History Of Thrombotic Thrombocytopenic Purpura Research Articles

Imaging findings in a rare case of alveolar, hepatic and splenic sarcoidosis presenting with thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is an acute haematological disorder characterized by severe ADAMTS13 enzyme deficiency, leading to consumptive thrombocytopenia, mechanical haemolysis, and organ damage. Its association with multisystemic sarcoidosis is extremely rare and, to the best of our knowledge, described in only two cases so far. We present the case of a 52-year-old woman with TTP and antibodies anti-ADAMTS13, showing computed tomography (CT) and magnetic resonance imaging (MRI) evidence of pulmonary, hepatic, and splenic lesions initially reported as ischemic/inflammatory changes. A follow-up MRI of the abdomen revealed increased evidence of the liver lesions, focal intrahepatic bile duct dilatation, splenic lesions, and enlarged hepatic hilar nodes. The follow-up chest CT showed increased evidence of the parenchymal lung consolidations. Given the radiological persistence of those alterations and the history of TTP, the hypothesis of an IgG4-related disease was then made. The IgG4 levels were found to be normal, while the histological examination of the liver revealed non-necrotizing granulomatous chronic inflammation. Elevated levels of angiotensin-converting enzyme were found, and the QuantiFERON-TB Gold test was negative for tuberculosis infection. Thus, the overall clinical picture was consistent with multisystemic sarcoidosis (alveolar, hepatic, and splenic). The diagnosis of sarcoidosis, already challenging due to the variability of its clinical presentation, can become even more complicated when it manifests with uncommon haematological manifestations such as TTP, along with non-specific extra-pulmonary involvement. While imaging aids in documenting organ damage, the definitive diagnosis of sarcoidosis necessitates histologic confirmation of noncaseating granulomas and the exclusion of other possible granulomatous diseases.

PRESENTATION OF ACUTE CEREBROVASCULAR ACCIDENT IN A YOUNG ADULT WITH THROMBOTIC THROMBOCYTOPENIA PURPURA (TTP)

PRESENTATION OF ACUTE CEREBROVASCULAR ACCIDENT IN A YOUNG ADULT WITH THROMBOTIC THROMBOCYTOPENIA PURPURA (TTP)

Single-Center Experience of the Utility of a Rapid ADAMTS13 Assay

Introduction: Antibody-mediated thrombotic thrombocytopenic purpura (TTP) is a rare disease with significant morbidity and mortality, requiring prompt diagnosis and intervention. The advent of rituximab use (off-label) for TTP in 2002 not only established a novel therapy for refractory disease, but also raised the possibility of prophylactic therapy. Prophylactic rituximab was found by Westwood et al. to be effective in normalizing ADAMTS13 when activity dropped ≤15% in a retrospective cohort study (Blood Advances, 2017). Treatment paradigms in TTP are changing as evidence builds for prophylactic therapy, but we remain without large, randomized data to guide who would benefit most from prophylactic rituximab.The use of a rapid assay for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) has been shown to significantly reduce therapeutic plasma exchange (TPE) by ruling-in or -out suspected cases of TTP (Connell et al., Transfusion 2016). The role of rapid ADAMTS13 testing in assessment of response to TPE in acute TTP as well as surveillance of TTP patients in remission continues to be explored. We describe the utilization of a rapid ADAMTS13 assay and its role in the decision to use early or prophylactic rituximab in patients with TTP at the largest referral center for TTP in Rhode Island.Methods: Following IRB approval, demographic data for patients who underwent rapid ADAMTS13 testing from 1/1/13-2/28/17 at Rhode Island Hospital (Providence, RI) was obtained. Patients were deemed to have TTP if they had thrombocytopenia with microangiopathic hemolytic anemia (MAHA) and ADAMTS13 ≤ 10%, or thrombocytopenia with MAHA and a history of TTP. Each patient admission for TTP was recorded as a separate event. Data analysis was performed using Wilcoxon rank sum and Fisher's exact tests.Results: Ninety patients had ADAMTS13 testing from 1/1/13 to 2/28/17. Seven patients were excluded due to age less than 18 years. The remaining 83 patient charts were reviewed. Sixteen events of acquired TTP were diagnosed in 11 patients. Pregnancy-associated TTP did not occur, although 1 relapse of TTP had a history of post-partum TTP. Of the remaining patients, 5 had a history of TTP and underwent surveillance testing of ADAMTS13. One patient had congenital TTP. Diagnoses other than TTP were characterized in 66 patients (Figure 1). The most common other diagnosis found in patients who underwent ADAMTS13 testing was sepsis (n=12).When comparing patients who received rituximab during acute event (n=9) to those that did not (n=7) in 16 TTP events, we observed no statistically significant correlation between rituximab use and age, sex, presenting platelet count, presenting ADAMTS13 activity, presenting ADAMTS13 inhibitor value, days to platelet count normalization, or days of TPE (Table 1). We also observed no significant difference in days of TPE or days to platelet count normalization when comparing patients who received rituximab ≤ 5 days of diagnosis (n=5) versus those who received rituximab > 5 days from diagnosis but during the event (n=4). There was no significant change in rapid ADAMTS13 activity assay use, TPE use or rituximab use by year, from 2013-2016.In three patients with a history of acquired TTP, routine follow-up ADAMTS13 activity assay revealed decreased activity prior to the development of thrombocytopenia. These patients had an ADAMTS13 activity of 1%, 22%, 57% with platelet counts of 166k, 334k, 224k respectively. These patients had a history of 4, 7 and 8 prior events of TTP, respectively. Following the administration of 4 doses of weekly rituximab 375mg/m2, all had improvement in ADAMTS13 activity to >95%, none requiring TPE. These patients are recurrence-free after 7 months, 19 months, and 3 months of follow-up.Conclusions: In our single center retrospective study, early use of rituximab does not appear to confer immediate benefit through reduction of TPE or days to platelet normalization. Routine monitoring of ADAMTS13 activity by rapid assay, in conjunction with rituximab therapy as needed, has been shown to effectively normalize ADAMTS13 activity and possibly prevent relapse in three patients with history of relapsed TTP. Our experience provides evidence against the inpatient use of rituximab in relapsed TTP, and provides justification for the development of a protocol for the routine follow-up of TTP patients with implementation of prophylactic rituximab. [Display omitted] DisclosuresReagan:Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Speakers Bureau.

