Zhang Q, Meng F, Cao Y
… +3 more, Zhu X, Zhang Y, Xiao Y
Case Rep Hematol
· 2025 · PMID 41199911
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A patient with Burkitt's lymphoma developed upper gastrointestinal adverse events during immune consolidation therapy following chemotherapy combined with autologous stem cell transplantation. Subsequent administration o...A patient with Burkitt's lymphoma developed upper gastrointestinal adverse events during immune consolidation therapy following chemotherapy combined with autologous stem cell transplantation. Subsequent administration of vedolizumab as adjunctive therapy resulted in improvement of the patient's symptoms. This case is expected to provide a reference for the expanded application of PD-1 inhibitors in non-Hodgkin's lymphoma.
Chang S, Pan Z, Zhang Y
… +5 more, Zhang Y, Sun J, Guo Y, Guo X, Guo Z
Case Rep Hematol
· 2025 · PMID 41199910
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Many tyrosine kinase inhibitors show nonspecific activity against multiple kinases, causing off-target effects when used in a broad patient population. This study evaluated the effectiveness of gilteritinib combined with...Many tyrosine kinase inhibitors show nonspecific activity against multiple kinases, causing off-target effects when used in a broad patient population. This study evaluated the effectiveness of gilteritinib combined with venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS) with wild-type , who currently lack targeted therapy. After a 28-day cycle of venetoclax-gilteritinib therapy, one patient with R/R AML and other genetic alterations achieved minimal residual disease (MRD)-positive complete remission (CR) with incomplete hematologic recovery (CRi). Another patient with R/R -mutated MDS/AML achieved morphologic leukemia-free state (MLFS) after one cycle, but cytopenias persisted across two cycles. A patient with R/R -mutated AML related to myelodysplasia did not respond (NR) after two cycles, although the blast percentage in bone marrow (BM) and peripheral blood (PB) decreased by 50%. In a patient with R/R AML carrying an in-frame bZIP-mutated , NR and disease progression occurred after one cycle, but elevated white blood cell (WBC) counts declined after treatment initiation and lasted for 2 weeks. These findings suggest that combining gilteritinib with venetoclax may reduce tumor burden in R/R AML/MDS patients with wild-type .
Wan Hanafi HH, Mohd Sabri NM, Muhamat Yusoff R
… +4 more, Nizam Akbar NA, Mohd Noor NH, Hussain FA, Husin A
Case Rep Hematol
· 2025 · PMID 41194785
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Secondary acute myeloid leukemia (sAML) typically arises from a prior myeloid malignancy or as a complication of cytotoxic therapy for other cancers. Rarely, it may develop without antecedent treatment, particularly in l...Secondary acute myeloid leukemia (sAML) typically arises from a prior myeloid malignancy or as a complication of cytotoxic therapy for other cancers. Rarely, it may develop without antecedent treatment, particularly in lymphoid malignancies. We report an unusual case of sAML in a treatment-naïve patient previously diagnosed with primary testicular diffuse large B-cell lymphoma (DLBCL). A 58-year-old male initially presented with Stage 1E primary testicular DLBCL and declined recommended treatment. Five years later, he developed symptoms and laboratory features of acute myeloid leukemia (AML), confirmed as monocytic subtype (M5) via immunophenotyping. Despite planned hypomethylating agent-based therapy, he succumbed during bridging treatment. This case highlights the diagnostic importance of immunophenotyping and an uncommon clinical trajectory from untreated lymphoid malignancy to sAML.
