Unexplained Thrombocytopenia Research Articles

Incidental identification of neonatal babesiosis: a case report

BackgroundEvaluation of suspected neonatal sepsis rarely considers diagnostic workup for vector-borne illnesses, as these are generally infrequent etiologies in the febrile neonate. Babesiosis -- a zoonosis caused by apicomplexan parasites of the genus Babesia and spread to humans by the Ixodes scapularis tick -- can either be clinically silent, or symptomatic with fever, constitutional symptoms, as well as anemia and thrombocytopenia. We report here a rare case of neonatal babesiosis that was incidentally identified during routine workup for neonatal sepsis.Case presentationA full-term male neonate with fever was admitted to the hospital for sepsis evaluation. On routine complete blood count with manual differential blood smear, parasites were incidentally detected, later identified as Babesia microti. On review of maternal history, there was antenatal history of unexplained thrombocytopenia and anemia, and post-hoc review of peripartum maternal blood smear showed rare intra-erythrocytic parasites, which were confirmed as B. microti by PCR testing of maternal blood. Ultimately, the infant was successfully treated with azithromycin and atovaquone, received a red blood cell transfusion for symptomatic anemia, and remained well at his outpatient follow-up visit.ConclusionThis unusual case highlights the importance of including neonatal babesiosis in the differential diagnosis for neonatal sepsis in endemic regions, including careful review of maternal antenatal exposure history and labs, and consideration of peripheral blood smear in suggestive cases.

Clinical Characteristics and Treatment Courses of Trauma-Induced Thrombotic Microangiopathy: A Retrospective Study.

Introduction: Thrombotic microangiopathy (TMA), defined by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, is not widely recognized as being trauma-related. This study aimed to describe the clinical features and outcomes of trauma-induced TMA (t-TMA) to assist in early diagnosis and management. Methods: A retrospective review was conducted on 30 trauma patients diagnosed with t-TMA between 2014 and 2019. Demographic, clinical, and laboratory data, as well as treatment methods, were analyzed. Results: Thrombocytopenia (<50,000/µL) occurred, on average, 2.9 days post-trauma, with diagnosis following 3.6 days later. Patients had a mean age of 67.6 years, and 63.3% were male. Clinical presentations included acute kidney injury (AKI) requiring renal replacement therapy (86.7%), altered mental status (53.3%), non-infectious fever (50%), and digital necrosis (43.3%). Eighteen patients were treated with therapeutic plasma exchange (TPE) alone, nine with TPE and methylprednisolone, and three with methylprednisolone alone. Remission was achieved in 96.7% of all cases. The mean TPE duration was 6.1 days, prolonged by prior platelet transfusions. The mortality rate was 26.7% (8/30), with sepsis being the most common cause of death (five patients), particularly for those treated with TPE and methylprednisolone. Conclusions: Trauma-induced TMA should be suspected in trauma patients presenting with unexplained thrombocytopenia, AKI, and elevated LDH. Early diagnosis and prompt treatment are crucial, while unnecessary platelet transfusions should be avoided. Careful infection management is critical to improving patient outcomes, particularly if patients are treated with TPE and methylprednisolone.

Case Description: “Are You Sure the Platelet Count is Only 2???” Cesarean Section in the Setting of Severe Thrombocytopenia

Gestational thrombocytopenia, preeclampsia, and immune thrombocytopenia are commonly recognized etiologies of low platelet counts representing the vast majority of encountered gestational cases (86-100%). However, there are many other rare causes. The following case details a patient with three prior pregnancies, each remarkable for profound unexplained thrombocytopenia, which promptly normalized following delivery. It further details her fourth pregnancy, similar thrombocytopenia, an investigation into the causes, balancing platelet transfusion against the risk of alloimmunization, in-hospital treatment, and her eventual anesthetic, resuscitation, and delivery.

Atypical Presentations of Pediatric-acquired Thrombotic Thrombocytopenic Purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) in children is a rare, severe thrombotic microangiopathy. This condition is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia due to reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. A retrospective case series evaluating data collected from the medical files of 4 children diagnosed with iTTP. The presented case series depicts a variety of iTTP presentations: 1 case of primary iTTP, 1 case induced by Shiga toxin, 1 associated with RAS-associated autoimmune leukoproliferative disease (RALD), and 1 initial manifestation of systemic lupus erythematosus (SLE). Notably, 2 patients recovered without undergoing plasma exchange. Early ADAMTS13 testing in children with unexplained hemolysis or thrombocytopenia is crucial. The diverse underlying causes, including infections and autoimmune disorders, underscore the complexity of iTTP in the pediatric population. These cases highlight the necessity for personalized treatment approaches that consider each patient's unique clinical situation and potential alternatives or modifications to conventional therapeutic regimens.

