COMMON MORPHOLOGICAL ABNORMALITIES OF …

1 7 Learning Guide: WBC: neutrophil GranulocytesFigure 6. neutrophil granulocyte with hypersegmented 5. Pelger-Hu t cells with defective nuclear segmentation. A: Lack of nuclear lobes B: Bi-lobed nucleusFigure 5 AFigure 5 BCOMMON MORPHOLOGICAL ABNORMALITIES OF neutrophil GRANULOCYTESSome of the more COMMON ABNORMALITIES of neutrophil morphology that can be seen in peripheral blood are described ,12 1. PELGER HU T ANOMALYP elger Hu t anomaly is a rare benign autosomal dominant disorder characterized by defective nuclear segmentation (hypo-segmentation of the nucleus in neutrophils (Figure 5). Nuclei are bi-lobed, dumbbell-shaped or do not have lobes at all. It is important to differentiate from the acquired hypo-segmentation of the neutrophil nucleus, also called pseudo-Pelger Hu t anomaly, which has been observed in sepsis, myelodysplastic syndromes, hematological malignancies and in patients on certain transplant medications or other drugs.)

2 2. neutrophil NUCLEAR HYPER-SEGMENTATIONN eutrophil nuclear hypersegmentation is the presence of more than five nuclear lobes in the neutrophils (Figure 6). The presence of hypersegmented neutrophils is a sensitive and specific sign of megaloblastic anemia, associated with vitamin B12 or folate deficiency. Less frequently, it can be seen in other disorders such as chronic infection, myelodysplastic syndrome, iron deficiency, hypogonadism and chronic myelogenous leukemia. 3. D HLE BODIESD hle bodies are single or multiple blue or grayish-blue cytoplasmic inclusions, representing free ribosomes or rough endoplasmic reticulum, usually situated at the periphery and protruding beyond the normal contour of the cell (Figure 7). They may be associated with myeloid left shifts, normal pregnancy, infections, various neoplasms and severe 7. D hle body in a segmented Guide: WBC: neutrophil Granulocytes4.

3 TOXIC GRANULATION Toxic granulation refers to the presence of prominent purplish or blue-black granules (Figures 8 and 9) in the cytoplasm of segmented and band neutrophils in patients with severe infections and other inflammatory conditions. These granules are actually primary granules, normally dominating the cytoplasm of promyelocytes and early neutrophilic myelocytes. Toxic granules are myeloperoxidase TOXIC VACUOLIZATION Toxic vacuolization is the presence of vacuoles in the cytoplasm of neutrophils in response to severe infections or inflammatory conditions (Figure 9). Vacuoles represent increased phagocytic activity and may suggest sepsis. Toxic vacuolization may be associated with toxic granulation and D hle bodies. Vacuoles may also form as an artefact in neutrophils and monocytes in blood films if the smear is made after several hours of storage of the blood sample.

4 6. dysplastic /HYPOGRANULAR NEUTROPHILSThe presence of dysplastic neutrophils is a characteristic feature of myelodysplastic syndromes but has also been noticed in leukemoid reactions, multiple myeloma and drug sensitivity reactions. Morphologically, the normal synchronous maturation of nucleus and cytoplasm is lost. As a result, the primary and secondary granules in the cytoplasm are often decreased or absent, causing the cytoplasm to appear pale and bluish. The nucleus may show abnormal lobulation (hypo- or hypersegmentation or even ring forms). Figure 10 demonstrates an example of a peripheral smear from a patient with myelodysplastic syndrome, showing hypogranular cytoplasm and atypical nuclei in neutrophils. Figure 8. Segmented neutrophil with toxic 9. Band neutrophil with cytoplasmic vacuolization and toxic 10. neutrophil granulocytes with hypogranular cytoplasm and atypical nuclear Guide: WBC: neutrophil GranulocytesNeutrophils are the most abundant white blood cell type in human blood .

5 They comprise approximately 40% to 70% of total circulating count of neutrophils varies by age and shows other demographic differences. Table 1 shows example reference ranges by age in the healthy ABNORMALITIES OF neutrophil GRANULOCYTESAGENEUTROPHIL COUNT (x 109/L) % NEUTROPHILAt 255 -746 months1 . 5 -7. 325-404 235-50 Adult1 . 8-7. 740-85 TABLE 1. EXPECTED RANGE OF neutrophil GRANULOCYTES IN HEALTHY INDIVIDUALS*Laboratories are recommended to establish, or, at least, verify their own reference is an abnormally low concentration of neutrophils in blood . Neutropenia may be selective or part of a general pancytopenia. When the absolute neutrophil level falls below 109/L tthe patient is susceptible to (sometimes recurrent or life threatening) , neutropenia is considered acute when it develops over hours to a few days, usually caused by rapid neutrophil use/destruction or else impaired production.

