Thrombotic Thrombocytopenic Purpura: Lessons from Clinical Cases, A case series

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Elkourashy, Tamader Mashhadi, Amna Al-Kuwari, Sara Al-Abdulla, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5867341/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Thrombotic Thrombocytopenic Purpura (TTP) is a rare yet life-threatening complication during pregnancy, with maternal mortality rates historically exceeding 90% before the advent of therapeutic plasma exchange (TPE), which has been the cornerstone of treatment for several decades. Rituximab has become increasingly important for managing refractory or relapsing TTP, particularly during pregnancy, due to its effectiveness in reducing relapses. In severe or recurrent cases, caplacizumab has emerged as a valuable agent, rapidly controlling acute episodes by preventing platelet aggregation and reducing microvascular thrombosis, which is critical in reducing organ damage and improving survival. Monitoring ADAMTS13 activity has become crucial in distinguishing between congenital and acquired TTP, guiding treatment decisions, and preventing relapses. This case series includes both acquired and congenital TTP cases, and in one severe case with multiple relapses, we used caplacizumab to stabilize the patient's condition. The findings underscore the importance of early diagnosis, individualized treatment, and proactive management in improving maternal and neonatal outcomes. Thrombotic thrombocytopenia purpura ADAMTS-13 thrombocytopenia therapeutic plasma exchange pregnancy caplacizumab Rituximab Figures Figure 1 Figure 2 Background Thrombotic Thrombocytopenic Purpura (TTP) is a rare but serious complication in pregnancy, with an estimated incidence of 1 in 25,000 pregnancies. ( 1 ) It is caused by a deficiency of the ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) enzyme ( 2 ), leading to the accumulation of von Willebrand factor (vWF) multimers, which promote platelet aggregation and thrombosis.( 3 ) Approximately half the cases present in the third trimester, TTP during pregnancy can pose a diagnostic challenge due to its overlapping features with other thrombotic microangiopathies (TMAs), such as preeclampsia, Hemolysis, Elevated Liver enzymes, and Low Platelet count (HELLP) syndrome, disseminated intravascular coagulation (DIC), and antiphospholipid syndrome (APS). ( 4 , 5 ) and other conditions. The diagnosis is further challenged by a wide spectrum of clinical presentations that TTP can exhibit, ranging from mild symptoms to life-threatening illness. Thus, a high index of suspicion is required to initiate treatment promptly, as untreated TTP carries a significant risk of maternal mortality. ( 6 ) The prompt use of therapeutic plasma exchange (TPE) has dramatically reduced the previously high mortality rate associated with TTP, making it the cornerstone of treatment. ( 7 ) In addition to TPE, immunosuppressive therapies such as corticosteroids and rituximab, ( 8 ) as well as newer agents like caplacizumab, may be employed depending on disease severity and recurrence to further control the immune response and reduce thrombosis risk.( 9 ) This case series presents three pregnancy-related TTP cases, discussing their clinical presentations, the therapeutic approaches taken, and the role of interdisciplinary collaboration in managing this complex and life-threatening condition. Case report 1 A 34-year-old Gravida 7 Para 6 woman at 33 weeks’ gestation presented with a headache, dysuria, and dark-colored urine. She denied neurological symptoms aside from the headache. Initial laboratory investigations showed thrombocytopenia (9x10 9 /L), normocytic normochromic anemia, elevated bilirubin, and LDH, normal coagulation profile, normal kidney and liver functions and abnormal peripheral smear suggestive of MAHA. See Table 1 . TTP was suspected, and TPE was initiated in addition to steroids. Initial response to TPE was positive, but platelet counts began to decline after 7 days. ADAMTS13 activity returned at 36% (Reference range > 70%), consistent with cTTP. This result may have been affected by TPE, as the test was sent a few days after starting treatment. On hospital day 10, platelet count dropped below 50,000 × 10 9 /L. She was then started on dexamethasone pulse (40 mg IV daily for 4 days) and trial of intravenous immunoglobulin (IVIG) therapy to further improve her platelet counts. The platelet counts responded again with subsequent rise in counts and decline in hemolysis workup. On day 13, after 11 sessions of TPE, induction of labor was initiated at 35 + 4 weeks when the platelet count reached 66 × 10 9 /L. Platelet counts further increased to 118 then 123 × 10 9 /L with a stable hemoglobin level. However, due to failed induction, the patient underwent a LSCS (lower segment cesarean section) on day 15, delivering a healthy male baby. Postoperatively, the patient received two additional TPE sessions. A complete workup, including a CT (Computed Tomography) scan of the thorax, abdomen, and pelvis, combined with a negative autoimmune screen, ruled out secondary causes such as malignancy. She was discharged on postoperative day 8 on tapering prednisolone with a stable hemoglobin 10.2 gm/dl, hematocrit of 31% and platelets of 369 × 10 9 /L, after a total of 11 TPE sessions. One year later, the patient conceived spontaneously and had a normal pregnancy without any complications. She was regularly followed during pregnancy in obstetric hematology clinic by complete blood counts and hemolytic markers which were always within range. She delivered at 38 weeks with a caesarean section. Figure 1 illustrates the platelet counts in the three patients before and after treatment. Case report 2 A 24-year-old primigravida at 31 weeks’ gestation presented with sudden-onset speech difficulty and right-sided weakness, suggestive of stroke. She denied any additional symptoms except for transient numbness and paresthesia in her right upper limb two months prior, which resolved spontaneously. Pregnancy had been uneventful until this point. She was normotensive on presentation. Laboratory evaluation initially revealed normocytic normochromic anemia (Hgb of 9.5 g/dL, hematocrit of 28.4%), thrombocytopenia; manual platelet counts of 81 × 10⁹/L, normal fibrinogen, normal coagulation profile (APTT/PT/INR), normal total bilirubin (7 µmol/L), normal liver function tests (AST/ALT), and normal serum creatinine. The initial peripheral smear showed moderate normochromic normocytic anemia with a few schistocytes, some reactive lymphocytes, and moderate thrombocytopenia, raising suspicion of gestational thrombocytopenia (GT) or ITP. Brain MRI confirmed a left middle cerebral artery stroke and a possible carotid dissection. Later the labs were repeated and showed an obvious drop in Hgb to 8.4 g/dL, hematocrit to 25.3%, platelet count to 37 × 10⁹/L and increased red cell fragmentation on peripheral smear. These findings were in favor of microangiopathic hemolytic anemia, with positive hemolytic markers: elevated LDH levels at 514 U/L, low haptoglobin at < 10 mg/dL, and negative DAT. Autoimmune and thrombophilia screens came back negative. TTP was highly suspected. TPE started promptly in addition to high-dose methylprednisolone and packed red blood cell transfusions to alleviate her anemia prior to TPE. Lab evaluations showed a gradual decrease in hemolysis and RBC fragmentation. Platelet counts improved over 5 days of daily TPE. On day 6, the patient underwent a primary cesarean section under spinal anesthesia at a platelet count of 93 × 10⁹/L, with normal coagulation studies, Hgb of 10.2 g/dL, and hematocrit of 30.1%. TPE was held that day, and only fresh frozen plasma (FFP) was given. The delivery was uneventful, and the patient required 4 more TPE sessions postpartum. ADAMTS13 testing showed 5% activity (reference range > 70%) with no inhibitor, confirming a diagnosis of hereditary TTP (hTTP). The patient required an additional 4 TPE sessions until total recovery was achieved. Total of 7 TPE received. She was discharged on postoperative day 11 on oral prednisolone with a stable hematocrit of 31.1%, Hgb of 10.4 g/dL, and platelet count of 292 × 10⁹/L. The neurology team recommended continuing antiplatelet medications for 6 months. She was then transferred to a rehabilitation center for further care. ADAMTS13 activity was repeated twice after delivery and confirmed activity below 10% (reference range > 70%) with the absence of inhibitors. Custom gene testing for the ADAMTS13 gene by next-generation sequencing (NGS) also came back negative. Follow-up visits with routine labs showed that the patient remained in remission. Case report 3 A 36-year-old Gravida 4 Para 2 woman at 37 + 4 weeks gestation was admitted with severe thrombocytopenia (22 × 10⁹/L) discovered on routine testing. She had a history of low platelets in a prior pregnancy, which resolved postpartum, and history of a transient ischemic attack (TIA) 3 months after delivery, kept on low-dose aspirin but not fully investigated. Her thrombophilia screen was negative except for heterozygous factor V Leiden mutation. Her current pregnancy had been uneventful until admission, where she presented with hypertension (130/90 mmHg). Initial laboratory evaluation upon admission revealed normocytic normochromic anemia with Hgb of 10.5 g/dL, hematocrit of 29.3%, platelets of 22 × 10⁹/L, elevated LDH at 860 U/L, fibrinogen of 4.45 mg/L, uric acid of 395 µmol/L, proteinuria + 2 on dipstick, urinary protein ratio of 26.31 mg/mmol, normal APTT/PT/INR, normal total bilirubin, mildly elevated AST of 34 U/L, normal ALT, and normal creatinine. Peripheral smear showed a picture compatible with MAHA. The initial working diagnosis was preeclampsia with atypical HELLP syndrome versus TTP. A shared decision was made for an emergency cesarean section, which was performed on day 1 of hospital admission, under general anesthesia. Postoperatively, the patient's platelet count continued to decline, and a diagnosis of TTP was made. Plasma exchange was immediately initiated after optimizing her hemoglobin via packed red blood cell transfusion. Treatment continued with daily TPE sessions for 1 week until platelet count reached 194 × 10⁹/L. Once TPE was stopped, platelet count dropped dramatically to 15 × 10⁹/L within 2 days, with a flare of MAHA features in the peripheral smear. Hence, TPE was immediately resumed with the addition of Rituximab on the first day and IV methylprednisolone pulse. All secondary causes were ruled out, including a negative full autoimmune panel, negative viral serology, and negative PET-CT for malignancy. IV Rituximab was continued on a weekly basis along with daily TPE for another week until platelet count reached > 150 × 10⁹/L for 2 consecutive readings. TPE was held, and platelet count continued to rise to 244 × 10⁹/L. She was discharged on tapering steroids, weekly Rituximab in the daycare unit, and aspirin, with the plan for close observation, including CBC checks every other day as an outpatient. Afterwards, the results of ADAMTS13 testing were received, confirming a diagnosis of acquired TTP (aTTP) based on low ADAMTS13 activity and the presence of an inhibitor. Unfortunately, the patient experienced an imminent relapse 6 days after discharge, with a fall of platelet counts down to 23 × 10⁹/L, Hgb of 10.1 g/dL, and hematocrit of 28.4%. She was readmitted with resumption of TPE, and Caplacizumab was requested as a lifesaving medication in this situation. During the second relapse admission, the patient received a total of 4 doses of Rituximab, along with daily Caplacizumab for 22 days and 12 sessions of TPE. The platelet counts showed excellent clinical response with a subsequent decline in hemolysis markers. Once the platelet counts stabilized, the patient was kept under observation as an inpatient to ensure no more relapses. The patient was discharged with a stable hemoglobin of 10.4 g/dL, hematocrit of 31%, and platelets of 244 × 10⁹/L, on oral prednisolone (tapering dose), with close follow-up and a plan for 2 more doses of Rituximab as an outpatient. During follow-up, the patient did not experience any further relapses. Steroids were tapered gradually, and the central venous catheter used for plasma exchange was removed after ensuring a stable platelet count. Overall, the patient's condition settled and recovered completely without any consequences. No signs of relapse were observed during follow-up for up to 2 years later. Figure 2 illustrates platelet, and reticulocyte counts over time in case 3, showing fluctuations corresponding to presentation, different modalities of treatment, relapses and the eventual stabilization of platelet levels. Table 1 provides a summary of laboratory values of each case before and after treatment Demography (Age, gravidity, GA) Case 1 Case 2 Case 3 34Y/G7P6/33w 24Y/G1P0/31w 36Y/G4P2/37 + 4w Clinical presentation New-onset headache, and dark-colored urine Sudden onset inability to speak, right facial and limb weakness Routine labs revealed a low platelet count Lab value Reference range Initial values After treatment Initial values After treatment Initial values After treatment Hemoglobin (gm/dL) 12.0–15.0 9.5 9 10.9 11.6 10.5 11.8 Platelets (x10 9 /L) 150–400 9 149 31 140 22 326 Prothrombin time (sec) 9.7–11.8 10.1 10.3 11.6 10.3 9.8 10.5 INR - 1.0 1.0 1.0 1.0 0.9 1.0 Urea (mmol/L) 2.76–8.07 3.60 2.6 2.6 4.2 7.3 5.6 Creatinine (umol/L) 44–80 49 42 42 60 77 67 Bilirubin T (umol/L) 0–21 28.0 4 9 7 10 3 LDH (U/L) 135–214 874 145 510 183 860 206 ALT (U/L) 0.0–33.0 9.4 20.8 8 9 11 13 AST (U/L) 0–32 28 14 18 13 34 11 Alk Phos (U/L) 35.0-104.0 114 58 77 68 143 49 ADAMAST13 ADAMST13 36% (reference > 70%) 5% (> 70%) < 0.03 (Normal 0.68- 1.63 IU/ml) ADAMST13 Inhibitor (normal < 0.4) Negative Negative 0.8, Positive Peripheral smear (P.S) Moderate normochromic normocytic anemia with anisocytosis, moderate polychromasia and moderate increase in schistocytes. Mild shift to left in leukocytes with marked thrombocytopenia Moderate normocytic normochromic anemia with moderate number of schistocytes (3%), few polychromatophilic cells and few microspherocytes. There is leukocytosis with neutrophilia. Platelets are markedly reduced. mild normocytic normochromic anemia with reticulocytosis, moderate number of schistocytes (7%), polychromasia and few microspherocytes There is leukocytosis with mild neutrophilia and shift to left. Platelets are markedly reduced. ALT, alanine aminotransferase; AST, aspartate aminotransferase; Alk Phos, alkaline phosphatase; LDH, lactate dehydrogenase; INR, international normalized ratio; GA, gestational age; G, gravidity; P, parity; Y, years; T, total; ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs 13; P.S., peripheral smear. Discussion TTP during pregnancy can manifest as a new-onset condition or a recurrence in women with a prior history of TTP, often triggered by pregnancy's physiological changes. ( 7 ) Approximately 46% of TTP cases occur in the third trimester (after 30 weeks), 38% between 20 and 29 weeks, 15% before 20 weeks. However, if a thrombotic microangiopathy (TMA) is detected in the first trimester, TTP is more likely to be the underlying cause. ( 8 ) In aTTP, the disease onset is typically sudden and severe (hyperacute). In congenital cTTP, isolated thrombocytopenia usually appears before hemolysis, especially in the second and third trimesters, which can lead to misdiagnosis as gestational thrombocytopenia (GT) or immune thrombocytopenia (ITP) due to its relatively gradual onset. ( 5 ) Further assessment is required to exclude both GT and ITP.( 10 ) In Case 2, the initial suspicion was GT or ITP, but repeated testing over the next day revealed worsening anemia, thrombocytopenia, and red cell fragmentation, confirmed the diagnosis of MAHA. Historically, the diagnosis of TTP relied on a pentad of symptoms—MAHA, thrombocytopenia, neurological and renal manifestations, and fever - but only 10% of patients present with all five classic signs. ( 11 ) In practice, the presence of MAHA and thrombocytopenia alone should prompt further investigation to rule out TTP and other TMAs such as preeclampsia with severe features, HELLP syndrome, DIC, APS, acute fatty liver in pregnancy, Anti-Neutrophil Cytoplasmic Antibodies (ANCA)-associated vasculitis, and complement-mediated hemolytic uremic syndrome (cHUS). ( 4 , 5 , 11 ) Additionally, some features of TTP can overlap with these conditions, complicating diagnosis. ( 11 , 12 ) Moreover, TTP can co-occur with PE with severe features, sepsis, HELLP, and other autoimmune diseases in approximately 25% of cases. ( 4 , 13 ) In our three cases, the diagnosis of TTP was based on the presence of severe thrombocytopenia (platelet counts of 9, 31, and 22 × 10⁹/L), with a median platelet count of 22 × 10⁹/L) and MAHA, confirmed by the presence of schistocytes in peripheral smears. Moderate schistocyte levels in case 1 and 3% in case 2, and 7% in case 3 were consistent with the diagnosis of MAHA, indicating ongoing hemolysis. Hemoglobin levels were initially low, reflecting anemia from hemolysis, but improved post-treatment. Elevated LDH levels in all cases suggested red cell destruction and tissue ischemia, both of which normalized following treatment. ( 14 ) Negative Direct Antiglobulin Test (DAT) results confirmed non-immune hemolysis, and normal PT values ruled out disseminated intravascular coagulation (DIC).( 15 ) See Table 1 The hallmark of TTP pathophysiology is a deficiency or depletion of ADAMTS13, a von Willebrand factor (vWF) cleaving protein responsible for breaking down large vWF multimers into smaller, less active forms.( 16 ) Without sufficient ADAMTS13 activity, ultra-large vWF multimers accumulate, leading to MAHA, severe thrombocytopenia, and thrombotic complications. ( 13 ) Most acute TTP cases are aTTP and triggered by infections or other stressors that induce autoantibodies against ADAMTS13, reducing its activity to critical levels (< 10%).