CM 3(2)
LEUCOSIS.
LEUKOCYTOSIS. LEUKOPENIAS. LEUKAEMOID REACTION.
Leucosis
Leukemia (leucosis) is a tumour, which arises from bloodforming cells and is primary damages bone marrow. The most characteristic signs of leucosis is the filling bone marrow by malignant cells of the local origin. It can be leucocytes and their predecessors, erhytroblasts, megacaryoblasts. They are made multiple copies in quantities, overcome a natural barrier between bone marrow and blood and get in vessels channel. There is leucocytosis – very often, though also unessential symptom of leucosis.
The reason why quantitative and qualitative diagnosis based on the cellular components of the blood is so important is that blood cells are easily accessible indicators of disturbances in their organs of origin or degradation – which are much less easily accessible.
Thus, disturbances in the erythrocyte, granulocyte, and thrombocyte series allow important conclusions to be drawn about bone marrow function, just as disturbances of the lymphatic cells indicate reactions or disease states of the specialized lymphopoietic organs (basically, the lymph nodes, spleen, and the diffuse lymphatic intestinal organ). All blood cells derive from a common stem cell. Under the influences of local and humoral factors, stem cells differentiate into different cell lines.
Erythropoiesis and thrombopoiesis proceed independently once the stem cell stage has been passed, whereas monocytopoiesis and granulocytopoiesis are quite closely “related.” Lymphocytopoiesis is the most independent among the remaining cell series. Granulocytes, monocytes, and lymphocytes are collectively called leukocytes (white blood cells), a term that has been retained since the days before staining methods were available, when the only distinction that could be made was between erythrocytes (red blood cells) and the rest.
Figure. Scheme of hematopoiesis
All these cells are eukaryotic, that is, they are made up of a nucleus, sometimes with visible nucleoli, surrounded by cytoplasm, which may include various kinds of organelles, granulations, and vacuoles. Despite the common origin of all the cells, ordinary light microscopy reveals fundamental and characteristic differences in the nuclear chromatin structure in the different cell series and their various stages of maturation.
The developing cells in the granulocyte series (myeloblasts and promyelocytes), for example, showa delicate, fine “net-like” (reticular) structure. Careful microscopic examination (using fine focus adjustment to view different depth levels) reveals a detailed nuclear structure that resembles fine or coarse gravel. With progressive stages of nuclear maturation in this series (myelocytes, metamyelocytes, and band or staff cells), the chromatin condenses into bands or streaks, giving the nucleus – which at the same time is adopting a characteristic curved shape –a spotted and striped pattern.
Lymphocytes, on the other hand – particularly in their circulating forms – always have large, solid-looking nuclei. Like cross-sections through geological slate, homogeneous, dense chromatin bands alternate with lighter interruptions and fissures.
Each of these cell series contains precursors that can divide (blast precursors) andmature or almostmature forms that cao longer divide; the morphological differences between these correspond not to steps in mitosis, but result from continuous “maturation processes” of the cell nucleus and cytoplasm.
Once this is understood, it becomes easier not to be too rigid about morphological distinctions between certain cell stages. The blastic precursors usually reside in the hematopoietic organs (bone marrow and lymph nodes). Since, however, a strict blood – bone marrow barrier does not exist (blasts are kept out of the bloodstream essentially only by their limited plasticity, i.e., their inability to cross the diffusion barrier into the bloodstream), it is in principle possible for any cell type to be found in peripheral blood, and when cell production is increased, the statistical frequency with which they cross into the bloodstream will naturally rise as well.
Conventionally, cells are sorted left to right from immature to mature, so an increased level of immature cells in the bloodstream causes a “left shift” in the composition of a cell series—although it must be said that only in the precursor stages of granulopoiesis are the cell morphologies sufficiently distinct for this left shift to show up clearly.
The distribution of white blood cells outside their places of origin cannot be inferred simply from a drop of capillary blood. This is because the majority of white cells remain out of circulation, “marginated” in the epithelial lining of vessel walls or in extravascular spaces, from where they may be quickly recruited back to the bloodstream.
This phenomenon explains why white cell counts can vary rapidly without or before any change has taken place in the rate of their production.
Cell functions. A brief indication of the functions of the various cell groups follows. Neutrophil granulocytes with segmented nuclei serve mostly to defend against bacteria. Predominantly outside the vascular system, in “inflamed” tissue, they phagocytose and lyse bacteria. The blood merely transports the granulocytes to their site of action.
The function of eosinophilic granulocytes is defense against parasites; they have a direct cytotoxic action on parasites and their eggs and larvae. They also play a role in the down-regulation of anaphylactic shock reactions and autoimmune responses, thus controlling the influence of basophilic cells.
The main function of basophilic granulocytes and their tissue-bound equivalents (tissue mast cells) is to regulate circulation through the release of substances such as histamine, serotonin, and heparin. These tissue hormones increase vascular permeability at the site of various local antigen activity and thus regulate the influx of the other inflammatory cells.
