine independent predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura patients.

Results

Among the 4032 patients (mean age 47.5 years, 67.7% women, and 36.9% white) with thrombotic thrombocytopenic purpura who also underwent plasmapheresis, in-hospital mortality was 11.1%. Independent predictors of increased in-hospital mortality were older age (odds ratio [OR] 1.03; 95% confidence interval [CI], 1.02-1.04; P <.001), acute myocardial infarction (OR 1.89; 95% CI, 1.24-2.88; P = .003), acute renal failure (OR 2.75; 95% CI, 2.11-3.58; P <.001), congestive heart failure (OR 1.66; 95% CI, 1.17-2.34; P = .004), acute cerebrovascular disease (OR 2.68; 95% CI, 1.87-3.85; P <.001), cancer (OR 2.49; 95% CI, 1.83-3.40; P <.001), and sepsis (OR 2.59; 95% CI, 1.88-3.59; P <.001). Independent predictors of acute myocardial infarction were older age (OR 1.03; 95% CI, 1.02-1.04; P <.001), smoking (OR 1.60; 95% CI, 1.14-2.24; P = .007), known coronary artery disease (OR 2.59; 95% CI, 1.76-3.81; P <.001), and congestive heart failure (OR 2.40; 95% CI, 1.71-3.37; P <.001).

Conclusion

In this large national database, patients with thrombotic thrombocytopenic purpura had an in-hospital mortality rate of 11.1% and an acute myocardial infarction rate of 5.7%. Predictors of in-hospital mortality were older age, acute myocardial infarction, acute renal failure, congestive heart failure, acute cerebrovascular disease, cancer, and sepsis. Predictors of acute myocardial infarction were older age, smoking, known coronary artery disease, and congestive heart failure.     

Treatment of Resistant Thrombotic Thrombocytopenic Purpura with Rituximab and Cyclophosphamide

Thrombotic thrombocytopenic purpura (TTP) is an uncommon acquired disease in adults, especially young women, characterized by fever, neurologic manifestations, microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Treatment with plasmapheresis has increased the survival rate from 10% to greater than 90%. Still, a subset of patients with resistant TTP fail to respond to plasmapheresis or remain dependent on this procedure. We report such a patient who was successfully treated with rituximab and cyclophosphamide. She has now been disease free for more than 6 months. This novel treatment modality for TTP has been described for only a few patients. A well-controlled clinical trial is warranted to determine the role and place of this therapeutic approach in the management of TTP.     

Reactive Hemophagocytic Syndrome Associated with Thrombotic Thrombocytopenic Purpura During Therapeutic Plasma Exchange

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, cytopenia, splenomegaly, and lymphohistiocytic proliferation with hemophagocytosis. Sporadic, familial, and reactive HLH varieties exist. The latter, also termed the reactive hemophagocytic syndrome (RHS), has been associated with a variety of infectious and noninfectious etiologies. Activation of monocytes in RHS is due to stimulation by high levels of activating cytokines. RHS has not been associated previously with thrombotic thrombocytopenic purpura (TTP). TTP is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal impairment, and fever. We report on a 33 year old male patient with a classic picture of TTP who initially responded to therapeutic plasma exchange but then became refractory to treatment and developed RHS. It is likely that a specific pathophysiology involving the activation of neutrophils during TPE is present for the development of cytokine‐induced hemophagocytosis during TTP treatment. The consequent development of RHS possibly caused early TTP relapse.     

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

Abstract: 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.     

ticlopidine-Associated Thrombotic Thrombocytopenic Purpura With an IgG-Type Inhibitor to von Willebrand Factor-Cleaving Protease Activity