Treatment and Follow-up Data for Young Patients with a Gne Defect and Congenital Thrombocytopenia

Congenital thrombocytopenia can be associated not only with a reduced production, but also with an accelerated degradation of platelets. Sialic acid binds to platelet surface glycoproteins and protects platelets from degradation via the Ashwell-Morell receptor. The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. According to OMIM alterations in GNE are autosomal recessive associated with adult-onset progressive GNE myopathy (with or without thrombocytopenia) and autosomal dominant with sialuria. In recent years, biallelic GNE mutations located mainly in the N-acetylmannosamine (ManNAc) kinase domain of GNE have been described in children/young adults with otherwise unexplained thrombocytopenia. Recently, we identified compound heterozygous GNE variants in a young girl (Pt.1) with life-threatening intracranial bleeding and severe congenital thrombocytopenia (lowest platelet count 5 x 10 9/L), who needed weekly platelet transfusions. We showed decreased α2,3 sialic acid and increased terminal galactose and α2,6 sialic acid moieties in the girl´s platelets. She received hematopoietic stem cell transplantation (HSCT) at 2,3 years, which normalized platelet counts and function. Follow-up data showed normalized platelet function (20 months after HSCT) and counts (20, 21, and 23 months after HSCT). Following HSCT, the platelet lectin profile was markedly different from before transplantation with an increase in α2,3 sialic acid recognizing lectins WGA and MAL I compared with data before transplantation, indicating that sialic acid moieties have been normalized. Additionally, we identified a biallelic GNE variant in two siblings (Pt.2 and Pt.3) affected by congenital thrombocytopenia. Pt.2 is a 1,8-year-old boy with thrombocytopenia since birth (lowest platelet count 6 x10 9/L) who needed weekly platelet transfusions. His 17-year-old sister (Pt.3) presented with lifelong thrombocytopenia and suspected chronic immune thrombocytopenia; however, therapy with immunoglobulin and steroids did not elevate the platelets. The parents and two other siblings were clinically not affected. Flow cytometry performed for the affected siblings showed severely decreased thrombin-induced platelet CD62 and CD63 exposure hinting at an impaired α- and δ-granule secretion. NGS identified a homozygous GNE variant (NM_001128227.3:c.1727G&amp;gt;C, p.Gly576Ala) with damaging prediction to be present in both siblings. The parents and two healthy siblings are heterozygous carriers of this variant. The nucleotide change c.1726G&amp;gt;C leading to Gly576Arg has been described compound heterozygous in a patient with GNE myopathy. For the sister (Pt.3) lectin binding analysis showed decreased α-2,3 sialylation (MAA) and increased terminal galactose (RCA120) expression on platelets. This pattern is consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. She had received therapy with romiplostim since she was 12, resulting in stable platelet counts (&amp;gt; 50 x10 9/L). At the age of 1 year, Pt.2 also started with romiplostim therapy. During the 8-month treatment, platelet counts were mainly stable above 30 x 10 9/L. Only two transfusions were necessary when platelet counts dropped to 18 and 11 x 10 9/L. In conclusion, this research elucidates novel associations between GNE mutations, specifically within the ManNAc kinase domain, and congenital thrombocytopenia. These findings were derived from studying three patients carrying such mutations, underscoring this discovery's potential broad relevance. Importantly, this alteration in the GNE gene, traditionally associated with GNE myopathy, prompts us to anticipate and closely monitor the potential future development of this neuromuscular condition in these patients. Of particular interest is the effectiveness of romiplostim in ameliorating thrombocytopenia in these cases. Both siblings in our study exhibited stable, acceptable platelet counts in response to this therapy, suggesting that romiplostim might offer a promising therapeutic strategy for managing congenital thrombocytopenia linked to GNE mutations.

