Introduction to the Physiology and Pathophysiology of the Hematopoietic System
Date: Thursday, January 15, 2009 @ 04:49:32 :: Topic: Hematology
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).
Cell Systems
All blood cells derive froma 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.
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 can no 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.
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.
Principles of Regulation and Dysregulation in the Blood Cell Series and their Diagnostic Implications
Quantitative and qualitative equilibrium between all blood cells is maintained under normal conditions through regulation by humoral factors, which ensure a balance between cell production (mostly in the bone marrow) and cell degradation (mostly in the spleen, liver, bone marrow, and the diffuse reticular tissue).
Compensatory increases in cell production are induced by cell loss or increased cell demand. This compensatory process can lead to qualitative changes in the composition of the blood, e.g., the occurrence of nucleated red cell precursors compensating for blood loss or increased oxygen requirement, or following deficiency of certain metabolites (in the restitution phase, e.g., during iron or vitamin supplementation).
Similarly, during acute immune reactions, which lead to an increased demand for cells, immature leukocyte forms may appear (“left shift”).
Increased cell counts in one series can lead to suppression of cell production in another series.
The classic example is the suppression of erythrocyte production (the pathomechanical details of which are incompletely understood) during infectious/toxic reactions, which affect the white cells (“infectious anemia”).
Metabolite deficiency as a pathogenic stimulus affects the erythrocyte series first and most frequently.
Although other cell series are also affected, this series, with its high turnover, is the one most vulnerable tometabolite deficiencies.
Iron deficiency, for example, rapidly leads to reduced hemoglobin in the erythrocytes, while vitamin B12 and/or folic acid deficiency will result in complex disturbances in cell formation.
Eventually, these disturbances will start to showeffects in the other cell series aswell.
Toxic influences on cell production usually affect all cell series.
The effects of toxic chemicals (including alcohol), irradiation, chronic infections, or tumor load, for example, usually lead to a greater or lesser degree of suppression in all the blood cell series, lymphocytes and thrombocytes being the most resistant.
The most extreme result of toxic effects is panmyelophthisis (the synonym “aplastic anemia” ignores the fact that the leukocyte and thrombocyte series are usually also affected).
Autoimmune and allergic processes may selectively affect a single cell series.
Results of this include “allergic” agranulocytosis, immunohemolytic anemia, and thrombocytopenia triggered by either infection or medication.
Autoimmune suppression of the pluripotent stem cells can also occur, causing panmyelophthisis.
Malignant dedifferentiation can basically occur in cells of any lineage at any stage where the cells are able to divide, causing chronic or acute clinical manifestations.
These deviations from normal differentiation occur most frequently in the white cell series, causing “leukemias.”
Recent data indicate that in fact in these cases the remaining cell series also become distorted, perhaps via generalized atypical stem cell formation.
Erythroblastosis, polycythemia, and essential thrombocythemia are examples showing that malignant processes can also manifest themselves primarily in the erythrocyte or thrombocyte series.
Malignant “transformations” always affect blood cell precursors that are still capable of dividing, and the result is an accumulation of identical, constantly self-reproducing blastocytes.
These are not necessarily always observed in the bloodstream, but can remain in the bone marrow.
That is why, in “leukemia,” it is often not the number of cells, but the increasing lack of normal cells that is the indicative hematological finding.
All disturbances of bone marrow function are accompanied by quantitative and/or qualitative changes in the composition of blood cells or blood proteins.
Consequently, in most disorders, careful analysis of changes in the blood together with clinical findings and other laboratory data produces the same information as bone marrow cytology.
The relationship between the production site (bone marrow) and the destination (the blood) is rarely so fundamentally disturbed that hematological analysis and humoral parameters will not suffice for a diagnosis.
This is virtually always true for hypoplastic–anaplastic processes in one or all cell series with resulting cytopenia but without hematological signs of malignant cell proliferation.
|