A 41-year-old Japanese man complained of a left-sided visual disturbance. Imaging by magnetic resonance angiography revealed a narrowing of the left internal cervical artery. Thus, ticlopidine (Tc) administration was started at a daily dose of 300 mg. However, 2 weeks later, severe thrombocytopenia, fever, nausea, and psychiatric symptoms developed; Tc was therefore discontinued. Based on the diagnostic hallmark of 5 clinical signs, the patient's disease was diagnosed as thrombotic thrombocytopenic purpura (TTP). Daily plasmapheresis was performed for the first 4 days, and the patient's clinical signs gradually improved. Von Willebrand factor-cleaving protease (vWF-CPase) activity in his plasma was less than 3% of that of the control sample at diagnosis, but that value recovered steadily following plasmapheresis. In addition, immunoglobulin G purified from the patient plasma inhibited vWF-CPase activity in normal plasma with a specific activity of 0.8 Bethesda units/mg. No sign of TTP relapse has been noted following cessation of Tc. Thus, it was concluded that the patient developed TTP by producing an inhibitory autoantibody against vWF-CPase activity that was presumably triggered by Tc administration.     

Membrane Plasma Exchange for the Treatment of Thrombotic Thrombocytopenic Purpura

The aim of our report is to present our 11‐year experience with therapeutic membrane plasma exchange therapy for the treatment of idiopathic thrombotic thrombocytopenic purpura syndrome (TTP). In 56 patients, membrane plasma exchange therapy was initiated immediately and performed once or twice daily until the platelet count normalized. During each plasma exchange procedure, 1–1.5 plasma volumes (3606 ± 991 mL) were replaced with fresh frozen plasma. In 37 females and 19 males (44 ± 21 years), 1066 plasma exchange procedures were performed. The average duration of treatment was 23 ± 17 days. The average number of plasma exchanges was 19 ± 17 per patient. Renal impairment was detected in 36% of patients. At the initiation of plasma exchange treatment, the average platelet count was 31 ± 30 × 10⁹/L and reached 199 ± 95 × 10⁹/L thereafter. Fifty‐two of 56 (93%) patients demonstrated an excellent response to plasma exchange therapy, of whom 48 patients (86%) attained complete remission with a platelet count of more than 100 × 10⁹/L. Four patients died soon after the initiation of plasma exchange therapy, when only 1–3 procedures had been performed. During the follow‐up period, six patients with complete remission had 1–5 subsequent relapses each year. One of them died of acute hemolytic reaction during the tapering of plasma exchange procedures. Three patients underwent additional splenectomy. Our experience with primary TTP supports the plasma exchange treatment with fresh frozen plasma as a mandatory, up‐to‐date therapy. Close monitoring during all 1066 procedures showed no serious side‐effects.     

Thrombotic Thrombocytopenic Purpura in a Patient with Rheumatoid Arthritis Treated by Plasmapheresis

Abstract: Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and neurologic symptoms. TTP is associated with many diseases and several therapeutic drugs. We report the rare case of a patient with rheumatoid arthritis who developed TTP that was not associated with drug therapy, 18 months after the onset of rheumatoid arthritis. She recovered from the TTP following daily sessions of therapeutic plasma exchange (TPE) with fresh frozen plasma replacement and glucocorticoid therapy. Recent pathogenic mechanisms are reviewed as they relate to von Willebrand factor. In this report of the rare association of TTP with rheumatoid arthritis, an immediate relationship is likely because both are of an immune nature. Awareness of the possible development of TTP in rheumatoid arthritis is important for early diagnosis and treatment.     

A Case of HIV Infection with Thrombocytopenia: Assosiation of HIV,Thrombotic Thrombocytopenic Purpura and Brucellosis

To report a case of HIV infection presenting with thrombotic thrombocytopenic purpura (TTP) and brucellosis that responded well to plasmapheresis and anti-infective therapy. A 64-year-old woman with moderate confusion, fever and pancytopenia was admitted. HIV infection history was taken from her family and she was not receiving antiretroviral therapy last one year. She had generalized purpuric skin lesions. Wright tube agglutination test was found positive with a 1:160 dilution and the patient was diagnosed as brucellosis. Detailed literature search showed brucellosis as a possible cause of TTP. Patient was treated by plasma exchange/fresh frozen plasma and antimicrobials and the response was excellent. Although brucellosis seems to explain the clinical picture of this patient, it is revealed that broad differential diagnosis is needed to reach uncommon diagnosis like TTP particularly in HIV infected patients.     