Eradication therapy may decrease the risk of immune thrombocytopenia after Helicobacter pylori infection: a retrospective cohort study in Taiwan

BackgroundHelicobacter pylori (HP) eradication therapy (HPE) is recommended for patients with unexplained immune thrombocytopenia (ITP); however, the role of HPE in preventing ITP in patients with HP infection remains unclear. Therefore, this study was designed to clarify it.MethodsThis study was conducted at a tertiary medical center and included all adult patients with HP infection between January 1, 2016 and December 31, 2018. We compared the risk of developing ITP between patients with and without HPE. All patients were followed up until December 31, 2020.ResultsAfter excluding patients with thrombocytopenia, 1995 adult patients with HP infection, including 1188 patients with HPE and 807 patients without HPE, were included in this study. The mean age of the patients with HPE was 57.9 years, whereas that of those without HPE was 61.6 years. The percentage of males was 56% in patients with HPE and 59% in those without HPE. Patients without HPE had a higher risk of ITP than those with HPE after adjusting for age, sex, the Charlson Comorbidity Index, and comorbidities [adjusted odds ratio (OR) 1.76; 95% confidence interval (CI) 1.16–2.68]. Stratified analyses showed that the higher risk was found only in males (adjusted OR: 1.70; 95% CI 1.03–2.80). In addition to HPE, male sex and anemia were independent predictors of ITP in patients with HP infection.ConclusionThis study showed that adult patients with HP infection not receiving HPE had a higher risk of developing ITP. We suggest that HPE should be considered, particularly in males and those who have anemia, to prevent ITP.

Fatal cerebral venous sinus thrombosis with preceding thrombocytopenia in a patient with new-onset eosinophilic granulomatosis with polyangiitis.

A previously healthy, 44-year-old, female patient was hospitalised for acute abdominal pain and bilateral pneumonia. Eosinophilic granulomatosis with polyangiitis (EGPA) was diagnosed on the basis of eosinophilia, eosinophilic tissue inflammation, polyneuropathy, and bilateral pneumonia. She had a fatal cerebral venous sinus thrombosis following thrombocytopenia, which was apparently caused by platelet consumption. It may have been possible to prevent the deterioration of the venous thrombosis by starting immunosuppressive or anticoagulant therapy earlier. If a patient with EGPA presents with unexplained thrombocytopenia, the physician should assess for physical findings or laboratory abnormalities suggestive of thrombosis. Additionally, if the patient complains of headache or nausea with normal head computed tomography findings, magnetic resonance imaging or magnetic resonance venography should be performed to assess for cerebral venous sinus thrombosis.

Abstract 11896: Spontaneous Heparin-Induced Thrombocytopenia Presenting as Acute Stent Thromboses Following an Acute St-Segment Elevation Myocardial Infarction

Introduction: Spontaneous heparin-induced thrombocytopenia (HIT) is a rare clinical variant that develops without prior exposure to heparin. We present a 40-year-old man who was diagnosed with spontaneous HIT after an acute ST-segment elevation myocardial infarction complicated by multiple acute stent thromboses and left ventricular (LV) thrombus. Case: A 40-year-old previously healthy man with no known history of heparin exposure presented to our emergency department with an acute ST-segment elevation myocardial infarction. Emergent coronary angiography revealed a severely thrombotic 100% occlusion of his distal left anterior descending artery for which thrombectomy and percutaneous coronary intervention (PCI) were performed with placement of a drug eluting stent. Prior to angiography, the patient received 4000 units of unfractionated heparin and an additional 2000 units intra-arterially during the case. Labs prior to PCI revealed thrombocytopenia and HIT enzyme-linked immunoassay testing was sent. He underwent repeat angiography two additional times during his course for recurrent chest pain which both revealed acute stent thrombosis. HIT testing eventually returned positive for the presence of platelet factor 4 antibodies. A subsequent serotonin release assay returned positive, confirming the diagnosis of HIT. A transthoracic echocardiogram during his hospitalization also revealed an LV thrombus. Discussion: Heparin-induced thrombocytopenia (HIT) is traditionally diagnosed after thrombocytopenia develops 5 to 10 days after exposure to heparin. However, there have been rare reports of a spontaneous form of HIT that can occur without prior exposure to heparin. This case highlights a rare presentation of spontaneous HIT. Although infrequent, cardiologists should be aware of atypical presentations of HIT, since almost all patients will receive heparin prior to or during coronary angiography and coronary interventions. Spontaneous HIT should be considered in all patients who present with unexplained thrombocytopenia with arterial and/or venous thrombi. Failure to recognize this clinical entity could lead to potentially life-threatening thrombotic complications from further administration of heparin.

Chronic disseminated intravascular coagulation in a patient with Takayasu arteritis.

