Days Of Plasma Exchange Research Articles

Pregnancy and Immune Mediated Thrombotic Thrombocytopenic Purpura (iTTP); A Descriptive Analysis from the U.S. Thrombotic Microangiopathy (USTMA) Registry

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia without an alternative explanation, confirmed by severely deficient ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) to <10%. It is caused by autoantibodies against the ADAMTS13 protease. Pregnancy can precipitate iTTP, but the diagnosis and treatment are challenging, since it is often difficult to differentiate from other TMAs associated with pregnancy The aim of this study was to describe the clinical presentation, treatment, and outcomes of pregnancy related iTTP. Methods: Data was obtained from the USTMA retrospective database, including 15 large USTMA referral centers. Patients were identified based on the diagnosis of iTTP provoked by pregnancy between 9/6/1990 and 6/18/2018. The study cohort included participants with a clinical diagnosis of iTTP, confirmed by ADAMTS13 activity <10% who had a pregnancy or recent delivery within 30 days of presenting with iTTP. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX (plasma exchange) discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX. Maternal and fetal outcomes were additionally collected from 7/15 sites. Results: 42 patients had 55 iTTP episodes provoked by pregnancy. Median age for patients was 29. Sixteen (38.1%) were white, 20 (47.6%) were black. The most common presenting symptoms were headache and fatigue in 11/55 (20%) episodes. Thirty nine (70.9%) episodes had a platelet count <30 x10 9/L, and 46 (83.6%) had laboratory findings concerning for hemolysis as evidenced by elevated lactate dehydrogenase (LDH) and/or schistocytes present on peripheral smear. Only 5 (9%) episodes presented with a creatinine >2 mg/dL. ADAMTS13 activity was documented in 33 (60%) episodes and was <10% in 30 (90.9%) (Table 1). Treatment with PLEX was described in 30 (54.5%) episodes with a median duration of 6 days (2-26 days). Further immunosuppression included prednisone in 38 (69.1%) episodes and rituximab in 11 (20%), of which 7 (63.6%) had no future exacerbations or relapses during the study period.Seventeen (40.5%) patients had a prior diagnosis of iTTP. There were 10 exacerbations in 8 patients (19%), and 34 relapses in 13 (30%) patients after the 55-pregnancy provoked iTTP episodes. Five of those relapses were triggered again by pregnancy. Pregnancy related outcomes were obtained in 16 patients. Twenty five percent (4/16) of patients had a prior history of iTTP; median time of last iTTP to current presentation was 34 months (10-108). Of 16 patients, iTTP occurred with first pregnancy in 8 patients. Of the remaining eight patients, iTTP occurred in the eleventh (n=1), ninth (n=1), sixth (n=1), fifth (n=1), fourth (n=2), and unknown (n=2) pregnancy. Only 13 of 16 patients had further pregnancy specific outcomes available (Table 2). Preeclampsia was noted in 3 patients. Seven and 1 patients, presented with iTTP within 30 days postpartum or after miscarriage, respectively. The remaining patients (n=5) developed iTTP during the antepartum period. Of these, 2 pregnancies were terminated due to iTTP (second trimester and third trimester). One of the three remaining pregnancies resulted in fetal demise at 24 weeks. The latter two patients delivered healthy infants. There were no maternal deaths in our cohort. Conclusions: This is first multicenter descriptive analysis of pregnancy related iTTP from the USTMA registry. The clinical presentation of this cohort is consistent with iTTP triggered by other causes, and the low rate of acute kidney injury is helpful in identifying iTTP from other TMAs in pregnancy. We observed that pregnancy is a risk not only for acute episodes of iTTP in first pregnancy, but also in subsequent pregnancies and in the relapse setting of those with previous diagnosis of iTTP. While there was a 20% and 30% exacerbation and relapse rate respectively, maternal mortality was not observed. Rituximab did not affect maternal mortality. Fetal mortality was affected by iTTP in the antepartum period. These findings will serve as bases of prospective USTMA study for standardize management of this population.

