hematology2 Flashcards
Transfusion related lung injury (TRALI)
is acute lung injury (development of diffuse lung infiltrates, problems breathing and difficulty maintaining peripheral oxygen saturation on room air) within 6 hours of a transfusion. Vigorous ventilatory support may be required but the syndrome resolves quickly in 90% of those affected. The risk is 1/5,000-1/3,000 per transfusion depending on the product (all products can cause this reaction).
Transfusion associated circulatory overload (TACO)
is volume (fluid overload) related to excessive amounts of products and/or cardiac dysfunction. Diuretics will help resolve the problem.
Monocytes
derived from myeloid/ monocyte precursor under stimulation of GM-CSF and M-CSF, these cells have a shorter development time in the bone marrow (7 days), move to the peripheral blood for 3-5 days. Some then emigrate to tissues where they develop into tissue based macrophages lasting for days-months. (liver-kuffer cell) Major functions of these cells is to a) migrate from blood to sites of infection and provide effector phagocytic cells to remove microbes, dead and dying inflammatory cells, and debris; b) filter out microbes from blood stream (spleen-macrophage); c) process and present antigens to the adaptive immune system; and, d) remove apoptotic cells.
Neutrophil
The polymorphonuclear leukocyte (PMN), neutrophil or granulocyte is produced in the marrow (GM-CSF, G-CSF), remains there for a few days (10-14 days, under stress 5 days) in a storage pool held in reserve to fight infections, is subsequently released into peripheral blood (6hrs) where it may marginate between the post-capillary venules and the laminar blood flow. After 6 hrs, the neutrophil moves into the tissues where it turns over in 1-2 days. The neutrophil is a major component of the innate immune system migrating quickly to the site of infection where it ingests and kills microbes. It is the prototypic first responder but is also important in stimulating wound healing and tissue repair. Prolifer pool (mitotic compartment) is smaller in number of cells than the storage compartment where maturation occurs. Absolute neutrophil count=bands and segs.
Eosinophil
Produced in the bone marrow under the influence of IL-5, its maturation and kinetics are like neutrophils. The eosinophil, however, is slightly larger, has prominent eosinophilic (red/orange) granules and bilobed nucleus. Mature cell 12-14 micron dia. After transversing the peripheral blood, eosinophils move to mucosal surfaces (GI tract, tracheobronchial tree, etc.) where they survive for weeks. These cells play a role in allergic reactions, parasitic infections and response to tumors. They can play the role of a phagocyte and be immunostimulatory or immunoinhibitory. Will release ROS onto large parasite without actualy engulfing them. Roles allergies, parasite infection, response to tumors: may be immuno-enhancing or immuno-suppressive.
Basophil
After production in the marrow, basophils spend most of their life in tissues. Similar in size to eosinophils, they have prominent basophilic (blue-purple) primary granules and receptors for IgE. These cells appear to play a major role in hypersensitivity (allergic) reactions. Larger than neutrophil, smaller than monocyte.
Neutropenia
is defined as a decrease in the absolute neutrophil count (bands and segs) below accepted norms. This may vary with age (<250/μl a very severe risk (sepsis, pneumonia). We work on the assumption that the decrease in blood levels represent a decrease in storage. This is not always true and you need bone marrow sample to check.
Clinical and Labooratory Findings of neutropenia:
Once defined, the workup of neutropenia should include a thorough history investigating the duration or periodicity of the low counts and associated symptoms or signs; numbers, sites, and agents involved in infections; exposure to drugs and toxins; and family history of recurrent infections, immune disorders or hematologic abnormalities. A complete physical exam should be performed with special attention paid to infected sites; teeth and gums, lymph nodes, liver, spleen and other findings (nails, skin, dysmorphic features, etc.). Initial laboratory investigations include an initial CBC with a white blood cell differential and review of leukocyte morphology. For chronic neutropenia, counts twice weekly for six weeks will define the extent and persistence of the neutropenia. Blood chemistries (LDH, SGOT, SGPT, uric acid, alkaline phosphatase), neutrophil antibodies (due to related autoimmune disorder) and a bone marrow aspirate and biopsy may be essential to defining the specific cause of neutropenia. Other tests may be necessary to diagnose the disease or syndrome responsible for neutropenia.