( 17 ) In contrast, cTTP, accounting for less than 5% of cases, results from mutations in the ADAMTS13 gene and is confirmed through genetic testing. ( 11 ) Pregnancy increases the risk of TTP due to physiological changes, including heightened procoagulant factors and reduced fibrinolytic activity, which can trigger symptoms in women with already low ADAMTS13 levels, particularly those with cTTP. ( 18 ) Additionally, vWF levels rise from the first trimester and remain elevated through six weeks postpartum, further decreasing ADAMTS13 levels due to increased consumption. 20 These changes are most pronounced in the third trimester corresponding with the peak incidence of TTP during these periods. ( 11 , 15 ) The risk of TTP extends beyond pregnancy into the postpartum period.( 19 ) In our cases, the patients presented at 33 weeks, 31 weeks, and 37 + 4 weeks of gestation, with a median gestational age of 33 weeks and a median patient age of 34 years. This aligns with the typical pattern of acute TTP, which often presents in the third trimester and in women in their third to fourth decade of life.( 3 ) A high index of suspicion is crucial, as untreated TTP is fatal, with complications such as renal failure, cerebral infarction, and myocardial infarction. ( 5 , 8 ) Advances in treatment, particularly with therapeutic plasma exchange (TPE), have reduced the mortality rate from over 90% to 10–15%. ( 20 ) TTP is a medical emergency and daily TPE should be initiated immediately upon suspicion of TTP, without waiting for ADAMTS13 levels or autoantibodies (results can take several days). ( 20 ) Supportive treatments, including corticosteroids, IVIG, 14 rituximab ( 21 ), and newer agents like caplacizumab, may be used depending on disease severity or recurrence. ( 22 ) In pregnancy, management mirrors that of non-pregnant patients, though fetal drug toxicity should be considered. If TPE is unavailable, plasma infusion may be used, especially in hTTP.(23) All three of our cases received daily TPE. After confirming severe thrombocytopenia in the setting of MAHA, testing for ADAMTS13 levels is essential to establish the diagnosis. Antibody testing differentiates between cTTP and aTTP. ( 24 ) In our cases, case 3 was diagnosed with aTTP due to ADAMTS13 deficiency and the presence of antibodies, while cases 1 and 2 were diagnosed with cTTP based on the absence of antibodies. In case 1, the sample was sent a few days after TPE initiation, resulting in an ADAMTS13 activity level of 36%, which was likely affected by the treatment. This underscores the importance of sending samples for ADAMTS13 testing before starting TPE, as TPE can artificially increase ADAMTS13 levels, potentially altering the diagnostic accuracy.( 25 ) Unlike conditions such as HELLP or ITP, where delivery can improve the condition, premature delivery is not a treatment for TTP and is generally offered only for clear obstetric reasons, such as fetal distress or severe maternal complications. ( 26 ), However, if maternal and fetal conditions are stable, induction at 35–36 weeks can be considered to minimize risks for both mother and baby. This approach ensures reasonable fetal maturity while continuing TTP-specific treatments like TPE and immunosuppression to manage ADAMTS13 deficiency.( 5 ) If platelet counts do not improve after a few days of TPE, other causes of thrombocytopenia should be investigated. ( 27 ) In acquired aTTP, TPE is the cornerstone of treatment, but immunosuppressive therapies such as corticosteroids (e.g., prednisolone) are necessary to reduce the production of autoantibodies against ADAMTS13. ( 8 ) Additionally, in severe cases, rituximab, which targets B cells, is used and has proven effective in reducing hospital stays and relapses with minimal side effects. Rituximab is administered weekly (375 mg/m² for 4–6 weeks) and timed immediately after TPE, allowing at least 24 hours before the next session to avoid its washout. ( 4 ) Rituximab use in pregnancy requires a careful risk-benefit analysis. It is safer in the first trimester due to minimal placental transfer ( 28 ) but can cause transient neonatal B-cell depletion in the second and third trimesters. ( 29 ) Nevertheless, in life-threatening cases like aTTP, the benefits of rituximab outweigh the risks, as uncontrolled disease poses a greater danger to both mother and fetus.( 21 ) Newer agents like caplacizumab help manage recurrence and control the immune response. Caplacizumab is a humanized immunoglobulin that targets the A1 domain of von Willebrand factor (vWF), preventing its interaction with platelet receptor glycoprotein Ib-IX-V and inhibiting platelet adhesion and aggregation, which are central to the pathophysiology of TTP.( 30 ) Approved by the FDA in 2019 for the treatment of aTTP, in addition to TPE and immunosuppression,( 31 ) it rapidly normalizes platelet counts, reduces exacerbations, and prevents end-organ damage by inhibiting microvascular thrombi formation, as demonstrated in the TITAN and HERCULES trials.( 32 ) Although caplacizumab does not address the underlying ADAMTS13 deficiency, treatment should continue until ADAMTS13 activity recovers to prevent relapses. Its high cost ( 33 ) and limited safety data in pregnancy, due to the exclusion of pregnant women from major clinical trials, require careful consideration.( 18 ) In case 3 of aTTP, rituximab was initially used. Despite treatment with TPE, steroids, and rituximab, two relapses occurred. Platelet counts had dropped to 28 × 10⁹/L during the first relapse and 15 × 10⁹/L during the second, prompting the use of caplacizumab, in conjunction with steroids, TPE, and rituximab. Caplacizumab led to a rapid recovery, stabilizing platelet levels at 238 × 10⁹/L and reducing schistocytes to 2.2% by discharge. Triple therapy, which combines TPE, immunosuppression with corticosteroids and rituximab, and caplacizumab, addresses the three key aspects of iTTP pathophysiology: TPE replenishes ADAMTS13, rituximab suppresses anti-ADAMTS13 antibodies, and caplacizumab prevents platelet-vWF interaction, rapidly normalizing platelet counts, reducing microthrombi formation, and lowering the risk of exacerbations and life-threatening complications associated with refractory TTP.( 34 ) Though costly, caplacizumab was justified by its ability to prevent further microvascular thrombi formation and protect against end-organ damage in a patient with multiple relapses, failed prior therapies, and high mortality risk. ( 22 ) Low-dose aspirin (LDA) and low molecular weight heparin (LMWH) as enoxaparin may be considered in pregnant women with TTP once platelet counts exceed 50,000/µL, primarily to reduce the risk of placental vascular damage or venous thromboembolism. ( 20 ) However, these therapies are usually not routinely required in all TTP cases. Aspirin is prescribed only when there is a specific obstetric indication, as clot formation in TTP is driven by ULVWF-mediated platelet clumping, not cyclooxygenase-mediated aggregation. Enoxaparin is considered based on the patient's individual thrombotic risk.( 5 , 11 ) In hereditary cTTP, close monitoring of newborns is essential due to the risk of severe complications such as hemolysis, anemia, jaundice, and neonatal hyperbilirubinemia, which may require exchange transfusions. Delayed diagnosis or misdiagnosis can result in severe thrombocytopenia, organ damage, and even neonatal death. ( 35 ) None of the newborns in our case series developed complications at birth. In future pregnancies, women with cTTP face a high relapse risk due to persistent ADAMTS13 deficiency, requiring regular plasma infusions. For aTTP, relapse depends on ADAMTS13 recovery. Maintaining ADAMTS13 activity above 20–25% through trimester checks and monthly monitoring of CBC, LDH, and hemolytic markers is crucial. Treatment adjustments are needed if abnormalities arise. For those receiving rituximab, pregnancy should be delayed for 6 to 12 months. ( 5 ) Conclusion Thrombotic thrombocytopenic purpura (TTP) during pregnancy presents significant diagnostic and management challenges due to its rarity and life-threatening potential. Early recognition, timely diagnosis, and prompt initiation of therapeutic plasma exchange (TPE) is critical for improving both maternal and fetal outcomes. Even though not all centers have immediate access to ADAMTS13 testing, ensuring that TPE is readily available is vital, as treatment should begin if TTP is suspected. Delayed treatment can lead to severe complications, posing increased risks for both the mother and the fetus. Monoclonal antibodies, such as rituximab, play a vital role in managing acquired TTP (aTTP), working synergistically with TPE. Although caplacizumab is costly, it can be lifesaving, particularly in cases of severe or recurrent relapses, where the risk of mortality is high. This case series highlights the importance of interdisciplinary collaboration among obstetricians, hematologists, and