Abstract 087: Cocaine‐Induced Acute Spinal Cord Ischemia Syndrome

Introduction Acute spinal cord ischemia syndrome (ASCIS) is a rare disease that is thought to comprise roughly only 1.2% of all strokes [1, 2]. These strokes primarily occur in the anterior spinal cord artery (ASA) and/or the posterior spinal cord artery (PCA) territory and can have widely variable clinical presentation. The use of recreational cocaine in young adults is well known to be responsible for acute ischemic and hemorrhagic strokes in individuals who lack other vascular risk factors. What is significantly rarer with few reported cases, however, is cocaine‐related ASCIS as the etiology of non‐traumatic acute spinal cord myelopathy [3‐7]. Methods N/A Results A 40‐year‐old female with a history of type I Diabetes mellitus, bipolar disorder, and polysubstance abuse presented with acute‐onset bilateral lower limb weakness, sensory loss, neck pain, and bladder incontinence. On admission, she reported using intravenous crack cocaine in the evening before admission and experiencing a fall in the bathroom a few hours after. She was unable to move her lower limbs following this fall. On examination, there was flaccid weakness in both lower extremities with decreased pinprick sensation below the T4 level and absent sensation below the thighs on both sides. She had no trauma preceding her symptoms and denied any recent vaccinations or travel history. An urgent CT (computed tomography) scan of the cervical, thoracic, and lumbar spine ruled out any obvious traumatic injury. Her urine drug screen was positive for cocaine, opiate, cannabinoid, and benzodiazepine. MRI (Magnetic Resonance Imaging) of the brain without contrast was unremarkable. MRI of the spine with contrast demonstrated two areas of T2 hyperintensities from C5‐C6 and T4 to the conus with cord expansion. The lesion in the thoracic spinal cord showed contrast enhancement and spared the dorsal column. Lumbar puncture was traumatic and showed elevated protein (>300 mg/dl) as well as elevated glucose (186 mg/dl). CSF studies, including meningitis/encephalitis panel, gram stain and culture, flow cytometry, cytology, and oligoclonal bands were negative. Serum autoimmune myelopathy panel, serum Aquaporin‐4 antibodies and MOG (Myelin Oligodendrocyte Glycoprotein) antibodies were negative. The other etiologies of non‐traumatic myelopathy, including HIV, Treponema pallidum, and HTLV‐I/II antibodies, were negative. A diagnostic spinal angiogram was completed with no evidence of arteriovenous fistula or aortic dissection. She completed five days of plasma exchange without any improvement and was transferred to an acute rehabilitation facility. At four months follow‐up, she continues to be flaccid in her lower limbs and requires a urinary catheter leading to frequent urinary tract infections. Conclusion While cocaine‐related cerebrovascular events are well documented, very few cases of cocaine‐related ASCIS have been described. The mechanism is thought to be multifactorial due vasospasm, cerebral vasculitis, vascular thrombosis, cardioembolism from cocaine‐induced myocardial infarction or cardiomyopathy, and hypertensive surges [9]. Due to the scarcity of these events, the patient outcomes are unclear. Other studies on outcomes of spinal cord ischemia have shown that ASIA Impairment Scale (AIS) score, lesion level, and patient age were the strongest predictors of neurologic and functional outcomes, whereas etiology of the ischemia had no effect on outcomes [10].

A Descriptive Analysis of Immune Thrombotic Thrombocytopenic Purpura (iTTP) Patients with Fatal Outcomes in the U.S. Thrombotic Microangiopathy (USTMA) TTP Registry

