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ABSTRACT Thrombocytopenic purpura (TTP) is a hematologic emergency that may occur with PD‐L1 immunotherapy. New or worsening anemia and thrombocytopenia in patients started on PD‐L1 inhibitors should raise suspicion for TTP and prompt workup for thrombotic microangiopathy.

Abstract Introduction: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy due to a severely deficient ADAMTS13 activity caused by ADAMTS13 autoantibodies. Pregnancy is a recognized risk for precipitating acute episodes of iTTP. iTTP is immediately life-threatening to both mother and fetus. This scoping review explores the neonatal outcomes of pregnant mothers with iTTP. Methods: We performed a comprehensive literature search (1990 to 2023) in major scientific databases using the Ovid MEDLINE, Embase, EBM Reviews (Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), and Scopus to identify studies related to iTTP and pregnancy outcomes. Eligible studies included those published in English that reported women with a diagnosis of iTTP that later become pregnant, or women that were initially diagnosed with iTTP during pregnancy or postpartum. Cases were included if there was documentation of confirmed ADAMTS13 deficiency and ADAMTS13 inhibitor was positive or if the author indicated cases were acquired or iTTP. Results were displayed descriptively. Two authors reviewed titles and abstracts, and a third author resolved conflicts. Relevant studies were extracted and analyzed descriptively. Results: 125 publications underwent full review; 52 publications (38 manuscripts, 13 abstracts) consisting of case series (n=18) and case reports (n=33) were included in final analysis. 1 review article with a case series was also included. Data regarding 206 pregnancies (antepartum iTTP: n=91, postpartum iTTP: n=24, and pregnancies in patients with a history (hx) of iTTP but no iTTP during current pregnancy: n=91) from 158 patients was included. Antepartum iTTP presented in the first, second and third trimesters in 21%, 38.7%, and 40 % respectively. When reported (n=67), plasma exchange (TPE) was used in 92.5% cases of iTTP. In 3 pregnancies, FFP was used instead of TPE, Rituximab was used in 19 (7 antepartum) and caplacizumab was used in 6 (2 antepartum) cases of ITTP. Of pregnancies with antepartum iTTP or with a hx of iTTP (n=182), fetal outcomes were available in 161 pregnancies. Of these, there were 46 fetal deaths (28.6%) and 31/46 (67.4%) occurred in those with antepartum iTTP. Fetal outcomes were available in 84/91 pregnancies with a hx of iTTP with no acute iTTP at current pregnancy and 82% (69/84) resulted in a live birth. ADAMTS13 activity was available in 58/91 pregnancies with a hx of iTTP with no acute iTTP and 88 % of these pregnancies had ADAMTS13> 20%. Of pregnancies with a hx of iTTP and available ADAMTS13, there were 7 fetal deaths; one was unrelated to iTTP. The remainder occurred in the first trimester (n=4) and second trimester (n=2); ADAMTS13 was < 20% in 3 patients, and > 20% in 3 patients. Of those with pregnancy losses with ADAMTS13> 20%, one patient had two other miscarriages (one before diagnosis of iTTP and one after diagnosis but no ADAMTS13 available). Another had a pregnancy with a live birth 2 years later (no ADAMTS13 available) and the third patient had ADAMTS13> 20% with a positive inhibitor. In pregnancies with both fetal outcomes and ADAMTS13 activity (n=53), live-births trended towards higher ADAMTS13 activities compared to fetal demise (p, 0.066). There were 5 maternal deaths associated with pregnancy (antepartum iTTP:4, postpartum iTTP: 1). Of those not receiving TPE (n=5), one pregnancy was associated with maternal and fetal death due to late iTTP recognition, one patient was lost to follow-up post-delivery to a live infant. The other three patients received FFP, and steroids; one of these patients suffered a fetal loss. Fetal outcomes were available in 5/7 pregnancies using antepartum rituximab and 4/5 were associated with fetal demise. In pregnancies using antepartum caplacizumab, there was one fetal death and one live birth. Conclusions: Pregnancy in patients with a diagnosis of iTTP carries significant associated morbidity and mortality. To our knowledge, this is the most comprehensive report on fetal mortality. With 28.6% of fetal demise, it is significantly higher than the fetal mortality in the general population (5.5 fetal deaths per 1000 live births). In the current cohort, 82% of pregnancies occurring in women with a hx of iTTP but without acute iTTP resulted in a live birth. This supports benefit of optimizing ADAMTS13 activity in women with a hx of iTTP interested in pregnancy.