Blackman J, Blackman JT, Pauranik A
… +1 more, Freeman AT
Case Rep Hematol
· 2025 · PMID 41194784
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Central nervous system involvement in multiple myeloma (MM-CNS) is a condition with poor prognosis and no clear treatment options. Standard regimens, including proteasome inhibitors (PIs) and immunomodulatory (IMiD) agen...Central nervous system involvement in multiple myeloma (MM-CNS) is a condition with poor prognosis and no clear treatment options. Standard regimens, including proteasome inhibitors (PIs) and immunomodulatory (IMiD) agents, provide minimal benefit in this setting, highlighting the need for novel therapies. Teclistamab, a bispecific T-cell engager (BiTE) targeting B-cell maturation agent (BCMA) and CD3, has demonstrated robust systemic activity in heavily pretreated MM but its role in CNS disease remains undefined, as patients with CNS involvement have been excluded from pivotal trials. We present the case of a 62-year-old female with high-risk MM who developed extensive leptomeningeal myelomatosis following multiple lines of therapy including autologous transplantation, PI- and IMiD-based regimens, and palliative radiotherapy. Upon presentation with confusion, aphasia, and ataxia, MRI revealed diffuse leptomeningeal enhancement. The patient elected to proceed with teclistamab therapy. Following two cycles, she achieved a very good partial serologic response and MRI demonstrated marked radiologic improvement with resolution of cerebellar nodularity and sulcal enhancement. However, functional recovery was not observed, and the treatment was discontinued after three cycles due to clinical decline and infectious complications. She subsequently transitioned to supportive care and passed away 1 month later. This case report documents one of the first reports of teclistamab demonstrating radiologic improvement in leptomeningeal disease in MM-CNS. While the patient's overall outcome was poor, the observed CNS response supports the biologic plausibility of BiTE penetration and activity in the CNS. These findings suggest the urgent need for prospective studies of BCMA-directed bispecific antibodies in MM-CNS, as well as earlier intervention prior to functional decline.
Al-Bazaz M, Forstreuter A, Hammada I
… +6 more, Hille J, Wagner JN, Reinert J, Wehrhahn J, Bokemeyer C, Fiedler W
Case Rep Hematol
· 2025 · PMID 41180818
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CASE: We present the case of a 60-year-old male patient with a common B-cell acute lymphoblastic leukemia (ALL) who carried the rare t(8; 22)(p11; q11) :: chromosomal translocation. BACKGROUND/OBJECTIVES: The presence of...CASE: We present the case of a 60-year-old male patient with a common B-cell acute lymphoblastic leukemia (ALL) who carried the rare t(8; 22)(p11; q11) :: chromosomal translocation. BACKGROUND/OBJECTIVES: The presence of the t(8; 22)(p11; q11) :: translocation, identified by cytogenetics including Fluorescence In Situ Hybridization (FISH) is known for its association with aggressive disease. Given the dismal prognosis, an early search for a stem cell donor was initiated. METHODS: The patient was treated according to the German Multicenter ALL (GMALL) Study Group consensus recommendations. The disease was refractory to the first cycle of induction chemotherapy. However, after the second induction, cytological remission was achieved. Nevertheless, minimal residual disease (MRD) positivity persisted (IGH rearrangement detected by PCR) after the first consolidation therapy, giving indication for a stem cell transplantation (SCT). RESULTS: Thirty days post-transplant, no MRD was detected, and complete chimerism was measured for the months following transplantation. However, the patient died in the context of severe graft-versus-host disease and infectious complications 6 months after the SCT. CONCLUSIONS: This case highlights the importance of detailed molecular analysis in the initial diagnostics of ALL. Identification of specific chromosomal translocations can provide critical insights for risk assessment and aid decision-making in intensify therapeutic approaches. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03011372, NCT04659616.
Shihab R, Mosleh S, Takhman M
… +5 more, Yousef F, Salim M, Abuabed A, Abueisheh S, Abed M
Case Rep Hematol
· 2025 · PMID 41169669
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We report a pediatric patient with xeroderma pigmentosum (XP) who developed hemophagocytic lymphohistiocytosis (HLH) secondary to Brucella infection-an exceedingly rare occurrence. XP is a rare autosomal recessive geneti...We report a pediatric patient with xeroderma pigmentosum (XP) who developed hemophagocytic lymphohistiocytosis (HLH) secondary to Brucella infection-an exceedingly rare occurrence. XP is a rare autosomal recessive genetic disorder characterized by extreme ultraviolet radiation (UVR) sensitivity due to the inability to repair DNA pyrimidine dimers caused by UV exposure. This defect leads to a markedly increased risk of skin cancer and progressive neurological degeneration (Leung, 2022). HLH is a rare, potentially fatal hypersensitivity syndrome characterized by excessive activation and impaired downregulation of T-lymphocytes and macrophages. This dysregulation results in an overproduction of proinflammatory cytokines, destruction of blood cells, and subsequent tissue and organ damage (Fisman, 2000). While secondary HLH may follow various infections, Brucella-induced HLH is rare (Wolska, 2006), and to our knowledge, this is the first reported case in a patient with XP.
