Hematopoietic tissue, in adulthood in red bone marrow, at fetal stage of development in liver and spleen, contains pluripotent stem cells, which under the influence of hematopoietic growth factors differentiate into erythroid, myeloid and lymphoid precursors. These stem cells replicate themselves, so that their count is maintained the same during the entire life.
While lymphocytes originating from lymphoid precursors require additional ‘upbringing’ in thymus and bone marrow, and later on are produced not only in bone marrow but also in the spleen and lymphnodes, all other precursor cells proliferate and mature in the bone marrow, and they enter blood from there. These processes are influenced by two renal hormones: erythropoietin, necessary for proliferation and maturation of erythrocytes, and thrombopoietin proliferation and maturation of megakaryocytes and thrombocytes.
Mature erythrocytes are without nucleus and cell organelles. Their lifespan is 110 – 120 days, as compared with neutrophil granulocytes which differentiate from precursors in 7 days but their lifespan is only 10 hours. Stem cell transplantation is of no use to treat disorders of mature erythrocytes.
But it can treat disturbances of erythropoiesis, that normally takes 7 days, with a speed of production of 1.6 million of erythrocytes per second, such as:
1/ insufficient quantity or quality of hematopietic stem cells, i.e. aplastic anemia, with panmyelopathy or acute myeloid leukemia;
2/ temporary, i.e. due to viral infection, or chronic lack of erythroid precursors caused by antibodies against erythropoietin, or against membrane proteins of precursor cells;
3/ lack of erythropoietin due to renal insufficiency;
4/ activation of erythropoiesis suppressing interleukins by chronic inflammations and tumors;
5/ disorders of cell differentiation caused by gene defects, lack of folic acid (reserve in liver for 2 – 4 months) or lack of vitamin B12 (reserve in liver for 3 years);
6/ failure of hemoglobin synthesis.
Genetic disorders of hemoglobin(Hb) are the most common single gene disorder. According to the World Health Organization 5% of world population suffers from various genetic disorders of hemoglobin, and approximately 300, 000 severely disabled homozygotes is born every year.
A 80 years’ old female that suffered from recurrent epistaxis as a result of unsuccessful nasal septal deviation, and resulting persistent anemia, diagnosed by bone marrow biopsy as aplastic because the patient’s bone marrow could no longer compensate chronic blood loss. In 1982 alone the patient received 57 blood transfusions. In December 1982 the 1st fetal cell transplantation of mesenchyme, spleen, liver, bone marrow, was carried out. In 1983 the patient received 25 blood transfusions, and in November 1983 2nd cell transplantation of mesenchyme, liver, placenta, adrenal cortex, bone marrow, was done. In 1984 the patient received 17 blood transfusions, and in November 1984 cell transplantation of mesenchyme, placenta, liver, bone marrow, osteoblasts, was carried out. In January 1985 the patient received 4 blood transfusions, but none for the next 13 months, and in February 1986 the blood count was normal. In February 1986 as a result of severe influenza, the aplastic anemia became active again and patient received two units of packed red cells, followed by fetal cell transplantation of mesenchyme, placenta, liver, bone marrow, osteoblasts. Since that time the patient has been well. 
Genetic disorders of hemoglobin are divided into three groups:
1/ Structural hemoglobin variants with qualitative abnormality, i.e. structural abnormality of polypeptide chains of globin molecules, which amount to about 700.
Sickle cell anemia (drepanocytosis), AR disorder, occurs in Equatorial Africa, and to some degree in Mediterranean region and central India. Substitution of one of 146 aminoacids in the ß-chain of Hb A by a point mutation creates Hb S. This new hemoglobin, different in its physical and chemical properties from Hb A, causes deformation of erythrocytes into a sickle or demi-moon shape. Sickling of erythrocytes is observed only in homozygotes, solely under lower oxygen pressure as found in capillaries and venules. In homozygotes the severe form of the disease occurs: chronic hemolytic anemia with crises caused by obstruction of blood vessels and painful infarcts in various tissues, such as bones, spleen, lungs. Heterozygotes, i.e. carriers of ‘sickle cell trait’, AD disorder, are asymptomatic, but have a partially increased resitance to Plasmodium falciparum, because HbS makes replication of this parasites in erythrocytes difficult.
