Hematology

Hematopoiesis
Haematopoiesis describes the process by which the cellular components of the blood are
formed. The predominant site of haematopoiesis is the bone marrow. Here we find the
multipotent hematopoietic stem cells (HSCs). The HSCs are able to differentiate into both
myeloid or lymphoid cell lineages. Furthermore, the ability to self-renew facilitates continued
production of blood cells. Haematopoiesis is essential to the continued production of all blood
cell lineages. Three major cell types exist; red blood cells (erythrocytes), white blood cells
(leucocytes) and platelets (thrombocytes).
https://commons.wikimedia.org/wiki/File:Hematopoiesis_(human)_diagram.png
• Blood is composed of haematocrit and plasma:
• Haematocrit (45%): composed of erythrocytes and it is the densest
component of blood.
• Plasma (55%): composed of water (primary component), protein
(e.g. albumin, immunoglobulins, fibrinogen) and non-protein
components (e.g. vitamins, lipids, hormones).
• Buffy coat (<1%): contains leucocytes and platelets.

The regulation of haematopoiesis is dependent on glycoprotein

growth factors, which drive the proliferation and differentiation of
progenitor cells.
Examples of growth factors include:
• Erythropoietin (EPO)
• Thrombopoietin (TPO)
• Interleukins (e.g. IL-3, IL-6, IL-7, IL-11) https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.istockphoto.com%2Fillustrations%2Fblood-test-tube&psig=AOvVaw2LTRRDUr-
i_KsD_fQh_WDi&ust=1668357459452000&source=images&cd=vfe&ved=0CBAQjRxqFwoTCMiw0_-JqfsCFQAAAAAdAAAAABAX

• Colony-stimulating factors (e.g. M-CSF, G-GSF)

• Negative regulators (e.g. TNF-alpha, TGF-beta)
Anemias
 Anemia
Anemia occurs when the haemoglobin (Hb) concentration is too low.

Anemia can be classified according to severity into:

1) Mild: ♀ Hb 12.0 - 10.0 g/dL, ♂Hb 13.0 - 10.0 g/dL.

2) Moderate: Hb 9.9 - 8.0 g/dL.
3) Severe: Hb 7.9 - 6.5 g/dl.
4) Life-threatening: Hb <6.5 g/dL.
 Signs and symptoms
Reducing the amount of oxygen delivered to the tissues can be manifested by:
1) Dyspnea.
2) Decreased exercise tolerance.
3) Fatigue.
4) Tachycardia.
5) Pale skin.
 Diagnostic management
The order of the diagnostic approach to an anemic patient:

1) Establish mean blood cell volume (MCV).

2) Determination of the mechanism of anemia: on the basis of the absolute reticulocyte count (RET).
3) Establish a detailed cause within a specific mechanism.
 Types on anemia

The mean corpuscularvolume (MCV) describes the mean volume of erythrocytes and is measured in
femtolitres (fL).
The standard range for erythrocytes is 80-100fL (sometimes the norm is defined as 82-99fL). In
accordance with MCV, we distinguish anemia:
1) Microcytic <80 fL
2) Normocytic 80-100 fL
3) Macrocytic >100fL
https://www.khanacademy.org/test-prep/mcat/biological-sciences-practice/biological-sciences-practice-tut/e/a-clinical-approach-to-
anemia--solve-the-case
Microcytic axnemia
Hemoglobin occupies more than 90% of the erythrocyte volume.
The reduction in the volume of the red blood cell indicates a defect in its synthesis.
Microcytic anemia is characterized by a reduced red blood cell volume due to insufficient
production of Hb:

↓ MCV
(MCV <80 fL)
Microcytic anemia
Hemoglobin synthesis may be lowered due to:

1) Insufficient amount of iron reaching the bone marrow:

- iron deficiency anemia,

- anemia of chronic diseases.

2) Impaired heme production:

- sideroblastic anemia.

3) Impaired a/b globin synthesis:

- alpha and beta thalassemia.
Iron deficiency aneamia

It is the most common type of anemia and it accounts for approximately 60–80% of all
cases. Due to the insufficient amount of iron, the synthesis of heme and hemoglobin is
reduced. The resulting erythrocytes are smaller than normal due to the lower hemoglobin
content.
 Iron deficiency anemia
The main causes of iron deficiency are:

1) Chronic blood loss

2) Increased demand with insufficient iron supply

3) Impaired iron absorption (Crohn disease, after gastrectomy etc.)