Takayasu arteritis (TA) is a large-vessel vasculitis that predominantly affects the aorta and although it usually causes stenosis, aneurysms have been reported in ∼10-25% of the patients. Here, we present a male TA patient with chronic disseminated intravascular coagulation (DIC) as a rare complication of endovascular grafted aortic aneurysm (AA). Chronic DIC usually presents as mild or even hidden clinical symptoms, and early diagnosis of this condition can only be possible with laboratory tests. Due to the silent clinical scenario, this complication should be kept in mind among AA patients with unexplained thrombocytopenia or coagulation abnormalities.

S2908 Liver Transplant for Management of Neurological Wilson Disease in a Patient With Preserved Liver Function

Introduction: The role of orthotopic liver transplant (OLT) solely for the management of neurological Wilson disease (WD) is unclear. We present a patient with WD who underwent OLT for neurological deterioration with compensated cirrhosis. Case Description/Methods: A 19-year-old male presented with three-month history of dysarthria, akinesia, and fine tremors. His past medical history was remarkable for unexplained splenomegaly and thrombocytopenia. He denied history and risk factors for liver disease. Physical exam showed slurred speech, bilateral hand tremors, spasticity of the lower extremities, and absence of Kayser-Fleischer ring. Labs were unremarkable, except for platelets of 79 k/uL. MRI brain showed bilateral, symmetric hyper-intensity in the basal ganglia, lateral thalami and midbrain on T2-weighted images. (Figure) CT liver revealed cirrhosis, portal hypertension, and mild splenomegaly. Copper metabolism study confirmed low serum copper (8 µmol/L) and high 24-hr urine copper (234 µg/d) consistent with diagnosis of WD. He was promptly started on Zinc and Trientine 250 mg daily. After one month, the patient was re-admitted for worsening dysphagia, dysarthria and rigidity, eventually becoming bedridden with inability to talk and eat requiring G-tube placed). Liver biopsy showed cirrhosis with little inflammatory activity and abundant copper on Rhodanine stain ( >600 mcg/g). The patient underwent OLT after being granted a Metabolic MELD exception of 40 due to medically unresponsive neurological impairment, with preserved liver function (calculated MELD 8). Post-OLT, he had gradual neurological improvement, except persistent dystonia and spasticity. Serum ceruloplasmin levels normalized but repeat MRI showed persistent signal alterations at the basal ganglia and brainstem. At 16 month follow-up, his neurological recovery remained largely stagnant with minimal improvement in extrapyramidal symptoms. Discussion: OLT for management of neurological WD remains highly debatable. Most data on neurological recovery after LT are based on patients with mixed liver and neurological involvement with success rate of 62%. In our patient, he failed to display complete neurological recovery 1.5 years after OLT despite initial improvement. The rapid neurologic deterioration that led to OLT occurred after initiation of chelation therapy which may indicate paradoxical worsening. Additional research is needed to determine the timing of OLT and role of medical optimization prior to OLT in patients with neurological WD.Figure 1.: (A) MRI Brain with contrast showing (T2/FLAIR) hyperintensity and mild edema symmetrically in the caudate heads, putamina, ventral lateral thalami, and midbrain. Findings are suspicious for Wilson Disease. (B) Cirrhotic nodules accompanying mild chronic inflammation (Hematoxylin and eosin, 100X). (C) The liver cells of this cirrhotic nodule are extensively filled with copper (Rhodanine stain, 100X) (D) The liver cells show bright red granules of copper in the cytoplasm (Rhodanine stain, 200X).

Heparin-induced thrombocytopenia post-cardiovascular interventional therapy: a case report

BackgroundHeparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction characterized by thrombocytopenia and thromboembolism. Herein, we present a case of HIT with subcutaneous hemorrhage after cardiovascular interventional therapy.Case presentationA 74-year-old man was admitted to the hospital for elective atrial fibrillation (AF) catheter ablation and left atrial appendage closure because of intermittent dizziness and palpitations. At presentation, the routine laboratory test results showed no abnormalities. He received subcutaneous enoxaparin for stroke prevention and unfractionated heparin for intraprocedural anticoagulation during coronary angiography and the AF procedure. On the second day after the AF procedure, the patient developed profound thrombocytopenia, moderate anemia, and mild subcutaneous hematoma. Blood tests and imaging examinations excluded acute hemolysis and other active bleeding. A 4Ts score of 5 and markedly positive platelet factor 4 IgG antibody established the diagnosis of HIT. Due to progressive subcutaneous hemorrhage in the thighs that could not be suppressed by pressure dressing, the patient received platelet transfusion and rivaroxaban for anticoagulation. The following days, the patient remained clinically stable from the hemorrhage, and his platelet count recovered. No thrombotic events occurred during hospitalization or follow-up.ConclusionThis case emphasizes the significance of suspecting HIT in patients with unexplained rapid thrombocytopenia after frequent heparin exposure. Decision-making regarding alternative anticoagulation and platelet transfusion in HIT with hemorrhage must be based on unique patient characteristics.

Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies.

Rare cases of COVID‐19 vaccinated individuals develop anti‐platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine‐induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti‐PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV‐19‐associated VITT from similar clinical disorders, namely heparin‐induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S‐associated VITT patients are uniformly strongly positive in PF4‐polyanion enzyme‐linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4‐dependent p‐selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S‐associated VITT. Most Ad26.COV2.S‐associated VITT antibodies persisted for >5 months in PF4‐polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140‐150 x 103/µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4‐polyanion ELISAs and functional assay are non‐specific and detect all three conditions. Here, we report that a novel un‐complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV‐19, from both spontaneous HIT, HIT and commonly‐encountered HIT‐suspected patients who are PF4/polyanion ELISA‐positive but negative in functional assays. In summary, Ad26.COV2.S‐associated VITT antibodies are persistent, and the un‐complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis.

Challenges in the diagnosis and management of gaucher's disease in a young adult libyan arab female

Gaucher's disease is a rare lysosomal storage disease that can present with a wide range of clinical symptoms according to type and severity, ranging from mild general wellbeing, organomegaly, pancytopenia, neurological symptoms, lung involvement, and even death, making the diagnosis and work up challenging to reach a diagnosis. We report a Libyan Arab female presented with bruises after minor trauma, bone aches, and fatigue. A 35-year-old female from Libyan–Arab ethnicity attended the hematology clinic complaining of bruises after minor trauma, bone aches, and undue fatigability. She mentioned and evident from her medical record that she has been suffering from these complaints for 5 years and does not have any definite diagnosis. Mild splenomegaly was the only finding on clinical examination this time. There was no fever and no lymphadenopathy. Thrombocytopenia with a platelet count 90 × 10 and quot; 3/ml, and splenomegaly of 16 cm was found on investigations. She was diagnosed with cryptogenic thrombocytopenia, and she was advised for a follow-up visit. Our patient attended a follow-up visit twice in the next 18 months with similar complaints of manageable bruising, bone pain, and fatigability. Hematology reports showed thrombocytopenia in each visit. An ultrasonogram of the abdomen revealed a gallbladder stone and spleen have a size of 17 cm. Bone marrow biopsy was done, and a blood test confirmed glucocerebrosidase enzyme deficiency. Considering the diagnosis of Gaucher's disease, treatment with imiglucerase infusion was started. Unfortunately, she failed to continue the treatment due to a shortage of supply of the medication. A few months later, she got pregnant and developed threatened abortion, which ended with a miscarriage. This case illustrates the need to consider this disease in the differential diagnoses when dealing with unexplained thrombocytopenia, anemia, hepatomegaly, and splenomegaly. There are several challenges in the diagnosis and treatment of Gaucher's disease, particularly in resource-limited settings.

Primary Care Physician-Based Telemedicine in Non-Malignant Hematology: Prospective Analysis of 790 Consecutive Cases