Abstract Background Thrombotic Thrombocytopenic Purpura (TTP) is a rare, typically acquired disorder due to an immune-mediated deficiency of ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand Factor (vWF). In the absence of ADAMTS13 activity, ultra-large vWF multimers accumulate, promoting widespread platelet aggregation and microvascular thrombosis. This consumptive cascade leads to thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological symptoms, and rarely renal dysfunction. Although therapeutic plasma exchange (TPE) has long been the cornerstone of TTP treatment, the FDA approved Caplacizumab as a first-line treatment for TTP in 2019. This drug is a bivalent single-domain antibody that binds to the A1 domain of vWF and prevents its interaction with platelets, thus effectively interrupting the pathogenic cascade, which is associated with a risk of bleeding. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, comprising data from 152 healthcare organizations. Adults (≥18 years) with a diagnosis of TTP who received Caplacizumab plus TPE were compared to patients with TTP who received TPE alone. 1:1 propensity score matching (PSM) was performed to balance characteristics between cohorts. The primary outcomes assessed were all-cause mortality and major bleeding events over a period of 1 month. Results A total of 4084 patients with TTP were identified, of whom 356 received caplacizumab with TPE and 3728 received TPE. After PSM, 2 balanced cohorts were created: C+P (Caplacizumab + TPE), P only (TPE), each comprising 356 patients. The average age in C+P and P only, after PSM, was 50.4 +/- 16.2 and 50.8 +/- 16.2 years, respectively. Females formed 65.7% of both C+P and P only, and males accounted for 28.4% and 28.7% of C+P and P only, respectively. 2.8% patients in C+P and 7.06% patients in P only had all-cause mortality at the end of 1 month. One-month all-cause mortality was significantly lower in C+P (2.8%) compared to P only (7.06%), with an odds ratio (OR) of 0.385 (95% CI 0.182 to 0.814, p=0.010). Upon assessment of bleeding outcomes, no statistically significant risk difference was noted between the 2 groups, with the odds ratio being 0.974 (95% CI 0.399 to 2.379, p=0.954). Conclusion Our large database study suggests that the addition of caplacizumab to standard TPE therapy is associated with a reduction in one-month all-cause mortality in patients with TTP, without a corresponding increase in major bleeding. However, given the lack of granular clinical data, such as contraindications to caplacizumab use, it is possible that patients who received TPE alone were inherently at a higher risk. As such, while these findings support the potential benefit of early caplacizumab use, they should be interpreted with caution and warrant prospective validation to confirm causality and assess long-term outcomes.

Abstract Background Pregnancy is a known trigger for thrombotic thrombocytopenia purpura (TTP); however, there is limited data on the impact of a TTP diagnosis on pregnancy outcomes. Study design We used retrospective data from the National Inpatient Sample database to identify all hospital admissions of pregnant patients (≥18 years), with and without TTP from 2012 to 2021 using ICD‐9/10 codes. To describe the impact of TTP on maternal and fetal morbidity, we identified different morbidity indicators using standard CDC definitions. Results We identified 7,397,411 pregnancy hospitalizations with a mean age of 29 years. Of these, 233 had TTP , with 73 receiving therapeutic plasma exchange ( TPE ) during admission, which was treated as a surrogate for active TTP . Severe maternal morbidity rates were several‐fold higher in women with TTP (133 per 100 admissions; 95% CI 112–155) compared to those without TTP (6.75 per 100 admissions; 95% CI 6.74–6.79) ( p < 0.001). This included significantly higher rates of acute myocardial infarction, acute renal failure, acute respiratory distress syndrome ( ARDS ), disseminated intravascular coagulation ( DIC ), pulmonary edema/acute heart failure, puerperal cerebrovascular disorders, sepsis, shock, air/thrombotic embolism, blood transfusion, and mechanical ventilation. Amongst fetal outcomes, fetal growth restriction (6.9% vs. 2.3%) was more common in TTP , while there was no statistical difference between the two groups in rates of preterm delivery. In the multivariate analysis, Charlson comorbidity index ( CCI ) ≥ 1 and age ≥ 35 years were associated with higher likelihood of morbidity. Conclusion Pregnancy associated with TTP is associated with inferior maternal and fetal health outcomes.