Classifications of neutropenia
Based on initial evaluation, neutropenias can be classified as those with a decreased bone marrow production (primary or secondary) or those with a normal or near normal reserve but increased turnover. Included in the former are Kostmann Syndrome, Shwachman-Diamond Syndrome, cyclic neutropenia and idiopathic neutropenia while the latter is usually associated with infection, drugs, antibody-associated neutropenia or hypersplenism. Infection or drug related neutropenia can be related to an increase in turnover or decreased production or both. A number of syndromes have normal production but increase in peripheral utilization or transit time through peripheral blood. Most do not have problems with severe, recurrent infections. Acute is less then three months, it is related to infections, antibiotics or other drugs. Chronic neutropenia are more complicated and congenital type last for your whole life.
Infectious Complications of Neutropenia
Patients with severe neutropenia and production defects are predisposed to bacterial or fungal infections. Staphylococcus aureus and gram-negative bacteria are the most common pathogens, but other microbes can cause infection as well. The most common sites and types include septicemia, cellulitis, skin abscesses, pneumonia, and perirectal abscesses. Sinusitis, aphthous ulcers, gingivitis, and periodontal disease cause significant problems.
Decreased production neutropenia
: Several acquired disorders which decrease the production and/or bone marrow reserve (storage pool) are included in this category. Chemotherapy drugs used for malignant conditions are a major cause of neutropenia related to direct effects on stem cells and myeloid precursors. Exposure to these drugs markedly reduces production and may leave the patient at high risk for severe infection. Other drugs (chloramphenicol, etc.) may also have a direct toxic effect on precursors and cause severe neutropenia. Immune mechanisms with antibiotics can cause neutropenia. Hypersensitivity to Dilantin or phenobarbital can cause neutropenia. One of the more common causes of acute neutropenia is viral infections (EBV, varicella, measles, CMV, hepatitis, HIV). The mechanism for infection include increased utilization, complement mediated margination, marrow suppression/failure (direct effect), cytokine/ chemokine induced margination, and antigbody production. These may directly suppress marrow production or cause an increase in turnover peripherally, either directly related to consumption in tissues or indirectly related to effects of antibodies. Finally, nutritional deficiencies, such as folate, B12, copper or protein/calorie malnutrition can cause ineffective myelopoiesis and neutropenia due to intramedullary death secondary to effects of deficiency on replication. As with some other disorders in this category, the neutropenia can be associated with other cytopenias (anemia, thrombocytopenia).
Kostmann syndrome
with severe peripheral neutropenia and marked decrease in myeloid production beyond promyelocytes, leads to a high risk for infection and death before 2 years of age unless patients receive aggressive management. The mechanism is apoptosis of myeloid precursors associated with elastase (ELA-2) or HAX-1gene mutations, therefore in the marrow you see myeloid hypoplasia, severe maturation arrest promyelocyte/myelocyte stage. Rarely, defects in G-CSF receptor. Some patients survive to develop myeloid leukemia or myelodysplastic syndrome (MDS). Recent identification of elastase gene mutations and early apoptosis of precursors may provide a clue to the etiology of some cases. Inheritance may be autosomal recessive or dominant; or, in some cases, the disease has a sporadic presentation.