critical care teams to ensure the most effective, tailored treatment strategies. Abbreviations ADAMTS13: A disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 APS: Antiphospholipid syndrome aTTP: Acquired TTP CS: Cesarean section cTTP: Congenital TTP DIC: Disseminated Intravascular Coagulation HELLP: Hemolysis, Elevated Liver enzymes, and Low Platelet count ICU: Intensive care unit ITP: Immune thrombocytopenia IVIG: Intravenous immunoglobulin GT: gestational thrombocytopenia MAHA: Microangiopathic hemolytic anemia PLT: Platelet TMAs: Thrombotic microangiopathies TPE: Therapeutic plasma exchange TTP: Thrombotic thrombocytopenic purpura TIA: Transient ischemic attack Declarations This manuscript is original work and has not been submitted or under consideration for publication elsewhere. All authors have reviewed and approved the manuscript. Ethical Approval and consent to participate The case report was approved by the Hamad Medical Corporation’s Medical Research Center under the Number (MRC-04-23-393) Consent for publication Written informed consent for the publication of patient information was obtained from the patient before the submission of this manuscript. Availability of data and material Data pertaining to this case can be obtained by contacting the corresponding author. Competing interests The authors have no known competing interests that could have influenced this paper. Funding Qatar National Library (QNL) open-access forum Authors contribution SAK contributed to the manuscript writing, editing and literature review. GS contributed to preparation, reviewing and editing of manuscript. TM, AK, and SA contributed to drafting and editing of manuscript. All authors reviewed and gave final approval of the version to be published. 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Blood. 2011;117(5):1499–506. Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2486–95. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, et al. Comparison of Plasma Exchange with Plasma Infusion in the Treatment of Thrombotic Thrombocytopenic Purpura. N Engl J Med. 1991;325(6):393–7. Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology. 2018;2018(1):530–8. Cataland S. The use of ADAMTS13 assays in thrombotic microangiopathies. Clin Adv Hematol Oncol HO. 2021;19(11):687–9. Pishko AM, Marshall AL. Thrombocytopenia in pregnancy. Hematology. 2022;2022(1):303–11. Coppo P, Froissart A. Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange. Hematology. 2015;2015(1):637–43. Das G, Damotte V, Gelfand JM, Bevan C, Cree BAC, Do L, et al. Rituximab before and during pregnancy: A systematic review, and a case series in MS and NMOSD. Neurol Neuroimmunol Neuroinflammation. 2018;5(3):e453. Beltagy A, Aghamajidi A, Trespidi L, Ossola W, Meroni PL. Biologics During Pregnancy and Breastfeeding Among Women With Rheumatic Diseases: Safety Clinical Evidence on the Road. Front Pharmacol. 2021;12:621247. Scully M, Cataland SR, Peyvandi F, Coppo P, Knöbl P, Kremer Hovinga JA, et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019;380(4):335–46. U.S. Food and Drug Administration. FDA Approves Caplacizumab-Yhdp for the Treatment of Acquired Thrombotic Thrombocytopenic Purpura (aTTP). https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approved-caplacizumab-yhdp . Accessed October 6, 2024. Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016;374(6):511–22. Goshua G, Sinha P, Hendrickson JE, Tormey C, Bendapudi PK, Lee AI. Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura. Blood. 2021;137(7):969–76. Coppo P, Bubenheim M, Azoulay E, Galicier L, Malot S, Bigé N, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood. 2021;137(6):733–42. Von Krogh AS, Quist-Paulsen P, Waage A, Langseth ØO, Thorstensen K, Brudevold R, et al. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J Thromb Haemost. 2016;14(1):73–82. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5867341","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":405667847,"identity":"b62e0bab-0ff9-4020-88e1-ea01deb41bae","order_by":0,"name":"Sarah A. Elkourashy","email":"data:image/png;base64,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","orcid":"","institution":"National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation","correspondingAuthor":true,"prefix":"","firstName":"Sarah","middleName":"A.","lastName":"Elkourashy","suffix":""},{"id":405667848,"identity":"9beec46d-e117-413e-aa3a-54c04003d89c","order_by":1,"name":"Tamader Mashhadi","email":"","orcid":"","institution":"Hamad Medical Corporation","correspondingAuthor":false,"prefix":"","firstName":"Tamader","middleName":"","lastName":"Mashhadi","suffix":""},{"id":405667849,"identity":"852ad053-f834-460a-a95b-79b5e3559c59","order_by":2,"name":"Amna Al-Kuwari","email":"","orcid":"","institution":"Qatar University","correspondingAuthor":false,"prefix":"","firstName":"Amna","middleName":"","lastName":"Al-Kuwari","suffix":""},{"id":405667850,"identity":"71ab196c-810d-42dd-9016-ab8dccc01a0b","order_by":3,"name":"Sara Al-Abdulla","email":"","orcid":"","institution":"Qatar University","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Al-Abdulla","suffix":""},{"id":405667851,"identity":"8cc748bf-fbc8-460c-8b2c-827db076d540","order_by":4,"name":"Gamal Sayed","email":"","orcid":"","institution":"Hamad Medical Corporation","correspondingAuthor":false,"prefix":"","firstName":"Gamal","middleName":"","lastName":"Sayed","suffix":""}],"badges":[],"createdAt":"2025-01-20 15:53:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5867341/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5867341/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74691859,"identity":"ee0a8c57-9382-4911-a6b0-fccf2864cf81","added_by":"auto","created_at":"2025-01-24 18:46:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":297591,"visible":true,"origin":"","legend":"\u003cp\u003eillustrates the platelet counts in three patients diagnosed with thrombotic thrombocytopenic purpura (TTP) before and after treatment.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5867341/v1/24d7139249f8f79fc1b7087d.png"},{"id":74692380,"identity":"9c470346-fd1d-41d0-9864-08cb0d9e2dd4","added_by":"auto","created_at":"2025-01-24 18:54:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":552359,"visible":true,"origin":"","legend":"\u003cp\u003eCase 3: illustrates platelet and reticulocyte counts over period of treatment, showing fluctuations corresponding to treatment events such as TPE, rituximab, and caplacizumab administration. The graph highlights two relapses and the eventual stabilization of platelet levels following combination therapy.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5867341/v1/f855f2c239118a69da75a869.png"},{"id":91619803,"identity":"5e9e882a-d8cb-4c80-96b5-77b24c237a09","added_by":"auto","created_at":"2025-09-18 11:17:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1392809,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5867341/v1/4ad35e02-9209-47c8-94a7-c0c6d4a029d7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Thrombotic Thrombocytopenic Purpura: Lessons from Clinical Cases, A case series","fulltext":[{"header":"Background","content":"\u003cp\u003eThrombotic Thrombocytopenic Purpura (TTP) is a rare but serious complication in pregnancy, with an estimated incidence of 1 in 25,000 pregnancies. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) It is caused by a deficiency of the ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) enzyme (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), leading to the accumulation of von Willebrand factor (vWF) multimers, which promote platelet aggregation and thrombosis.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eApproximately half the cases present in the third trimester, TTP during pregnancy can pose a diagnostic challenge due to its overlapping features with other thrombotic microangiopathies (TMAs), such as preeclampsia, Hemolysis, Elevated Liver enzymes, and Low Platelet count (HELLP) syndrome, disseminated intravascular coagulation (DIC), and antiphospholipid syndrome (APS). (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and other conditions.\u003c/p\u003e \u003cp\u003eThe diagnosis is further challenged by a wide spectrum of clinical presentations that TTP can exhibit, ranging from mild symptoms to life-threatening illness. Thus, a high index of suspicion is required to initiate treatment promptly, as untreated TTP carries a significant risk of maternal mortality. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe prompt use of therapeutic plasma exchange (TPE) has dramatically reduced the previously high mortality rate associated with TTP, making it the cornerstone of treatment. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) In addition to TPE, immunosuppressive therapies such as corticosteroids and rituximab, (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) as well as newer agents like caplacizumab, may be employed depending on disease severity and recurrence to further control the immune response and reduce thrombosis risk.