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematologic emergency caused by ADAMTS13 deficiency, leading to microvascular thrombosis, haemolytic anaemia, thrombocytopenia, and end-organ damage. Neurological symptoms occur in up to 90% of cases and are frequently misdiagnosed as stroke. Prompt recognition and treatment reduce the mortality rate from over 90% to 10–20%. Case presentation: A 70-year-old woman with no significant medical history presented with acute aphasia and right-sided facial and upper extremity numbness. Five days prior, she had experienced fatigue, headache, and bruising. On admission, she had stable vitals with mild aphasia and purpuric ecchymoses noted on examination. Laboratory findings revealed haemolytic anaemia (haemoglobin 7.8 g/dl, lactate dehydrogenase 875 U/l, total bilirubin 2.4 mg/dl), thrombocytopenia (35 ×109/l), and unremarkable coagulation studies (partial thromboplastin time 30 sec, prothrombin time-international normalized ratio 1, fibrinogen 370 mg/dl, D-dimer 2.15 ng/ml). Peripheral smear showed no schistocytes but noted 2+spherocytes. Stroke was ruled out with brain magnetic resonance imaging/magnetic resonance angiography. Given the bicytopenia with possible haemolysis along with new neurological symptoms, TTP was considered in the differential diagnosis. A PLASMIC score of 5 suggested a high probability of TTP. Plasma exchange and corticosteroids were initiated within 5 hours of presentation. ADAMTS13 activity <1% confirmed the diagnosis 4 days after presentation. After five plasma exchange sessions, the patient’s platelet count normalized and neurologic deficits resolved by discharge. Conclusion: This case underscores the importance of considering TTP in stroke mimics, even in the absence of schistocytes, if clinical suspicion is high. Early recognition and initiation of treatment significantly improve patient outcomes.

AbstractBackgroundImmune thrombotic thrombocytopenic purpura (iTTP) is a hematologic disorder characterized by severe acquired deficiency in ADAMTS13, resulting in thrombotic microangiopathy and death if untreated. Plasma exchange (PLEX) is the backbone of iTTP management and has improved survival in this disorder. Guidelines suggest initiation of PLEX within 4–8 h of presentation; however, there is little evidence to guide the precise timing of PLEX, and barriers exist to its timely deployment.Study design and methodsWe examined determinants of time between symptom onset to PLEX initiation (S2P) and hospital presentation to PLEX initiation (door to PLEX, D2P) in a large iTTP research cohort at an academic medical center.ResultsIn 225 cases occurring in 143 unique patients, the median (IQR) S2P time was 4.28 (1.92–7.47) days. In linear mixed effects regression analysis, increased S2P was associated with greater distance from a participating apheresis center (p = .01) and higher presenting platelet count (p = .046), while relapse presentation was associated with shorter S2P (p = .036). The median (IQR) D2P time was 8.4 (5.03–15.63) h. Longer D2P time was associated with a higher presenting platelet count (p = .002) and trended towards association with male sex (p = .057). Increased S2P and D2P times were not associated with hospital length of stay, mortality, or the composite of mortality and ICU stay.ConclusionOur data show that different factors contribute to the interval between symptom onset and presentation versus the time between presentation and initiation of therapy in iTTP.

ABSTRACTImmune thrombotic thrombocytopenic purpura (iTTP) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular occlusion secondary to acquired ADAMTS13 deficiency. Contemporary data regarding iTTP treatment practices in the US, including the use of caplacizumab, are lacking. We aimed to characterize the demographics and therapies, including medications and apheresis practices, in patients with iTTP in the US. We retrospectively analyzed iTTP cases at 15 sites in the US that provide comprehensive care for patients with iTTP. The time‐period assessed was from January 1, 2017 to December 31, 2021. Our primary objective was to analyze data by iTTP episode, inclusive of initial episodes and relapses. A total of 390 iTTP episodes were reported for 280 unique individuals (187 females, 93 males). Thirty‐day mortality was 3.7% (14/374), and 6‐month mortality was 7.4% (27/367). TPE details were reported for 343 episodes, among which 261 underwent at least one procedure (median 6, IQR 3–11). Among the 261 episodes with at least one therapeutic plasma exchange (TPE) performed, 82.0% (214/261) used only plasma. Caplacizumab was used either alone or in combination with other agents in 43 (11.0%) episodes. Management strategies for iTTP remain varied across centers in the US, with a variety of combinations for TPE replacement fluids and therapeutic agents, as well as limited use of caplacizumab. Further research and standardization of treatment regimens may further reduce mortality in this condition.

