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(From Dr. Coutinho, 15 Sept 2000, by Brian Buschman)
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Hematopoiesis happens in the bone marrow, lymph nodes and spleen. All blood cells come from pluripotent stem cells and differentiate into different colonies. All formed elements of blood come from the stem cells.
The stem cells divide early on into the lymphoid stem series and the myeloid stem series.
1) The organs of the lymphoid series include the thymus, spleen and lymph nodes. They produce T-cells and B-cells.
2) The myeloid tissues are the bone marrow and it produces RBCs, platelets (via megakaryocytes) and granulocytes/monocytes. In an adult the ratio of fat to hemopoetic elements is near 1:1 in the marrow.
Anemias are a reduction below normal limits of circulating, functional RBCs. Anemias are classified by the mechanisms of the anemia. It includes blood loss, increased rate of destruction, and impaired production.
Acute blood loss is simply a loss of volume while chronic blood loss is a change in the mechanisms that causes the rate of destruction to be greater then the rate of production.
With blood loss anemias the blood will be normocytic (normal size) and normochromic (normal color). You can tell blood loss occurred a few days prior because there will be an increase in reticulocytes.
This is a premature destruction of RBCs with accumulation of heme metabolism breakdown products and an increase in erythropoiesis. It can be:
1) Extravascular hemolysis is when the RBCs escape and are eaten by the mononuclear phagocyte system.
2) Intravascular when the hemolysis is in the vascular compartment.
There are two types of mechanisms for the hemolysis:
1) Intrinsic causes are from problems within the RBC such as it has a defective membrane, enzymes system or such.
2) Extrinsic problems are usually acquired and include chemical injury, cell trauma, infections and other causes that are outside the RBC.
Hereditary Spherocytosis is an inherited disorder (autosomal dominant) where thr RBCs become spherical and vulnerable to splenic sequestration.
The problem is that proteins like spectrin which normally bind the cytoskeleton to the PM become interrupted. The cell assumes the smallest shape (a sphere) and it’s surface-to-volume ratio becomes reduced.
Most spherocytosis patients present with anemia, splenomegally and jaundice. They have a mild to moderate hemolytic anemia. As the membrane becomes injured MHC becomes increased. 20-30% of patients will remain asymptomatic.
Morphologically the patient will have spherical RBCs which obviously lack the central zone of pallor. They are digested by the spleen since they are defective and deformed hence the splenomegally. The patient needs a spleenectomy.
Glucose-6-phosphat dehydrogenase deficiency is a X-linked disease that is most common in blacks, Jews and Arab people. G6PD is the enzyme that converts NADP to NADPH which is used to reduce glutathione which protects against Ox-radicals. Problems are associated with Ox-radical damage. When exposed Hb damage makes “Heinz” bodies which are chopped out in the spleen by macrophages. It looks like they just took a bite out of the cell.
This happens 2-3 days after exposure to Ox-compounds. The process lasts until only younger RBCs are left since it only effects the older ones. It is a self-limiting condition. In the recovery phase there are lots of reticulocytes.
There are hundreds of forms but we need to know type A is for African Americans and Type B is the overall most common.
Sickle cell disease is characterized by a point mutation on the Hb gene on chromosome 11. It is prominent in blacks. The pathology is a sickle shape caused by polymerization of the HbS molecule when they are in the deoxygenated state. It causes problems with the membrane including detachment from the cytoskeleton and decreased membrane phosphorylation. (Two diseases cause RBC PM to detach form the cytoskeleton, SCD and hereditary spherocytosis.) The membrane damage causes a loss of H2O and K+ and in increase in intracellular Ca2+.
The severity of SCD is affected by:
1) It will be worse in homozygous individuals and less in heterozygotes since the HbA does not sickle. Also the HbF inhibits sickling.
2) The concentration of Hb. As it goes up so does sickling. Therefore dehydration complicates the problem. IV therapy is important for treating acute attacks.
3) Low pH and O2 increase sickling. Most sickling happens in the periphery for this reason.
Clinically you see:
1) Severe anemia with hyperbilirubinemia and reticulocytosis (elevated reticulocytes count).
2) Increased susceptibility to infections.
3) Painful episodes from ischemic regions during attacks.
4) Manifestation of other symptoms like “hand-foot”, seizures or just about whatever, especially things from ischema.
SCD’s morphology will show anemia, increased bilirubin, thrombosis and capillary stasis. The capillary stasis is caused by capillaries being clogged by the bad cells and the thrombosis from those cells causing internal bleeding.
Bone marrow is hyperplastic. In children splenomegaly can be seen but in adult it shrinks due to clogging of vessels from sickle cells. It effectively results in autospleenectomy.
Thalassemias are a lack of production of either a or b Hb chains. You can have the other one elevated but that is only part of a compensatory mechanism trying to make sufficient volume of the one that is deficient. Thalassemias lead to premature destruction of the RBCs.
Point mutations, not deletions lead to the reduction of b chains. This leads to free, insoluble a chains left as inclusions which causes membrane damage. It shortens the life of RBCs and causes apoptosis of bone marrow precursors.
b-thalassemia causes hyperplasia of marrow from EPO stimulation, impaired bone growth and can cause secondary hemochromatosis.