Shwachman-Diamond syndrome
is characterized by neutropenia (90% at sometime during their clinical course), pancreatic insufficiency with fat malabsorption, bony abnormalities (metaphyseal chondrodysplasia and Erlenmeyer flask deformities of long bones), and growth delay. Half of patients develop aplastic anemia or MDS/leukemia due to stem cell failure. Autosomal recessive inheritance is described in most cases and the gene defect(s) have been recently described. Abnormalities include apoptosis in precursors and a possible defect in “nurse” cells in the marrow stroma providing support for the developing myeloid cells. Pancreatic function may improve over time. Defects in the Schwachman-Diamond gene have recently been reported. Many have defect in SBDS gene. 25% develop marrow aplasia, 25% develop MDS/AML. Management: Pancreatic enzyme replacement; G-CSF, Aggressive antibiotic therapy and supportive care for infection, BMT for severe complications.
Cyclic neutropenia
is characterized by severe peripheral neutropenia for 5-7 days with specific periodicity (15-25 day cycles). Recurrent fevers and mouth ulcers may accompany infections during the time of neutropenia. At other times in the cycle, the ANC is normal and there is no greater risk for infection. This condition has also been linked to apoptosis in marrow precursors and mutations in the gene for elastase causing apoptosis in precursors and cyclic hematopoiesis. Autosomal recessive, dominant and sporadic patterns have been reported. Infections, mouth ulcers during neutropenia; improvement with age. Some have cycles in platelet and retic count. Management: Aggressive antibiotic and supportive care for infection, G-CSF daily or alternate days
Chronic Idiopathic Neutropenia
Mechanism/Inheritance/Genetics: Myeloid hypoplasia and maturation arrest at myelocyte, metamyelocyte or band stage, No specific inheritance identified, sporadic. Clinical features: Moderate to severe neutropenia, Recurrent infections (skin, sino-pulmonary tract, etc.), No other associated findings, No neutrophil antibodies detected. Management: Usually responsive to G-CSF
Chronic benign neutropenia of childhood
results from production of antibodies which cross-react with neutrophils. These children (median age 8-11 months, most before 14 months) have a very low ANC chronically but may increase their counts in association with infection. There is usually no increased risk for severe infections, and the neutropenia resolves after a median duration of 20 months (range 6-54 months). Supportive care and reassurance are the hallmarks of management.
Autoimmune neutropenia
may be caused by antibodies to specific determinants on the neutrophil. Marrow production is normal to increased, storage pool is normal to slightly decreased. Neutropenia is due to increased turnover, vascular compartment decreased. It may be seen in association with Systemic Lupus Erythematosus (SLE), Evan’s Syndrome, or Felty’s Syndrome. May also find thrombocytopenia, autoimmune hemolytic anemia, or other hematologic antibodies. In these cases, antibodies to red cells, platelets or coagulation proteins (lupus anticoagulants) may also be seen. With passive transfer of antibody from mother’s circulation attacking baby’s cells causing neutropenia, alloimmune neutropenia shares a common pathophysiology with Rh hemolytic disease and alloimmune thrombocytopenia of the newborn. Transplacental passage of neonatal cells which contain antigens not expressed by maternal cells into the maternal circulation sensitizes the mother to produce antibodies against the infant’s antigens. Accumulation of IgG class antibodies by the fetus provides a pool of antibodies which bind the infant’s neutrophils and cause neutropenia. The neutropenia may last for 2-4 weeks and, occasionally, 3-4 months, and occasional infections are seen. Affected patients may be asymptomatic or may develop skin infections, and rarely pneumonia, sepsis or meningitis. Commonly confused with neutropenia caused by sepsis. Marrow shows myeloid hyperplasia with maturation arrest at mature precursors (don’t delete that storage pool). Some drugs cause antibody mediated neutropenia which resolves with discontinuation of the drug.
Splenomegaly and hypersplenism
cause neutropenia related to excessive sequestration of neutrophils in the spleen and may be associated with sequestration of red cells and platelets as well. Severe infection, particularly with bacterial pathogens and activation of complement (specifically C5a) may result in excessive demargination of neutrophils and pseudoneutropenia.