Background:Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy (TMA) occurring due to an acquired deficiency in ADAMTS13. Mortality due to iTTP is estimated at 10% with current standard treatment that consists of plasma exchange (PLEX) and corticosteroids. The United States TMA (USTMA) registry incorporates 15 large US referral centers across the nation, and includes patients diagnosed with iTTP between 1985 and 2019. We sought to perform a descriptive analysis on the patients with fatal outcomes attributable to acute iTTP episodes in the registry.Methods:We utilized the USTMA registry (n=771) and analyzed twenty-two baseline patient demographics, presenting symptoms, and laboratory findings. The study cohort included participants with iTTP diagnosis based on the presence of thrombocytopenia (platelet count <100 /µL), microangiopathic hemolyic anemia (hemoglobin less than the lower limit of normal with schistocytes on the peripheral blood smear), and either ADAMTS13 activity <10% or ADAMTS13 activity <20% with an anti-ADAMTS13 inhibitor or antibody. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX, as per the international working group definitions 1.Results:A total of 33 patients (4.28%) in the USTMA cohort died during acute iTTP episodes. The patient demographics and initial presenting lab values are summarized in Table 1.Time of death (Figure 1):22 patients (66.7%) died during the initial iTTP episode, and within 30 days of presentation.3 patients (9.0%) died during disease exacerbation of the initial episode.8 patients (24.2%) died due to disease relapse.Median time to death at initial presentation/exacerbation (n=25) = 8 days [IQR: 4-19]Median time to death due to relapse = 1.6 years [IQR: 1.1-5.7]Patient demographics and presenting features (Table 1):Median age = 51 years [IQR: 27.8-60]Sex = 54.5% female, 45.5% malePresence of neurologic symptoms on presentation: 22 (66.7%)Presence of any symptoms on presentation: 32 (97%)Conclusion:Patients with fatal outcomes due to acute iTTP episodes presented with variable symptoms and baseline characteristics. While the vast majority of deaths occurred during the initial acute episode, death also occurred during exacerbation of the initial episode or subsequent disease relapse. Vigilant laboratory and clinical monitoring both after achieving initial remission and during long-term follow-up are necessary, to allow detection of disease exacerbation and relapse, and potentially prevent iTTP-related deaths.1. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood. 2021;137(14):1855-1861. [Display omitted] DisclosuresMazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria.

ADAMS-TS13 Inhibitor Level and Risk of Relapse in Acquired Idiopathic Thrombotic Thrombocytopenic Purpura

▪Introduction:Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to reduced activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13). This disorder can be due to a congenital deficiency state or be acquired (immune TTP (iTTP)) due to an antibody which either inhibits or causes clearance of ADAMTS13.The aim of our study was to determine whether ADAMTS13 inhibitor titer at initial presentation could serve as a predictor of refractory disease and relapse in iTTP. We also measured clinical outcomes across different gender and racial subgroups.Methods:The United States Thrombotic Microangiopathy (USTMA) iTTP registry was used to extract patient information for two academic institutions in Eastern North Carolina.Descriptive statistics were used to analyze the data. The first iTTP episode recorded in the data base was used as the index episode. All patients included in the final analysis had an ADAMTS13 activity of <10%. An inhibitor level of 5 Bethesda units was arbitrarily chosen as the cutoff between low (<5) and high (>/5) inhibitor level. Response time was defined as the number of days of plasma exchange (PEX) required to achieve a platelet count of 150,000 for two consecutive days. Relapse was defined as occurrence of a new episode of iTTP 30 days after achievement of response. Refractory disease was defined as persistence of thrombocytopenia or absence of a sustained platelet count increment or platelet counts of < 50,000 despite 4-7 days of plasma exchanges and steroid treatment. Rituximab resistance was defined as lack of platelet recovery to more than 150,000 within 11 to 14 days of administration of the first dose of Rituximab.Results:A total of 161 patients with iTTP were identified. Ten patients had ADAMTS13 activity >10% and 15 patients did not have a reported inhibitor level. These subjects were not included in the final analysis.The cohort had 28% male (n =38/136) and 72% (n=98/136) female patients. There were more African American patients 73% (n=99/136) than Caucasians 24% (n=32/136). There were also 2 Hispanic, 1 Native American and 2 patients with unidentified race.Median ADAMTS3 inhibitor titer was 1.05 (Range 0-87). Forty three patients with ADAMTS13 activity <10 % had an inhibitor level of 0 (i.e undetectable).They were included in the low inhibitor group.Overall, 88% patients (n=120/136) had low inhibitor level and only 12% (n=16/136) had a high inhibitor. Thirteen percent females (n=13/98) and 8% (n=3/38) males had a high inhibitor level (p=0.387). Fourteen percent (n=14/99) African Americans and 6 % (n=2/32) Caucasians had a high inhibitor, p=0.23.In the low inhibitor group 30% (n=36/120) patients suffered at least one episode of relapse whereas 31% (n=5/16) had relapsed in the high inhibitor group.The median time to response was 6 days (range 1-76) in the low inhibitor group and 7 days (range 4-20) in the high inhibitor group (p=0.61). While looking at the various subgroups, median time to response for males was 6 days (range 4-21), females 6 days (range 1-76) , African Americans 6 days (range 3-29) , and Caucasians 6 days (range 1-76).The frequency of refractory disease was 31 % (n=5/16) in the high inhibitor group and 29% (n=34/119) in the low inhibitor group. At the time of enrollment in the registry, Rituximab was not a part of first line therapy. Only 26 out of 136 patients had received Rituximab. In the low inhibitor group 5 patients displayed Rituximab resistance whereas there were no patients in the high inhibitor group with Rituximab resistance.Conclusion:When evaluating patients presenting with iTTP in two centers in North Carolina, no correlation was found between a high inhibitor levels of >/ 5 Bethesda units and risk of relapse or refractory disease. A larger study is needed to evaluate this further. DisclosuresNo relevant conflicts of interest to declare.