Introduction: In-person hematology appointments (IHA) are not available in most hospitals and outpatient centers in the state of Santa Catarina, Brazil. Primary care physician (PCP) based hematology telemedicine consultation (HTC) has the potential of being a valuable and cost-effective tool for patients and PCPs. While it has not been previously assessed in our country, it may avoid unnecessary IHA, which frequently require traveling to major cities, reduce waiting times for an IHA, and advise PCPs on better assessing patients that may need a hematology referral.Methods: Sistema Integrado Catarinense de Telemedicina is a statewide online tool to which all public health system PCPs have access. It enables PCPs to set up asynchronous HTCs that are randomly distributed to reference hematology treatment centers. HEMOSC Joinville is one such center and is responsible for approximately one fifth of all HTCs. We prospectively assessed all HTC requests in non-malignant hematology between August 2019 and July 2021 for main clinical features that prompted a hematology referral. All cases with confirmed or likely diagnosis of hematological malignancy under the 2017 World Health Organization (WHO) classification were excluded. WHO anemia definition and severity classification was observed. Severe neutropenia and thrombocytopenia required counts below 500 and 50,000 per microliter. For every HTC, a single diagnostic hypothesis in hematology (DHH) was established based on patient data provided by the PCP.Results: Seven hundred and ninety consecutive patients aged 15 or older were included. Median age at HTC was 55 years (interquartile range, IQR: 39-70), with 282 patients (36%) aged 60 or more. Sixty percent of patients (n=472) were women, with 26 pregnant women (3%) at a median gestational age of 15 weeks (IQR: 12-21). Major DHHs were iron deficiency anemia (n=123, 16%), anemia of undetermined cause (n=107, 14%) and unexplained thrombocytopenia (n=102, 13%). Cytopenias accounted for 499 (63%) of all DHHs. Abnormal complete blood count (CBC) or coagulation tests were the sole reason for HTC, in the absence of any attributable clinical finding, in 597 cases (76%). DHHs were adequately formulated by PCP in 140 cases (18%). CBC information was provided in 594 cases (75%), with mild anemia (n=188, 32%) being the most frequent finding. Median hemoglobin when anemia was the DHH was 10 g/dL (IQR: 8.7 - 11.1). Absence of red blood cell (RBC) indices, differential leukocyte counts and platelet counts were seen in 261 (44%), 441 (74%) and 251 (42%) cases. CBC was collected in excess of 60 days prior to HTC in 118 patients (20%) and no CBC information was provided for 196 patients (25%), 31% of which (n=60) had a cytopenia as DHH. Blood transfusions were reported within 60 days of HTC in 49 patients (6%), and an emergency department evaluation was suggested by the hematology specialist for 72 patients (9%). One hundred and ninety (24%) patients were referred to an IHA after HTC, of which 21 (3%), 115 (15%) and 54 (7%) received low, intermediate and high priority for an appointment.Conclusions: Over the reported two-year period, HTC has prevented 3 in every 4 IHA in our patient population. This is especially relevant considering the need for social distancing and the socioeconomic impacts of the COVID-19 pandemic. Follow-up analyses of these patients to identify IHA at a later date and the confirmation of hematological diagnosis are in order. This study also uncovers inappropriate CBC interpretation and reporting, and failure to associate clinical symptoms and patient history to laboratory findings, which in turn demands providing PCPs with continued medical education in hematology. [Display omitted] DisclosuresBoettcher: Novartis: Speakers Bureau.

Bone Marrow Findings in Renal Patients: A Single Renal Specialist Center Experience.

ObjectiveThis study evaluated the importance of bone marrow aspiration and trephine biopsy (BM) for the diagnosis of underlying hematological abnormalities in renal patients.MethodsThis cross-sectional study on BM was carried out between August 2010 and April 2019, in our specialist renal center for various unexplained hematological abnormalities in patients with renal diseases [chronic kidney disease (CKD), end-stage renal disease (ESRD) requiring maintenance hemodialysis (MHD), patients with normal renal function but other nephrology and urology issues like stone disease and nephrotic syndrome].ResultsOut of 176 reported BM examinations, 48 (27.3%) were done on ESRD patients on MHD (CKD-D), and 69 (39.2%) on CKD patients not on MHD (CKD-nD). Fifty-nine (33.5%) BM were done on patients with normal renal function (n-CKD). The indication for BM was pancytopenia 50 (28.4%), unexplained anemia 39 (22.2%), and unexplained thrombocytopenia 43 (24.4%). In 91 (51.7%) patients BM was normal. In 30 (17%) patients multiple myeloma (MM) was diagnosed on BM, out of which 18 (26.1%), nine (18%), three (5.3%) were CKD-nD, CKD-D, and n-CKD patients, respectively. In 11 (6.3%) patients BM was suggestive of myelodysplasia (MD), out of these 11 patients, five (10%) were CKD-D patients.ConclusionBM is an underutilized method of diagnosis of hematological abnormalities in renal patients. Our study revealed the importance of BM examination, especially in patients with CKD.