A Case of Thrombotic Thrombocytopenic Purpura Refractory to Plasma Exchange

Abstract: We experienced a case of thrombotic thrombocytopenic purpura (TTP) finally relieved after 74 sessions of plasma exchange (PE). The patient was a 56‐year‐old male. In August 1999, he was examined in emergency because of brown urine and a lowered level of consciousness. As TTP was suspected according to the laboratory findings of abnormally high lactate dehydrogenase and total bilirubin, decreased platelet counts, and numerous fragmented erythrocytes, he was admitted to the ICU of our hospital. Immediately after admission, PE was started consecutively. Upon concomitant use of antiplatelet drugs and prostacyclin, the level of platelet counts recovered to 100,000/μl once, but decreased again. Thus, in addition to the PE, prednisolone and vincristine were administrated, which elevated the level of platelet counts to 200,000 to 300,000/μl. Since the erythrocyte fragmentation was noted frequently, PE was continued twice a week. From the 60th day of admission onward, however, his body temperature rose above 40°C with a rapid increase of C‐reactive protein. A blood culture detected methicillin‐resistant Staphylococcus aureus (MRSA) which derived from a left lung abscess. During the course of anti‐MRSA treatment, he presented acute renal failure and acute hepatic dysfunction, but survived because of the combined therapy. He was discharged on the 180th day of admission. These results suggest that a combined therapy of steroid and vincristine is effective to treat TTP refractory to PE, but careful attention should be paid to the complications caused by immunosuppression.     

Rituximab Provided Long-Term Remission in a Patient with Refractory Relapsing Thrombotic Thrombocytopenic Purpura

We describe a 69-year-old man with refractory relapsing thrombotic thrombocytopenic purpura (TTP) successfully treated with rituximab. The patient had once been successfully treated with plasmapheresis and vincristine, but he had relapsed after a short period. Although plasmapheresis, vincristine, and splenectomy could not achieve a consistent elevation of the platelet count, rituximab administration provided sustained remission for more than 7 months. Rituximab should be considered as a therapeutic alternative for refractory TTP.     

急性胰腺炎相关血栓性血小板减少性紫癜1例

病例:患者男,44岁,2 d前早餐后出现左上腹疼痛,放射至后背,伴恶心;1 d前因病情加重至外院就诊,淀粉酶405 U/L,血小板9×10^9/L,血红蛋白111 g/L。因诊断不明且病情加重于2018年12月31日转入我院,患者既往无特殊病史、无服用抗血小板药物史。体格检查:体温36.8℃,脉搏108次/min,呼吸15次/min,血压172/116 mm Hg(1 mm Hg=0.133 kPa),BMI 29.03 kg/m 2;嗜睡;腹肌紧张,上腹部压痛,无反跳痛。     

Myocardial Infarction njury Is Relatively Common at Presentation of Acute Thrombotic Thrombocytopenic Purpura: The Indiana University Experience

Abstract: Although widespread vascular thrombosis is common in thrombotic thrombocytopenic purpura (TTP), there have been no prospective studies on the extent of injury to specific organs. Following successful resuscitation and plasma exchange of an index patient with widespread organ dysfunction, cardiogenic shock, and elevated cardiac troponin‐I levels, we prospectively studied and identified 2 more individuals (of 10 consecutive patients) with evidence of myocardial injury/infarction at presentation of acute TTP. These data suggest that cardiac troponin‐I measurements should be considered during initial evaluation of all patients with acute TTP.     

Demonstration of Immune Complexes in Thrombotic Thrombocytopenic Purpura and Effect of Exchange Transfusion

A 30-year-old man with clinical and laboratory features of thrombotic thrombocytopenic purpura (ITP) underwent exchange transfusion with 9 units of whole blood over a 24-h period. Then, the neurological, renal, and haematological manifestations resolved and the patient recovered completely. Serial plasma samples were obtained before and at 8 h intervals during the exchange transfusion. A convalescent plasma sample was obtained 14 and 80 d later. Immune complexes were demonstrated in the pre-exchange transfusion plasma, by polyethylene glycol (PEG) gradient sedimentation, separated by electrophoresis and analysed immunochemically. There were shown to be light, medium and high molecular weight sedimentation zones in the PEG gradients. The medium zone consisted of immune complexes containing platelet membrane asrociated antigens and IgG antibody; the heavy and light zones only showed the presence of IgG. There was progressive clearance of these zones by the exchange transfusion with the convalescent specimens showing a marked decrease in all zones, especially those of the middle molecular weight (which on analysis represent true immune complexes). The clearance of these immune complexes from the circulation by exchange transfusion could explain the clinical response seen in the patient.     