O23 A series of catastrophic events

Case report - IntroductionCatastrophic antiphospholipid syndrome (CAPS) is a rare, life-threatening disease occurring in up to 1% of antiphospholipid syndrome (APS) cases. It was first defined in 1992 and remains a difficult to treat entity with a mortality rate of 37%. We describe a patient with systemic lupus erythematosus (SLE) and CAPS presenting with simultaneous multi-organ injuries who was successfully managed with ‘triple’ therapy including cyclophosphamide.Case report - Case descriptionA 42-year-old female presented to her local hospital with chest pain and worsening vision. She had a background of SLE, triple antibody-positive APS (previous DVT, pregnancy loss and strokes), hypertension, a metallic mitral valve, a previous myocardial infarction and pre-existing visual impairment due to a prior intra-cerebral bleed related to anticoagulation. Examination revealed a faint malar rash, cortical blindness and long tract neurological signs. Her ECG showed ischaemic changes and the admission troponin was significantly raised (3773ng/L). An echocardiogram showed new left ventricular dysfunction and a subsequent cardiac MRI was in keeping with coronary artery disease. Investigations showed an acute kidney injury, newly deranged liver function tests and a raised INR (>11, with no bleeding). Complement was normal with a low dsDNA titre. Urinalysis revealed proteinuria and a protein creatinine ratio measured 176mg/mmol. MRI diffusion weighted brain imaging showed acute bilateral occipital and left fronto-parietal infarcts. She had symptoms of a lupus flare with arthralgia and a butterfly facial rash. COVID-19 PCR tests were negative and she had not been recently vaccinated. She was diagnosed with CAPS and transferred to St Thomas’ hospital intensive care.On arrival, she received 1mg intravenous vitamin K followed by triple therapy for CAPS: an unfractionated heparin infusion, oral prednisolone 40mg daily, 5 days of plasma exchange and, given her background of SLE, she was treated with intravenous cyclophosphamide (according to the EUROLUPUS regimen). Intravenous methylprednisolone was avoided due to a previous hypertensive encephalopathy reaction. She responded rapidly. Her troponin fell from a peak of 5054 to 294ng/L, her creatinine settled at a new baseline (232umol/L) and her liver function normalised. She was switched back to warfarin due to her metallic valve and started on aspirin for cardiovascular secondary prevention. She required physical and occupational therapy due to her strokes but recovered well.Case report - DiscussionAccording to the 2003 criteria, CAPS can be classified as definite when there is evidence of: ≥3 organs involved, development of manifestations simultaneously or within a week, confirmation by imaging and/or histopathology of small vessel occlusion and positive antiphospholipid antibodies. Probable CAPS is when 3 out of the 4 criteria are present. In this case, three organs were confirmed to be involved with imaging showing cerebral and cardiac ischaemia. Her creatinine rose from a base of 190 to 289umol/L coupled with a high protein creatinine ratio confirming renal involvement. A Budd-Chiari syndrome was also suspected due to deranged liver function tests and INR, though imaging performed after therapy did not confirm this. A biopsy of any of these four organs was not feasible given the severity of her presentation and coagulopathy. There are no randomised controlled trials but data from the CAPS registry guides treatment and management follows a logical approach: anticoagulation to treat thrombosis, glucocorticoids for inflammation and plasma exchange (or IVIG) to remove the circulating autoantibodies. Triple therapy was associated with a reduced mortality compared to no treatment (28.6% versus 75%, respectively).Following analyses from the CAPS registry we also chose to treat with cyclophosphamide, which is associated with improved survival in patients with SLE. This decision was based on the clinical features of an SLE flare as opposed to serological grounds. There have been reports of rituximab and eculizumab being used successfully in CAPS, though generally as a last resort. As complement activation is seen in animal models of antiphospholipid syndrome thrombosis and rituximab is often used in refractory SLE, they may prove to be promising agents for refractory CAPS.Case report - Key learning pointsPrompt recognition and early treatment is vital in managing CAPSTriple therapy with anticoagulation, glucocorticoids and plasma exchange / IVIG is associated with better survival in CAPSCyclophosphamide is associated with better survival in patients with CAPS and concomitant SLE