A 10 years old Turkish boy diagnosed with sickle cell anemia at the age of 5, was brought to the hospital in Germany at the age of 9 ½ from Turkey in moribund condition, with sepsis, pronounced anemia, no response to any treatment. His height was 132 cm, and weight 18 kgm, i.e. there was an extreme cachexia, leg ulcers, bilateral basal pneumonia, hepatomegaly, Hb 4.8g%, Hct 27.2, Erythrocytes 1,76 million, anisocytosis, poikilocytosis, many sickle cells. Stabilization of clinical state by transfusion of whole blood and erythorocyte concentrates was obtained, but sepsis continued unabated. Cell transplantation of spleen and bone marrow was carried out and in 3 days fever of over 40º finally subsided. The same cell transplants were implanted two more times 4 weeks apart. Skeletal abnormalities were corrected within 6 weeks , patient gained 8 kgm, and after 4 months was discharged home. There were no sickle cell crises during the next two years. 
2/ Quantitative abnormality of hemoglobin, i.e. where synthesis of structurally normal globin polypeptide chain is decreased or is absent, known as thalassemias.
alpha-thalassemias are usually caused by a major deletion from a-globin gene, which leads to a blockage of synthesis of a-chain, which affects production of Hb A, Hb F, and Hb A2. Patients suffer from microcytic anemia, icterus, splenomegaly with hypersplenism, as well as frequent infections, ulcuc cruris, cholelithiasis, and folic acid insufficiency. alpha-thalassemia with faulty a-chain leads to death in utero since HbF cannot be produced.
ß-thalassemias are caused by a point mutation in the sole gene for ß-globin chain. In homozygotes a serious anemia appears during the 1st – 2nd year of life since faulty ß-chain causes a lack of HbA. In untreated children growth retardation, icterus, and hepatosplenomegaly appear, as well as recurrent infections, cholelithiasis, and ulcus cruris. In untreated children there are by the age of 10 – 11 hepatic, cardiac, and endocrinologic disorders, as well as growth retardation and delay of sexual maturation due to hemochromatosis. Cell transplantation of spleen, liver, placenta, is advised, if necessary.
3/ Genetically caused persistence of fetal Hb, which is clinically insignificant.
Hemoglobin consists of four subunits and each of them is produced from three components:
a/ protoporphyrin, the lack of which is due to inborn enzymopathies known as porphyrias, or hereditary sideroblastic anemia;
b/ iron: Fe2+;
Properties of Hb depend upon the sequence of aminoacids, 141 in a-chain, 146 in ß-chain. Replacement of a single aminoacid by another one leads to sickle cell anemia, where HbS in its deoxygenated form aggregates, which causes a sickle shape of erythrocytes. Such erythrocytes are inflexible and cannot pass through capillaries, and thereby cause an obstruction of small vessels. HbS aggregation takes a few seconds so that obstruction takes place mainly in capillaries with long passage time, i.e. spleen, vasa recta in renal medulla. With systemic slowdown of blood flow, i.e. shock, or with hypoxia, i.e. high altitude, airplane flight, general anesthesia, obstruction can involve other organs, i.e. heart. Blood vessel obstruction causes further drop of pO2 and thereby additional ‘sickling’, and a ‘vitious circle’, or ‘crisis’, develops.
Hemoglobin can be lost from erythrocytes directly into blood, and this free hemoglobin is destined for degradation. This accounts for about 10% of hemoglobin that is degraded daily. The rest of Hb is broken down when old erythrocytes are removed by the cells of reticulo-endothelial system, i.e. histiocytes, certain splenic cells. Haptoglobin binds Hb in 1:1 ratio, and this complex is quickly taken up by the liver and broken down: in this way iron found in Hb can be preserved.
About 200 billion erythrocytes are broken down per day under normal circumstances, representing the release of about 25 mg of iron, or the volume of 20 mL of erythrocytes.
In principle fetal precursor cell transplantation of stomach/intestine, intestine, bone marrow, exocrine pancreas, placenta, is advised for the treatment of aplastic anemias.
Pernicious anemia is due to the lack of intrinsic factor, a glycoprotein secreted by stomach mucosa, that binds the vitamin B12, also known as extrinsic factor) from food. The complex of intrinsic factor plus extrinsic factor enters the intestine, and there are receptors in the terminal ileum that recognize the complex so that absorption can take place. Pernicious anemia is caused by the atrophy of gastric mucosa, that can be due to autoimmune disease.