SOLID ENDOBRONCHIAL ASPERGILLOMA: A RARE ENTITY

SESSION TITLE: Fellows Chest Infections Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Aspergillosis refers to disease caused by a fungus of the genus Aspergillus, with the most common species being A. fumigatus. The most commonly affected organs are the lungs. Aspergilloma is a mass more commonly known as a “fungus ball” consisting of fungal hyphae mixed with cellular debris and mucus. An aspergilloma usually forms within cavities in the lungs. It may occur in a person with normal immunity but with structurally abnormal lungs, with preexisting cavities that lead to airflow stasis [1]. Endobronchial aspergilloma (EBA) is a rare presentation of pulmonary aspergillosis with only a handful of reported cases in literature. Here we present a case of endobronchial aspergilloma with significant space occupying and obstructing mass. CASE PRESENTATION: A 57-year-old female with recent history of thrombotic thrombocytopenic purpura that was treated with plasmapheresis and a pertinent medical history of diabetes, COPD and is an active smoker. She was evaluated in the pulmonary office for a cavitary lung lesion and was admitted for further workup including bronchoscopy. CT chest was obtained which did reveal a cavitary lesion in the right upper lobe (Figure 1) and atelectasis of the right middle and lower lobe. She then underwent bronchoscopy, which revealed an obstructing mass in the right bronchus intermedius with abnormal changes in the mucosa distal to the mass (Figure 2). Closer examination revealed some bleeding from around the mass. Multiple biopsies were then obtained revealing abundant septate hyphae consistent with aspergillus. Patient was started intravenous voriconazole and subsequently switched to oral on discharge with plans for repeat follow up bronchoscopy in 6 months. DISCUSSION: EBA is a very rare entity and is typically encountered as an incidental finding on bronchoscopy. It is usually defined as a noninvasive type of aspergillosis. An endobronchial mass the aspergilloma can be mistaken for lung cancer and can also sometimes hide an underlying cancer [2,3]. It can be very easily diagnosed with histopathologic examination of endobronchial mass revealing the fungal elements. Review of literature revealed only a handful of published cases and 1 case series reporting EBA. There are no established treatment guidelines or recommendations for EBA [2]. Pulmonary aspergillosis with cavitary lesions in the parenchyma is treated surgically with limited role of systemic antifungal therapy. However EBA the current consensus seems to be bronchoscopic intervention followed by systemic antifungal therapy [2,3]. Short-term follow up bronchoscopy is recommended to evaluate for response to therapy [2]. CONCLUSIONS: EBA is a rare presentation and usually diagnosed incidentally during bronchoscopy. It can occur in immune competent patients with underlying structural lung disease. Much remains to be learned as the optimal treatment and duration of medical therapy is not yet established. Reference #1: Huang, D., Li B., Chu, H., Et al. Endobronchial Aspergilloma: A Case Report and Literature Review. Experimental and Therapeutic Medicine. 2017;14:547-554 Reference #2: Ma, J., Yun, E., Kim, Y., Et al. Endobronchial Aspergilloma: Report of 10 cases and Literature Review. Yonsei Medical Journal. 2011;52(5):787-792 Reference #3: Araujo, D., Figueiredo, M., Monteiro, P. Endobronchial Aspergilloma: An Unusual Presentation of Pulmonary Aspergillosis. Pulmonology. 2016;22(1):61-62 DISCLOSURES: No relevant relationships by Mohammed Ali, source=Web Response No relevant relationships by Humayun Anjum, source=Web Response No relevant relationships by Aisha Mujahid, source=Web Response No relevant relationships by Salim Surani, source=Web Response No relevant relationships by Abhay Vakil, source=Web Response