Plasma exchange for COVID-19 thrombo-inflammatory disease.

Severe COVID‐19 disease is a hyperinflammatory, pro‐thrombotic state. We undertook plasma exchange (PEX) to determine its effects on organ function and thrombo‐inflammatory markers.Seven critically ill adults with severe COVID‐19 respiratory failure (PaO2:FiO2 ratio < 200 mm Hg) requiring invasive or noninvasive ventilatory support and elevated thrombo‐inflammatory markers (LDH >800 IU/L and D‐dimer >1000 μg/L (or doubling from baseline) received PEX, daily, for a minimum of 5 days. No other immunomodulatory medications were initiated during this period. Seven patients matched for age and baseline biochemistry were a comparator group.Coagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen: ADAMTS13 ratio, Factor VIII and D‐dimers were all elevated. Following 5 days of PEX, plasma levels of all the above, and ferritin levels, were significantly reduced (P < .05) while lymphocyte counts normalized (P < .05). The PaO2:FiO2 ratio increased from a median interquartile range (IQR) of 11.6 (10.8‐19.7) kPa to 18.1 (16.0‐25.9) kPa (P < .05). Similar improvements were not observed in controls. Acute kidney injury (AKI) occurred among five patients in the control arm but not in patients receiving PEX.PEX improved oxygenation, decreased the incidence of AKI, normalized lymphocyte counts and reduced circulating thrombo‐inflammatory markers including D‐Dimer and VWF Ag:ADAMTS13 ratio.

Plasma Exchange for COVID-19 Thrombo-Inflammatory Disease

IntroductionSevere COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. A thrombotic phenotype rather than a coagulopathy is suggested and we undertook plasma exchange to determine its effects on organ function and thrombo-inflammatory markers.MethodsPlasma exchange was carried out in seven critically ill adults with severe COVID-19 respiratory failure (PaO2:FiO2 ratio <200 mmHg) requiring invasive or non-invasive ventilatory support and elevated thrombo-inflammatory markers (LDH>800 IU/L and D dimer>1000 µg/L (or doubling from baseline). Patients received a daily single volume 3 litre plasma exchange for a minimum of five days. No other immunomodulatory medications were initiated during this period. Effects on organ function, thrombo-inflammatory markers and complications were monitored. Seven patients matched for age and baseline biochemistry were a comparator group.ResultsCoagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen:ADAMTS13 ratio, Factor VIII and D-dimers were all elevated. Following five days of plasma exchange, plasma levels of all the above, and ferritin levels, were significantly reduced (p<0.05, Figure 1) while lymphocyte count normalized (p<0.05). The PaO2:FiO2 ratio increased from a median(IQR) of 11.6 (10.8- 19.7) kPa to 18.1 (16.0-25.9) kPa (p<0.05). Similar improvements were not observed in controls. Acute kidney injury (AKI) occurred among 5 patients in the control arm but not in patients who underwent plasma exchange.ConclusionPlasma exchange was associated with an improvement in oxygenation, decreased incidence of AKI, normalisation of lymphocytes and reduction in circulating thrombo-inflammatory markers including D-Dimer and VWF Ag:ADAMTS13 ratio.DisclosuresThomas:Ablynx: Honoraria, Other: Advisory Board; Bayer: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board. Scully:Takeda: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau.

