FC Flashcards
What is the general definition of anemia and how is it diagnosed?
Anemia can be defined as decreased hemoglobin content in red blood cells which implicates a potential condition of hypoxia of tissues generally counterbalanced by a series of compensatory mechanisms such as increased blood flow leading to tachycardia.
In order to diagnose anemia we have to look at specific threshold values of hemoglobin which change according to the sex of the patient:
• Men Hb < 13 g/dL
• Women Hb < 12 g/dL
Why is there a difference in the diagnostic threshold of Hb between men and women?
The difference is due to the effect of female steroid hormones which, acting on kidneys, induce a reduction of water filtration and a consequent accumulation of liquids : it is especially evident during first weeks of pregnancy, when there is a loss of 1.5/2 g of hemoglobin due to estrogens.
A common condition of reduction of hemoglobin occurs in fertile women even during menses when, due to the loss of blood, its value decreases to 10.5-11 g/dL.
What are some general clinical signs and symptoms of anemic patients?
Pallor, jaundice and petechiae in the skin. In black patients we may check the palms of hands or the conjunctiva.
Compensatory tachycardia. Splenomegaly due to spleen overload.
What are 1st level diagnostic tests? What are some important parameters?
Full blood count is important as it gives us Hb levels and other parameters. EDTA is used as an anticoagulant, hemolysis is induced putting the blood in a hypotonic solution so they lyse.
MCV : Mean Corpuscular Volume, defines how small or large on average are RBC giving us DDX between macrocytic and microcytic anemia.
RDW : RBC Distribution Width, measure the range of variation of the RBC volume.
What are reticulocytes? How are they measured and why are they important?
In case of presence of reticulocytes a certain increase in RDW will be seen (second peak). Reticulocytes, so called because they contain a reticular network of ribosomal RNA in the cytoplasm, are obtained during the last step of erythropoiesis in the bone marrow, and they are larger than normal red blood cells. They are counted through flowcytometry which should be always performed in order to assess the cause of anemia:
• Reduced production of RBCs : low levels of reticulocytes
• Increased destruction of RBCs (by hemolysis or haemorrhages) : high levels of reticulocytes
in a condition known as reticulocytosis, which arises as result of increased erythropoiesis induced to compensate the anemic state.
What are reticulocytes? How are they measured and why are they important?
They are immature RBCs that develop in the BM and then are released into the blood stream where they take a day to mature into RBCs. In case of presence of reticulocytes a certain increase in RDW will be seen (second peak). Reticulocytes, so called because they contain a reticular network of ribosomal RNA in the cytoplasm, are obtained during the last step of erythropoiesis in the bone marrow, and they are larger than normal red blood cells. They are counted through flowcytometry which should be always performed in order to assess the cause of anemia:
• Reduced production of RBCs : low levels of reticulocytes
• Increased destruction of RBCs (by hemolysis or haemorrhages) : high levels of reticulocytes
in a condition known as reticulocytosis, which arises as result of increased erythropoiesis induced to compensate the anemic state.
What is anisocytosis and poikilocytosis?
Anisocytosis is the presence of RBCs of different volumes while poikilocytosis is the presence of RBCs of different shapes.
What are schistocytes?
A schistocyte is a fragmented part of a red blood cell. Schistocytes are typically irregularly shaped, jagged, and have two pointed ends. They are reliable indicators of microangiopathy anemia.
What are second level diagnostics?
If the 1st level diagnostic tests cannot help us to find a diagnosis, we may go on through the second level blood tests which involve molecular tests as PCR or next generation sequencing in order to detect mutations associated with hereditary problems.
What is bone marrow aplasia? What are some examples? What can it be caused by?
Bone marrow aplasia refers to those hematologic conditions that are caused by a marked reduction and/or defect in the pluripotent or committed stem cells, or the failure of the bone marrow microenvironment to support hematopoiesis. The clinical outcome is anemia, leukopenia, and/or thrombocytopenia.
• Aplastic anemia : Occurs when the bone marrow doesn’t produce RBCs, WBCs and platelets anymore.
• Pure red cell aplasia : It is just limited to the erythroid lineage, meaning that the bone marrow stops producing RBCs only.
Bone marrow damage can be caused by : Autoimmune disorders, radiotherapy, chemotherapy, toxic drugs and viral infections such as Parvovirus, CMV or HHV-6.
What is CMV and why is it important?
Cytomegalovirus it is mild and presents flu like symptoms. It resides in macrophages and endothelial cells in all organs especially bone marrow, liver, spleen and brain. Immunosuppression by chemo or other toxic agents can cause reactivating of virus and specifically starts to infect HSC.
What are some deficiencies in constitutive factors?
Deficiencies in constitutive factors : B12, Iron, Folate, B6, B1 and proteins.
Macrocytic anemia : Caused by deficiencies in B12 and Folate.
Microcytic anemia : Caused by iron deficiency.
Haemolytic anemia
What is haemoglobin?
Haemoglobin is a tetramer composed by 4 globins and 4 eme-groups each of which is made in turn by protoporphyrin bound to ferrous iron (Fe2+) and 1 molecule of O2.