Erythrocytes live 120 days when their flexibility, osmotic and mechanical resistance, redox potential and energy production are normal; if abnormal, their survival is shortened, sometimes to a few days, and they are eliminated prematurely.
Causes of corpuscular hemolytic anemias are:
- defects of cell membrane causing hereditary spherocytosis: cytoskeletal defect causes inability of erythrocytes to assume their normal flexible flat ‘target-like’ shape, they are round instead, with lowered osmotic resistance, and thereby prematurely sequestered in spleen;
- enzyme defects that disrupt glucose metabolism of cells, i.e. lack of pyruvatkinase slows down Krebs cycle and OXPHOS with ultimate deficiency of ATP, lack of glucose-6-phosphate-dehydrogenase slows down pentose-phosphate cycle due to which free SH-groups of enzymes and membrane proteins, and phospholipids, are not protected from oxidation, defect of hexokinase leads to the lack of ATP and reduced glutathione;
- sickle cell anemia and thalassemias;
- inborn paroxysmal nocturnal hemoglobinuria with increased sensitivity of erythrocytes to complement, and resulting perforation of cell membrane.
Causes of extracorpuscular hemolytic anemias:
- mechanical damage, i.e. heart valve or arterial prostheses;
- immunological causes: transfusion reaction, Rh-incompatibility between mother and fetus;
- toxic, i.e. snake venoms.
Erythrocytes are phagocytized and digested in macrophages of bone marrow, liver and spleen, as usually.
Heme synthesis, porphyrias
Besides utilization in the structure of hemoglobin, heme is synthetized in nearly all organs and built into myoglobin, cytochrome P450, catalase, peroxidase, cytochromes of the respiratory chain. Lack of heme synthesis means absence of life.
Heme synthesis consist of eight reactions controlled by a heme via negative feedback.
The outcome of disorders of heme synthesis depends upon this negative feedback. If lack of heme cannot stimulate sufficiently the activity of Alpha-ALA-synthase, a sideroblastic anemia develops.
Defects of the enzymes of successive 8 reactions via negative feedback cause an enormously increased availability of ?-aminolevulate, and thereby substrates for all subsequent reactions, leading to primary porphyrias, with onset from birth until 20 years of age. Depending upon their solubility in water or lipids, the intermediary substrates are eliminated via urine, which turns red, or bile.
Acute intermittent porphyria is due to lowered activity of porfobilinogen-desaminase.
There are neurovisceral dysfunctions: tachycardia, nausea, emesis, constipation, and nervous and psychis disorders: pareses, seizures, coma, hallucinations.
Congenital erythropoietic porphyria is due to excess of uroporphyrinogen I, and from that also of coproporphyrinogen I, both of which do not metabolize further and stain diapers red, and later on also teeth. There is photosensitivity and hemolytic anemia.
Porphyria cutanea tarda, rather frequent, where due to light absorption (?=440 nm) by porphyrins O2-radicals are created that damage skin, and non-healing vesicles appear.
Hereditary coproporphyria, with increased levels of ?-ALA and porfobilinogen, that causes nervous, psychic and skin symptoms in children.
Protoporphyria with photosensitivity with burning, itching, skin pain, after UV exposure.
Primary hemochromatosis, AR disorder with incidence 1:400, more common in men, since women lose iron during menstruation. There is a markedly increased absorption of iron in the intestine, serum iron is higher, as well as transferrine iron content. Excessive accumulation of iron in the body, in the parenchymatous cells of liver, pancreas, and other organs, is toxic for cells, with participating creation of oxygen radicals, DNA damage, increased collagen production, triggered by iron. If liver fibrosis and cirrhosis develop, the risk of hepatocellular carcinoma grows 200 x. Pancreatic fibrosis, caused by siderosis, causes lack of insulin and diabetes mellitus. Accumulation of melanin and hemosiderin in sun exposed skin causes ‘bronze diabetes’. Siderosis causes in myocardium a cardiomyopathy with arrhythmias, and heart failure, with fatal outcome in young patients. Treatment is by phlebotomy once a week for 1 – 2 years. If diagnosed early, fetal precursor cell transplantation of intestine, liver, spleen, placenta, exocrine pancreas, cardiomyoblasts, is advised.