Case Rep Hematol
· 2025 · PMID 41164795
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Immune thrombocytopenia purpura (ITP) is initially treated with steroids, but TPO-RAs such as eltrombopag are used for chronic cases. Though effective, eltrombopag has been linked to thromboembolic events, with cerebral...Immune thrombocytopenia purpura (ITP) is initially treated with steroids, but TPO-RAs such as eltrombopag are used for chronic cases. Though effective, eltrombopag has been linked to thromboembolic events, with cerebral venous thrombosis (CVT) being a rare complication. A 20-year-old woman with ITP developed severe headaches, nausea, and vomiting five days after starting eltrombopag. CT scans revealed a dense clot in the right transverse sinus, indicating CVT. Lab data showed elevated platelet counts and D-dimer levels. MRV confirmed CVT, leading to the discontinuation of eltrombopag and initiation of anticoagulant therapy. Recurring thrombocytopenia necessitated further treatment adjustments, including rituximab and cyclosporine, resulting in improved platelet counts and CVT resolution. This case highlighted that CVT is a serious but rare side effect of eltrombopag in ITP patients. Early detection, prompt anticoagulation, and cautious TPO-RA management are crucial for preventing thromboembolic events.
Kahlon N, Baddam S, Kaur H
… +3 more, Singh P, Qureshi Z, Gowda AM
Case Rep Hematol
· 2025 · PMID 41141709
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Hydroxyurea is a cornerstone therapy for myeloproliferative disorders such as early-stage myelofibrosis. However, rare hypersensitivity reactions can complicate its use and require careful management. This case describes...Hydroxyurea is a cornerstone therapy for myeloproliferative disorders such as early-stage myelofibrosis. However, rare hypersensitivity reactions can complicate its use and require careful management. This case describes a patient with early-stage myelofibrosis, with JAK2 V617F mutation, and Grade 1 reticulin fibrosis on bone marrow biopsy. He was started on hydroxyurea 500 mg daily. The patient developed delayed hypersensitivity characterized by fever, chills, and fatigue. Symptoms initially resolved with self-discontinuation, but rechallenge twice with alternate-day dosing led to rapid recurrence following each dose. Discontinuation of hydroxyurea resolved symptoms permanently, and the patient was transitioned to ruxolitinib for management of the underlying disease. This case highlights the importance of recognizing hypersensitivity reactions during hydroxyurea therapy and implementing alternative strategies to optimize patient outcomes.
Takhman M, Hattab M, Shihab R
… +2 more, Sarama A, Mosleh S
Case Rep Hematol
· 2025 · PMID 41126990
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Gray platelet syndrome (GPS) is a rare inherited platelet disorder characterized by the presence of gray platelets on blood smears, resulting from a deficiency of -granules. The thrombocytopenia presents in a spectrum of...Gray platelet syndrome (GPS) is a rare inherited platelet disorder characterized by the presence of gray platelets on blood smears, resulting from a deficiency of -granules. The thrombocytopenia presents in a spectrum of bleeding tendencies, varying among different patients. We present a case of a 14-year-old male presenting with recurrent epistaxis, thrombocytopenia, hepatosplenomegaly, and recurrent infections that had not been diagnosed previously. Whole-exome gene sequencing revealed a homozygous likely pathogenic splice-site variant in the NBEAL2 gene, confirming the diagnosis of GPS, which is inherited in an autosomal recessive manner due to biallelic variants in NBEAL2. The patient had atypical hepatomegaly and low lymphocyte and monocyte counts, findings consistent with emerging evidence that GPS affects multiple hematopoietic lineages. It also contributes to immune dysregulation and results in increased susceptibility to autoimmune disorders, highlighting the need for guidelines to screen for autoimmune complications in GPS patients.
Chandrasekar AP, Koepsell SA, Williams SM
… +1 more, Bobr A
Case Rep Hematol
· 2025 · PMID 41103817
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BACKGROUND: Chronic RBC exchange (RCE) is an established therapeutic strategy used to prevent the development of serious complications in patients with sickle cell disease and beta thalassemia. A subset of these patients...BACKGROUND: Chronic RBC exchange (RCE) is an established therapeutic strategy used to prevent the development of serious complications in patients with sickle cell disease and beta thalassemia. A subset of these patients have an accelerated decline of transfused red cells, leading to suboptimal exchange transfusions since the preprocedure hematocrit (HCT) is too low to allow for isovolemic hemodilution. These patients often have concomitant splenomegaly. METHODS: In our institution, we had 3 patients who had rapid decline in HCT post-RCE and who underwent a splenectomy. We compared the pre- and postsplenectomy hemoglobin S and HCT values for two patients with sickle cell anemia and one with beta thalassemia, undergoing chronic RCE. RESULTS: We observed a significant increase in the preprocedure HCT, from a mean ± SD of 21.11 (±2.5) presplenectomy to 25.02 (±1.8) postsplenectomy ( < 0.0001). This was accompanied by a significant increase in the interval number of days between procedures, from 29.6 (±5.6) days to 34.8 (±7.2) days following splenectomy (=0.0046). Comparing pre- and postsplenectomy HCT values to the threshold HCT value required for isovolemic hemodilution (HCT = 23%) revealed that splenectomy resulted in a highly significant increase ( < 0.0001) above the threshold. DISCUSSION: Our observations here suggest that in a subset of patients, splenomegaly may result in accelerated decline of transfused red cells which improves following splenectomy, resulting in improved clinical parameters and more efficient RCE.