The main function of monocytes is the defense against bacteria, fungi, viruses, and foreign bodies. Defensive activities take place mostly outside the vessels by phagocytosis.
Monocytes also break down endogenous cells (e.g., erythrocytes) at the end of their life cycles, and they are assumed to perform a similar function in defense against tumors. Outside the bloodstream, monocytes develop into histiocytes; macrophages in the endothelium of the body cavities; epithelioid cells; foreign body macrophages (including Langhans’ giant cells); and many other cells. Lymphocytes are divided into two major basic groups according to function.
Thymus-dependent T-lymphocytes, which make up about 70% of lymphocytes, provide local defense against antigens fromorganic and inorganic foreign bodies in the form of delayed-type hypersensitivity, as classically exemplified by the tuberculin reaction. T-lymphocytes are divided into helper cells and suppressor cells.
The small group of NK (natural killer) cells, which have a direct cytotoxic function, is closely related to the T-cell group. The other group is the bone-marrow-dependent B-lymphocytes or Bcells, which make up about 20% of lymphocytes. Through their development into immunoglobulin-secreting plasma cells, B-lymphocytes are responsible for the entire humoral side of defense against viruses, bacteria, and allergens.
Erythrocytes are the oxygen carriers for all oxygen-dependent metabolic reactions in the organism. They are the only blood cells without nuclei, since this allows them to bind and exchange the greatest number of O2 molecules. Their physiological biconcave disk shape with a thick rim provides optimal plasticity.
Thrombocytes form the aggregates that, along with humoral coagulation factors, close up vascular lesions. During the aggregation process, in addition to the mechanical function, thrombocytic granules also release factors that promote coagulation. Thrombocytes develop from polyploid megakaryocytes in the bone marrow. They are the enucleated, fragmented cytoplasmic portions of these progenitor cells.
Classification of leucosis
On clinical picture leucosis divide on two groups – acute and chronic. This classification is entered into clinical practice and in a scientific turn-over at the end of ХІХ centuries Roux (1890) and Cabot (1894). The classification was based to duration of illness.
In 1964 in Cambridge the new classification was created, according to which to acute leucosis is believed such forms them, when the disorders of differentiation of cells took place. For want of acute leucosis differentiation bloodforming cells in base mass do not go further ІV classes. The grow up of cells, which do not mature, lead to accumulation blast cells ІІ, ІІІ and ІV classes. They there is more take territory of bone marrow at the expense of volume, which should be occupied normal hemopoietic elements. Eventually cells certain growth, which were accumulated much in bone marrow, leave in blood.
At the end of 70-th – beginning of the 80-th years of the last century the French, American and British experts created a modern, so-called FAB-classification of acute leucosis. It is constructed on stable morphological and cytochemical characteristics of leucosis cells. These characteristics reflect features them metabolism.
According to modern conception, all bloodforming at level of the ІІ class is divided into two shoot – myeloid and lymphoid. Therefore all acute leucosis divide on two groups – myeloblast and lymphoblast. They are represented by many nosologic forms.
Acute myeloblastic leucosis differentiate on five cytochemical signs – presence or absence in leucosis cells of the following substances: peroxidase, acid phosphatase, unspecific esterase, lipids and glycogen. To them belong undifferentiated leucosis.
Figure. Reaction of myeloblasts and other neutrophil cells for peroxidase
Figure. Reaction of myeloblasts and monoblasts for acid phosphatase
Figure. Reaction of monoblasts for alpha naftylatsetatesterase
Figure. Reaction with Sudan black for lipids
Figure. Reaction for acidic sulfated mucopolysaccharides
This group includes the following forms of acute leukemia:
M0 – acute undifferentiated leukemia.
Illustrations:
Blood:
red bone marrow:
red bone marrow, atypical cells:
М1 – acute myeloblastic leucosis without signs of maturing (worse 3 % of promyelocytes).
М2 – acute myeloblastic leucosis with signs of maturing (over 3 % of promyelocytes).
Illustrations: М1-М2:
Red bone marrow. Initial stage. Granular myeloblasts, Auer rod:
Red bone marrow. The total myeloid metaplasia:
Blood. Reaction of myeloblasts for peroxidase:
Blood. Reaction of myeloblasts for peroxidase:
М3 – acute promyelocytic leucosis (over 30 % of promyelocytes).
М4 – acute myelomonoblastic leucosis (over 20 % of promyelocytes and over 20 % of promonocytes).
(М4) – red bone marrow, reaction for esterase:
М5 – acute monoblastic leucosis.
М6 – acute erythroblastic leucosis.