4) Dietary deficiency (malnutrition)

5) Helicobacter pylori (competes for iron and impairs its absorption, causing anemia by atrophic inflammation
of stomach epitelium and consequent hypoacidity)
Iron deficiency anemia (IDA)
It's best to start the differential diagnosis of microcytic anemia with

assessment of iron stores. The following tests are used for this:

1) Iron (Fe) concentration - LOW

2) Total iron binding capacity (TIBC) - HIGH

3) Ferritin concentration - LOW

 Iron deficiency anemia – signs and symptoms
1) General symptoms of anemia - tachycardia, paleness, dyspnea, conjunctival pallor etc.

2) Signs and symptoms characteristic of iron deficiency anemia:

- Abnormal appetite (pica; appetite for clay, chalk, starch, ice, soil, paper)

- Glossitis (pain, burning and smoothing the surface of the tongue)

- Dry skin, nail changes (pale, brittle, with longitudinal grooves, koilonychia-spoon-shaped nails)

- Painful cracks, inflammation of the corners of the mouth (angular stomatitis, cheilitis)

- Restless legs syndrome (RLS)

Iron deficiency anemia - blood smear
↓ Hb; ↓ MCV; ↓ reticulocyte count !but! high erythroblastic
renewal in the bone marrow due to ↑EPO stymulation as a
compensation to a lower oxygen supply in anemia;

↑ RDW (red blood cell distribution width)

Low RBC, MCH, MCHC and high PLT (Iron is responsible for
thrombopoietin suppression, if there is an iron deficiency the
thrombopoietin levels are higher and stimulate platelets
production)

In a peripheral blood smear, erythrocytes are:

- hypochromic,
- various sizes (anisocytosis), including microcytic,
- different shapes (poikilocytosis).
Iron deficiency anemia

First of all, we determine the cause:

1) Endoscopy of the upper and lower gastrointestinal tract

2) Screening for helicobacter pylori
3) Test for occult blood in the stool
4) Screening for celiac disease
5) Urinalysis
6) Gynecological examination
Iron deficiency anemia

Treatment:

Oral iron preparation in a dose corresponding to 50–100mg of elemental iron daily. The
effectiveness of treatment is demonstrated by the increase in the number of reticulocytes after
~7 days and the increase in hemoglobin by 1-2g/dL in ~2 weeks after iron administration. The
treatment is continued for 3 months after Hb and ferritin levels are normalized.
In patients with very high iron loss or intolerance of oral iron preparations it should be given
parenterally (intravenous administration).
Syderoblastic anemia

It is caused by a congenital or acquired disorder of heme synthesis.

In this type of anemia, iron does not get incorporated into the protoporphyrin ring,
preventing hemoglobin from forming.
As a result, microcytic hypochromic anemia develops.
The unused iron in the bone marrow accumulates in the mitochondria of the erythroblasts in
the form of a ring around their nuclei → we call them ring sideroblasts. The unused iron
accumulates in the body causing a secondary hemochromatosis with multi-organ dysfunction.
Signs and symptoms:
- General symptoms of anemia tachycardia, paleness, dyspnea, conjunctival pallor etc.
- Symptoms of iron overload (hemochromatosis): gray-to-brown mucocutaneous
hyperpigmentation particularly in sun-exposed parts of the body, impaired glucose tolerance
and diabetes, arrhythmias, cardiomyopathy, heart failure, hepatomegaly
or cirrhosis, splenomegaly, arthropathy, adrenal insufficiency
Syderoblastic anemia
↓Hb, congenital:↓MCV, acquired:↑MCV, ↑RDW, ↓ reticulocyte counts.
↑ Fe; N/↓ TIBC;↑ Ferritin.
In the bone marrow, sideroblastic iron is stored in red blood cells in the form of ring
sideroblasts. In the peripheral blood, many erythrocytes contain Pappenheimer bodies.
Congenital form → vitamin B6 at a dose of 50-100mg/day.
Acquired form → removing the cause.
To combat iron overload - chelating drugs (desferrioxamine). Severe cases → RBC transfusions.
 Thalassemia
It is a disorder of hemoglobin synthesis caused by a congenital defect in the synthesis of globin chains. The most
common disorders are alpha-thalassemia and beta-thalassemia. As a result of an imbalance in the number of
globin chains, erythrocytes they are microcytic and hypochromic. Toxic inclusions of a poorly synthesized chain
cause the breakdown of erythroblasts. Aggregation of deficient globin chains leads to the breakdown of red
blood cells in the marrow and spleen, which makes this one microcytic anemia is exceptionally haemolytic.
 Thalassemia - symptoms
1) General symptoms of anemia.
2) Symptoms of hemolysis:
- cholelithiasis,
- jaundice,
- enlargement of the liver and spleen.
3) Bone (ex. skull) deformities and osteoporosis due to hematopoietic bone marrow hyperactivity.
 Normocytic anemia
Normocytic anemia is characterized by a normal red blood cell volume.
MCV 80 - 100 fL
Increased reticulocytosis (RET) indicates excessive loss of red blood cells due to haemolysis or external/internal
bleeding. Low reticulocytosis may indicate impaired bone marrow function.