Thrombotic Thrombocytopenic Purpura and Atypical Hemolytic Uremic Syndrome in Pregnancy: A Single Center Retrospective Review

Introduction: Thrombotic Thrombocytopenic Purpura (TTP) is a rare, life-threatening disorder characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and is often associated with renal failure and neurologic manifestations. There are congenital and acquired forms of TTP both diagnosed by severe deficiency in ADAMTS13 a von Willebrand factor cleaving protease. Atypical Hemolytic Uremic Syndrome (aHUS), is also a rare disease with MAHA, thrombocytopenia, and acute kidney injury not related with Escherichia coli 0157:H7 infections and is caused by unregulated activation of the alternate complement pathway. Although established that pregnancy may predispose to TTP and aHUS, little is understood regarding outcomes and effect on subsequent pregnancies. We report clinical outcomes of patients with TTP and aHUS during pregnancy at University of Florida (UFH). Methods: Pregnant patients between age 18- 45 admitted to UFH between January 2010 - December 2016 with clinical diagnosis of TMA (TTP, atypical HUS, HUS, drug induced HUS,) were identified by ICD 9/10 codes (ICD 10- CM - M31.1, ICD-9-CM 446, ICD 10 - D59.3 , ICD 09 - 283.11, Z34 and V22, O09 and V23). A total of 55 patients were identified of which 2 patients had TTP and 1 had aHUS. Data including demographics, race, gestational age at diagnosis of TMA, timing of ADAMTS13 testing, presence of fever, diarrhea, neurological symptoms, petechiae, bleeding , laboratory data (complete blood count, complete metabolic profile, coagulation panel, LDH ) , peripheral smear results; timing of plasmapheresis(PLEX), use of rituximab/ eculizumab, length of stay, 30 day readmission rate, days required for platelet recovery, number of PLEX sessions conducted were obtained and documented on an excel sheet. Given that 3 patients met study criteria, descriptive analysis was performed. Results: Of the 2 patients with TTP, patient 1 had 5 pregnancies and patient 2 had 1 pregnancy (fig 1). Altered mental status was the common feature in both patients (fig 3). Diagnosis of TTP was made on day 1 with confirmation of diagnosis between day 3-5. They were started on plasma infusion, steroids and plasmapheresis within 24 hrs. Response to treatment was variable with time to platelet recovery ranging between 3-10 days. Both patients remained in remission while not pregnant. Amongst the 6 pregnancies between them 1 resulted in Intrauterine Fetal Death, 2 elective abortions and 3 live births. Maternal survival was 100%. Patient 1 was eventually found to have ADAMTS 13 inhibitor and sarcoidosis and none of them had congenital TTP. Patient 3 presented with features of HELLP at 31 week of gestation and had emergent c- section after which she developed acute kidney injury, worsening thrombocytopenia and anemia. Was initially treated for TTP and started on PLEX, with minimal response after 5 sessions. ADAMTS 13 >35% and kidney biopsy showed TMA. She was diagnosed with aHUS and started on eculizumab, after which she showed clinical improvement. Subsequent follow up showed that there were no long-term health concerns in the children. Discussion: The diagnosis of TTP and aHUS during pregnancy can be challenging, as this condition mimics several other diseases like HELLP and acute fatty liver of pregnancy. Owing to the devastating nature, it is imperative to make the right diagnosis in a timely manner. Hematologists are often also asked to estimate risk of recurrence of TTP during pregnancy and also impact on the pregnancy itself. Jiang et al using the Oklahoma (TTP-HUS) Registry showed that women with a previous history of TTP, the frequency of recurrence is low and pregnancy outcomes are positive. Our review showed favorable outcome of pregnancy in patients with TTP and aHUS when diagnosis is made in a timely manner and treated appropriately i.e, PLEX within 24 hours of diagnosis. Our study also demonstrates that in patients with aHUS, PLEX stabilized the patient, but complete response is achieved only with Eculizumab, a humanized recombinant monoclonal antibody that inhibits the terminal pathway of complement activation by blocking the activation of complement protein C5. Without eculizumab, the abnormal pattern of complement activation and TMA are likely to persist with the risk of irreversible organ damage. Our study has limitations owing to the small study population. TTP and aHUS in pregnancy are however very rare and we hope to add to the existing literature. Disclosures Rajasekhar: Alexion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: direct payment for serving on Hematology Board Question Writing Task Force.