(М6) – red bone marrow. Erythroblasts. Myeloblasts with Auer rod:
М7 – acute megacaryoblastic leucosis, red bone marrow:
Acute lymphoid leukemia is distinguished for cytochemical, and morphological features. There are following forms:
1. Acute leucosis general type
2. T-lymphoblastic leucosis,
3. B-lymphoblastic leucosis.
Illustrations:
Acute lymphoblastic leukemia (blood). Lymphocytes (2) and lymphoblasts (1):
Acute lymphoblastic leukemia (blood):
.
Acute lymphoblastic leukemia (red bone marrow):
Acute В-lymphoblastic leukemia (red bone marrow). Big lymphoblasts:
Acute lymphoblastic leukemia (red bone marrow). The initial stage:
Acute lymphoblastic leukemia (red bone marrow). The total lymphoblastic metaplasia:
:
In the FBA-classification, as against Cambridge, unusual is that acute undifferentiated leucosis belongs to group myeloid leucosis. Before it selected separately or even carried to lymphoid. The rearrangement is explained that now amount acute undifferentiated leucosis was sharply reduced in connection with selection as separate nosologic form of leucosis general type from cells – predecessors in – lymphocytes. And those leucosis, which have remained in group undifferentiated, are very similar on leucosis of myeloid line.
Chronic leucosis differ from acute, that the cells bone marrow mature normally (up to V І class), but proliferate in very plenty. Chronic leucosis passes in the development three stages:
1. Chronic stage, during which the illness represents a benign tumour and can be treatment.
2. The stage of accelerated development of illness, during which illness progresses in the party malignisation. Dynamics of illness it is ever more and leaves from under control. The treatment becomes all less effective.
3. The stage crisis of blastic cells, during which illness is exposed to radical transformation: chronic leucosis passes in acute (in 70 % – in acute myeloblastic, in 30 % – in acute lymphoblastic). Crisis of blastic cells approaches suddenly and becomes the reason of majority patients death.
Chronic leucosis also are divided on myeloid and lymphoid. To myeloid leucosis belong myelocytic leucosis.
The change in the cellular composition of the red bone marrow as an indicator of progression of chronic myelocytic leukemia indicate the following figures.
Chronic myelocytic leukemia (blood). Chronic stage:
Chronic myelocytic leukemia (blood). Stage of blast cells crisis:
Chronic myelocytic leukemia (red bone marrow). Extensive stage:
Chronic myelocytic leukemia (red bone marrow). Stage of blast cells crisis:
Chronic myelocytic leukemia (blood). Neutrophils at different stages of maturation:
Chronic myelocytic leukemia (blood). Rejuvenation of blood cell in dynamics of leukemia progression:
Chronic myelocytic leukemia with eosinophilia (red bone marrow):
Chronic myelocytic leukemia, eosinophilic variant, (red bone marrow):
Chronic myelocytic leukemia, basophilic variant (red bone marrow). Extensive stage:
:
Chronic myelocytic leukemia, basophilic variant (red bone marrow). Stage of blast cells crisis:
Chronic monocytic leukemia (blood):
1. Chronic erythroblastic leucosis.
2. Chronic megacaryocytic leucosis.
Chronic lymphoid leucosis
1. Chronic B-lymphocytic leucosis.
Chronic B-lymphocytic leucosis (blood):
Chronic lymphocytic leucosis (blood). Gumpreht bodies:
Chronic lymphocytic leucosis (red bone marrow). The total lymphoid metaplasia
Chronic lymphocytic leucosis (red bone marrow). The total lymphoid metaplasia
2. Chronic Т– lymphocytic leucosis.
3. Haircell leucosis.
Chronic haircell lymphocytic leucosis (blood):
Chronic haircell lymphocytic leucosis (blood):
Chronic haircell lymphocytic leucosis (blood). The reaction for acid phosphatase:
:
Etiology and pathogenesis of the leucosis
On modern conception, leucosis arise on genetic, mutational basis. The speech does about specific of bloodforming cells mutations, which result to superexpression of cells oncogenes, or protooncogenes. These genes are an integral part of cells genome and answer for proliferation of cells. Cells oncogenes vitally are necessary. Without them would become impossible fill of the cells, worn out and lost during vitality. At the same time cells oncogenes, as has appeared, have latent blastomogenic potentions. Excessive expression them the regeneratioormal of bone marrow cells in leucosis stipulates.
To major etiological factors, which are capable to transform protooncogenes in active oncogenes, the chemical agents, ionising rays and retroviruses concern. It is know a few mechanisms of the cell oncogenes activation.
Point mutations.
Consider, that in most cases protooncogenes are activated as a result of structural changes them under influence of the chemical and physical agents.
From chemical substances in this plan the most better is investigated benzol. There is an increased risk to be ill leucosis on productions, where is used benzol: chemical clearing of materials with use of the solvents benzolcontaining, production of film materials on the basis of rubber, paper and woodworking an industry. The mechanism of chemical leucosogenesis consists that chemical leucosogenes cause chromosomal and genes mutations. Some from these mutations seize cells oncogenes or them regulatory genes environment and initiate leucosis transformation of bone marrow cells.