The major form is a severe abnormal cell where Hb collects in the middle. Individuals are dependent on transfusions. AbF is high. It leads to growth retardation, early death, hepatosplenomegaly. Marrow transplantation is a cure.
The minor form can be mild or completely asymptomatic. There is mild marrow hyperplasia with increased AbA2 levels.
AbA2 is elevated in
the minor but not the major forms.
Normally people, more commonly Asians, have less then the normal four a-chain genes. Under normal circumstances all four contribute equally to the production of a-chains so the loss of one has the same effect as the loss of another. The severity of the disease varies with number of missing genes:
1) There is a silent, asymptomatic, condition resulting from being one gene short.
2) Two missing genes leads to a minor a-thalassemia but few effects.
3) b-chains are elevated when there are three missing a-chain genes.
4) Hydrops fetalis is the condition in which all four a-chains are missing. Hydrops fetalis will lead to fetal death without intrauterine transfusions.
Paroxysomal nocturnal hemoglobinuria is a very rare disorder that is hemolytic due to an acquired defect in RBC membranes. It is likely to have venous thrombosis that is often fatal. PNH is often involved with acute leukemia or aplastic anemia.
Warm antibody hemolytic anemia is the most common form of Immunohemolytic anemia. Half of the cases of WAHA are idiopathic and half of them are secondary to conditions like SLE, lymphomas, drugs, etc.
In WAHA antibodies (mostly IgG) are active at 37o and lead to partial phagocytosis causing membrane damage. For some reason it only leads to a partial phagocytosis. This leads the spleen to get rid of the damaged RBCs and causes splenomegaly.
Cold antibody immune hemolytic anemia is where there is IgM that binds to RBCs at temperatures near freezing, hence it’s called cold agglutinulas. Acute cold agglutinins may be seen in the recovery phase of some mycoplasm pneumonia and infectious mononucleosis. With lymphoproliferative disorders chronic cold agglutinulas may be seen.
Microangiopathic hemolytic anemia, MAHA, is caused by physical damage to RBCs as they squeeze through small vessels. The RBCs may appear as burr cells, helmet cells or triangular cells. This is most common with small vessels caused by:
1) DIC – disseminated intravascular coagulation which is a fibrin deposit that constricts the vessels.
2) TTP – Thrombic thrombocytopenia purpara.
3) HUS – Hemolytic uremic syndrome.
Megaloblastic anemias are caused by problems with DNA synthesis usually from vitamin B12 or foliate deficiently. It is megaloblastic because despite nuclear immaturity there is plenty of RNA produced leading to excess cytoplasmic junk.
Peripheral blood will have varied size and shape (oval) RBCs. Occasionally they will have a nucleus. Anemia occurs because megaloblasts accumulate in marrow taking up the space so there are fewer cells overall to do the hemopoetic work.
Neutrophils are also larger (macropolymorphonuclear) and have more lobes. Neutrophils in megaloblastic anemias tend to have 5-6 lobes.
The bone marrow is hypercellular yet erythropoiesis is reduced due to destruction of cells in the kidney.
Premature destruction of platelets and granulocytes also occurs causing leukopenia and thrombocytopenia.
Vitamin B12 is needed to properly synthesize DNA and it is taken up in the guy with IF that is made by parietal cells. PA is caused by antibodies working to cut off the B12 supply which leads to depleted stores and then to problems. Antibodies may be against:
1) Abs may bind to IF or B12
2) They may prevent the uptake of the IF-B12 complex.
3) They may bind to parietal cells to prevent the production of IF.
The form which binds the parietal cells also cuts off the stomach acid supply an is seen with idiopathic chronic gastritis. It is believed that stomach damage is the cause not a result of the parietal cell Abs.
Being an autoimmune disease PA is associated with thyroiditis and adrenalitis. (Inflammation of the thyroid and adrenal.)
It causes moderate to severe megaloblastic anemia, leukopenia, thrombocytopenia. Other symptoms are neurologic changes, low serious B12, achlorhydria (low HCl) and improvement after B12 therapy.
Folic acid deficiency results in an anemia similar to that of vitamin B12 deficiency but it does not cause neurologic damage.
Iron deficiency anemia. The body stores Fe as hemosiderin and ferritin. Ferritin is a protein-Fe complex. It is a good measure of Fe level. In normal serum ferritin is less then 12mcgms/L but is elevated in Fe overload. Transferrin is what normally transports Fe in the blood.
IDA is most common in toddlers and women of menstruating age. It is caused by:
1) Dietary lack
2) Impaired absorption
3) Increased requirement
4) Chronic blood loss
IDA is a microcytic, hypochromic anemia. It is associated with Plummer-Vinson Syndrome being atrophy of the tongue and concave changes in the nails (koilonychias). The marrow is hyperactive but does not have the Fe to make Hb.
Clinically the symptoms are usually related to the cause of the IDA. Diagnosis is by lab studies with low serum Fe and high Fe binding capacity. Transferrin saturation is low <15%. If Fe is low the number of transferrin receptors on the cells is high.