Endoscopic Ultrasound-Guided, Needle-Based Probe Confocal Laser Endomicroscopy (nCLE) of Intrapancreatic Accessory Spleen: Case Report and Literature Review

Introduction: Accessory spleens are often incidental findings on imaging and usually present as a solid mass at splenic hilum or other organs such as pancreas. Most patients with accessory spleens are asymptomatic however abdominal pain has been associated with an accessory spleen. Intrapancreatic accessory spleen (IPAS) can mimic a pancreatic neuroendocrine tumor (NET) on imaging studies and therefore posing a diagnostic dilemma. We present a case of IPAS in which the concomitant use of nCLE and fine needle aspiration (FNA) helped make the diagnosis. A 24 year old female referred for EUS for a pancreatic mass on CT scan. She presented with abdominal pain and during the workup a 3cm x 2.9cm round hypervascular hypodense mass in the tail of the pancreas was found. Her past medical history is significant for second degree relative with pancreatic cancer. Patient has a past medical history of Thrombotic Thrombocytopenic Purpura (TTP) and she underwent splenectomy 5 years ago for profound thrombocytopenia. On EUS a 2.8cm x 2.9cm round homogenous hypoechoic mass in pancreatic tail was identified. Initially the mass was punctured using a 19-G needle that was pre-loaded with AQ-Flex 19 probe inside the needle before puncture in lieu of the stylet. Fluorescein (2.5mL of 10 % fluorescein sodium) was injected simultaneously with probe insertion. Numerous thick white bands with floating small black particles inside the bands suggestive of network of blood vessels and floating Erythrocytes. Interrogation of the mass did not identify any finger-like papillary projections, crypt-like structures or dark aggregates of cells which is seen in a villous structure or neoplastic cells. Then 4 passes using a 22 G FNA needle was performed with onsite pathology and endomicroscopy review supported the final diagnosis of IPAS. Discussion: Accessory spleen is a rare entity which can be seen in the splenic hilum or at the tail of the pancreas. In 3000 autopsies reported by Halpert et al, 364 accessory spleens were found in which 17% were IPAS. Accessory spleens can be acquired entities (splenosis) which is the auto transplantation of splenic tissue in abnormal locations as a result of trauma or post splenectomy. This is the first case that incorporates real-time endomicroscopy and onsite pathology to diagnose IPAS. Patients with IPAS may undergo distal pancreatectomy because they mimic a hypervascular NET on CT and MRI scans. Onsite pathology and endomicroscopy review increases the diagnostic accuracy for differentiating between IPAS and pancreatic NET. In patients with a hypervascular mass in the tail of pancreas addition of real time nCLE to traditional FNA can increase the diagnosis yield of EUS and potentially prevent unnecessary surgery.Figure 1Figure 2Figure 3

Natural history of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

The differential diagnosis of thrombotic microangiopathy (TMA) has become clearer following the establishment of the relationships between (1) diarrhea-associated hemolytic uremic syndrome (HUS) and Shiga toxin-producing Escherichia coli-HUS (STEC-HUS), (2) a markedly reduced ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) level and typical thrombotic thrombocytopenic purpura (TTP), and (3) abnormalities in the complement regulatory system and atypical HUS (aHUS). These TMAs include typical TTP, other forms of TMA, STEC-HUS, and aHUS. The pathological mechanisms of TMA still overlap among several forms of TMA. With respect to the management of TMA, the use of plasma exchange (PE) for typical TTP, additional steroid therapy for TMA and rituximab for typical TTP with a high titer of the inhibitor of ADAMTS-13, as well as eculizumab for aHUS, have also been established. Although several issues remain in the pathophysiology and management of TMA, new findings will hopefully resolve these problems in the near future.

Preemptive Rituximab Infusions Efficiently Prevent Relapses In Acquired Thrombotic Thrombocytopenic Purpura. Experience Of The French Thrombotic Microangiopathies Reference Center