From the physical agents strongest leucosogenic by action has ionising rays. Is exactly proved, that increase of frequency leucosis take place after nuclear bombardment of Hiroshima and Nagasaki in 1945. The appearance leucosis is fixed also in case of use ionising radiation with the medical purpose – in the patients with ancilosing spondilitis (Bechterev’s illness), myelomic illness, lymphogranulomatosis, autoimmune diseases, some dermatoses. The approximately 25-35 % of cells, mainly lymphocytes, after therapeutical of an irradiation contain chromosomal aberrations as ring chromosomes, dicentric chromosomes and acentric of fragments.
It is known leucosogenic action of radioactive isotopes. The radioactive phosphorum, which is used for treatment erythremia, caused acute leucosis at 15-18 % of the patients.
It was detected also chromosomal aberrations in the specialists as a result of professional irradiation. Here, first of all, the staff belongs which serves nuclear reactors. The anomalies of chromosomes are found too in the people which have got in to breakedawn with throw away of radiation.
Chromosomal aberrations.
The precise correlation between lay out oncogenes and specific translocations of chromosomes is marked. It is established, that cell oncogenes frequently place just in those sites chromosomes, where it is easy and naturally there are their breaks with consequent translocations of deleted fragments. From here also there was an assumption, that translocations can be by original activators protooncogenes.
To the present time in chromosomes of malignant cells more than 80 points are registered, where the breaks are observed. The analysis of distribution has shown these malignant spesific points and localization protooncogenes in genome of the person, that the majority protooncogenes places just in zones of specific breaks chromosomes.
Significant practical interest in the plan of the analysis of chromosomal role aberrations in activation of protooncogenes represent chromosomal and genes of illness, which are characterized by increased instability of chromosomes. To them belong Dawn’s illness, Fankony’s anemia, Blum’s syndrome, Louis-Bar’s syndrome and etc.
It is established, that among patients with Dawn’s illness the frequency leucosis in 20 times is higher, than among persones without Dawn’s illness. Fankony’s anemia the diverse deviations karyotype from norm are found: chromatide breaks, acentric fragmentation, dicentric chromosomes, chromatide exchanges. In children with the Blum’s syndrome large percent of breaks chromosomes, as for want of Fankony’s anemia is observed. The frequency of exchanges between sister chromatides in 9 times is higher, than in the healthy people. The chromosomal instability consists in breaks and translocations of a long shoulder of 14-th chromosome in Louis-Bar’s syndrome.
The persones burdened with any of these illnesses, are exposed to strong risk of development in them malignant tumor, including leucosis. The approximately half of patients with Fankony’s anemia suffers acute myeloid leucosis. About 80 % of the patients with Louis–Bar’s syndrome are sick lymphoid leucosis or various lymphomas.
With the help of precision methods of differential colouring chromosomes it was possible to clarify, that for each type leucosis are characteristic specific chromosomal aberrations. The most better is investigated translocation 9/22, characteristic for chronic myelocytic leucosis. This anomaly for the first time was described in 1960 in Philadelphia (USA). Changed chromosome have named philadelphian. That chromosome will be derivated in result reciprocal translocation between 9-th and 22-nd chromosome. Long shoulder of 9-th chromosome contains protooncogene abl (Abelson’s), which in mice causes leucosis, and long shoulder of 22-nd chromosome contains protooncogene sis, which causes sarcoma in haired monkeys.
For want of mutual translocation protooncogene Abelson’s 22-nd moves from 9-th chromosome on long shoulder of protooncogene, and the fragment of long shoulder of 22-nd chromosome moves on 9-th chromosome. Redislocation of oncogenes abl and sis is not equivalent.
The appearance of oncogene sis in structure of 9-th chromosome is not reflected in vital activity of bone marrow stem cell. In other words, expression of oncogene sis in bone marrow cells does not occur. Absolutely 22-nd in another way behaves oncogene abl in structure chromosome. It is exposed very high expression as transcription abnormal RNA. Such RNA is not present neither iormal bone marrow cells, nor in leucosis cells, where there is not 9/22. Therefore consider, that exactly the activation Abelson’s oncogene is that critical mechanism, which initiates development chronic myelocytes leucosis.
Expression of Abelson’s oncogene in bone marrow to a cell stipulate appearance in it special oncoprotein with molecular weight 210 kD and by thyrosine activity. This oncoproteine is coded simultaneously Abelson’s oncogene from 9-th chromosome and site 22-nd chromosome, which adjoins to the point of break.
The data about a role of chromosome aberrations in leucosis ethiology can be generalized as follows. The anomalies karyotype only when can cause leucosis, if they seize chromosome locuses, where are located protooncogenes. The activation stipulates these protooncogenes pathological proliferation and leucosis. Each chromosome has so-called fragile sites, which can be identified with the help of differential colouring. Just here there are deletion, inversions and translocation, which become by the initiators of activation protooncogenes more often. Therefore, all hereditary syndromes, with which is peculiar high chromosomal instability, should be considered as causes factors of leucosogenesis.