Introduction: Thrombotic thrombocytopenic purpura (TTP) has been previously described in pregnancy, however there is limited data available on the impact of TTP in this subset of patients. In this analysis, we evaluate the maternal and fetal morbidity outcomes of TTP in hospitalized pregnant patients. Methods: We used retrospective data from the National Inpatient Sample (NIS) to identify all hospital admissions of pregnant patients with and without TTP from 2012 to 2021 using ICD-9/10 codes. To describe the impact of TTP on maternal and fetal morbidity, we identified different morbidity indicators using standard Centers for Disease Control and Prevention (CDC) definitions with a particular focus on preeclampsia/eclampsia, thromboembolic events (venous and arterial), other organ failure, maternal morbidity and fetal outcomes including intrauterine growth restriction (IUGR) and fetal loss. To account for the effects of acute TTP during pregnancy versus a history of TTP, we separately analyzed hospitalizations that included plasma therapeutic plasma exchange (TPE). Predictors of maternal/fetal morbidities in pregnant TTP patients were determined using multivariable logistic regression analysis. Results: We identified 7,514,304 pregnancy hospitalizations with a mean age of 29 years. Of these, 234 women had a diagnosis of TTP, with 74 receiving TPE during admission (acute TTP during pregnancy). Compared to pregnancy-related hospitalizations in women without TTP, those with TTP were more likely to be African American, admitted to urban teaching hospitals, have lower income, and have a higher Charlson Comorbidity Index (CCI). Most maternal morbidity outcomes were significantly higher in hospitalizations with TTP as compared to those without TTP including increased eclampsia (2.1% vs 0.08%), acute myocardial infarction (1.7% vs 0.01%, p&lt;0.001), puerperal cerebrovascular disorders (8.1% vs 0.7%, p&lt;0.001), cardiac arrest (0.9% vs 0.01%), acute renal failure (35% vs 0.2%, p&lt;0.001), adult respiratory distress syndrome (ARDS) (6.4% vs 0.06%, p&lt;0.001), disseminated intravascular coagulation (DIC) (18% vs 0.2%, p&lt;0.001), pulmonary edema/acute heart failure (5.1% vs 0.1%, p&lt;0.001), sepsis (9% vs 0.22%, p&lt;0.001), shock (6.4% vs 0.1%, p&lt;0.001), air/thrombotic embolism (3.0% vs 0.05%, p&lt;0.001), blood transfusion requirement (25.6 vs 1.28%, p&lt;0.001), and ventilation requirement (6.4% vs 0.06%, p&lt;0.001). There was also a higher need for cesarean sections in TTP hospitalizations compared to non-TTP (57.1% vs 36.9%). For fetal morbidity outcomes, intrauterine growth restriction (IUGR) was more common in TTP hospitalizations (6.8% vs 2.4%, p&lt;0.001), while there was no statistical difference between the two groups in the rates of preterm delivery (3.9% vs 3.3%, p=0.651). In-hospital mortality (1.7% vs 0.02%, p&lt;0.001), and length of stay (11 vs 3 days, p&lt;0.001) were also significantly higher in hospitalizations with TTP. Patients with TTP who received TPE during the hospital stay had worse maternal morbidity outcomes than those who did not, likely reflecting the active nature of the disease in this cohort. In the multivariate analysis, CCI ≥ 1 (OR 3.52, 95% CI, 1.64-7.54) and receipt of TPE (OR 2.99, 95% CI, 1.52-5.86) were associated with higher likelihood of maternal/fetal morbidity in TTP hospitalizations. Conclusion: In conclusion, TTP has a significant impact on hospitalized pregnant patients, both on maternal and fetal outcomes. Further studies are needed to assess risk factors associated with TTP in pregnancy and ideal treatment regimens for these patients.

AbstractPrior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5‐year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere—winter (December–February); spring (March–May); summer (June–August); autumn (September–November) and Southern Hemisphere—winter (June–August); spring (September–November); summer (December–February); autumn (March–May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%–31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.