Context Acquired thrombotic thrombocytopenic purpura (TTP) results from a severe, antibody-mediated, deficiency in the von Willebrand factor-cleaving protease ADAMTS13. Rituximab is increasingly used in this indication in patients with a suboptimal response to plasma exchange. When severe acquired ADAMTS13 deficiency persists during remission, the estimated incidence rate is of 0.4/year. So far, it is still controversial whether preemptive rituximab efficiently prevents relapses in these patients. Patients and methods We defined two groups of patients with a history of acquired TTP who displayed a persistent severe ADAMTS13 deficiency during remission. Patients of group 1 were treated with preemptive infusions of rituximab. Patients of group 2 were managed in centers in which preemptive rituximab infusions were not the standard of care. The relapse incidence was evaluated and compared between both groups. Patients were treated according to National recommendations and enrolled from 12 French centers during a 12-year period. Patients were explored for ADAMTS13 activity and peripheral B-cell count every 3 months. Only patients with a > 12-month follow-up after rituximab administration are reported here. Median (25th - 75th percentile) was determined for all continuous variables. Wilcoxon’s test was used to compare continuous variables and the chi-square test or Fisher’s exact test to compare binary data. Relapse-free survival was compared between both groups using the Kaplan-Meier estimator with the corresponding 95% confidence interval. Results Forty-eight patients (20.6%) with a history of acquired TTP displayed a persistent severe ADAMTS13 deficiency on remission or experienced a subsequent severe ADAMTS13 deficiency (24 cases each) after a median follow-up of 17 months (12-29 months). Anti-ADAMTS13 antibodies concentration was 44 U/mL (24-59 U/mL). Thirty patients received preemptive infusions of rituximab (group 1), whereas 18 others had no therapeutical intervention (group 2). In group 1, 16 patients experienced a past history of TTP with a median number of 2 (1-3) episodes, corresponding to a relapse incidence of 0.22 (0-0.57)/year. Rituximab infusions were performed 14.5 months (6.5-27.4 months) after the last TTP episode. A median number of 4 (1-4) rituximab infusions were performed. The median follow-up between the first preemptive infusion of rituximab and the last ADAMTS13 evaluation is of 36 months (24-65 months). After preemptive rituximab administration, only 3 patients experienced a clinical relapse (0 [0] episode/year), corresponding to a significant reduction in the relapse incidence (P < .01). ADAMTS13 activity was 58.5% (30.5%-86.3%). Three months after the first rituximab infusion, ADAMTS13 activity was 46% (30-68); it further increased until the 12th month, and subsequently decreased. Accordingly, B-cell lymphocytes remained undetectable until the 6th month, and progressively increased at the 9th month to reach normal values at the 18th month. Nine patients (30%) required one (5 cases), two (2 cases), three (1 case) or ten (1 case) additional courses of rituximab for a further decrease or a persistent undetectable ADAMTS13 activity, which allowed to maintain a detectable ADAMTS13 activity in all but one patients. The time between two consecutive courses of rituximab was 26 months (5-59 months). At the end of follow-up, ADAMTS13 activity remained normal in 18 patients; 10 patients had a moderate ADAMTS13 deficiency, and 2 patients had a persistently undetectable ADAMTS13 activity. In four patients (13%), rituximab alone failed to increase durably ADAMTS13 activity, which required additional immunosuppressive drugs. In group 2, 14 patients relapsed after a 66-month follow-up (36-105 months), corresponding to a higher relapse incidence than in patients who received preemptive infusions of rituximab (0.23 [0.1-0.46] relapse/year, P<.01). Moreover, 2 patients died of TTP in group 2, whereas no fatal outcome was recorded in group 1. Relapse free survival over time was significantly longer in group 1 (Log-rank test: P = .049). Five patients experienced adverse effects including benign infections in 2 cases. Conclusion Rituximab efficiently prevents TTP relapses in most patients with a persistent acquired ADAMTS13 deficiency, with acceptable side effects. Disclosures: Off Label Use: Rituximab Rituximab may prevent relapses in acquired thrombotic thrombocytopenic purpura.

Case report: use of thienopyridines in a patient with acquired idiopathic thrombotic thrombocytopenic purpura

Thienopyridines are commonly used anti-platelet drugs that may be associated with the development of secondary, drug-induced thrombotic thrombocytopenic purpura (TTP), a rare but potentially life threatening condition. We report the case of a 70year-old man with a history of recurrent idiopathic TTP episodes who was treated with clopidogrel and then ticlopidine for thromboprophylaxis after percutaneous coronary intervention. Treatment was successful with no signs of TTP recurrence. Platelet counts and ADAMTS13 activity levels remained normal for months after the initiation of anti-platelet therapy, with no reappearance of anti-ADAMTS13 autoantibodies. This report demonstrates that thienopyridines do not necessarily induce TTP in patients with a history of TTP who are in disease remission.

A case of severe ADAMTS 13 deficiency presenting as thrombotic thrombocytopenic purpura in pregnancy

Thrombotic thrombocytopenic purpura is a rare life-threatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by the absent or severe deficiency of the von Willebrand Factor-cleaving protease named ADAMTS13. Pregnancy is a well recognized factor precipitating the appearance of the disease both in women that had reduced levels of ADAMTS13 activity prior to gestation and in those with other inherited or acquired thrombophilic syndromes. We report a 25-year old woman with severe ADAMTS13 deficiency presented early in her 1st pregnancy and relapsed in two subsequent gestations. This presentation is uncommon for thrombotic thrombocytopenic purpura is associated with pregnancy (ADAMTS13 deficiency < 5%, without an inhibitor). In the first pregnancy she started with daily plasma exchange 1.5 x volume, corticosteroids and IV immunoglobulin and finally entered remission after 23 sessions and termination of pregnancy. In the second pregnancy she did not receive prophylactic treatment and relapsed in the 3rd trimester. Prophylactic treatment during the third pregnancy with plasma infusions proved also ineffective to prevent relapse. Many issues regarding treatment and prevention of thrombotic thrombocytopenic purpura relapses in subsequent pregnancies are unclear. Proposed guidelines recommend that the same treatment should be performed on pregnant and non pregnant patients without modification of plasma replacement dose according to ADAMTS13 levels. In addition, many authors suggest that pregnant patients with history of thrombotic thrombocytopenic purpura and severe deficiency of ADAMTS13 levels should received prophylactic treatment for prevention of relapses in the subsequent pregnancies. Severe ADAMTS 13 deficiency may present as thrombotic thrombocytopenic purpura of pregnancy. Pregnant women with thrombotic thrombocytopenic purpura and especially with severe deficiency of ADAMTS13 levels require specific consideration regarding treatment and prophylaxis in subsequent pregnancies.