Management of Kostmanns’ Syndrome
Aggressive treatment of infections, G-CSF 3-100 mcg/kg/day to keep ANC >1,000/ml, Consider BMT for poor response to G-CSF; AML; MDS
Infectious Complications
Patients with severe neutropenia and production defects are predisposed to bacterial or fungal infections. Staphylococcus aureus and gram-negative bacteria are the most common pathogens, but other microbes can cause infection as well. The most common sites and types include septicemia, cellulitis, skin abscesses, pneumonia, and perirectal abscesses. Sinusitis, aphthous ulcers, gingivitis, and periodontal disease cause significant problems.
Management of secondary neutropenias
Withdraw unnecessary drugs and eliminate toxins, Treatment of underlying disorder, Replacement of specific deficiency, Aggressive management of infections, Supportive care including prophylactic antibiotics, G-CSF in some conditions (e.g., chemotherapy)
Autoimmune neutropenia management
Treat primary autoimmune disorder and/or hematologic antibodies. G-CSF may be helpful if marrow storage pool depleted.
Alloimmune neutropenia treatment
Antibiotics and supportive care for infections. IVIG infusion not always effective. Consider G-CSF in face of severe infection
Treatment strategies for neutropenia
Define the type of neutropenia. For undefined cases or those with severe congenital syndromes associated with ANC 38.5°C, complete appropriate cultures (including blood) and treat with antibiotics. For severe infections, aggressive attempts at identifying infected site and involved organisms. Initiate broad spectrum antibiotics and change to specific antibiotics when organisms are identified. In some syndromes, prophylactic antibiotics are helpful. For severe cases, G-CSF given at a dose of 3-5 μg/kg subcutaneously every day will normalize production.
Leukocytosis
an increase in total number of WBCs beyond normal values. Think of infection, inflammation, non-specific physiologic stress, or malignancy (leukemia). Left shift is a term referring to changes in the white cell differential with an increase in segs and bands and possibly some immature myeloid precursors usually only found in marrow (metamyelocytes or myelocytes). Specific implications for leukocytosis depends on the cell lines which are increased.
Neutrophilia
is defined as an ANC >7,500 cells/μl outside the neonatal age range (7-13,000/μl is normal range for newborns). This may be caused by increased production (infection or inflammation, myeloproliferative disorders, drugs such as lithium, tumors, or stress-related leukemoid reactions). Other reasons include increased release from storage pool (e.g., steroids, acute infection, stress, endotoxin), decreased egress from the circulation (steroids, splenectomy, leukocyte adhesion deficiency) and reduced margination (epinephrine, exercise, stress).
Basophilia
Increase in peripheral basophils is seen primarily in drug or food hypersensitivity or urticaria. It may also be seen in infection or inflammation (rheumatoid arthritis, ulcerative colitis, influenza, chickenpox, smallpox, tuberculosis) as well as myeloproliferative diseases (CML, myeloid metaplasia).
Eosinophilia
An absolute count >350/ul is abnormal. The etiologies fall into three main categories: allergies/allergic disorders (asthma, atopic dermatitis, hay fever, hives, etc.), parasitic infections, and drug reactions (allergic). Rarer causes include pemphigus, tumors or malignancies, and other infections like chronic active hepatitis. Hypereosinophilic syndromes and eosinophilic leukemia are rare.
Monocytosis
Usually thought of with an absolute monocyte count of >1,000/μl in newborns and >500/μl in children and adults. Monocytosis may be found in hematologic (pre) malignancies (AML, pre-leukemia states, lymphoma, Hodgkin’s disease), collagen vascular diseases (SLE, RA), granulomatous diseases (sarcoid, ulcerative colitis, Crohn’s disease), infections (subacute bacterial endocarditis, syphilis, tuberculosis, protozoal rickettsial, and Pertussis infections), and carcinoma.