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThis case series presents three pregnancy-related TTP cases, discussing their clinical presentations, the therapeutic approaches taken, and the role of interdisciplinary collaboration in managing this complex and life-threatening condition.\u003c/p\u003e"},{"header":"Case report 1","content":"\u003cp\u003eA 34-year-old Gravida 7 Para 6 woman at 33 weeks’ gestation presented with a headache, dysuria, and dark-colored urine. She denied neurological symptoms aside from the headache. Initial laboratory investigations showed thrombocytopenia (9x10\u003csup\u003e9\u003c/sup\u003e/L), normocytic normochromic anemia, elevated bilirubin, and LDH, normal coagulation profile, normal kidney and liver functions and abnormal peripheral smear suggestive of MAHA. See Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eTTP was suspected, and TPE was initiated in addition to steroids. Initial response to TPE was positive, but platelet counts began to decline after 7 days. ADAMTS13 activity returned at 36% (Reference range \u0026gt; 70%), consistent with cTTP. This result may have been affected by TPE, as the test was sent a few days after starting treatment.\u003c/p\u003e \u003cp\u003eOn hospital day 10, platelet count dropped below 50,000 × 10\u003csup\u003e9\u003c/sup\u003e/L. She was then started on dexamethasone pulse (40 mg IV daily for 4 days) and trial of intravenous immunoglobulin (IVIG) therapy to further improve her platelet counts. The platelet counts responded again with subsequent rise in counts and decline in hemolysis workup.\u003c/p\u003e \u003cp\u003eOn day 13, after 11 sessions of TPE, induction of labor was initiated at 35 + 4 weeks when the platelet count reached 66 × 10\u003csup\u003e9\u003c/sup\u003e/L. Platelet counts further increased to 118 then 123 × 10\u003csup\u003e9\u003c/sup\u003e/L with a stable hemoglobin level. However, due to failed induction, the patient underwent a LSCS (lower segment cesarean section) on day 15, delivering a healthy male baby. Postoperatively, the patient received two additional TPE sessions.\u003c/p\u003e \u003cp\u003eA complete workup, including a CT (Computed Tomography) scan of the thorax, abdomen, and pelvis, combined with a negative autoimmune screen, ruled out secondary causes such as malignancy.\u003c/p\u003e \u003cp\u003eShe was discharged on postoperative day 8 on tapering prednisolone with a stable hemoglobin 10.2 gm/dl, hematocrit of 31% and platelets of 369 × 10\u003csup\u003e9\u003c/sup\u003e/L, after a total of 11 TPE sessions.\u003c/p\u003e \u003cp\u003eOne year later, the patient conceived spontaneously and had a normal pregnancy without any complications. She was regularly followed during pregnancy in obstetric hematology clinic by complete blood counts and hemolytic markers which were always within range. She delivered at 38 weeks with a caesarean section.\u003c/p\u003e \u003cp\u003eFigure 1 illustrates the platelet counts in the three patients before and after treatment.\u003c/p\u003e "},{"header":"Case report 2","content":"\u003cp\u003eA 24-year-old primigravida at 31 weeks’ gestation presented with sudden-onset speech difficulty and right-sided weakness, suggestive of stroke. She denied any additional symptoms except for transient numbness and paresthesia in her right upper limb two months prior, which resolved spontaneously. Pregnancy had been uneventful until this point. She was normotensive on presentation.\u003c/p\u003e\u003cp\u003eLaboratory evaluation initially revealed normocytic normochromic anemia (Hgb of 9.5 g/dL, hematocrit of 28.4%), thrombocytopenia; manual platelet counts of 81 × 10⁹/L, normal fibrinogen, normal coagulation profile (APTT/PT/INR), normal total bilirubin (7 µmol/L), normal liver function tests (AST/ALT), and normal serum creatinine. The initial peripheral smear showed moderate normochromic normocytic anemia with a few schistocytes, some reactive lymphocytes, and moderate thrombocytopenia, raising suspicion of gestational thrombocytopenia (GT) or ITP.\u003c/p\u003e\u003cp\u003eBrain MRI confirmed a left middle cerebral artery stroke and a possible carotid dissection. Later the labs were repeated and showed an obvious drop in Hgb to 8.4 g/dL, hematocrit to 25.3%, platelet count to 37 × 10⁹/L and increased red cell fragmentation on peripheral smear. These findings were in favor of microangiopathic hemolytic anemia, with positive hemolytic markers: elevated LDH levels at 514 U/L, low haptoglobin at \u0026lt; 10 mg/dL, and negative DAT. Autoimmune and thrombophilia screens came back negative.\u003c/p\u003e\u003cp\u003eTTP was highly suspected. TPE started promptly in addition to high-dose methylprednisolone and packed red blood cell transfusions to alleviate her anemia prior to TPE. Lab evaluations showed a gradual decrease in hemolysis and RBC fragmentation. Platelet counts improved over 5 days of daily TPE.\u003c/p\u003e\u003cp\u003eOn day 6, the patient underwent a primary cesarean section under spinal anesthesia at a platelet count of 93 × 10⁹/L, with normal coagulation studies, Hgb of 10.2 g/dL, and hematocrit of 30.1%. TPE was held that day, and only fresh frozen plasma (FFP) was given. The delivery was uneventful, and the patient required 4 more TPE sessions postpartum. ADAMTS13 testing showed 5% activity (reference range \u0026gt; 70%) with no inhibitor, confirming a diagnosis of hereditary TTP (hTTP). The patient required an additional 4 TPE sessions until total recovery was achieved. Total of 7 TPE received. She was discharged on postoperative day 11 on oral prednisolone with a stable hematocrit of 31.1%, Hgb of 10.4 g/dL, and platelet count of 292 × 10⁹/L.\u003c/p\u003e\u003cp\u003eThe neurology team recommended continuing antiplatelet medications for 6 months. She was then transferred to a rehabilitation center for further care. ADAMTS13 activity was repeated twice after delivery and confirmed activity below 10% (reference range \u0026gt; 70%) with the absence of inhibitors. Custom gene testing for the ADAMTS13 gene by next-generation sequencing (NGS) also came back negative.\u003c/p\u003e\u003cp\u003eFollow-up visits with routine labs showed that the patient remained in remission.\u003c/p\u003e"},{"header":"Case report 3","content":"\u003cp\u003eA 36-year-old Gravida 4 Para 2 woman at 37\u0026thinsp;+\u0026thinsp;4 weeks gestation was admitted with severe thrombocytopenia (22 \u0026times; 10⁹/L) discovered on routine testing. She had a history of low platelets in a prior pregnancy, which resolved postpartum, and history of a transient ischemic attack (TIA) 3 months after delivery, kept on low-dose aspirin but not fully investigated. Her thrombophilia screen was negative except for heterozygous factor V Leiden mutation.\u003c/p\u003e \u003cp\u003eHer current pregnancy had been uneventful until admission, where she presented with hypertension (130/90 mmHg). Initial laboratory evaluation upon admission revealed normocytic normochromic anemia with Hgb of 10.5 g/dL, hematocrit of 29.3%, platelets of 22 \u0026times; 10⁹/L, elevated LDH at 860 U/L, fibrinogen of 4.45 mg/L, uric acid of 395 \u0026micro;mol/L, proteinuria\u0026thinsp;+\u0026thinsp;2 on dipstick, urinary protein ratio of 26.31 mg/mmol, normal APTT/PT/INR, normal total bilirubin, mildly elevated AST of 34 U/L, normal ALT, and normal creatinine. Peripheral smear showed a picture compatible with MAHA.\u003c/p\u003e \u003cp\u003eThe initial working diagnosis was preeclampsia with atypical HELLP syndrome versus TTP. A shared decision was made for an emergency cesarean section, which was performed on day 1 of hospital admission, under general anesthesia.\u003c/p\u003e \u003cp\u003ePostoperatively, the patient's platelet count continued to decline, and a diagnosis of TTP was made. Plasma exchange was immediately initiated after optimizing her hemoglobin via packed red blood cell transfusion. Treatment continued with daily TPE sessions for 1 week until platelet count reached 194 \u0026times; 10⁹/L. Once TPE was stopped, platelet count dropped dramatically to 15 \u0026times; 10⁹/L within 2 days, with a flare of MAHA features in the peripheral smear. Hence, TPE was immediately resumed with the addition of Rituximab on the first day and IV methylprednisolone pulse.\u003c/p\u003e \u003cp\u003eAll secondary causes were ruled out, including a negative full autoimmune panel, negative viral serology, and negative PET-CT for malignancy.\u003c/p\u003e \u003cp\u003eIV Rituximab was continued on a weekly basis along with daily TPE for another week until platelet count reached\u0026thinsp;\u0026gt;\u0026thinsp;150 \u0026times; 10⁹/L for 2 consecutive readings. TPE was held, and platelet count continued to rise to 244 \u0026times; 10⁹/L. She was discharged on tapering steroids, weekly Rituximab in the daycare unit, and aspirin, with the plan for close observation, including CBC checks every other day as an outpatient. Afterwards, the results of ADAMTS13 testing were received, confirming a diagnosis of acquired TTP (aTTP) based on low ADAMTS13 activity and the presence of an inhibitor.