Presentation, Treatment, and Outcome for Twenty Consecutive Patients with Human Immunodeficiency Virus (HIV) Associated Thrombotic Microangiopathies (TMA).

AbstractAbstract 1432▪TMAs occur frequently in association with HIV, although the exact mechanism leading to hemolysis is unclear (Crum-Cianflone NF, Weekes J, and Bavaro M., AIDS Patient Care and STDs. 2008, 22:771-778.) Thrombotic microangiopathies comprise a spectrum of diseases including thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS). The role of HIV infection in the development of TTP has been a topic of some controversy. Overlap between TTP and HIV associated pathological entities, including malignancy and malignant hypertension, may complicate the clinical presentation (Benjamin et al., CID. 2009, 48: 1129–1136). However, patients meeting a clinical diagnosis of TTP are treated successfully with plasma infusion therapy (Novitzky et al., B J Haematol. 2005, 128:373-379) suggesting a molecular process resulting in the depletion of plasma components. Such processes would include TTP/HUS and defects in complement regulation, but not disseminated malignancy or malignant hypertension. To further characterize the biology and outcome of TMA in HIV-infected patients, we reviewed the experience with these patients at the University of Maryland Greenebaum Cancer Center. All patients were from greater Baltimore, a city with 37.7 new HIV cases per 100,000 population, the second highest among U.S. cities (Baltimore City HIV/AIDS Statistics Fact Sheet, April 18, 2008. Department of Health and Mental Hygiene, State of Maryland). After obtaining IRB approval, we identified cases by review of all TMA patients treated by our plasma exchange service between 2000 and 2008. Twenty-one episodes of TMA occurred in twenty patients with HIV. One patient had had a prior episode of TMA, one in 1995 preceding our review, and one with multiple episodes in 2002 and then again in 2008. The median age of our patients was 43 years, all were African American, seven were men and fourteen were women. Seven patients were also infected with hepatitis C, one with hepatitis B, and two with both hepatitis B and C. Median CD4 cell count for all patients was 70 × 106 cell/L. Twelve patients were on or previously prescribed antiretroviral medications and eight patients were not. There was no significant difference in CD4 counts between these groups. Three patients were diagnosed with HIV at the time of TTP presentation. Median duration of HIV infection prior to presenting with TMA was 7 years. Median LDH was 3301 units/L with all but two patients having a value greater than 1000 units/L. One of these patients had an LDH of 507 units/L. The other patient (LDH 274 units/L) had a history of TTP 6 years prior that responded to plasma exchange. Neurologic abnormalities were found in nine patients (excluding dizziness) and diminished renal function (Cr > 1.5 mg/dL) was noted in fourteen patients. ADAMTS13 levels were not measured. The median number of plasma exchanges was 13, with seven patients requiring more than 20 treatments. Four patients were treated with rituximab following failure of plasma exchange. Five patients died. Among these patients HIV viral load was variable ranging from undetectable to >750,000 copies, however four patients had CD4 cell counts < 50 × 106 cells/L. All but one patient with CD4 cell counts ≥ 50 × 106 cells/L responded to plasma exchange. Two patients with CD4 counts below 10 × 106 cells/L responded to plasma exchange. Of the patients treated with rituximab, two patients had a prompt, favorable response and two ultimately died (Evans et al., AIDS Patient Care and STDs, 2010, 24: 349-52). One of the patients who died had a CD4 count of 2 at the time of rituximab treatment. The other patient had a history of previous TMA in 2002 that eventually responded to 32 plasma exchange treatments. In 2008, she again presented with TMA with thrombocytopenia, and was treated with 19 plasma exchanges prior to receiving rituximab. Her CD4 count at that time was 138 × 106 cells/L. She did respond promptly to rituximab, but developed further thrombocytopenia 2 months later. On this final presentation she was diagnosed with lymphoma, to which she ultimately succumbed. HIV-associated TMA meeting clinical criteria for TTP is generally responsive to standard treatment with plasma exchange, however alternative diagnoses must be excluded. Rituximab may be effective in carefully chosen patients failing plasma exchange. Disclosures:No relevant conflicts of interest to declare.