Mitochondrial dynamics and reactive oxygen species initiate thrombopoiesis from mature megakaryocytes

Blood platelets are essential for controlling hemostasis. They are released by megakaryocytes (MKs) located in the bone marrow, upon extension of cytoplasmic protrusions into the lumen of bone marrow sinusoids. Their number increases in postpulmonary capillaries, suggesting a role for oxygen gradient in thrombopoiesis (ie, platelet biogenesis). In this study, we show that initiation of thrombopoiesis from human mature MKs was enhanced under hyperoxia or during pro-oxidant treatments, whereas antioxidants dampened it. Quenching mitochondrial reactive oxygen species (mtROS) with MitoTEMPO decreased thrombopoiesis, whereas genetically enhancing mtROS by deacetylation-null sirtuin-3 expression increased it. Blocking cytosolic ROS production by NOX inhibitors had no impact. Classification according to the cell roundness index delineated 3 stages of thrombopoiesis in mature MKs. Early-stage round MKs exhibited the highest index, which correlated with low mtROS levels, a mitochondrial tubular network, and the mitochondrial recruitment of the fission activator Drp1. Intermediate MKs at the onset of thrombopoiesis showed high mtROS levels and small, well-delineated mitochondria. Terminal MKs showed the lowest roundness index and long proplatelet extensions. Inhibiting Drp1-dependent mitochondrial fission of mature MKs by Mdivi-1 favored a tubular mitochondrial network and lowered both mtROS levels and intermediate MKs proportion, whereas enhancing Drp1 activity genetically had opposite effects. Reciprocally, quenching mtROS limited mitochondrial fission in round MKs. These data demonstrate a functional coupling between ROS and mitochondrial fission in MKs, which is crucial for the onset of thrombopoiesis. They provide new molecular cues that control initiation of platelet biogenesis and may help elucidate some unexplained thrombocytopenia.

When Should We Think of Myelodysplasia or Bone Marrow Failure in a Thrombocytopenic Patient? A Practical Approach to Diagnosis.

Thrombocytopenia can arise from various conditions, including myelodysplastic syndromes (MDS) and bone marrow failure (BMF) syndromes. Meticulous assessment of the peripheral blood smear, identification of accompanying clinical conditions, and characterization of the clinical course are important for initial assessment of unexplained thrombocytopenia. Increased awareness is required to identify patients with suspected MDS or BMF, who are in need of further investigations by a step-wise approach. Bone marrow cytomorphology, histopathology, and cytogenetics are complemented by myeloid next-generation sequencing (NGS) panels. Such panels are helpful to distinguish reactive cytopenia from clonal conditions. MDS are caused by mutations in the hematopoietic stem/progenitor cells, characterized by cytopenia and dysplasia, and an inherent risk of leukemic progression. Aplastic anemia (AA), the most frequent acquired BMF, is immunologically driven and characterized by an empty bone marrow. Diagnosis remains challenging due to overlaps with other hematological disorders. Congenital BMF, certainly rare in adulthood, can present atypically with thrombocytopenia and can be misdiagnosed. Analyses for chromosome fragility, telomere length, and germline gene sequencing are needed. Interdisciplinary expert teams contribute to diagnosis, prognostication, and choice of therapy for patients with suspected MDS and BMF. With this review we aim to increase the awareness and provide practical approaches for diagnosis of these conditions in suspicious cases presenting with thrombocytopenia.

Screening for Gaucher's disease in unexplained spleenomegaly and/or thrombocytopenia: An observational study

Gaucher's disease is a hereditary disease that can be diagnosed by determination of acid beta glucosidase enzyme activity on leucocytes but it's diagnosis is mostly delayed due to limited availability of test. The aim of the study was to determine prevalence of Gaucher's disease in patients of unexplained spleenomegaly and/or thrombocytopenia using dried blood spot filter test. This prospective cross sectional study was conducted after approval from Institutional ethical committee in 222 subjects, assuming 3.6% prevalence of the disease among unexplained cases of splenomegaly with 95% confidence interval, 0.05 α error, 80% power and with an absolute allowable error of 2.5%. After implementation of the diagnostic algorithm, samples from the patients were collected on dried blood pot filter paper and sent for analysis. Patients who tested positive by screening test were confirmed through mutational analysis done from the same sample. Data was expressed as mean, proportions and percentages. Mann Whitney test, Chi square test and Fisher's exact test were used for analysis. The prevalence of Gaucher's disease in our study population was 2.7% (CI 0.54 to 4.86) with the odds ratio for gender calculated as 3(95% CI 0.344 to 26.134). The results of this study show that the use of an appropriate diagnostic algorithm and DBS filter test facilitate early diagnosis and management of a rare disease, thereby saving a lot of medical resources while simultaneously improving the quality of life in patients.