\u003c/p\u003e \u003cp\u003eUnfortunately, the patient experienced an imminent relapse 6 days after discharge, with a fall of platelet counts down to 23 \u0026times; 10⁹/L, Hgb of 10.1 g/dL, and hematocrit of 28.4%. She was readmitted with resumption of TPE, and Caplacizumab was requested as a lifesaving medication in this situation.\u003c/p\u003e \u003cp\u003eDuring the second relapse admission, the patient received a total of 4 doses of Rituximab, along with daily Caplacizumab for 22 days and 12 sessions of TPE. The platelet counts showed excellent clinical response with a subsequent decline in hemolysis markers. Once the platelet counts stabilized, the patient was kept under observation as an inpatient to ensure no more relapses. The patient was discharged with a stable hemoglobin of 10.4 g/dL, hematocrit of 31%, and platelets of 244 \u0026times; 10⁹/L, on oral prednisolone (tapering dose), with close follow-up and a plan for 2 more doses of Rituximab as an outpatient.\u003c/p\u003e \u003cp\u003eDuring follow-up, the patient did not experience any further relapses. Steroids were tapered gradually, and the central venous catheter used for plasma exchange was removed after ensuring a stable platelet count. Overall, the patient's condition settled and recovered completely without any consequences. No signs of relapse were observed during follow-up for up to 2 years later.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates platelet, and reticulocyte counts over time in case 3, showing fluctuations corresponding to presentation, different modalities of treatment, relapses and the eventual stabilization of platelet levels.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eprovides a summary of laboratory values of each case before and after treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eDemography\u003c/p\u003e \u003cp\u003e(Age, gravidity, GA)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eCase 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eCase 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eCase 3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e34Y/G7P6/33w\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e24Y/G1P0/31w\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e36Y/G4P2/37\u0026thinsp;+\u0026thinsp;4w\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eClinical presentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eNew-onset headache, and dark-colored urine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eSudden onset inability to speak, right facial and limb weakness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eRoutine labs revealed a low platelet count\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLab value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInitial\u003c/p\u003e \u003cp\u003evalues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInitial\u003c/p\u003e \u003cp\u003evalues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eInitial\u003c/p\u003e \u003cp\u003evalues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (gm/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.0\u0026ndash;15.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003cp\u003e(x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150\u0026ndash;400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e326\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProthrombin time (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.7\u0026ndash;11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrea (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.76\u0026ndash;8.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u0026ndash;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilirubin T (umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH\u003c/p\u003e \u003cp\u003e(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135\u0026ndash;214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e860\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e206\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003cp\u003e(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.0\u0026ndash;33.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003cp\u003e(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlk Phos (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.0-104.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eADAMAST13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADAMST13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e36% (reference\u0026thinsp;\u0026gt;\u0026thinsp;70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e5% (\u0026gt;\u0026thinsp;70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.03\u003c/p\u003e \u003cp\u003e(Normal 0.68-\u003c/p\u003e \u003cp\u003e1.63 IU/ml)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADAMST13 Inhibitor\u003c/p\u003e \u003cp\u003e(normal\u0026thinsp;\u0026lt;\u0026thinsp;0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0.8, Positive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePeripheral smear (P.S)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eModerate normochromic normocytic anemia with anisocytosis, moderate polychromasia and moderate increase in schistocytes. Mild shift to left in leukocytes with marked thrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eModerate normocytic normochromic anemia with moderate number of schistocytes (3%),\u003c/p\u003e \u003cp\u003efew polychromatophilic cells and few microspherocytes.\u003c/p\u003e \u003cp\u003eThere is leukocytosis with neutrophilia.\u003c/p\u003e \u003cp\u003ePlatelets are markedly reduced.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003emild normocytic normochromic anemia with reticulocytosis, moderate number of schistocytes (7%), polychromasia and few microspherocytes\u003c/p\u003e \u003cp\u003eThere is leukocytosis with mild neutrophilia and shift to left.\u003c/p\u003e \u003cp\u003ePlatelets are markedly reduced.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eALT, alanine aminotransferase; AST, aspartate aminotransferase; Alk Phos, alkaline phosphatase; LDH, lactate dehydrogenase; INR, international normalized ratio; GA, gestational age; G, gravidity; P, parity; Y, years; T, total; ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs 13; P.S., peripheral smear.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTTP during pregnancy can manifest as a new-onset condition or a recurrence in women with a prior history of TTP, often triggered by pregnancy\u0026apos;s physiological changes. (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e) Approximately 46% of TTP cases occur in the third trimester (after 30 weeks), 38% between 20 and 29 weeks, 15% before 20 weeks. However, if a thrombotic microangiopathy (TMA) is detected in the first trimester, TTP is more likely to be the underlying cause. (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn aTTP, the disease onset is typically sudden and severe (hyperacute). In congenital cTTP, isolated thrombocytopenia usually appears before hemolysis, especially in the second and third trimesters, which can lead to misdiagnosis as gestational thrombocytopenia (GT) or immune thrombocytopenia (ITP) due to its relatively gradual onset. (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e) Further assessment is required to exclude both GT and ITP.(\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e) In Case 2, the initial suspicion was GT or ITP, but repeated testing over the next day revealed worsening anemia, thrombocytopenia, and red cell fragmentation, confirmed the diagnosis of MAHA.\u003c/p\u003e\n\u003cp\u003eHistorically, the diagnosis of TTP relied on a pentad of symptoms\u0026mdash;MAHA, thrombocytopenia, neurological and renal manifestations, and fever - but only 10% of patients present with all five classic signs. (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e) In practice, the presence of MAHA and thrombocytopenia alone should prompt further investigation to rule out TTP and other TMAs such as preeclampsia with severe features, HELLP syndrome, DIC, APS, acute fatty liver in pregnancy, Anti-Neutrophil Cytoplasmic Antibodies (ANCA)-associated vasculitis, and complement-mediated hemolytic uremic syndrome (cHUS). (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e) Additionally, some features of TTP can overlap with these conditions, complicating diagnosis. (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e) Moreover, TTP can co-occur with PE with severe features, sepsis, HELLP, and other autoimmune diseases in approximately 25% of cases. (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn our three cases, the diagnosis of TTP was based on the presence of severe thrombocytopenia (platelet counts of 9, 31, and 22 \u0026times; 10⁹/L), with a median platelet count of 22 \u0026times; 10⁹/L) and MAHA, confirmed by the presence of schistocytes in peripheral smears. Moderate schistocyte levels in case 1 and 3% in case 2, and 7% in case 3 were consistent with the diagnosis of MAHA, indicating ongoing hemolysis. Hemoglobin levels were initially low, reflecting anemia from hemolysis, but improved post-treatment. Elevated LDH levels in all cases suggested red cell destruction and tissue ischemia, both of which normalized following treatment. (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e) Negative Direct Antiglobulin Test (DAT) results confirmed non-immune hemolysis, and normal PT values ruled out disseminated intravascular coagulation (DIC).