Thrombotic thrombocytopenic purpura and pregnancy

Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening disorder associated with a deficiency in the enzyme ADAMTS 13. It is diagnosed by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and widespread microvascular thrombosis resulting in organ ischaemia. Approximately 70% of TTP cases occur in women and nearly half of these women are of childbearing age. Pregnancy is a recognised precipitating cause of TTP in between 10‐25% of all cases and includes patients with acquired antibody mediated TTP and congenital TTP, often presenting in adult hood. The availability of ADAMTS 13 assays allows differentiation between congenital and acquired TTP and appropriate treatment plans. There is also a subsequent risk of TTP relapse in women with previous non‐pregnancy related TTP. Presentation may occur at any stage in pregnancy or in the post partum period. This would suggest an hormonal influence as well as the reduction in ADAMTS 13 from the second trimester, related to pregnancy associated increase in Von Willebrand Factor. Differentiation from other pregnancy associated microangiopathies, such as pre‐eclampsia, HELLP (haemolysis, elevated liver enzymes and low platelets) or HUS (haemolytic Uraemic Syndrome) may be clinically difficult, but necessary, in part, because of differences in treatment. HELLP and pre‐eclampsia require delivery and HUS supportive care. TTP requires urgent treatment with plasma exchange (PEX) to attain remission, but also to prevent fetal abnormalities resulting from placental thrombosis. Presented is a review of the literature of pregnancy associated TTP and our experience of treatment of patients who present with TTP during pregnancy and monitoring of women who have had a history of TTP. Positive outcome in pregnancy has been associated with regular monitoring of routine laboratory parameters and ADAMTS 13 activity. All patients maintain low dose aspirin therapy and low molecular weight heparin is started in those women where an increased thrombotic risk is determined. The aim is to optimise implantation and preservation of placental function, especially in women with previous pregnancy loss, as abnormalities of the uteroplacental circulation resulting in insufficiency are established early in the first trimester. A significant reduction in ADAMTS 13 activity or reduction in platelet count below the normal range, PEX is undertaken to prevent any further deterioration. Frank relapse is treated with daily PEX. In women with a congenital TTP phenotype, regular treatment through pregnancy has been successfully undertaken. It is very difficult to devise evidence based guidelines for pregnancy in women with a history of TTP. In our cohort, patients with ADAMTS 13 activity &lt; 5% at presentation in the current pregnancy had a history of TTP precipitated during pregnancy or recurrent TTP episodes, such that the chance of further exacerbation during pregnancy was considered to be high. Indeed, cases 1, 2 and 4 have demonstrated ADAMTS 13 activity &lt; 5% before and after these pregnancies and only case 3 and 5 had further TTP episodes following pregnancy. Therefore the intensive monitoring and treatment was based on the high probability of relapse during pregnancy. Indeed, in Patients with normal ADAMTS 13 activity at the start of pregnancy were continually monitored, but did not have a TTP relapse. In Conclusion: a multidisciplinary approach to pregnancy care with regular monitoring of routine laboratory parameters and ADAMTS 13 activity during pregnancy allows pre‐emptive treatment of patients who are at risk from TTP relapse.

Successful Pregnancy Outcome in 5 Patients with Thrombotic Thrombocytopenic Purpura.

Pregnancy is an initiating event for acute thrombotic thrombocytopenic purpura (TTP). Patients with a history of TTP have a high risk of relapse during pregnancy with associated maternal and fetal morbidity/mortality. We report 5 TTP patients who underwent serial clinical and laboratory monitoring (haemoglobin, platelets, blood film, reticulocytes, lactate dehydrogenase (LDH), ADAMTS-13 activity and IgG antibodies) and treatment within a specialist obstetric/haematology clinic, resulting in successful pregnancy outcomes. Patients: Cases 1 and 2 presented with TTP in their first pregnancy and had second trimester fetal losses. Case 3 had four TTP relapses and soon after achievement of clinical remission became pregnant. Case 4 had a single acute episode of TTP 6 years prior to pregnancy and normal ADAMTS 13 activity at the onset of pregnancy. Case 5 presented with acute TTP and a left sided stroke at 16 weeks gestation. ADAMTS-13 activity was <5% at onset of pregnancy in cases 1–3 and at presentation of TTP during pregnancy in case 5. Only case 3 had IgG antibodies to ADAMTS13. Cases 1–3 received regular plasma exchange (PEX) every 2 weeks initially, starting during the first trimester, with ADAMTS 13 activity levels maintained >15% during pregnancy (range 15–78%, normal range 66–126%) by collagen binding assay. Case 4 had normal laboratory parameters, including serial ADAMTS 13 activity levels, throughout pregnancy, requiring no specific therapy for TTP. Case 5 received intensive PEX (84 procedures) and pulsed methylprednisolone during pregnancy. Rituximab (375mg/m2, weekly for 4 weeks) was given at 28 weeks gestation with no observed toxicity except asymptomatic transient neonatal neutropenia. All 5 cases continued low dose aspirin (75 mg daily) throughout pregnancy. Case 1 and 2 received prophylactic low molecular weight heparin (LMWH) and cases 3 and 5 received treatment doses of LMWH for pulmunory emboli and TTP associated stroke at presentation. Live healthy infants were delivered in all 5 cases in the third trimester (31–41 weeks). These data suggest successful pregnancy outcome is achievable in patients with a history of TTP/acute TTP with therapy based on close clinical and laboratory monitoring. Regular PEX in patients with a history of TTP and severely reduced ADAMTS 13 activity/IgG antibodies to ADAMTS 13 at the onset of pregnancy was associated with successful pregnancy outcome. Serial ADAMTS 13 activity and antibody levels during pregnancy and post-partum provided a useful adjunct to decision making on intensity of treatment.