Haemoglobin undergoes a switch from the fetal to the adult kind changing the 2 globin chains which are coupled with the alpha ones:
• Hb F fetal type
• Hb A adult type
• Hb A2 variant of the normal adult type
This switch occurs as result of an epigenetic process which consists in activation of repressor of gamma gene called BCL11, following the exposure to high oxygen content. If we knockout the BCL11 the gamma gene starts to produce again the gamma chain.
How do the sites of hematopoiesis vary according to age?
In the prenatal age it occurs early on in the yolk sac followed by spleen and liver. The liver is the main site in the prenatal age. Then after birth the BM takes place.
What are hemoglobinopathies? How are they classified?
They are disorders of Hb, nearly always hereditary and can be asymptomatic, mild, severe or even cause death in utero.
They are distinguished based on qualitative (Sickle cell anemia) and quantitative (B thalassemia) dysfunctions.
Structural defects include abnormal variants of HB like HB s and HB c. Quantitative defects include a reduced glob in chain synthesis.
How are erythrocytes infected by malaria and what is the pathogenic mechanism?
P. Falciparum is the worst parasite causing malaria. It depletes the RBCs of ATP as it is needed for its Krebs cycle. The RBCs then explode due to lack of energy. Specific drugs are used to inhibit the plasmodium from competing for the ATP.
What is sickle cell disease? What due patients with this disease risk?
RBCs who bare the SS mutation have a sickle cell appearance due to the Hb that looses the capacity to be in solution and precipitates. Since they loose their ability to go in any kind of tissue the can cause thrombi. The main sites of a vaso occlusive crises are lungs, bone, liver and spleen.
SCD is associated to Sepsis, the major cause of death, because the enlargement of the spleen impedes its from properly phagocytosing circulating bacteria.
Stroke is also highly associated due to thrombi.
What are some prognostic factors and criteria in SCD patients?
- Number of crises in a year: more than 8 crises in a year (quite every month) for example, is a strong indicator of severity.
- Brain MRI. The MRI of a patient with a severe form and high risk of developing large strokes, we can see very small strokes, so if an MRI appears clean-> no risk; if it has several spots of infarction which are asymptomatic, it’s an indicator for severity.
Negative prognostic factors : Dactylitis within 1 year of age, WBCs > 13,000/mm3 within 10 years), Hb < 7 g/dL within 2 years, Hb-F < 8.6%-> an Hb-F higher is positive (protective) prognosis, Frequent pain crisis, Pulmonary crisis, neurological crisis and lack of response to hydroxyurea.
What if a patient only has one copy of Hb-S?
Heterozygosis for Hb-S, usually no clinical problems, can present with hematuria and isostenuria (incapacity to concentrate urine) due to renal papillary necrosis. Patients need to keep hydrated and avoid strenuous physical exercise.
What is Beta Thalassemia? What are the different mutations? Difference between homozygous and heterozygous patients?
Beta thalassemia is a quantitative defect. There is a genetic mutation that results in reduced or absent synthesis of the Hb’s b chain and associates to a variety of clinical manifestations. We can have different mutations which can can be : Beta 0 with no production of b chain or Beta+ were there is some production but less than normal.
A heterozygous patient is asymptomatic or presents very mild symptoms while homozygous patients presents thalassemia major.
How is Beta Thalassemia classified?
Beta-thalassemic patients are distinguished in three groups: beta-thalassemia minor, intermedia and major.
Patients affected by beta-thalassemia minor are heterozygous carriers of the thalassemic mutation. Beta thalassemia intermedia patients are anemic but not transfusion dependent which is the most important factor in determining the severity of the disease. Nowadays it’s called Non transfusion dependent thalassemia (NTDT).
Beta-thalassemia major, ( TDT-> transfusion dependent thalassemia), patients carry a homozygous mutation and are transfusion-dependent. Transfusions are required to
bring Hb levels to normal values and to avoid all the beta-thalassemia- related complications.
What is hemosiderosis? Why is it associated to blood transfusions in Beta Thalassemic patients?
Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin. There are different types, the one associated to B thalassemic patients is called transfusional hemosiderosis.
The accumulation of iron due to frequent transfusions, which the body cannot physiologically eliminate, can cause cardiomyopathies, impairment of endocrine glands and liver damage.
What is the effect of chemotherapy on neutrophil count? How does it change based on the dose? Is it reversible?
The effect of chemo on neutrophil count is dose dependent. A small dose will induce small drop in peripheral neutrophil count, probably wouldn’t even reach the threshold for neutropenia. A medium dose results in absolute neutropenia and a 10% higher chance of neutropenic fever. A higher dose would approach 0 neutrophil count.
Chemotherapy affects only the progenitor cells and not the stem cells. Therefore after chemotherapy is interrupted, the progenitors and the mature cells are recovered. In other words it is an induced reversible aplasia.
What is a Myeloablative regimen of chemotherapy?
If we increase the dose even further, for example 100 times, then we reach the so-called myeloablative regimen. This means that the count will reach 0 and never recover, even upon interruption of the therapy. Plotting the dose of chemotherapy against days of aplasia. As the dose of chemo increases, also the length of aplasia increases : It is a direct correlation. This is true up to a point where the dose becomes so high that the days of aplasia become infinite, in other words recovery will never occur.