Successful Treatment of Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura with Fresh Frozen Plasma and Plasma Exchange

ABSTRACT. Four patients with hemolytic uremic syndrome (HUS) and seven with thrombotic thrombocytopenic purpura (TTP) were treated with infusions of fresh frozen plasma (FFP). In one patient with HUS and Ave patients with TTP this treatment was combined with plasma exchange (PE). The additional treatment varied; corticosteroids, antiplatelet drugs, heparin and blood exchange. All but one patient recovered completely in spite of severe illness with uremia, oliguria and/or cerebral symptoms during the acute phase. The results were surprisingly good in comparison with other published series. The success must in the first place be attributed to early diagnosis and to the infusions of FFP. PE seemed to potentiate the effect of FFP.     

Successful Rituximab Treatment in Thrombotic Thrombocytopenic Purpura Patients Complicated by Other Autoimmune Disorders: Two Case Reports

We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m²) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.     

Apheresis and the Thrombotic Thrombocytopenic Purpura Syndrome: Current Advances in Diagnosis,Pathophysiology, and Management

Endeavors to optimize the management of thrombotic thrombocytopenic purpura (TTP) syndrome and improve mortality and relapse rates are hindered by its poorly understood pathophysiology. Variability in the application of therapeutic plasma exchange (TPE), including replacement fluid strategies, desirable endpoints in the platelet count, serum lactate dehydrogenase concentration, and the use of a TPE taper, limit comparisons among published studies. The diversity of adjunctive therapies such as antiplatelet agents, steroids, and splenectomy further clouds comparisons. Recent progress in the diagnosis, pathophysiology, and management of TTP syndrome are summarized. The possible role of occult infection and newly emerging associations such as ticlopidine therapy are discussed. Advances in possible pathogenic mechanisms, the rationale for different replacement fluids including the recently licensed solvent-detergent treated plasma, and progress in the apheresis management of TTP syndrome are presented.     

Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody‐mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor, interferon‐γ and IL‐17a) were measured in 20 acute TTP patients and 49 remission cases. Anti‐ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL‐6 and IL‐10 levels were significantly higher in the acute vs. remission groups, IL‐6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL‐10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti‐ADAMTS13 IgG (r_s = 0·604, P = 0·017) and IL‐10 (r_s = 0·692, P = 0·006). No anti‐ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti‐ADAMTS13 IgG antibody and IL‐10 levels.     

左西孟旦对心力衰竭危重患者死亡率影响的Meta分析

目的:研究左西孟旦对心力衰竭(心衰)危重患者死亡率的影响。方法:在Pub Med、EMBASE、Cochrane心血管组数据库中收集左西孟旦与其他干预措施的随机对照研究,文献检索时间从各数据库建库时间至2014-07。根据Jadad量表评价纳入文献的质量并提取资料。对符合质量标准的对照研究(无剂量及给药方式的限制)采用Rev Man 5.2进行Meta分析。根据纳入标准最终入选37篇文献,共入选病例4 470例。结果:左西孟旦与对照组相比能降低心脏相关疾病所致心衰危重患者的死亡率[危险比(RR):0.85;95%可信区间(CI):0.75~0.97;P=0.02],并能降低心脏手术所致心衰危重患者的死亡率(RR:0.49;95%CI:0.28~0.85;P=0.01)。与多巴酚丁胺进一步比较,左西孟旦能降低心衰危重患者的死亡率(RR:0.84;95%CI:0.73~0.98;P=0.02),并能降低缺血性心脏病所致心衰危重患者的死亡率(RR:0.85;95%CI:0.73~0.99;P=0.04)。结论:左西孟旦能降低心脏相关疾病、心脏手术及缺血性心脏病所致心衰危重患者的死亡率。