Thrombotic thrombocytopenic purpura.

This overview summarizes the history of thrombotic thrombocytopenic purpura (TTP) from its initial recognition in 1924 as a most often fatal disease to the discovery in 1997 of ADAMTS-13 deficiency as a major risk factor for acute disease manifestation. The cloning of the metalloprotease, ADAMTS-13, an essential regulator of the extremely adhesive unusually large von Willebrand factor (VWF) multimers secreted by endothelial cells, as well as ADAMTS-13 structure and function are reviewed. The complex, initially devised assays for ADAMTS-13 activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant 73-amino acid VWF peptide as substrate will hopefully be useful. Hereditary TTP caused by homozygous or double heterozygous ADAMTS-13 mutations and the nature of the mutations so far identified are discussed. Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and--if untreated--frequently results in death. Acquired TTP is often but not always associated with severe, autoantibody-mediated ADAMTS-13 deficiency. The pathogenesis of cases without severe deficiency of the VWF-cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS-13 activity. Survivors of acute TTP, especially those with autoantibody-induced ADAMTS-13 deficiency, are at a high risk for relapse, as are patients with hereditary TTP. Patients with thrombotic microangiopathies (TMA) associated with hematopoietic stem cell transplantation, neo-plasia and several drugs, usually have normal or only moderately reduced ADAMTS-13 activity, with the exception of ticlopidine-induced TMA. Diarrhea-positive-hemolytic uremic syndrome (D+ HUS), mainly occurring in children is due to enterohemorrhagic Escherichia coli infection, and cases with atypical, D- HUS may be associated with factor H abnormalities. Treatment of acquired idiopathic TTP involves plasma exchange with fresh frozen plasma (FFP), and probably immunosuppression with corticosteroids is indicated. We believe that, at present, patients without severe acquired ADAMTS-13 deficiency should be treated with plasma exchange as well, until better strategies become available. Constitutional TTP can be treated by simple FFP infusion that rapidly reverses acute disease and--given prophylactically every 2-3 weeks--prevents relapses. There remains a large research agenda to improve diagnosis of TMA, gain further insight into the pathophysiology of the various TMA and to improve and possibly tailor the management of affected patients.

Myocardial infarction in a patient with thrombotic thrombocytopenic purpura

A 63-year-old male with a prior history of thrombotic thrombocytopenic purpura was admitted with sudden onset of syncope. He denied chest pain. His initial blood chemistries were consistent with acute relapse of thrombotic thrombocytopenic purpura as indicated by microangiopathic hemolytic anemia and thrombocytopenia. The patient had evidence of myocardial injury as indicated by elevation of cardiac enzymes. A 12-lead electrocardiogram demonstrated ST elevation (up to 5 mm) in leads V 2 to V 6. The patient was treated with plasma exchange with fresh frozen plasma in addition to nitroglycerin, metoprolol and prednisone in a tapering dose. After reviewing the literature, we believe that the etiology of myocardial damage remains elusive, but may be secondary to an autoimmune phenomenon resulting in microthrombosis and myocarditis. We were unable to find any documentation about any specific treatment in such patients. Further studies are awaited regarding appropriate treatment of patients with thrombotic thrombocytopenic purpura and acute electrocardiographic changes.

Thrombotic thrombocytopenic purpura: medical and biological monitoring of six pregnancies

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare cause of severe thrombocytopenia in pregnancy. Methods: Six pregnancies in five patients with TTP were followed prospectively over 5 years. Ultralarge von Willebrand factor (ULvWF) multimers and cleaving protease (cp) levels were measured. Results: TTP relapsed, complicating four of the six pregnancies. Of three patients who relapsed, two had complete or partial vWF-cleaving protease (vWF-cp) deficiency, and one had a normal vWF-cleaving protease level. In all three we found abnormal UL multimers. The two women who did not relapse had normal vWF-cleaving protease level and an absence or loss of UL multimers. Conclusions: Pregnant patients with a history of TTP must be followed in a tertiary obstetric unit with plasmapheresis available. Influence of vWF-cleaving protease and vWF multimeric abnormalities on TTP relapsing during pregnancy has to be evaluated in a further multicentre study.

Unilateral emboli in a patient with thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is a rare disease most commonly associated with microangiopathic hemolytic anemia, thrombocytopenia, fever, neurologic disorders, and renal dysfunction. We describe a patient with a history of thrombotic thrombocytopenic purpura that had been quiescent for 4 months; he had a 3-week history of painful purpuric lesions on the left hand only. He also had mottling and a livedoid purpura of the distal fingertips, splinter hemorrhages of the left fingernails, and a decreased radial pulse. Findings of a biopsy specimen revealed multiple capillary and small vessel thromboses. Contrast aortography demonstrated a pseudoaneurysm of the proximal descending thoracic aorta with stenosis of the left subclavian artery at its origin and an associated thrombus.