Case Rep Hematol
· 2025 · PMID 41089728
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This case illustrates the importance of medical and dental healthcare awareness of how amyloidosis may affect the oral mucosa. Careful, thorough examinations, and anamnesis in a stepwise manner, with communication betwee...This case illustrates the importance of medical and dental healthcare awareness of how amyloidosis may affect the oral mucosa. Careful, thorough examinations, and anamnesis in a stepwise manner, with communication between professions, are necessary to ensure an early diagnosis and avoid unnecessary suffering. In this case, the patient's medical history should have been taken into consideration when examining the oral cavity, as it might have been an indicator for the healthcare providers as to which tests were needed.
Okabe Y, Rodriguez JI, Edmunds J
… +1 more, Dhliwayo NL
Case Rep Hematol
· 2025 · PMID 41059479
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Factor V Leiden (FVL) and the prothrombin 20210A gene mutation are two common genetic predispositions to hypercoagulability. We present a complex case of recurrent venous thromboembolism (VTE) in a 50-year-old woman with...Factor V Leiden (FVL) and the prothrombin 20210A gene mutation are two common genetic predispositions to hypercoagulability. We present a complex case of recurrent venous thromboembolism (VTE) in a 50-year-old woman with double heterozygosity for FVL and prothrombin G20210A, complicated by heparin-induced thrombocytopenia (HIT) and May-Thurner syndrome. Following a recent orthopedic surgery and a sedentary postoperative course, the patient developed extensive bilateral deep vein thrombosis (DVT) and a saddle pulmonary embolism. Initial anticoagulation with heparin was complicated by progressive thrombocytopenia and confirmed HIT, prompting transition to bivalirudin and subsequently argatroban. Despite therapeutic anticoagulation and multiple interventional procedures, the patient experienced repeated thrombotic events. After increasing the therapeutic aPTT goal for argatroban, she ultimately stabilized and was successfully transitioned to oral apixaban. This case highlights the synergistic risk posed by the combination of inherited thrombophilia, structural venous abnormalities, and acquired prothrombotic conditions. It provides insight into the complex nature of proper anticoagulation strategies in these individual cases. Our use of argatroban with higher aPTT goals may provide guidance in future cases of refractory VTE. Further studies are needed to better understand the optimal therapies and management for patients with hereditary and acquired thrombophilia.
J Pecorin P, A MM, Olson G
… +3 more, Flammersfeld E, Tekreeti MA, Atisha P
Case Rep Hematol
· 2025 · PMID 41018683
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Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome is a rare disorder that is frequently misdiagnosed due to its heterogeneous presentation and overlap with chron...Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome is a rare disorder that is frequently misdiagnosed due to its heterogeneous presentation and overlap with chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnosis requires the presence of polyneuropathy and a monoclonal plasma cell disorder, along with additional major and minor criteria. We present a 73-year-old woman with progressive weakness, volume overload, and weight loss, initially diagnosed with CIDP. Despite IVIG therapy, her symptoms worsened. Notably, no monoclonal peak was detected on serum protein electrophoresis (SPEP) or immunofixation, complicating the diagnosis. However, markedly elevated vascular endothelial growth factor (VEGF) levels (11.245 pg/mL) and bone marrow biopsy findings of a monoclonal plasma cell disorder confirmed POEMS syndrome. She also developed multiple thromboembolic events, highlighting the syndrome's prothrombotic nature. This case underscores the importance of maintaining high suspicion for POEMS syndrome in the setting of undifferentiated polyneuropathy, even in the absence of a monoclonal peak on SPEP. VEGF measurement and bone marrow biopsy are crucial for diagnosis in such cases. Early recognition and treatment, including plasma cell-directed therapy and anticoagulation, are essential to improving patient outcomes and preventing irreversible complications.