(\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e) See Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eThe hallmark of TTP pathophysiology is a deficiency or depletion of ADAMTS13, a von Willebrand factor (vWF) cleaving protein responsible for breaking down large vWF multimers into smaller, less active forms.(\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) Without sufficient ADAMTS13 activity, ultra-large vWF multimers accumulate, leading to MAHA, severe thrombocytopenia, and thrombotic complications. (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eMost acute TTP cases are aTTP and triggered by infections or other stressors that induce autoantibodies against ADAMTS13, reducing its activity to critical levels (\u0026lt;\u0026thinsp;10%).(\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e) In contrast, cTTP, accounting for less than 5% of cases, results from mutations in the ADAMTS13 gene and is confirmed through genetic testing. (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003ePregnancy increases the risk of TTP due to physiological changes, including heightened procoagulant factors and reduced fibrinolytic activity, which can trigger symptoms in women with already low ADAMTS13 levels, particularly those with cTTP. (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e) Additionally, vWF levels rise from the first trimester and remain elevated through six weeks postpartum, further decreasing ADAMTS13 levels due to increased consumption. \u003csup\u003e20\u003c/sup\u003e These changes are most pronounced in the third trimester corresponding with the peak incidence of TTP during these periods. (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e) The risk of TTP extends beyond pregnancy into the postpartum period.(\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn our cases, the patients presented at 33 weeks, 31 weeks, and 37\u0026thinsp;+\u0026thinsp;4 weeks of gestation, with a median gestational age of 33 weeks and a median patient age of 34 years. This aligns with the typical pattern of acute TTP, which often presents in the third trimester and in women in their third to fourth decade of life.(\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eA high index of suspicion is crucial, as untreated TTP is fatal, with complications such as renal failure, cerebral infarction, and myocardial infarction. (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e) Advances in treatment, particularly with therapeutic plasma exchange (TPE), have reduced the mortality rate from over 90% to 10\u0026ndash;15%. (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eTTP is a medical emergency and daily TPE should be initiated immediately upon suspicion of TTP, without waiting for ADAMTS13 levels or autoantibodies (results can take several days). (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e) Supportive treatments, including corticosteroids, IVIG,\u003csup\u003e14\u003c/sup\u003e rituximab (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e), and newer agents like caplacizumab, may be used depending on disease severity or recurrence. (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e) In pregnancy, management mirrors that of non-pregnant patients, though fetal drug toxicity should be considered. If TPE is unavailable, plasma infusion may be used, especially in \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehTTP.(23)\u003c/span\u003e\u003c/span\u003e All three of our cases received daily TPE.\u003c/p\u003e\n\u003cp\u003eAfter confirming severe thrombocytopenia in the setting of MAHA, testing for ADAMTS13 levels is essential to establish the diagnosis. Antibody testing differentiates between cTTP and aTTP. (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn our cases, case 3 was diagnosed with aTTP due to ADAMTS13 deficiency and the presence of antibodies, while cases 1 and 2 were diagnosed with cTTP based on the absence of antibodies. In case 1, the sample was sent a few days after TPE initiation, resulting in an ADAMTS13 activity level of 36%, which was likely affected by the treatment. This underscores the importance of sending samples for ADAMTS13 testing before starting TPE, as TPE can artificially increase ADAMTS13 levels, potentially altering the diagnostic accuracy.(\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eUnlike conditions such as HELLP or ITP, where delivery can improve the condition, premature delivery is not a treatment for TTP and is generally offered only for clear obstetric reasons, such as fetal distress or severe maternal complications. (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e), However, if maternal and fetal conditions are stable, induction at 35\u0026ndash;36 weeks can be considered to minimize risks for both mother and baby. This approach ensures reasonable fetal maturity while continuing TTP-specific treatments like TPE and immunosuppression to manage ADAMTS13 deficiency.(\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e) If platelet counts do not improve after a few days of TPE, other causes of thrombocytopenia should be investigated. (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn acquired aTTP, TPE is the cornerstone of treatment, but immunosuppressive therapies such as corticosteroids (e.g., prednisolone) are necessary to reduce the production of autoantibodies against ADAMTS13. (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e) Additionally, in severe cases, rituximab, which targets B cells, is used and has proven effective in reducing hospital stays and relapses with minimal side effects. Rituximab is administered weekly (375 mg/m\u0026sup2; for 4\u0026ndash;6 weeks) and timed immediately after TPE, allowing at least 24 hours before the next session to avoid its washout. (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) Rituximab use in pregnancy requires a careful risk-benefit analysis. It is safer in the first trimester due to minimal placental transfer (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e) but can cause transient neonatal B-cell depletion in the second and third trimesters. (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e) Nevertheless, in life-threatening cases like aTTP, the benefits of rituximab outweigh the risks, as uncontrolled disease poses a greater danger to both mother and fetus.(\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eNewer agents like caplacizumab help manage recurrence and control the immune response. Caplacizumab is a humanized immunoglobulin that targets the A1 domain of von Willebrand factor (vWF), preventing its interaction with platelet receptor glycoprotein Ib-IX-V and inhibiting platelet adhesion and aggregation, which are central to the pathophysiology of TTP.(\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e) Approved by the FDA in 2019 for the treatment of aTTP, in addition to TPE and immunosuppression,(\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e) it rapidly normalizes platelet counts, reduces exacerbations, and prevents end-organ damage by inhibiting microvascular thrombi formation, as demonstrated in the TITAN and HERCULES trials.(\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eAlthough caplacizumab does not address the underlying ADAMTS13 deficiency, treatment should continue until ADAMTS13 activity recovers to prevent relapses. Its high cost (\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e) and limited safety data in pregnancy, due to the exclusion of pregnant women from major clinical trials, require careful consideration.(\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn case 3 of aTTP, rituximab was initially used. Despite treatment with TPE, steroids, and rituximab, two relapses occurred. Platelet counts had dropped to 28 \u0026times; 10⁹/L during the first relapse and 15 \u0026times; 10⁹/L during the second, prompting the use of caplacizumab, in conjunction with steroids, TPE, and rituximab. Caplacizumab led to a rapid recovery, stabilizing platelet levels at 238 \u0026times; 10⁹/L and reducing schistocytes to 2.2% by discharge.