UNASSIGNED: During the last decades, the pathogenesis of cold agglutinin disease (CAD) has been well elucidated and shown to be complex. Several documented or investigational therapies have been made available. This development has resulted in major therapeutic advances, but also in challenges in choice of therapy.
UNASSIGNED: In this review, we address each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation. We also discuss the heterogeneous clinical features and their relation to specific steps in pathogenesis, in particular with respect to the impact of complement involvement. CAD can be classified into three clinical phenotypes with consequences for established treatments as well as development of new therapies. Some promising future treatment approaches - beyond chemoimmunotherapy and complement inhibition - are reviewed.
UNASSIGNED: The patient\'s individual clinical profile regarding complement involvement and hemolytic versus non-hemolytic features is important for the choice of treatment. Further development of treatment approaches is encouraged, and some candidate drugs are promising irrespective of clinical phenotype. Patients with CAD requiring therapy should be considered for inclusion in clinical trials.

Wilson\'s disease (WD) is an autosomal recessive disorder that impairs copper metabolism. Copper accumulates in vital organs such as the brain, liver, and kidneys. The disease typically starts with copper accumulation in the liver and can initially present as acute hepatitis and hepatomegaly. Hemolytic anemia is a typically uncommon complication of WD. We present the case of a healthy 18-year-old female who presented with hemolytic anemia and quickly decompensated to fulminant hepatic failure requiring a liver transplant due to previously undiagnosed WD. This case recognizes the importance of early diagnosis as treatment can be lifesaving.

Brown recluse spider bites can lead to severe reactions such as skin necrosis,hemolytic anemia, and multiorgan failure, which can be life-threatening. Therapeutic plasma exchange has been reported to provide clinical benefit for such cases. In thisreport, we present a case of a brown recluse spider bite that was successfully treated with therapeutic plasma exchange and compare it with previous case reports.

Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare autosomal recessive genetic disorder caused by a homozygous mutation of the ACP5 gene. Spondyloenchondrodysplasia is a type of immune-osseous dysplasia manifesting with skeletal dysplasia, immunologic dysfunction, and neurological manifestations. We report the case of a six-year-old boy with SPENCDI who presented with post-viral illness Coombs-positive hemolytic anemia, thrombocytopenia, and fever, based on which he was diagnosed with Evans syndrome. He was previously diagnosed with spastic diplegia, short stature, and celiac disease. The diagnosis was confirmed with genetic testing which displayed a homozygous frameshift mutation of the ACP5 gene c.549del p.(Gln184Serfs*28). This case report discusses the clinical presentation of SPENCDI and highlights the importance of considering this rare genetic disorder in patients presenting with short stature, immunologic dysregulation, and neurological involvement.

Background: Hemoglobinopathies are common inherited blood disorders in our Mediterranean area. The main structural hemoglobin variants are hemoglobin S and hemoglobin C, due to their prevalence. We conducted this retrospective study to investigate and characterize hemoglobin C patients referred to the National Center for Thalassemia and Genetic Counseling and the management of hemoglobin C disease in Damascus. Materials and Methods: The study included patients referred to the National Center for Thalassemia and Genetic Counseling in Damascus between 2000 and 2022 for hemoglobin C detection. Gender, age, geographical origin, hemoglobin electrophoresis profile, and blood transfusion were considered for hemoglobin C patient classification. Blood transfusion in five consecutive years and linear regression with hemoglobin S and C values were determined. Results: 30 (14 males and 16 females) out of 624 patients between 3 and 46 years old (mean ± SD: 17.3 ± 9.7 years) showed hemoglobin C disease. Only eight patients (one male and seven females) received blood transfusions, and the remaining patients (13 males and 9 females) did not receive any transfusion. Only one patient with 100% hemoglobin C was detected; 19 showed HbSC, and 10 had HbAC. There was a significant correlation between hemoglobin S and geographical origin (P-value=0). Conclusion: A Homozygote hemoglobin C patient has mild hemolytic anemia, whereas the hemoglobin C 100% patient has only a one-time blood transfusion (he was 17 years old) in our study. The inherited combination of hemoglobin C and S is less severe than hemoglobin S alone. There is a significant relationship between hemoglobin S and geographical origin (p-value=0).