Virus transduction.
On leucosogenic properties retroviruses divide on two groups – fast-transformed (viruses acute leucosis) and slow- transformed (viruses of chronic leucosis).
Retroviruses of the acute leucosis differ by that their gene has an additional gene. It represents cells oncogene, which was snatched out from genome of cell and is built in virus RNA. Only now of it to name uncellular, and virus oncogene. Just this additional gene consider as the specific factor, which causes malignant transformation of a cell, and the process of massage cells oncogene through a virus is named virus transduction.
After repeated introduce in a cell virus (form cells) oncogene shows high propensity to expression. The reason, first of all, that it is seized by virus without surrounding regulatoring repressors genes. The second reason that a DNA-copy retrovirus is not absolutely exactly reading out return transcriptase. When the again created virus particles are introduced into the following cell, their DNA-copies with an additional gene (virus oncogene) are built in cell by the gene and easily expression – or because mutational virus oncogene becomes inaccessible repressoring gene to environment, or because this environment in general is absent.
Highoncogenic retroviruses – the most effective leucosogenes. It is explained by that presence in them oncogenes have cell origin and iorm answer for proliferation of cells. Therefore in conditions of loss genome and epigenome control they are exposed stronger expression, than for want of chemical and physical mutation.
Insertion of provirus.
Most of viruses leucosis belongs not to fasttransformational, and to slowtransformational retroviruses. They do not contain oncogenes and induce experimental leucosis in an animal less effectively, than fasttransformational. Slowtransformational retroviruses cause transformation of cells because their DNA-copies are inserted in cells by a gene near to cells oncogene. The presence of another’s DNA somehow activates cells oncogene up to very high level expression.
Genes amplification.
This increase of copies of separate genes in reply to change of the external environment. In leucosis cells are detected amplificated of copy some protooncogenes. In itself amplification of oncogene does not concern to initiating events in leucogenesis. It is connected to a progression already of initiated cells. But in any case amplification of gene results in increase of level expressed RNA and precisely is proportional to level amplificated DNA.
Leucosis clone
The pathogenetical analysis of leucosis is compound. The first question, which arises for want of consideration pathogenesis leucosis: which cells bone marrow are targets for action various leucosogenis of factors – ionising rays, chemical leucosogenes retroviruses? The modern researches testify that cells – targets are stem cell of bone marrow, though it is possible, that cells ІІ and ІІІ classes also can be involved in process leucosogenesis. However stem of cell much earlier and more often are included in leucosis process, therefore submission about leucosis as about “ illnesses of stem cells” now dominates.
The second major question of pathogenesis arises on base of transformation by one stem cell or many simultaneously?
Normal hemopoiesis is polyclonic. It provides valuablis and uniform development all shoots of bloodforming lymphoid myeloid erythroid megacaryoblastic. For want of leucosis the picture varies. For want of leucosisе the special pathological autonomous clone of the transformed cells will be derivated. Cells of this clone have selective advantage before other cells – they are capable to very intensive proliteration. The cells of leucosic clone can be differentiated in the party anyone called above shoot. Already there will be no uniform development of all shoots. On the contrary, any one of them, originating from transformed stem cell, will prevail above others and to supplant their from bone marrow.
It is proved, that all cells leucosis of clone occur from one transformed cell. The system character of leucosis testifies like against this rule. It’s leucosis very fast inclusions all bloodforming tissue. However, all this only external symptom, which does not reflect true events. Actually all weight leucosis cells, where they were not, (in other words, all leucosis the clone) is descendants by one transformed stem cell. The difference from usual tumours consists only that metastasing for want of leucosis begins at very early stages of illness.
Leucosis clone – is not homogeneous. It consists of cells of two populations – proliferational (G1) and non- proliferational (G0). Proliferational population makes only 10 % leucosis cells. Others 90 % of cells not proliferational. On proliferational of ability the population G1 differs from normal cells. It proliferative the activity much below also makes approximately 40 % of activity of normal cells. For example, the time of reproduction of normal cells bone marrow is equal to 12-20 hours. The time of reproduction leucosis cells in 4-5 times more also makes 40-80 hours.
How then to explain, what proliferational cell of leucosis a clone for short time give huge cells weight? It’s they make only 10 % of total leucosis cells and are made multiple copies in 4-5 times slower, thaormal cells. It’s founded, that affair here not in speed of division, and in an amount of divisions. Iormal bone marrow sten cell has enough 5-10 divisions, that it has reached up to myelocyte. For want of leucosis the amount of divisions is sharply increased. Leucosis the cell becomes not submit to a limit Heiflick’s. For want of acute leucosis cell in addition to completely lose ability to differentiation. Their maturing, as a rule, does not go further blast forms (ІV classes).