Atypical haemolytic uraemic syndrome in the eculizumab era: presentation, response to treatment and evaluation of an eculizumab withdrawal strategy.

The complement inhibitor, eculizumab, has revolutionised the management of atypical haemolytic uraemic syndrome (aHUS), although the optimum treatment duration is debated. Twenty-two cases of acute aHUS managed with eculizumab were retrospectively reviewed, including outcomes after eculizumab withdrawal. Although 41% had an associated complement genetic abnormality, mutation status did not affect severity of clinical presentation. Sixty-four percent required renal replacement acutely, with a high incidence of nephrotic range proteinuria (47%). Eculizumab followed a median of 6days of plasma exchange. After a median duration of therapy of 11weeks (range 1-227), haematological recovery was seen in 100%, while 81% achieved at least partial renal recovery (median increase in estimated glomerular filtration rate (eGFR) 49ml/min/1·73m2 ). At median duration of follow-up of 85weeks (range 4-255), 54·5% had eGFR≥60ml/min/1·73m2 , 27% had CKD, 14% were on dialysis, and 4·5% had died. Eculizumab was withdrawn in 59% (13/22) cases following complete haematological and renal recovery. Three of these 13 patients (23%) subsequently relapsed, with defined triggers in 2/3, but all made a full recovery with rapid resumption of eculizumab. There was a significant association between higher presenting creatinine and poorer renal outcomes. A strategy of eculizumab withdrawal in selected cases is both safe and cost effective.

Integrated Efficacy Results from the Phase II and Phase III Studies with Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Integrated Efficacy Results from the Phase II and Phase III Studies with Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Thrombotic Thrombocytopenic Purpura (TTP) Management at Foothills Medical Centre: A Retrospective Analysis Between 2005-2010 (Tertiary Centre, Calgary)

TTP is a rare condition of microangiopathic hemolytic anemia and thrombocytopenia with a reported incidence of 4 cases per million people. Untreated mortality is reported to be as high as 90%; plasma exchange (PLEX) has significantly reduced this to 28%. Given the heterogeneity in presentation and severity at diagnosis, there is a wide range of practice with regards to exchanges, management of refractory disease and relapse. The British Committee for Standards in Hematology (BCSH) released clinical guidelines first in 2003, updated in 2012 outlining evidence based approach to practice. Our goal was to examine clinical practices and effect on outcomes at our tertiary centre during 2005-2010, between release of the first and second edition guidelines.Patients were retrospectively identified by searching for the TTP diagnostic code with admission dates between 2005-2010. They were excluded if they were not primarily treated in Calgary, or their thrombotic microangiopathy (TMA) was felt to be due to another diagnosis.Thirty eight patients were identified, with an average age of 48.8 years, and mostly female (men=8 patients, 21%). Ten patients were excluded for alternate diagnoses or main treatment outside Calgary. TTP was classified as primary in 15/45 (39%), and in 33 patients (87%) this was their first episode. Secondary causes included underlying autoimmune disease (24% of patients), malignancy (16% of patients), and pregnancy (4% of patients). 4% of patients were receiving active chemotherapy at the time of diagnosis of TTP. ADAMTS13 level and inhibitor (antibodies) were only examined in 10 cases (26%), and reported in fewer. Measurement of antigen, activity and inhibitors is strongly emphasized in the literature for accurate diagnosis of TTP compared with hemolytic uremic syndrome (HUS), other TMA or congenital TTP, and this was underutilized in this tertiary centre likely due to laboratory availability.Duration in hospital was often long, with an average of 29 days. This is likely due to the frequency of refractory disease, seen in more than half of patients (23/38, 61%). 24% of cases were fatal; this result is consistent with previously reported mortality rates in the era of PLEX. 5 of 9 fatalities were associated with malignancy where there is felt to be no benefit from PLEX, although interestingly 2 patients with malignancy received 5 to 7 days of PLEX, recovered and were discharged from hospital. Two fatalities had a delay of 48 hours or more to initiation of PLEX through misdiagnosis, one developed severe neurologic symptoms during line placement and the other presented atypically with hematuria. The most common complications of TTP included bleeding (16 patients, 42%), neurologic changes without stroke (16 patients, 42%), requirement for hemodialysis (9 patients, 24%), and radiologically identified stroke (6 patients, 16%).35 patients (92%) received PLEX, and the average number of days on PLEX was 16. Twice daily exchange at initiation or exacerbation was common (29%), as were tapers (60%), although literature now suggests tapering does not reduce relapses. Steroids are recommended in most cases for immunosuppression; only 21 of our patients (55%) received these in hospital. Secondary immunosuppression was occasionally instituted in refractory or relapsing cases including cyclophosphamide (13 patients, 34%), rituximab (5 patients, 13%), mycophenolate mofetil and vincristine (1 patient each, 3%). Rituximab is now routinely used in initial treatment to decrease relapses, for refractory disease, and occasionally as prophylaxis with low ADAMTS13 in asymptomatic patients, and other agents generally recommended against given its efficacy and safety, but this was not standardized in our group.Limitations for this project include small patient numbers, the change in definitions of HUS, TMA and TTP over time, and the retrospective nature of patient selection and data collection.In summary, diagnostic and treatment strategies for TTP have become significantly more standardized in the past 10 years. A protocolized strategy for initial investigations, PLEX and immunosuppressive therapies in line with previously published guidelines would be useful in our institution, potentially reduce relapses and improve rapidity of patient response, however our mortality statistics appear similar to those previously published. DisclosuresNo relevant conflicts of interest to declare.