Murray NP, Escobar C, Ramos E
… +2 more, Perez C, Hartman D
Case Rep Hematol
· 2025 · PMID 41001423
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Intravascular large B-cell lymphoma (IVLCBL) is a rare form of non-Hodgkin's lymphoma and is characterized by the growth of large B-cells within blood vessels and bone marrow sinusoids. A 55-year-old man presented with a...Intravascular large B-cell lymphoma (IVLCBL) is a rare form of non-Hodgkin's lymphoma and is characterized by the growth of large B-cells within blood vessels and bone marrow sinusoids. A 55-year-old man presented with a multiple endocrine failure which progressed to a pancytopenia. A bone marrow biopsy revealed a diffuse infiltration by large B-cells in the sinusoids consistent with intravascular lymphoma. After 6 cycles of R-CHOP, complete remission was achieved. Six months later, the patient relapsed presenting with a thrombotic microangiopathy which progressed to multiple organ failure and death.
Case Rep Hematol
· 2025 · PMID 40979895
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Intravascular large B-cell lymphoma (IVLBCL) has a high mortality rate, partly due to its heterogeneous presentation and rarity. We present a case of a 73-year-old woman who came into the emergency room in need of fluid...Intravascular large B-cell lymphoma (IVLBCL) has a high mortality rate, partly due to its heterogeneous presentation and rarity. We present a case of a 73-year-old woman who came into the emergency room in need of fluid resuscitation, interpreted as septic shock. However, broad-spectrum antibiotics gave no resolution, and no causative agent was found. Further physical examination showed proximal muscle weakness, Raynaud's phenomenon, and calcinosis cutis. During 3 weeks of admission, vasopressor support was required continuously due to a capillary leak syndrome. The patient passed away. The underlying malignancy was only revealed at autopsy. To the best of our knowledge, this is the first case of IVLBCL with hypovolemic shock due to systemic capillary leak syndrome in combination with a wide range of immunological phenomena.
Jones SE, Sellers J, Wheless MC
… +2 more, Fishman D, McKenzie RK
Case Rep Hematol
· 2025 · PMID 40958800
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In this case report, we present a patient with severe thrombocytopenia induced by adalimumab after 4 weeks of treatment for rheumatoid arthritis. This case adds to present literature regarding antitumor necrosis factor-a...In this case report, we present a patient with severe thrombocytopenia induced by adalimumab after 4 weeks of treatment for rheumatoid arthritis. This case adds to present literature regarding antitumor necrosis factor-alpha (TNF-α)-induced thrombocytopenia and explores the use of thrombopoietin receptor agonist medications in refractory drug-induced immune thrombocytopenia (DITP). A 57-year-old female with a history of rheumatoid arthritis presented to the emergency department for progressive petechial rash 4 days after her third dose of adalimumab. It was determined that the patient had immune thrombocytopenia caused by adalimumab and was initially treated with steroids and intravenous immunoglobulin (IVIG). Platelets remained undetectable; hence, romiplostim was initiated, after which platelets trended up to normal levels a week later. Anti-TNF-α agents carry the risk of severe side effects, including thrombocytopenia, which should be monitored closely in the first few months of therapy. The treatment of DITP is challenging, especially when the causative agent has a prolonged half-life.
Alarcon PR, Mehlich D, Shiraz F
… +1 more, Sanchez M
Case Rep Hematol
· 2025 · PMID 40937272
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Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome is a multisystem disorder, and it is often misdiagnosed with other entities including chronic inflammatory demyelinati...Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome is a multisystem disorder, and it is often misdiagnosed with other entities including chronic inflammatory demyelinating polyneuropathy (CIDP). Here, we present a case of a patient with presumed metastatic prostate cancer due to prostate-specific membrane antigen (PSMA) avid lesions and a history of neuropathy not responding to conventional treatment for CIDP. His physical exam findings, in addition to an appropriate workup, led to a diagnosis of POEMS syndrome. This case highlights the importance of a high index of clinical suspicion, even when imaging suggests otherwise.