Count show, that one leucose transformed stem cell for 40 divisions gives cells weight equal to 1 kg. This weight is considered critical. Just for want of such cell to weight begin to occur the first clinical signs of leucosis. It will be derivated approximately during 4-5 months.
The G0-population of leucosis cells executes role of reserve. These cells can long time stay in sleeping state both in bone marrow and in blood. From time to time they leave from vessels in serround tissue, subside there and give extramedullar centers of bloodforming. The correlation between two populations leucosis cells – G1 and G0 – determines state of leucosis process – progression, remission, recurrence.
Major chain of pathogenesis leucosis is oppression by leucosis cells normal of hemopoiesis. Select some mechanisms of this phenomenon. Firstly, leucosis cell are capable produced in redundant amount colonialstimulation factor – stimulator of myelopoiesis. Secondly, this factor acts on leucosis cell, than on the normal predecessors hemopoiesis stronger. Thirdly, leucosis of a cell have property selectively to oppress proliferation and differentiation of normal cells – predecessors with the help humoral inhibitors. Forthly, leucosis cell is more active, thaormal, answer to action of the growth factors.
Gradually pool of normal cells – predecessors is exhausted. Bone marrow is filled in leucosis with weight. This modification stipulates main clinical signs leucosis – metaplastic anemia, thrombocytopenia, hemorrhagic syndrome, secondary immunodeficiency, decrease of resistantion to infectious agents. The patients die or from bleeding in brain, or from an infection. In conditions immunedeficiency even saprofit flora can become pathogenic.
As was already told, the disorders of hemopoiesis for want of acute and chronic leucosis are not identical. These distinctions define an originality hematological picture for want of each them. For want of acute leucosis in peripheral blood will be a lot of young cells forms ІІ, ІІІ and ІV classes and there are not enough of mature cells VІ class for want of complete absence of the transition forms V classes. Absence of the transition forms in peripheral blood – very characteristic morphological difference acute leucosis from chronic. This hematological symptom is called leucemic failure (hiatus leucemicus).
The reason that the absolute majority of cells leucosis of a clone is not differentiated further of the blast forms. At the first they are stored in bone marrow, and then break in blood. Only single cells manage to pass usual path of differentiation and to get in blood in mature state. Let’s give for example acute myeloblastic leucosis. For want of it leucosis in peripheral blood will be much myeloblasts (ІV classes), of cells – predecessors ІІ-ІІІ classes and there are not enough of mature forms (sticknucleus and segmentnucleus neutrophils). Characteristics will be absence of the transition forms V classes – promyelocytes, myelocytes, metamyelocytes (leucemic failure).
Completely other hematological picture for want of chronic leucosis. As the maturing of cells goes up to the end, in blood there will be an abundance of cells of all classes – young, transition and mature. Leucomic failure is absent. For want of chronic myelocytic leucosis blood there will be cells – predecessor ІІ and ІІІ classes, myeloblasts (ІV classes), cell V classes – promyelocytes myelocytes metamyelocytes sticknucleus neutrophils and mature cells of the VІ class (neutrophils).
For want of chronic lymphocytic leucosis the picture of peripheral blood is characterized by the following features: it is a lot of mature lymphocytes, is prolymphocytes and lymphoblasts, and also desroyed cells lymphoid number (Gumprecht’s bodies).
Leukocytosis. Leukopenias. Leukaemoid reaction
Leukocytosis is an increase in the total white cell count. The most common cause is neutrophilia, followed by lymphocytosis. Much less commonly seen is an increase in eosinophils or monocytes. Leukocytosis is most frequently due to a normal bone marrow response to relatively benign causes such as inflammation, infection or drugs. However, more serious causes of leukocytosis include primary bone marrow pathology – leukaemia and myeloproliferative disorders.
When looking at an abnormal full blood count that reports a leukocytosis, it is important to look not only at the total number of white cells, but also the lineage (or lineages) that are increased, as well as the other components (haemoglobin, platelets).
Clinical findings such as weight loss and enlarged lymph nodes, liver and spleen may increase suspicion for an underlying bone marrow disorder.
Neutrophilia. Healthy neonates and pregnant women frequently have a physiologically normal mild neutrophilia. The various causes of neutrophilia are discussed in this section and can be classified into malignant and non-malignant causes. The most non-malignant common cause of neutrophilia is the bone marrow response to an ‘external’ stimulus. A neutrophilia is commonly associated with many bacterial infections (and some viral infections). Occasionally, immature cells of the granulocyte series (e.g. band forms, metamyelocytes and myelocytes), which are not normally seen in the peripheral blood, may also be seen with neutrophilia during infections. This is termed ‘left shift’. The neutrophilia, in part, is thought to be mediated from cytokine and complement release. Acute and chronic inflammation can stimulate bone marrow granulocyte production, resulting in an increase in the white cell count.