Neutrophil
Neutrophil function is critical to the first response of the host. Neutrophils move in the laminar flow of the blood but are initially pulled to areas of infection by interacting with endothelial cells in a rolling motion. This is followed by a more extensive process of firm adhesion mediated by a separate set of adhesion proteins. Passing through the junctions between endothelial cells (diapedesis), the cells move towards the offending organisms (chemotaxis), following the trail of chemoattractants (bacterial products, complement products such as C5a, cytokines and chemokines) up the concentration gradients to engage the microbial invader. At the site of infection, the microbe, properly opsonized with C3b or antibody, is enveloped by pseudopods which, like arms, embrace the organism. With fusion of the pseudopods, a phagosome is formed encasing the ingested particle in a small volume. Granules of each class fuse with the growing phagolysosome and the oxidase enzyme system is assembled in the membrane initiating the respiratory burst and generating reactive oxygen species (superoxide anion, O2-; hydrogen peroxide, H2O2; hypochlorous acid, HClO; and hydroxyl radical, .OH). Together, the reactive oxygen species (ROS) and oxygen independent mechanisms (defensins, lysozyme, cathepsins, proteases) are focused on the phagolysosome and lead to the death and dissolution of the microbe.
Function of neutrophil
The function of neutrophils and other phagocytic cells can be arbitrarily divided into four phases: adherence, chemotaxis, ingestion and degranulation/microbicidal activity. Each of these is induced through engagement of specific receptors which press into action the function of subcellular organelles through physiologic and biochemical processes. There is overlap in mechanisms used for two or more functions. For example, chemotaxis with protrusion of the pseudopod in the direction of movement shares a number of processes and organelles with cell motility (e.g., C5a, actin cytoskeleton, actin assembly). The differences in signaling which drive chemotaxis as distinct from ingestion are not completely understood and lie in the multiplicity of signaling pathways and effector mechanisms (involve C3bi receptors, which overlaps with CD11b/CD18). These are, however, integrated into a continuum of specific events leading in the correct sequence to ingestion and destruction of the microbe.
Chronic granulomatous disease (CGD)
a syndrome which represents abnormalities in oxidase components. Specific microbes are ingested normally but cannot be killed. Neutrophilia. Normal adherence, chemotaxis, ingestion and degranulation. Defect in oxidase enzyme system. No toxic oxygen metabolites produced. Absent or reduced ability to kill coagulase positive bacteria and fungi (e.g., staph, E-coli). Deficiency of gp91phox, p22phox, p47phox, or p67phox results in absence of respiratory burst and production of ROS. Recurrent infections, limit the lifespan of these patients, may be deeply in lung, liver, spleen, lymph nodes and bones. Infections may be local or disseminated, but production of granulomas in tissues is typical of the syndrome. MPO deficiency may be also categorized here because HClO production is decreased and efficient killing of Candida is limited.
Leukocyte adhesion deficiency I
results in neutrophilia (cant adhere), decreased adherence to endothelial surface leading to a defect in movement of neutrophil to infected tissue site. The molecular defect is a complete or partial deficiency of CD18 resulting in lack of expression of CD11b/CD18. It is autosomal recessive. The clinical presentation includeds recurrent soft tissue infections (skin, mucous membranes), gingivitis, mucositis, peridontitis, cellulitis, abscesses, delayed separation of umbilical cord/omphalitis, and poor wound healing.
Leukocyte adhesion deficiency II
Results in neutrophilia, decreased rolling on endothelial surface as a prelude to tight adherence. RBC are also affect from abnormal ABH antigens. The molecular defect is abnormal transferase resulting in abnormal fucosylation of adhesion molecules (causing other CNS problems) (Sialyl LeX) and poor interaction with selectins, autosomal recessive. The clinical presentation is recurrent infections, mental retardation, short stature, and craniofacial abnormalities.
Actin dysfunction
results in decreased chemotaxis, ingestion, and spreading. Results in increase infections and poor wound healing. Defect in actin associated proteins can also cause similar problems.
Specific granule deficiency
Results in decreased chemotaxis and microbicidal activity and milde neutropenia (abnormality in nuclear configuration). Have no specific granule. Results in recurrent skin and deep tissue infections. Molecular defect in failure to produce specific granules or their contents, defect in a transcription factor (CEBPε) results in decrease production of specific granule proteins, autosomal recessive.