Tsutsumi H, Kudo M, Maseki N
… +6 more, Kawamura M, Kobayashi K, Sekiguchi Y, Harada Y, Sadato D, Kobayashi H
Case Rep Hematol
· 2025 · PMID 40934040
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Chronic myelomonocytic leukemia (CMML) is a myeloproliferative disease characterized by monocyte-predominant hematopoiesis. It is sometimes complicated with cutaneous involvement known as leukemic cutis, which is associa...Chronic myelomonocytic leukemia (CMML) is a myeloproliferative disease characterized by monocyte-predominant hematopoiesis. It is sometimes complicated with cutaneous involvement known as leukemic cutis, which is associated with a poor prognosis. We report a patient with CMML who developed fever with knee joint swelling and pain. The patient was considered to have leukemic synovitis, and treatment with azacitidine improved her symptoms. Our case suggested that leukemic synovitis might indicate the indication for treatment, and arthrocentesis should be performed in patients with leukemia who present with joint swelling.
Gibson SK, Davis T, Vazquez M
… +2 more, Htet S, Wong E
Case Rep Hematol
· 2025 · PMID 40919235
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T-cell prolymphocytic leukaemia (T-PLL) is an aggressive and rare post-thymic T cell malignancy, highly refractory to conventional cytotoxic chemotherapeutics. While extranodal involvement is common, solid organ invasion...T-cell prolymphocytic leukaemia (T-PLL) is an aggressive and rare post-thymic T cell malignancy, highly refractory to conventional cytotoxic chemotherapeutics. While extranodal involvement is common, solid organ invasion is rare. We present the case of a 76-year-old man who developed acute renal failure secondary to T-PLL renal infiltration. On day four of his admission, prior to commencing alemtuzumab, his creatinine rose from 133 μmol/L to 390 μmol/L, with anuria. Renal biopsy demonstrated an infiltrate of monomorphic, mononuclear cells positive for a STAT5B mutation, consistent with T-PLL infiltration. He required haemodialysis, but was treated with pulsed methylprednisolone and alemtuzumab, with excellent renal recovery, although remission was not achieved. This case demonstrates that renal leukaemic infiltration must be considered in T-PLL patients with rapidly progressive renal failure, and that solid organ invasion should not contraindicate timely commencement of T-PLL-directed therapy with alemtuzumab.
Ataei-Azimi S, Bos MHA, Rahimi H
… +1 more, Mansouritorghabeh H
Case Rep Hematol
· 2025 · PMID 40919234
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Factor XIII (FXIII) deficiency is a rare coagulopathy with an estimated prevalence of approximately 1 in 1 to 2 million, affecting males and females with equal frequency. FXIII plays a critical role in hemostasis by stab...Factor XIII (FXIII) deficiency is a rare coagulopathy with an estimated prevalence of approximately 1 in 1 to 2 million, affecting males and females with equal frequency. FXIII plays a critical role in hemostasis by stabilizing fibrin clots through covalent cross-linking of fibrin monomers, thereby conferring mechanical resistance and durability to the clot structure. Clinically, FXIII deficiency presents with a spectrum of hemorrhagic manifestations including bleeding from the umbilical cord, intracranial hemorrhage, recurrent miscarriages, menorrhagia, epistaxis, gingival bleeding, and poor wound healing. Despite significant bleeding symptoms, routine primary hemostasis screening tests are typically within normal limits since FXIII acts downstream of clot formation. The clot solubility in 5-molar urea is widely used, especially in resource-limited settings. An 11-year-old female patient presented with symptoms including vomiting, lethargy, severe headache, and a subgaleal hematoma. Neurosurgical intervention confirmed intracranial hemorrhage. Her medical history was notable for neonatal umbilical cord bleeding, hematomas, and postdental extraction bleeding. Despite these clinical features, multiple clot solubility tests yielded normal results. Subsequent quantitative assessment of FXIII by chromogenic assay performed on the CS-5100 system revealed a markedly decreased FXIII activity level of 12.4%. This discrepancy highlights the limited insensitivity of the clot solubility test in detecting FXIII deficiency. Therefore, accurate diagnosis of FXIII deficiency necessitates a combined diagnostic approach incorporating both clot solubility testing and specific quantitative FXIII activity measurement. The clot stability test, despite its limitations in detecting FXIII deficiency, is frequently employed in developing countries for screening reduced FXIII levels due to its simplicity. However, the current findings indicate that in patients suspected of FXIII deficiency, accurate diagnosis necessitates the performance of both a clot stability test (5 M urea test) and a specific FXIII activity assay. A comprehensive medical and family history is fundamental to the clinical and laboratory approach to patients presenting with bleeding tendencies. Notably, a subset of patients exhibiting bleeding symptoms may exhibit normal findings on initial first-line hemostasis screening assays.