Examples include gout, rheumatoid arthritis and ulcerative colitis. Occasionally, there may be a marked increase in reactive white cells (>50 x 109/L) with ‘left shift’ in the blood; this is termed a ‘leukaemoid reaction’. Leukaemoid reactions can also be seen in severe septicaemia, pancreatitis and malignancies. The main differential diagnosis of a leukaemoid reaction is chronic myeloid leukaemia. A variety of medications can cause an increase in the peripheral neutrophil count. Common examples include gluco-corticosteroids (e.g. prednisone, dexa-methasone), lithium and granulocyte colony-stimulating factor. Physiological stress (such as vigorous exercise, seizures and acute myocardial infarction) can lead to a transient increase ieutrophils. This is thought to be due to the release of catecholamines, adrenaline and cortisol, which shifts more neutrophils into the circulation.
A moderate neutrophilia and lymphocytosis can be associated with either congenital or post-surgical asplenia, due to the absence of the spleen, which acts as a storage pool for neutrophils. The congenital causes for neutrophilia are very rare. Congenital idiopathic neutrophilia is a chronic form of leukocytosis in people who are otherwise healthy. The other blood counts are normal and there is no associated clinical disease. Leucocyte adhesion deficiency is another rare congenital disorder of neutrophil function. As a consequence, neutrophils are unable to leave the circulation in response to sites of infection, resulting in recurrent infections (mainly skin abscesses).
Malignant causes. Chronic myeloid leukaemia (CML) is a common myeloproliferative disease. In the chronic phase of CML, the peripheral blood shows a marked leucocytosis, usually >100 x 109/L. This is due to increased marrow production and results in the presence of granulocytes at different stages of maturation, in particular, mature neutrophils and myelocytes. Chronic neutrophilic leukaemia is a very rare myeloproliferative disorder characterised by sustained peripheral blood neutrophilia. Diagnosis is by excluding other causes of reactive neutrophilia and other myeloproliferative diseases. Polycythemia vera is a clonal haematopoietic stem cell disorder that results in an increase in red blood cell production (an increase in haemoglobin and haematocrit). Neutrophilia and basophilia are commonly seen in up to 20% of patients.
Lymphocytosis. Lymphocytosis is an absolute increase in the lymphocyte count above the reference range for a given age in a healthy individual. The normal absolute lymphocyte count is higher in childhood. This usually persists until age 4-6, following which the count falls to within the adult range. Therefore, it is important to use age-specific ranges when dealing with children. The various causes of lymphocytosis can be classified into malignant and reactive causes.
Reactive causes. Reactive lymphocytosis refers to lymphocytosis in a patient who does not have an underlying haematological disorder, with the lymphocytosis being a secondary reaction to infections, stress or other medical conditions. When this resolves, the lymphocyte count should normalise. Reactive lymphocytosis occurs during the course of many viral infections, including infectious mononucleosis (caused by the Epstein-Barr virus), rubella, cytomegalovirus, varicella and herpes zoster. One of the most common causes is EBV infection, in which there is often a characteristic reactive lymphocytosis. The peripheral lymphocyte count may often be as high as 20-30 x 109/L. Diagnosis is often made by a rapid slide test (‘monospot’ test) and/or testing for antibodies (IgG, IgM) specific for EBV.
While bacterial infections are an uncommon cause of lymphocytosis, a well-recognised example is infection with Bordetella pertussis, a gram- negative bacterium that is the aetiological agent of whooping cough. The total lymphocyte count can be up to 15-50 x 109/L. Transient stress-related lymphocytosis can be associated with myocardial infarction, trauma, obstetric complications or status epilepticus.
Malignant causes. Lymphoproliferative disorders occur when there is an increase in a malignant clone of lymphocytes. In chronic lymphocytic leukaemia, there is a clonal proliferation of small B lymphocytes in the peripheral blood, bone marrow and lymph nodes. This is perhaps the most common cause of lymphocytosis in individuals older than 60 years. The lymphocyte count in the peripheral blood is usually defined as >10 x 109/L, and the malignant B cells display characteristic immunophenotype on flow cytometry.A wide variety of lymphomas can occasionally result in a peripheral blood lymphocytosis with morphologically abnormal lymphocytes. Some of the lymphoproliferative disease with distinctive morphological features include mantle cell lymphoma, hairy cell leukaemia and Sezary syndrome – cutaneous T cell lymphoma.
Eosinophilia. Eosinophils play an important role in inflammatory and allergic responses, as well as defence against parasites. Eosinophilia can be due to reactive, idiopathic or malignant causes. Information regarding allergic symptoms, travel history, current and recent medications, and constitutional symptoms help when trying to work out the underlying cause of eosinophilia. For patients at risk of parasitic infections, stool specimens should be examined for ova, cysts and parasites. Eosinophilia may also occur as a reaction to lymphoid malignancies, espec-ially Hodgkin lymphoma and acute lymphoblastic leukaemia. The hypereosinophilic syndrome is defined by persistent eosinophilia >1.5 x 109/L (for more than six months); the absence of other causes of eosinophilia; and heterogeneous organ involvement (heart, lungs, skin).