- Anemia of chronic diseases (N or low MCV)

- Hemorrhagic anemia
- Hemolytic anemia (N or sometimes high MCV)
- Anemia in CKD
- Aplastic/hypoplastic anemia (N or sometimes high MCV)
Chronic disease anemia
It is the second most common cause of anemia in the population, after iron deficiency anemia.
The incidence is higher among the elderly. The development of anemia of chronic disease (ACD) is
complex and seems to be a result of immune system mobilization. Three mechanisms have been
known to play a role in ACD: iron reallocation off the serum, impaired proliferation and further
maturation of erythroid progenitors, and reduced life span of erythrocytes. 4–interleukin (IL)-1,
tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-6. Hepcidin serves as a ligand for
ferroportin, which exports iron into the plasma and is present on various cell membranes,
intestinal epithelial cells, macrophages, hepatocytes, and placental cells. Binding of hepcidin to
ferroportin results in internalization and proteolysis of the latter; thus, the iron is trapped inside
the cells, out of reach of erythropoiesis
Chronic disease anemia
States of stimulated cellular immunity with increased production of pro-
inflammatory cytokines and hepcidin result in reduced production of RBC and Hb.
The availability of iron to heme building is reduced by inhibited iron absorption from
the gastrointestinal tract and inhibition of its release from its stores, that is because of
high hepcidin concentration. Circulating cytokines desensitize erythropoietin receptors on
RBC precursors and induce their apoptosis.
Chronic disease anemia
In blood test: ↓Hb (rarely drops <9 g/dL), ↓/N MCV
↓reticulocyte count (RET), also low RBC, MCH, MCHC and high PLT (inflammatory in chronic
diseases stimulates platelets activation). RDW is in the norm.

Abnormalities typical for inflammation are observed: neutrophilia, monocytosis,

thrombocytosis (high PLT), ↑CRP.

Iron parameters:
↓Fe; ↓TIBC; N/↑ Ferritin (acute phase protein)
 Chronic disease anemia
Treatment:

1) Treatment of the underlying disease!!!