Corticosteroids and rituximab as adjunctive treatments for thrombotic thrombocytopenic purpura

Although treatment with plasma exchange increased the survival of patients with thrombotic thrombocytopenia purpura to 80% in the 1980s, no further increase of survival occurred over the next 20 years. However, more consistent use of adjuvant treatment with corticosteroids and rituximab in recent years has begun to further increase survival as well as decrease the frequency of relapse. With adjuvant treatment, durable remissions can be achieved more quickly, requiring fewer days of plasma exchange. Fewer days of plasma exchange have resulted in fewer complications, such as central venous catheter-related systemic infections. Future potential options for adjuvant treatment, recombinant ADAMTS13 to correct severe ADAMTS13 deficiency, and agents to block von Willebrand factor-mediated platelet thrombosis are being investigated.

Hematocrit and C-reactive protein predict treatment response times in ADAMTS13-deficient thrombotic microangiopathy

Thrombotic microangiopathy (TMA) syndromes are a heterogeneous group of microvascular syndromes that are typically treated with plasma exchange and other adjunctive therapies. Important pathogenic factors, such as ADAMTS13 deficiency, define distinct subsets of TMA. New treatments for TMA are being explored that are hypothesized to bring about remission more quickly. However, the existing factors that influence response to treatment time are poorly understood. We hypothesized that common laboratory parameters available at the time of treatment initiation might correlate with the number of days of plasma exchange required to induce remission. We therefore retrospectively compared pretreatment platelet counts, hematocrit levels, and C-reactive protein (CRP) levels to the number of days of plasma exchange treatment in 27 ADAMTS13-deficient TMA patients and 25 non-ADAMTS13-deficient patients that achieved remission. Using quantile regression analysis, we observed that in ADAMTS13-deficient patients, higher initial hematocrit levels significantly correlated with shorter treatment response times. In addition, for ADAMTS13-deficient patients, elevated levels of CRP correlated directly with longer response times. Higher platelet counts were associated with a nonsignificant trend toward shorter response times. In non-ADAMTS13-deficient TMA patients no significant correlations were observed. Our results suggest that when conducting clinical trials of adjunctive treatments for TMA, clinical data, including ADAMTS13 levels, pretreatment hematocrit levels, and CRP levels may be informative in interpreting response to treatment times.

ADAMTS-13 and Von Willebrand factor in relation to platelet response during plasma exchange in thrombotic thrombocytopenic purpura: a clue for disease mechanism?

ADAMTS-13 and Von Willebrand factor in relation to platelet response during plasma exchange in thrombotic thrombocytopenic purpura: a clue for disease mechanism?