Large Granular Lymphocytosis With Cytopenias After Allogeneic Blood or Marrow Transplantation: Clinical Characteristics and Response to Immunosuppressive Therapy

Large granular lymphocytosis (LGL)-or LGL leukemia-is a T- or NK-cell lymphoproliferative disorder that often results in cytopenias and autoimmune phenomena. Several studies have described LGL in a subset of patients after allogeneic blood or marrow transplantation (alloBMT), almost exclusively in the setting of asymptomatic lymphocytosis. Some have suggested an association with improved transplant-related outcomes. In contrast, clinically significant LGL after alloBMT is only described in small case reports. This study sought to assess the characteristics, significance, and response to treatment of LGL associated with unexplained anemia, thrombocytopenia, or neutropenia after alloBMT. We performed a retrospective analysis of 150 patients who were evaluated for LGL by peripheral blood flow cytometry (LGL flow) for unexplained cytopenias following initial engraftment after alloBMT from January 1 2012 to July 1, 2019. We identified patients with abnormally increased populations of LGL cells (LGL+) as assessed by Johns Hopkins Hematopathology. We collected demographic, transplantation, and LGL treatment information from electronic medical records. We compared LGL+ patients to patients with unexplained cytopenias with negative flow cytometry for LGL (LGL-) in this cohort. We also assessed change in blood counts after 4 weeks of immunosuppressive therapy in LGL+ patients. Cytopenias occurred at a median of 5.7 months (range 1-81) after alloBMT. The majority of the transplants were nonmyeloablative from haploidentical donors, and all patients received post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis, consistent with the overall alloBMT characteristics at our center. We identified 70 patients with LGL and cytopenias, representing 47% of those evaluated by flow cytometry. There were no significant demographic or transplant-related differences between LGL+ patients and LGL- patients. The median age was 59, and 63% were male. LGL+ patients were more likely to have had cytomegalovirus (CMV) viremia (73% versus 28%, P < .0001), but not acute or chronic graft-versus-host disease. LGL+ patients had higher absolute lymphocyte counts (1500 versus 485/ mm3, P < .0001), a trend toward lower absolute neutrophil count (660 versus 965/mm3, P=.17), and lower neutrophil to lymphocyte ratio (0.39 versus 1.71, P < .001). There were no differences in overall survival or relapse-free survival. Of those with T-cell LGL, 45 were assessed for T-cell receptor clonality. In all, 22% were clonal, 53% oligoclonal, 4% polyclonal, and 20% indeterminate. Thirty (43%) LGL+ patients received immunosuppressive therapy (IST) for cytopenias. First-line treatment was corticosteroids for 25 (83%). Among those treated, there was an increase in median absolute neutrophil count from 720 before treatment to 1990/mm3 after 4 weeks (P=.0017). Thrombocytopenia and anemia showed at most a mild improvement with IST. LGL was a common association with otherwise unexplained cytopenias after alloBMT, almost always after prior CMV infection. LGL in the setting of cytopenias did not predict improved transplantation outcomes compared to those with cytopenias without presence of LGL. IST was effective at improving neutropenia associated with LGL after alloBMT.

Whole exome sequencing for diagnosis of hereditary thrombocytopenia.

Hereditary thrombocytopenia comprises extremely diverse diseases that are difficult to diagnose by phenotypes alone. Definite diagnoses are helpful for patient (Pt) management.To evaluate the role of whole exome sequencing (WES) in these Pts.Cases with unexplained long-standing thrombocytopenia and/or suggestive features were enrolled to the observational study. Bleeding scores and blood smear were evaluated. The variant pathogenicity from WES was determined by bioinformatics combined with all other information including platelet aggregometry, flow cytometry, and electron microscopy (EM).Seven unrelated Pts were recruited. All were female with macrothrombocytopenia. Clinical bleeding was presented in four Pts; extra-hematological features were minimal and family history was negative in every Pt. WES successfully identified all the 11 responsible mutant alleles; of these, four have never been previously reported. Pt 1 with GNE-related thrombocytopenia showed reduced lectin binding by flow cytometry, increased glycogen granules by EM and a novel homozygous mutation in GNE. Pts 2 and 3 had phenotypic diagnoses of Bernard Soulier syndrome and novel homozygous mutations in GP1BB and GP1BA, respectively. Pt 4 had impaired microtubule structures, concomitant delta storage pool disease by EM and a novel heterozygous TUBB1 mutation. Pt 5 had sitosterolemia showing platelets with reduced ristocetin responses and a dilated membrane system on EM with compound heterozygous ABCG5 mutations. Pts 6 and 7 had MYH9 disorders with heterozygous mutations in MYH9.This study substantiates the benefits of WES in identifying underlying mutations of macrothrombocytopenia, expands mutational spectra of four genes, and provides detailed clinical features for further phenotype-genotype correlations.