2) Severe anemia - consider RBC

transfusion or erythropoietin/darbepoetin to avoid repeatable
transfusions
 Hemorrhagic anemia
It is a consequence of acute or chronic blood loss. Acute blood loss is most often post-trauma hemorrhage or
massive bleeding from the gastrointestinal tract (eg. duodenum/stomach ulcer, esophageal varices or
hemorrhage from sigmoid diverticulum), urinary track or from uterus/vagina.
↓Hb, MCV normal, ↑ reticulocyte counts (peak between days 7 and 10 after bleeding), ↑/N RDW.
Losing >30% of blood leads to symptoms of a hypovolemic shock.
Treatment: Stopping the hemorrhage first. To restore intravascular volume fill with crystalloids 3-5 times the
volume of blood lost until the time when the full blood is available.
 Hemolytic anemia
A type of normocytic/rarely macrocytic anemia.
Hemolytic anemia is a group of diseases that are characterized by reducing the time red blood cells survive from
their breakdown. Coexistence of normocytic or macrocytic anemia with elevated reticulocytosis and elevated
bilirubin, LDH and clinical features of hemolysis raises the suspicion of haemolysis.
Hemolytic anemia
Hemolysis can be extravascular (liver and spleen) as well as endovascular. Increased breakdown of
RBC causes ↑ free hemoglobin in plasma, hemoglobinuria, and ↓ haptoglobin levels. Increased
breakdown of RBC causes ↑bilirubin levels,↑urinary urobilinogen,↑LDH level, and
high reticulocytosis.
Signs and symptoms:
Jaundice, fever, dark urine and darker stool, splenomegaly, cholelithiasis (in patients with chronic
diseases with hemolysis, especially at a young age), abdominal/lumbar pain, and general symptoms
of anemia.
 Congenital spherocytosis
The most common congenital hemolytic anemia, caused by a disturbance in the structure of the erythrocyte
membrane. Erythrocyte survival time is shortened. The disease is usually mild. The main symptoms include:
- slight jaundice,
- splenomegaly
- anemia of varying severity depending on the mutation.
The primary treatment is splenectomy.
 Glucose-6-phosphate dehydrogenase (G-6-PD)
deficiency
Congenital hemolytic anemia

Glucose-6-phosphate dehydrogenase (G6PD) is a house keeping enzyme critical in the redox metabolism of all
aerobic cells. G6PD deficiency is the most common human enzyme defect. Glucose-6-phosphate dehydrogenase
(G-6-PD) deficiency is the most common enzymatic defect causing hemolytic anemia. Disease inheritance is X-
linked, so it affects mainly men. With this mutation, RBCs are unable to eliminate reactive oxygen species and
that leads to hemolysis and shorter survival time or RBCs.
Though majority remains clinically asymptomatic the risk of developing AHA still remains. Symptoms only occur
after exposure to environmental factors, the most important of which are favism beans (favoritism), drugs (e.g.
paracetamol, antimalarial, doxorubicin, nitrofurantoin, sulfamethoxazole, antipyretic, analgesics) and infections.
In case of profound anemia, a transfusion may be necessary. In other cases, folic acid is used.
 Sickle cell anemia
Sickle cell anemia is the most common inherited blood disorder in the world among black race.
It is inherited in an autosomal recessive manner, so its’ inheritance is regardless of gender.
Improperly constructed hemoglobin, the so-called hemoglobin S (HbS), polymerizes, changing the shape
of the blood cell, aggregating and resulting in vessel occlusion (microangiopathy) and hemolysis.
Microangiopathy manifests itself:
- presence of schistocytes in the blood smear,
- recurrent severe pain in the hands and feet (the most common and the earliest symptom),
- embolism of internal organs, priapism,
- splenomegaly.
 Read at home
Other types of hemolytic anemia:

Warm autoimmune hemolytic anemia (AIHA);

Cold agglutinin disease (CAD);
Hemolytic disease of the newborn (HDN);
A hemolytic transfusion reaction;
Microangiopathic haemolytic anemias;
Hemolysis in hypersplenism
Drug-induced hemolytic anemia
 Anemia in chronic kidney disease
Anemia developing in the course of chronic kidney disease is one of the first symptoms of kidney dysfunction.
It is based on:
- Insufficient production of erythropoietin
- Impairment of erythropoiesis and shortened survival of blood cells due to toxic metabolites accumulating in the circulation in
kidney diseases
- Loss of blood during procedures
- Loss of transferrin with urine in patients with nephrotic syndrome
Peripheral blood smear reveals the presence of normocytic, normochromic erythrocytes. Before it is determined that the anemia
is associated with chronic kidney disease, other pathologies should be ruled out.
↓ Hb, MCV normal; ↓ reticulocyte counts (RET); RDW in the standard.
In the course of chronic kidney disease, anemia should be assessed systematically. Identify and treat all equalizable causes of
anemia (including iron deficiency and inflammation) before starting treatment. According to the guidelines of the National Kidney
Foundation, treatment of anemia with erythropoiesis-stimulating drugs (ESA) should be started when the hemoglobin level is
<10g/dL, and then maintain its target concentration within the range of 11-12 g/dl.
 Aplastic anemia
Bone marrow failure resulted from bone marrow hypoplasia or aplasia leading to pancytopenia. The most
common cause is an autoimmune reaction of T lymphocytes against the hematopoietic stem cells. Less
commonly, it is a congenital defect or acquired damage to blood stem cells leading to the inhibition of cell
division and differentiation and the bone marrow becomes replaced with fat. We can divide aplastic anemia
into the following forms:
2) Acquired:
1) Congenital:
- Toxins (pesticides, arsenic and benzene)
- Fanconi anemia, - Radiation, durugs (paracetamol, Non-steroidal anti-inflammatory drugs (NSAIDs),
antibiotics and chemotherapy used to treat cancer
- congenital dyskeratosis,
- Treatments for other autoimmune diseases, such as rheumatoid arthritis (ex.methotrexate) and lupus
- congenital dyserythropoietic anemia, - Pregnancy - sometimes, this type of aplastic anemia improves on its own after childbirth