Babesiosis is a tick-borne illness that can cause a wide variety of symptoms based on the severity of the disease. Mild presentations can be difficult to identify, and as a result, treatment may be delayed. A 75-year-old male presented to the Emergency Department (ED) with weakness, leg pain, and a fall. He was found to be febrile and tachycardic on arrival, and lab work revealed thrombocytopenia and acute renal dysfunction. He was admitted and found to have a Babesiosis infection, requiring treatment with red blood cell exchange and plasma exchange therapy. Tick-borne illnesses should be included in the differential even in low-risk populations and non-endemic regions due to the severity of disease complications.

Ceftriaxone, a regularly used antibiotic for broad-spectrum coverage, is a rare cause of hemolytic anemia. Patients may present with truncal pain, nausea, vomiting, and an acute drop in hemoglobin within 48 hours of administration. Prompt recognition and initiation of treatment are essential. We describe a case of a 65-year-old woman being treated for osteomyelitis who developed hemolytic anemia, disseminated intravascular coagulation, and multi-system organ failure after being de-escalated from cefepime to ceftriaxone.

Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease.

Infantile pyknocytosis (IP) is a rare, probably misestimated, cause of non-immune neonatal hemolytic anemia evolving in two phases: an initial phase with severe jaundice, followed by a second phase with hemolytic anemia, which may require neonatal intensive care. The diagnosis of IP is based on the transient presence on blood smear of hyperdense, contracted, and/or spiculated red blood cells (pyknocytes), associated with the spontaneous resolution of clinico-biological features and the exclusion of other causes. If the etiology remains undetermined, some contributing factors, such as oxidative stress, have been proposed. We report the description of 16 patients with IP aiming at clarifying the circumstances associated with the development of this acquired disorder. In the acute phase, the mean hemoglobin nadir and pyknocyte count were 7.8 g/dL and 11%, respectively, and strikingly, Heinz bodies were evident in 50% of the newborns, but in 100% after prolonged incubation (4 hours). A high proportion of Mediterranean or African ancestry was noted in newborns, as well as a significant number of peripartum events, such as respiratory distress. If the etiology of IP is certainly multifactorial, our series reinforces the role of oxidative stress, which may, at least in part, find origin in desaturation episodes in newborns.

Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the SEC23B gene located on chromosome 20 result in this autosomal recessive disorder. In this case report, we present a case of CDA II with unique biopsy findings being detected via genetic testing. A female aged 30 years presented with major complaints of pallor weakness and easy fatiguability since childhood. The patient gave a history of 25 units of blood transfusion, the majority of which were transfused during pregnancy, followed by regular transfusions thereafter. On examination, all her vitals were in the normal range. Pallor, frontal bossing, and malocclusion of teeth were noted. Her laboratory workup showed the following: hemoglobin (Hb): 3.7 g/dl; mean corpuscular volume: 83 fl; mean corpuscular Hb: 29 g/dl; mean corpuscular Hb concentration: 34.9 g/dl; red cell distribution width: 30.4%; reticulocyte count (RC): 6.2%; corrected RC: 1.3%; lactate dehydrogenase: 441 IU/L; direct Coombs test/indirect Coombs test: negative; serum iron: 242 microgram/dl; transferrin saturation: 96.08%; ferritin: 1,880 ng/ml; and normal high-performance liquid chromatography and eosin-5\'-maleimide binding test. The peripheral blood film showed normocytic normochromic anemia with anisopoikilocytosis in the form of a few spherocytes. No immature cells were seen. After obtaining the patient\'s consent, we performed a hereditary hemolytic anemia gene analysis test, which showed homozygous missense variation in exon 12 of the SEC23B gene. The bone marrow examination showed hyperplasia in the erythroid series with dyserythropoiesis, and surprisingly, myelofibrosis grade I-II (WHO 2017) was also observed on biopsy. Patients with CDA type II generally present with variable degrees of anemia along with pallor, icterus, splenomegaly, gallstones, and iron overload. In our case, the diagnosis of CDA type II was made at an adult age. Also, evidence of myelofibrosis was noted in our case, making it worth reporting. The use of a hereditary hemolytic anemia gene analysis panel test came as a rescue for its exact diagnosis. This case report emphasizes the role of molecular genetic testing for early and accurate diagnosis, which, in turn, could help in appropriate treatment planning and proper genetic counseling. The prevalence of CDA type II is still vaguely known; hence, extensive workup of persistent anemias and proper follow-up would be beneficial.