\u003c/p\u003e\n\u003cp\u003eTriple therapy, which combines TPE, immunosuppression with corticosteroids and rituximab, and caplacizumab, addresses the three key aspects of iTTP pathophysiology: TPE replenishes ADAMTS13, rituximab suppresses anti-ADAMTS13 antibodies, and caplacizumab prevents platelet-vWF interaction, rapidly normalizing platelet counts, reducing microthrombi formation, and lowering the risk of exacerbations and life-threatening complications associated with refractory TTP.(\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eThough costly, caplacizumab was justified by its ability to prevent further microvascular thrombi formation and protect against end-organ damage in a patient with multiple relapses, failed prior therapies, and high mortality risk. (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eLow-dose aspirin (LDA) and low molecular weight heparin (LMWH) as enoxaparin may be considered in pregnant women with TTP once platelet counts exceed 50,000/\u0026micro;L, primarily to reduce the risk of placental vascular damage or venous thromboembolism. (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e) However, these therapies are usually not routinely required in all TTP cases. Aspirin is prescribed only when there is a specific obstetric indication, as clot formation in TTP is driven by ULVWF-mediated platelet clumping, not cyclooxygenase-mediated aggregation. Enoxaparin is considered based on the patient\u0026apos;s individual thrombotic risk.(\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eIn hereditary cTTP, close monitoring of newborns is essential due to the risk of severe complications such as hemolysis, anemia, jaundice, and neonatal hyperbilirubinemia, which may require exchange transfusions. Delayed diagnosis or misdiagnosis can result in severe thrombocytopenia, organ damage, and even neonatal death. (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e) None of the newborns in our case series developed complications at birth.\u003c/p\u003e\n\u003cp\u003eIn future pregnancies, women with cTTP face a high relapse risk due to persistent ADAMTS13 deficiency, requiring regular plasma infusions. For aTTP, relapse depends on ADAMTS13 recovery. Maintaining ADAMTS13 activity above 20\u0026ndash;25% through trimester checks and monthly monitoring of CBC, LDH, and hemolytic markers is crucial. Treatment adjustments are needed if abnormalities arise. For those receiving rituximab, pregnancy should be delayed for 6 to 12 months. (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThrombotic thrombocytopenic purpura (TTP) during pregnancy presents significant diagnostic and management challenges due to its rarity and life-threatening potential.\u003c/p\u003e \u003cp\u003eEarly recognition, timely diagnosis, and prompt initiation of therapeutic plasma exchange (TPE) is critical for improving both maternal and fetal outcomes. Even though not all centers have immediate access to ADAMTS13 testing, ensuring that TPE is readily available is vital, as treatment should begin if TTP is suspected. Delayed treatment can lead to severe complications, posing increased risks for both the mother and the fetus.\u003c/p\u003e \u003cp\u003eMonoclonal antibodies, such as rituximab, play a vital role in managing acquired TTP (aTTP), working synergistically with TPE. Although caplacizumab is costly, it can be lifesaving, particularly in cases of severe or recurrent relapses, where the risk of mortality is high.\u003c/p\u003e \u003cp\u003eThis case series highlights the importance of interdisciplinary collaboration among obstetricians, hematologists, and critical care teams to ensure the most effective, tailored treatment strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADAMTS13: A disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13\u003c/p\u003e\n\u003cp\u003eAPS: Antiphospholipid syndrome\u003c/p\u003e\n\u003cp\u003eaTTP: Acquired TTP\u003c/p\u003e\n\u003cp\u003eCS: Cesarean section\u003c/p\u003e\n\u003cp\u003ecTTP: Congenital TTP\u003c/p\u003e\n\u003cp\u003eDIC: Disseminated Intravascular Coagulation\u003c/p\u003e\n\u003cp\u003eHELLP: Hemolysis, Elevated Liver enzymes, and Low Platelet count\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ICU: Intensive care unit\u003c/p\u003e\n\u003cp\u003eITP: Immune thrombocytopenia\u003c/p\u003e\n\u003cp\u003eIVIG: Intravenous immunoglobulin\u003c/p\u003e\n\u003cp\u003eGT: gestational thrombocytopenia\u003c/p\u003e\n\u003cp\u003eMAHA: Microangiopathic hemolytic anemia\u003c/p\u003e\n\u003cp\u003ePLT: Platelet\u003c/p\u003e\n\u003cp\u003eTMAs: Thrombotic microangiopathies\u003c/p\u003e\n\u003cp\u003eTPE: Therapeutic plasma exchange\u003c/p\u003e\n\u003cp\u003eTTP: Thrombotic thrombocytopenic purpura\u003c/p\u003e\n\u003cp\u003eTIA: Transient ischemic attack\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis manuscript is original work and has not been submitted or under consideration for publication elsewhere. All authors have reviewed and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe case report was approved by the Hamad Medical Corporation’s Medical Research Center under the Number (MRC-04-23-393)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for the publication of patient information was obtained from the patient before the submission of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData pertaining to this case can be obtained by contacting the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no known competing interests that could have influenced this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQatar National Library (QNL) open-access forum\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSAK contributed to the manuscript writing, editing and literature review. GS contributed to preparation, reviewing and editing of manuscript. TM, AK, and SA contributed to drafting and editing of manuscript. All authors reviewed and gave final approval of the version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge Qatar National Library for funding this Open access article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSikka P, Chopra S, Aggarwal N, Suri V, Chandrasekaran A. Thrombotic thrombocytopenic purpura in the first trimester of pregnancy. Asian J Transfus Sci. 2013;7(1):79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor\u0026ndash;cleaving protease and its identification as a new member of the metalloproteinase family. 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Blood. 2021;137(7):969\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoppo P, Bubenheim M, Azoulay E, Galicier L, Malot S, Big\u0026eacute; N, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood. 2021;137(6):733\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVon Krogh AS, Quist-Paulsen P, Waage A, Langseth \u0026Oslash;O, Thorstensen K, Brudevold R, et al. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J Thromb Haemost. 2016;14(1):73\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Thrombotic thrombocytopenia purpura, ADAMTS-13, thrombocytopenia, therapeutic plasma exchange, pregnancy, caplacizumab, Rituximab","lastPublishedDoi":"10.21203/rs.3.rs-5867341/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5867341/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThrombotic Thrombocytopenic Purpura (TTP) is a rare yet life-threatening complication during pregnancy, with maternal mortality rates historically exceeding 90% before the advent of therapeutic plasma exchange (TPE), which has been the cornerstone of treatment for several decades.\u003c/p\u003e \u003cp\u003eRituximab has become increasingly important for managing refractory or relapsing TTP, particularly during pregnancy, due to its effectiveness in reducing relapses. In severe or recurrent cases, caplacizumab has emerged as a valuable agent, rapidly controlling acute episodes by preventing platelet aggregation and reducing microvascular thrombosis, which is critical in reducing organ damage and improving survival.\u003c/p\u003e \u003cp\u003eMonitoring ADAMTS13 activity has become crucial in distinguishing between congenital and acquired TTP, guiding treatment decisions, and preventing relapses. This case series includes both acquired and congenital TTP cases, and in one severe case with multiple relapses, we used caplacizumab to stabilize the patient's condition. The findings underscore the importance of early diagnosis, individualized treatment, and proactive management in improving maternal and neonatal outcomes.\u003c/p\u003e","manuscriptTitle":"Thrombotic Thrombocytopenic Purpura: Lessons from Clinical Cases, A case series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-24 18:46:52","doi":"10.21203/rs.3.rs-5867341/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98936bc3-df18-444d-8b2b-196f5be0f76d","owner":[],"postedDate":"January 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-18T11:09:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-24 18:46:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5867341","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5867341","identity":"rs-5867341","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}