- Blackfan-Diamond anemia, - Infectious diseases, such as hepatitis, Epstein-Barr virus, cytomegalovirus, parvovirus B19 and HIV

- Sometimes, cancer metastates from another part of the body can spread to the bone marrow and cause
- Shwachman-Diamond syndrome. aplastic anemia.
Aplastic anemia
↓ Hb, MCV normal,
↓↓↓ the number of reticulocytes (RET),
RDW in the standard.
Leukopenia with neutropenia (typically <1500/µl), thrombocytopenia (in severe cases
<10,000/µl), PANCYTOPENIA!!, and the number of hematopoietic cells is reduced in
aspiration biopsy of the bone marrow.
https://onlinelibrary.wiley.com/doi/full/10.1111/ejh.13153
 Pure Red Cell Aplasia (PRCA)
It is a bone marrow failure characterized by profound normocytic anemia, normochromic anemia,
reticulocytopenia and an almost complete absence of erythroblasts in the marrow, in which no other
irregularities are found.
 Macrocytic anemia
Macrocytic anemia is characterized by an increased volume of red blood cells:
↑ MCV
(MCV> 100 fL)
It is best to start the differential diagnosis of macrocytic anemia by finding whether the anemia is megaloblastic
or non-megoblastic. For differential diagnosis we should perform: peripheral blood smear and bone marrow
examination (demonstration of megaloblastic regeneration).
 Megaloblastic Anemia
Megaloblastic anemia is caused by disturbances in DNA synthesis in the cells of the red blood cell system. This
leads to the formation of large precursors of red blood cells (megaloblasts) and their mature forms, megalocytes
and macrocytes. Megaloblastic anemia is caused by a deficiency of vitamin B12 or folic acid. The only source of
vitamin B12 is meat or dairy. Vitamin B12 binds first to transcobalamin I, then to the intrinsic factor (IF) produced
by the parietal cells of the gastric mucosa.
It is absorbed in the ileum.

Every pathology affecting this mechanism, located in stomach or ileum can interrupt the process of B12
absorbtion (eg. Crohn disease, right hemicolectomy, gastrectomy, malabsorption, Addison-Biermer disease,
caused by the presence of autoantibodies directed against the parietal cells of the gastric mucosa or the intrinsic
factor (IF) itself). Other causes include strict vegan diet or infestation with broad fish tapeworm.
 Anemia due to folic acid deficiency
Megaloblastic anemia caused by a deficiency of folic acid necessary for the synthesis of nucleic acids and the
development of red blood cells. The main sources are green vegetables, citrus fruits and meat products. After
absorption from the digestive tract, it is converted to tetrahydrofolate, which requires the presence of vitamin B12.
 Main symptoms and signs of B12 deficiency
General symptoms of anemia and:
-Symptoms from the nervous system (nerve cells) - Vitamin B12 deficiency impairs the synthesis of the myelin
sheath and the production of neurotransmitters:
• Symptoms from central nervous system:
(cognitive impairment, dementia, depression, mania, mood swings, delusions, Lhermitte's sign),
• Symptoms from peripheral nervous system:
(paresthesia of the hands and feet, numbness of the limbs, gait disorders, micturition disorders, vegetative
disorders).
- Skin changes (slightly yellow skin, prematurely gray hair, in some patients acquired vitiligo, rarely
thrombocytopenic purpura),
- Gastrointestinal (impaired function of gastrointestinal epithelial cells) symptoms: loss of taste and weight loss,
burning tongue, nausea, constipation or diarrhoea.
 B12 deficiency - blood smear
↓Hb, ↑MCV
↓ number of reticulocytes (RET)
↑ RDW
Megalocytes (large, mature oval blood cells) and megaloblasts (immature cells) present in the peripheral
blood/bone marrow smear and immature granulocytes with an overly segmented nucleus. Leukopenia with
neutropenia, moderate thrombocytopenia and↓ vitamin B12 concentration or/and ↓folic acid.
 Macrocytic anemia
In many cases, bone marrow examination due to macrocytosis, especially insignificant intensity (100 - 110 fL),
turns out to be normoblastic erythropoiesis. The most common causes of this condition are:
- reticulocytosis after hemolytic and posthemorrhagic anemias,
- hypothyroidism,
- alcoholism.
- chronic liver diseases,
- pathologies of the bone marrow.
 Polycythemia