Monocytosis. Monocytes comprise less than 10% of leucocytes. The most common causes of a reactive monocytosis are infections and inflammatory conditions. Malignant causes of monocytosis include: chronic myelomonocytic leukaemia: this is a chronic haematological condition which has features of both myelodysplasia and myeloproliferation. Peripheral blood monocytosis (>1 x 109/L), dysplasia involving one or more myeloid lineages, and splenomegaly are common features. The median age of diagnosis is 65-75 years. Acute leukaemia: two subtypes of acute myeloid leukaemias can present with an elevated peripheral monocyte count. Juvenile myelomonocytic leukaemia: this is a very rare clonal haemopoietic disorder affecting children, usually younger than three years, although the age of presentation can range from one month to adolescence. Apart from a monocytosis (>1.0 x 109/L), other associated features include anaemia, splenomegaly and, occasionally, hepatomegaly.
Leukopenia. Neutropenia. A decrease in the total white cell count is invariably due to a decrease ieutrophils and/or lymphocytes. Neutropenia may be an isolated phenomenon or as part of a pancytopenia. The number of neutrophils in the peripheral blood is influenced by several factors, including age and ethnicity. The degree of neutropenia predicts the infection risk. Neutropenia is often categorised as mild, moderate or severe, based on the level of neutrophils: mild (neutrophil count 1.0-1.5 x 109/L); moderate (neutrophil count 0.5-1.0 x 109/L); severe (neutrophil count <0.5 x 109/L). Patients with severe neutropenia are at increased risk of developing life-threatening infections. Fever or other signs of infection are a medical emergency requiring prompt treatment with broad-spectrum antibiotics.
Primary inherited neutropenias are rare. Recurrent bacterial infections are the only significant consequence of neutropenia and, as noted, the risk is related to the degree of neutropenia. Acquired causes. Chronic idiopathic neutropenia/benign chronic neutropenia is a term used to describe chronic neutropenia for which there is no obvious cause. These patients most often have a benign course despite the degree of neutropenia. It is most commonly seen in women. Neutropenia is an early and consistent feature of megaloblastic anaemia due to either vitamin B12 or folate deficiency. There is usually associated macrocytic anaemia and thrombocytopenia.
Chemotherapy is the most common cause of drug-related neutropenia. The degree and duration of neutropenia is dependent on the agents used and the intensity of chemotherapy, combined with the patient’s pre-treatment bone marrow reserve. Certain groups of patients are at particular risk. These include the elderly and those with significant comorbidities, such as liver and renal dysfunction. Non-chemotherapy drugs can also cause neutropenia, either by immune-mediated destruction of circulating neutrophils, or by dose-dependent marrow suppression. The neutropenia usually develops within 1-2 weeks of starting the drugs. Drugs commonly associated with neutropenia include: psychotropic drugs (clozapine); anti-thyroid drugs (carbimazole, propylthiouracil); NSAIDs; anti-convulsants (phenytoin, valproate, carbamazepine); and antibiotics (vancomycin, cephalosporins).
An isolated neutropenia can be seen in patients with various autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and autoimmune haemolytic anaemia. Moderate to severe neutropenia can occur in newborn infants secondary to the passive transfer of maternal IgG antibodies directed against fetal neutrophils. The neutropenia is usually noted in an otherwise normal infant and usually resolves without significant sequelae.
Pure white cell aplasia is a very rare disorder characterised by the complete absence of granulopoiesis in the bone marrow. It is often associated with a thymoma. Hypersplenism. Diseases associated with splenomegaly and neutropenia include sarcoidosis, Gaucher’s disease and rheumatoid arthritis (Felty’s syndrome). In most cases, the neutropenia is not severe enough to warrant splenectomy.Infectious diseases Although the most common reaction to a bacterial infection is neutrophilia, occasionally, neutropenia can occur. Certain infections, such as typhoid fever, shigella enteritis and tuberculosis, are classically associated with neutropenia.
Lymphocytopenia. Lymphocytopenia is less common than neutropenia. The most common cause of lymphocytopenia is part of an acute response to stress (e.g. burns, infections, surgery and trauma) Lymphocytopenia is characteristic of HIV infections with an absolute reduction in CD4-positive T cells. As the disease progresses, there is increasing severity of lymphocytopenia. Lymphocytopenia can also be a feature of Hodgkin lymphoma, with a lymphocyte count of less than 0.6 x 109/L associated with an adverse prognosis. Congenital forms of lymphocytopenia include severe combined immuno-deficiency syndromes, which lead to a profound deficiency in B and T lymphocytes.
