COVID-19 infections are known to cause multi-organ complications. Hematological complications like autoimmune hemolytic anemia with a positive direct antiglobulin test (DAT), are commonly encountered. However, Coombs-negative hemolytic anemia is extremely rare. We report an interesting case of an elderly female with moderate-severe acute respiratory distress syndrome in the setting of COVID-19 pneumonia-causing Coombs-negative hemolytic anemia. This patient initially presented with sudden onset abdominal pain and vomiting, found to have an incarcerated inguinal hernia with small bowel obstruction (SBO) on imaging. Additionally, labs revealed positive COVID-19 antigen test and normocytic anemia. The hospital course was complicated by worsening hemolytic anemia and thrombocytopenia requiring blood products. Extensive workup for hemolysis in this patient with no prior hematological abnormalities, was negative for DAT and other conditions associated with or causative of hemolysis. At discharge, hemolytic parameters improved and on follow-up, hemoglobin returned to baseline, and repeat hemolytic parameters were normal. This case emphasizes the importance of considering SARS-CoV-2 along with other viral infections as one of the differentials for Coombs-negative hemolytic anemia.

Thrombocytopenia with concomitant anemia is a serious condition with a high mortality risk. Destruction of platelets, i.e., thrombocytopenia, can be secondary to either auto-antibodies (immune-mediated) or mechanical destruction (non-immune-mediated). The Coombs test is a widespread tool to differentiate between the two categories, resulting in different specific treatment approaches for each diagnosis. A peripheral blood smear can also help make the diagnosis; for instance, in cases of mechanical destruction such as thrombotic thrombocytopenic purpura (TTP), the red blood cell (RBC) shape looks fragmented, forming schistocytes. In rare instances, TTP can present with both schistocytes and a positive Coombs test, challenging the diagnosis of TTP. TTP is a hematological emergency requiring appropriate anticipation and the initiation of treatment prior to the confirmatory ADAMTS-13 test results. Mild forms of TTP can be managed with glucocorticoids and therapeutic plasma exchange. Refractory cases need more aggressive additional treatment with caplacizumab and rituximab. Caplacizumab is an expensive medication that is usually reserved for use after confirmation of a TTP diagnosis. The advantage of caplacizumab lies in its targeted mechanism of action against the A1 domain of the von Willebrand multimers that are normally destructed by the ADAMTS-13 enzyme. Here, we present a young female patient with confirmed TTP, and the initial diagnosis was challenged by the presence of antibodies with the Coombs test. Very little research has studied this rare instance and the appropriate treatment. Our case will save many future lives, as clinicians should be more aggressive in treating refractory TTP with a positive Coombs test.

Vitamin B12 deficiency is a multifactorial condition, with a wide range of clinical presentations from mild to severe anemia and anemia-related neurological deficits. Hemolysis is a unique cause but has increasingly been recognized lately as a possible B12 deficiency presentation. Our patient presented with hemolytic anemia, for which extensive workup has excluded the common hemolysis etiologies. Therefore, it was attributed to B12 deficiency and improved significantly after treatment. Our case highlights the significance of this unusual presentation and its clinical implementation.

Incremental changes in the diagnosis of breast cancer leave drastic impacts on patients. There are detrimental shifts in cost, psychological disorders in terms of depression, and morbidities. Stage IV breast cancer has a high mortality rate and was afflicting our patient who was diagnosed with metastatic breast cancer estrogen receptor/progesterone receptor (ER/PR) positive, human epidermal growth factor receptor 2 (HER-2) neo negative, and low Ki-67. Among the various management modalities and effective treatments, capecitabine was selected because of its benefits; however, there are several commonly known adverse effects when using capecitabine including non-immune hemolytic anemia, a very rare and unexpected side effect despite the many research and clinical trials performed. Immune mediate or Coombs positive hemolytic anemia was reported with the usage of capecitabine, but this patient developed Coombs negative or non-immune hemolytic anemia. Capecitabine, a form of fluoropyrimidine, hypothetically affects the erythrocyte membrane structure resulting in the destruction of these cells. Additionally, discontinuation of capecitabine in the patient led to the resolution of the condition; this made us more aware of the precise diagnosis, also considering that the bone marrow biopsy came back negative.

Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common enzyme deficiency. Mode of inheritance is X-linked recessive with a high prevalence in endogamous marriages, such as Jehovah\'s Witness. Oxidative triggers such as infection, ingestion of certain medications, certain types of food, and in rare instances diabetic ketoacidosis (DKA) may unmask the diagnosis by triggering a hemolytic event. We describe the case of a 43-year-old male with type 2 diabetes who presented with DKA and subsequently became anemic four days after his admission, with the hemoglobin continuing to fall. After extensive workup, it was found that the patient had G6PD confirmed by a low glucose-6-phosphate dehydrogenase assay. We hypothesized that the oxidative stress from the DKA unmasked G6PD induced hemolysis in our patient. During our literature search, we also noticed that hemolysis was delayed on average by four to seven days in these patients after the initiation of insulin therapy similar to our patient. It is postulated that the delayed onset of hemolysis may be due to high levels of glucose in the blood. Hyperglycemia may offset the effects of G6PD deficiency by increasing the production of G6PD. When the levels of glucose start falling, hemolysis becomes apparent.

Generally, within the ABO blood group system, the AB group is subdivided into two subtypes, A1B and A2B, with the A2B subtype considered to be the rarest and the A1B subtype the most common. Given that the A2B subtype is the rarest one, its presence is associated with many challenges. In this report, we present the case of a child with a chronic hemolytic disease with the A2B blood group but without anti-A1 lectin antibodies, as well as the challenges encountered.

Henna is a herb that is used in traditional medicine for medical purposes as well as in the field of cosmetic. It is one of the agents that can trigger hemolytic crisis in G6PD deficient patients but it is considered safe in patients with normal G6PD enzyme. Here we present a case of non-immune hemolytic anemia occurred after ingestion of a homemade solution containing henna powder. Therapeutic plasma exchange was performed daily for 3 subsequent days and the hemoglobin levels and hemolytic markers were improved dramatically. Laboratory test revealed a normal G6PD enzyme level six weeks after recovery. We would like to emphasize the possibility of unexpected adverse effects and undefined ingredients of herbal products. Therapeutic plasma exchange can be a promising treatment option in such cases.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder due to uncontrolled activation of macrophage and cytokine release, which can be due to either genetic causes (familial) or secondary to infections malignancy and other less common cause. Parvovirus B19 rarely causes HLH. Diagnosing HLH in sickle cell disease, which inherently has high ferritin levels and pancytopenia, is particularly challenging. We are reporting HLH as a complication with parvovirus B19 infection in the background of sickle beta-thalassemia. Based on our search of available medical literature, this is the first case of HLH complicating parvovirus B19 infection in a pediatric age group with sickle beta-thalassemia.

Vitamin B12 deficiency is classically associated with megaloblastic anemia. Possible cobalamin deficiency is not investigated once hemolysis is seen. Around 2.5% of cases can present as pseudo-thrombotic microangiopathy (TMA). A swift identification of this means the difference between an easy solution and a protracted one for the patient. A 74-year-old man with no past medical history presented with exertional dyspnea, fatigue, and increasing anorexia over two weeks. Physical examination including a neurological examination was normal. Laboratory tests revealed pancytopenia, unconjugated hyperbilirubinemia, elevated LDH (lactate dehydrogenase), low haptoglobin, and fragmented red blood cells (RBCs) on the peripheral smear, but normal FDP (fibrinogen degradation product) and fibrinogen. The absolute reticulocyte count was reduced as opposed to the expected elevation. Vitamin B12 levels were undetectable, and severe cobalamin deficiency from pernicious anemia was found to be the paramount etiology. Cobalamin deficiency causing pseudo-TMA baffles most physicians. Advanced pernicious anemia is thought to cause intramedullary hemolysis, resulting in peripheral pancytopenia. The fragile RBCs are easily sheared, producing schistocytosis without platelet microthrombi. In contrast to hemolytic anemias, reticulocyte count is low given the unavailability of B12 for erythropoiesis. Reticulocytopenia is a universal finding in cases of pseudo-TMA. Around 38.8% of cases with pseudo-TMA are misdiagnosed as thrombotic thrombocytopenic purpura and treated with plasma product therapy. Keeping an eye out for reticulocytopenia in cases of hemolysis could mean a world of difference for the patient.

Macrocytic anemia is usually associated with vitamin B12 or folate deficiency. However, folate deficiency was rarely reported as a cause of hemolytic anemia. We present a case of a young man with a history of alcohol abuse who initially presented with an acute on chronic abdominal pain and was found to have jaundice and scleral icterus. His liver enzymes were unremarkable, and his abdominal imaging did not reveal any acute pathology. However, he was found to have a severe non-immune hemolytic anemia secondary to folate deficiency.