6 Neutropenia is considered chronic when it lasts months to years, usually arising from reduced production or excessive splenic sequestration. Neutropenia may also arise from various disorders of bone marrow function resulting in a decreased rate of release of neutrophils into the circulation. It is a COMMON manifestation in several bone marrow failures, such as aplasia, leukemia or myelodysplasia. Neutropenia can be caused by an intrinsic defect in bone marrow myeloid cells in congenital and idiopathic neutropenias, or by factors extrinsic to bone marrow resulting in acquired Acquired neutropenia can be due to decreased production or increased destruction. The majority of neutropenias is an acquired condition,7 with infections being the most COMMON cause. Neutropenia is the most prevalent drug-induced blood dyscrasia. Neutropenia due to drugs can have different pathogenesis.

7 Antifolate and other chemotherapy drugs result in neutropenia via direct suppression of the bone marrow. Non-chemotherapy (idiosyncratic) drug-induced neutropenia is due to increased (usually immune-mediated) neutrophil destruction. 10 Learning Guide: WBC: neutrophil GranulocytesThe five drugs most frequently associated with idiosyncratic drug induced neutropenia in a recent study were carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and Leukemic and tumor cells can also sometimes replace normal bone marrow elements, which can result in cytopenias, including neutropenia. Table 2 lists the causes of 2. CAUSES OF NEUTROPENIASCAUSES OF CONGENITAL AND IDIOPATHIC NEUTROPENIASCAUSES OF ACQUIRED NEUTROPENIASS evere congenital neutropenia (Kostmann s disease)Neonatal alloimmune neutropeniaReticular dysgenesisAutoimmune neutropenia (which is present in certain conditions, , rheumatoid arthritis, systemic lupus erythematodes, scleroderma, etc.)

8 Familial benign chronic neutropeniaNeutropenia associated with viral infections ( , hepatitis, HIV, etc.)Chronic idiopathic neutropenia of adult (cytokine-mediated syndrome)Neutropenia associated with fungal, rickettsial and protozoal infectionsNeutropenia in agammaglobulinemiaNeutropenia associated with bacterial infections ( , Gram-negative septicemia)Neutropenia in patients with congenital chromosomal abnormalitiesDrug-induced neutropenia (chemotherapy-induced and idiosyncratic)Some rare metabolic disordersNeutropenia associated with splenomegaly (hypersplenia)Congenital dysgranulopoietic neutropeniaNeutropenia associated with bone marrow suppression (malignancies)NEUTROPHILIAN eutrophil counts are known to be physiologically elevated in pregnancy and in newborns, compared to other groups. When the neutrophil count is abnormally high compared to the demographic-specific reference range, it is called neutrophilia.

9 It is one of the most frequently observed blood count ,15,16 Shift neutrophilia, which is usually a transient condition, results from a shift of cells from the marginal to the circulating granulocyte pool without any quantitative change in the total blood granulocyte pool (TBGP). Strenuous exercise, electric shock, emotional states, vomiting, convulsions, paroxysmal tachycardia and epinephrine injection are the most frequent causes of shift Guide: WBC: neutrophil GranulocytesCAUSES OF PHYSIOLOGIC NEUTROPHILIACAUSES OF PATHOLOGIC NEUTROPHILIAN eonatesAcute infectionsAcute inflammations (surgery, burn, tissue necrosis, systemic autoimmune disorders, etc.)ExerciseEndocrine/metabolic disorders (Cushing syndrome, thyrotoxicosis, diabetes, uremia, gout, etc.)Acute hemorrhage and acute hemolysisEmotional StressMyeloproliferative neoplasmsMalignant diseases: carcinoma, lymphoma, other solid tumorsPregnancy, Parturition, LactationDrugs: adrenaline, corticosteroids, lithiumAsplenia and some rare inherited disordersTrue neutrophilia is either due to an increase in the rate of release of neutrophils from the bone marrow or an increase in the production of neutrophils (increased rate of granulocytopoiesis), resulting in a true increase in the TBGP.

10 The most COMMON cause of neutrophil leukocytosis is acute infection with a pyogenic microorganism. However, neutrophil leukocytosis also occurs in infections with certain non-pyogenic microorganisms ( , in poliomyelitis, herpes zoster and typhus). Neutrophilia is a hallmark of inflammation but can also be a manifestation of a myeloproliferative neoplasm such as chronic myeloid leukemia (CML). CML is characterized by an increased neutrophil count (usually > 50 x 109/L), associated with a left shift and prominent presence of myelocytes. Basophilia and/or eosinophilia may also be of neutrophilia7,12 are listed in the Table 3 SHIFT During increased production and accelerated release of neutrophils from the bone marrow, less mature forms can appear in the peripheral blood . The most frequently seen cell types are band neutrophils, but metamyelocytes and even earlier forms can be present.