Disturbances of hemostasis
System of hemostasis protects against bleeding and blood loss. It consists of plasma factors, platelets and vessel wall. Hemorrhagic diathesis is due to dysfunctions of coagulation or fibrinolytic system, platelets, or vascular wall defects.
Plasma factors are globular proteins of variable molecular weight. Plasmatic disturbances cause common hematomas and intraarticular bleeding, while damaged platelets and vessel wall are the cause of petechiae.
Hemophilia A, the most frequent genetic disorder of hemocoagulation, is XR disorder with incidence of 1:5000 to 1:10000 of newborn boys. Lack of factor VIII causes its failure as co-factor for the activation of Factor X, vitally important in the hemocoagulation cascade. Bleeding is most commonly localized in muscles and large joints of lower extremities, which are usually deformed: hemophilic arthropathy.
In Hemophilia A the risk is 5 – 10 times higher if maternal grandfather was over 40 years of age at the time of conception: since sons are getting chromosome Y from their fathers, mutation of gene for factor VIII must take place in maternal grandfather’s body, and then chromosome X is transmitted via the patient’s mother.
Hemophilia B occurs in 1:70000 of newborn boys, and is due to a lack of Factor IX.
Genetic thromboembolic diseases are the third most common group of diseases with lethal outcome, after myocardial infarction and cerebrovascular accident. They must be considered in repeated thromboembolic episodes in younger patients, in several members of the same family, or with involvement of unusual organs or tissues, and inadequate response to anticoagulants.
The quickly running process of coagulation is controlled by two groups of inhibitors:
1/ System of Protein C:
Activated Protein C resistance due to a mutation in heavy chain FV (‘Factor V Leiden’), present in 3 – 6 % of Europeans, causes thrombofilia predominantly in venous system, and is responsible for ~ 1/3 of all thromboembolic episodes, increased risk of deep venous thrombosis 30 – 140 x in homozygotes, as well as of ileofemoral thrombosis, pulmonary embolism, internal carotid artery embolism, etc., particularly where there is a trigger, such as injury, etc.
2/ Inhibitors of serine proteases:
There can be either their malfunction or an absence of antithrombin III with a loss of inhibition of coagulation factors IIa, IXa, and Xa in plasma.
Acquired coagulopathies are due to liver damage since most plasmatic factors are produced in the liver, or due to hypersplenism, where blood cells are sequestered.
Hemorrhagic diathesis due to platelet disorder develops when production of platelets is limited, or when their breakdown is increased.
Idiopathic thrombocytopenic purpura, or Werlhof disease, is an acute illness appearing 1 – 3 weeks after virus infection, while chronic illness is an autoimmune disease. A 62 years old female suffered of this illness for 42 years, and was hospitalized numerous times for skin and mucosal bleeding, menorhagia, splenomegaly. Fetal cell transplantation of osteoblasts, bone marrow and placenta, was carried out. Spontaneous bleeding stopped in a few weeks and blood platelet count became normal. Three years later the patient was hospitalized with acute cholecystitis and her physician was surprised to find no evidence of thrombocytopenia. Patient died 12 years later of congestive heart failure, but without any bleeding for the last 15 years of her life. 
Inborn thrombocytopenic purpura is AD or AR platelet disorder due to
- membrane defects, i.e. Bernard-Soulier syndrome or Glanzmann-Naegeli hrombasthenia;
- various defects of secretion or storage.
Acquired thrombocytopenia develops with uremia and with dysproteinemias.
Thrombocytopenic purpura due to blood vessel damage includes
- various forms of hereditary von Willebrand disease, with vascular endothelial defect and lack of von Willebrand factor, which leads to dysfunction of platelet adhesion and secondarily a lack of Factor VIII, e.g. von Willebrand Factor is a carrier of Factor VIII.
- inborn purpura simpex, Osler-Weber-Rendu disease, Schoenlein-Henoch purpura, or acquired scorbut from lack of vitamin C.
Dissolution of excessive thrombi is done by fibrinolytic system. Disturbances are either genetic or acquired.
Disorders of hemostasis have been treated by fetal precursor cell transplantation rarely due to availability of various blood transfusion products. Treatment of genetic thromboembolic diseases by fetal precursor cell transplantation should be investigated.
Blood represents 7% of body weight minus fat.