Myeloperoxidase deficiency
results in partial or complete deficiency of myeloperoxidase and mild defect in killing bacteria, significant defect in killing candida. The molecular defect is a post-translational modification defect in processing protein, autosomal recessive. Presentation is generally healthy, increase fungal infections when associated with diabetes.
Chediak Higashi Syndrome
Results in neutropenia, giant granules (leaky) in all leukocytes, abnormal degranulation, and major defect in movement, also decreased degranulation and microbicidal activity. The molecular defects are alterations in membrane fusion with formation of giant, leaky granules and other metabolic abnormalities in microtubule assembly. It effects all cells with granules (neurons). CHS gene has been identified, autosomal recessive. The clinical presentations are oculocutaneous albanism, nystagmus photophobia, recurrent infections of skin, mucous membranes and respiratory tract by bacteria, lymphoproliferative phase associated with EBV infection, fever, hepatosplenomegaly and hemophagocytic disorder, and neurodegenerative syndrome.
Respiratory Burst
plays an important role in the immune system. It is a crucial reaction that occurs in phagocytes to degrade internalized particles and bacteria. NADPH oxidase, an enzyme family in the vasculature (in particular, in vascular disease), produces superoxide, which spontaneously recombines with other molecules to produce reactive free radicals. The superoxide reacts with NO, resulting in the formation of peroxynitrite, reducing the bioactive NO needed to dilate terminal arterioles and feed arteries and resistance arteries. Superoxide anion, peroxynitrite, and other reactive oxygen species also lead to pathology via peroxidation of proteins and lipids, and via activation of redox-sensitive signaling cascades and protein nitrosylation. NADPH oxidase activation has been suggested to depend on prior PKC activation.[1] Myeloperoxidase uses the reactive oxygen species hydrogen peroxide to produce hypochlorous acid. Many vascular stimuli, including all those known to lead to insulin resistance, activate NADPH oxidase via both increased gene expression and complex activation mechanisms.
Complement disorders
The complement system comprises a group of plasma proteins activated by lectins, bacterial proteins, or surface bound IgG through two different pathways (classical or alternative). Sequential proteolytic interactions of complement proteins in a cascade lead to activated fragments which attach to membranes opsonizing the target cells for phagocytosis or which serve as chemotactic stimulants. Activation of the terminal components (C5-9) forms an amphiphilic cylinder which is inserted into the plasma membrane of the target (bacterium, cell, etc.) permitting free flow of intracellular constituents and lysis. Deficiencies of factors 1q, 4, and 2 are associated with an increased risk of systemic lupus erythematosus and other autoimmune or inflammatory vascular diseases. Primary deficiency of C3 results in inefficient opsonization of bacteria and recurrent bacterial infections (pneumococcus, H. influenzae, etc.). Defects in components C5-C9 have an associated increase in risk for Neisseria bacteria (meningitis, arthritis, sepsis).
Phagocytes disorder clinical findings
High rate of bacterial and fungal infections. Infections with atypical or unusual microorganisms (e.g., Aspergillus, disseminated candida, lymphadenitis due to Serratia and other gram negative organisms, infections with Cepacia Burkholderi. Catalase positive organisms in patients with CGD. Infections of exceptional severity. Peridontal disease in childhood. Recurrent infections in areas of the body, which interface with the microbial world. Infections occur at interface areas: skin (cellulitis, abscesses), sinopulmonary infections (pneumonia, sinusitis, gingivitis, ulcers, periodontal disease), perirectal infections. Deep infections may also occur.
Complement disorders clinical findings
Bacterial infections, which might be seen with antibody deficiency (e.g., pyogenic organisms, H. influenzae, S. pneumoniae). Terminal complement deficiencies (C5-C9) have problems with Neisseria organisms.