Anemia of chronic disease. With chronic disease there is impaired RBC production with reduced erythrocyte proliferation. There are three causes of chronic disease:
1) Chronic microbial infection like osteomyelitits.
2) Chronic immune disorders like rheumatoid arthritis.
3) Neoplasms like Hodgkin’s.
There is a low serum Fe level with a collection of macrophages in the marrow. This indicates a problem with the recycling of Fe as the macrophages need to come clean it up.
Aplastic anemia, is a failure of the polypotent stem cells to develop which leads to pancytopenia which is a trio of shortages including anemia, neutropenia and thrombocytopenia. The cause of aplastic anemia is usually idiopathic but some cases are caused by chemicals or infection.
The pathology of aplastic anemia includes:
1) Genetic damage to stem cells.
2) Immunologically mediated suppression that works against some of the cells. This is seen in about 70% of cases and can be helped with immunosuppression therapy.
Morphologically you can see hypocellular bone marrow and granulocytopenia leading to infections that cause hemorrhagic disease.
Clinically aplastic anemia will have a gradual onset and does not have splenomegaly since it does not have damaged cells to remove.
Increased bleeding may be from:
1) Increased fragility o the vessels.
2) Deficient/non-function of platelets.
3) Problems with coagulation.
4) More then one of the above.
Tests for bleeding disorders include:
1) Bleeding time (BT) which tests overall platelet number and function.
2) Platelet count (normal is 150,000-450,000)
3) PT (prothrombin time) tests for the presence of factors in the extrinsic and common pathways. (I, II, V, IIV, X)
4) PTT (partial thromboplastin time) tests for the presence of factors in the intrinsic and common pathways including I, II, V, IIV, IX, X, XI, XII.
Thrombocytopenia is a deficiency of platelets. Less then 150,000 but if the level drops below 20,000 spontaneous bleeding occurs. A patient will have prolonged BT but will have normal levels of PT, PTT. There will be bleeding of the skin, mucus membranes, GI and GU.
Idiopathic thrombocytopenia purpara is an autoimmune where IgG is produced against GpIIb-IIIa or GpIa-IX. Antibodies are on the surface and can lead to phagocytosis of the platelets. Splenectomy can be beneficial so it takes fewer cells out of the circulation.
Clinically there are increased megakaryocytes in marrow to make up for the defective platelets. The spleen also appears normal but it’s sinusoids get clogged with the accumulation of platelet globs. Since it’s a problem with platelets the PT and PTT will be normal but BT will be prolonged. With the bleeding problems bruising comes easily and patients bleed from the nose, gums and have an increased menstrual blood flow. It is seen three times more commonly in women then men.
Secondary forms of ITP may be seen in AIDS, SLE, post-viral and after drug therapy.
Acute idiopathic thrombocytopenia is a childhood disease with abrupt thrombocytopenia usually following a viral infection. It is usually a self-limiting disorder that resolves itself in 6 months or less but it can progress to a chronic disorder.
This includes HUS (hemolytic uremic syndrome) and TTP (Thrombotic thrombocytopenia purpara).
These are usually seen in adult women with a collection of symptoms including:
1) Thrombocytopenia
2) MAHA – microangiopathic hemolytic anemia.
3) Renal failure
4) Transient neurologic deficits
They are initiated by endothelial injury or activation of intravascular thrombosis. The things that cause thrombosis.
There are three broad classes of platelet disorders:
1) Defects of adhesion such as Bernard-Soülier syndrome which is an inherited deficiency of GpIb-IX.
2) Thrombasthemia is a defective platelet aggregation.
3) Storage pool disorder which is a disorder of platelet secretion (degranulation).
1) Aspirin and NSAIDS block cycloxygenase and suppress secretion (degranulation).
2) Uremia
It is a complex between VIII and vWF that works to activate X in the intrinsic pathway.
It’s receptor is the GpIb and it helps to stabilize factor VII. vWF is made by endothelial cells and megakaryocytes. It’s shortage is vonWillebrand’s disease which is autosomal dominant. It has spontaneous bleeding with prolonged BT.
Types 1 and 3 have reduced vWF.
Type 2 is defective vWF.
If vWF is low then VIII will also be in short supply in the blood.
An x-linked reduction in factor VIII which activated (with the help of vWF) the intrinsic pathway (X).
Clinically BT, platelet count and PT are normal but PTT is prolonged. Patients will have increased bruising.
Decreased IX (Christmas factor) via x-linked means. It is similar to hemophilia A. It again has normal platelet count, BT and PT but prolonged PTT.
Hemophilia B can present with hemorrhage or can be asymptomatic.
Disseminated intravascular coagulation has two major mechanisms by which it works.
1) Release of tissue factor or thromboplastic substances cause systemic coagulation.
2) Widespread endothelial injury.
Either case would cause lots of thrombosis all over the body.
It can lead to hemorrhagic diathesis from consumption of platelets and clotting factors. It can induce widespread fibrinolysis that can interfere with needed clots. In general it just messes up hemostasis.
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