1. Polycythemia vera,
2. Secondary polycythemia,
3. Gaisbock syndrome
Polycythemia vera
Philadelphia vera - myeloproliferative neoplasm characterized by a marked increase in the number of erythrocytes,
often accompanied by increased production of leukocytes and platelets, associated with a Janus kinase-2 (JAK2)
mutation (tyrosine kinase mutation, which leads to uncontrolled proliferation of erythrocyte progenitors).
Treatment: no need to do a routine bone marrow transplant! May be necessary if it turns into myelofibrosis or
acute myeloid leukemia.
Basic treatment: bloodletting, ASA (to prevent thrombotic events), hydroxyurea, imatynib
 Signs and symptoms
• headaches
• blurred vision
• cyanosis
• TIA and stroke
• thrombosis
• red skin – particularly in the face, hands and feet
• pruritus, especially after a hot shower
• tiredness
• high blood pressure
• dizziness
• discomfort in the abdomen
• confusion
 Gaisbock syndrome (pseudocythemia )
Inappropriate ratio between red blood cells and plasma, the primary cause of
which the blood plasma is reduced. Pseudocythemia is often caused by
hypovolemia (dehydration, diuretic drugs), the loss of body fluids, for
example through burns, dehydration. In this syndrome, which occurs mainly
in obese men (hypoventilation, increased diuresis, hypertension etc.),
hypertension contributes to a decrease in plasma volume, causing a relative
increase in the number of RBCs (pseudocythemia). Due to an increase in
blood viscosity and peripheral vascular resistance, pseudocythemia is
associated with a tendency to develop arterial or venous thrombosis. This
condition subsides after proper hydration of the body.
 Read at home!
Leukocytosis - causes, pathogenesis, symptoms
- neutrophilia, eosinophilia, monocytosis, lymphocytosis

Leukopenia - causes, pathogenesis, symptoms

- neutropenia, lymphocytopenia, eosinopenia
 Hematological neoplasms
There are two main groups-myeloid and lymphoid neoplasms. The main difference between the myeloid and
lymphoid malignancies is the dominant malignant cell line. On the other hand, due to the clinical course,
hematopoietic neoplasms can be divided into two types:
1) Acute - originate from immature cells, their feature is a fast, aggressive course, therefore, patients require
urgent diagnosis and immediate treatment.
2) Chronic - they concern mature cells, the course is slower, may go undiagnosed for years or may be diagnosed
accidentally, during a routine blood test.
 Myeloid neoplasms
Neoplasms of the bone marrow cells of the lineages from which erythrocytes, granulocytes, megakaryocytes
are formed. These neoplasms can be divided into three groups depending on the percentage of blasts in the
bone marrow:
1) Acute myeloid leukemias (AML)
(≥ 20% blasts or specific mutations, no signs of maturation)
2) Myelodysplastic syndromes (MDS)
(6-19% blasts, inefficient maturation)
3) Myeloproliferative neoplasms (MPNs)
(<20% blasts, effective maturation)
Remember! In bone marrow, up to 5% of blasts is the norm, but in the bood test physiologically there should
be NO blasts. 6–19% of blast cells in bone marrow - Myelodysplastic syndromes (MDS); Leukemia - ≥20% of
blast cells in bone marrow!!
 Myeloid neoplasms
Most myeloproliferative neoplasms (MPNs) contain mutations in tyrosine kinases, which stimulate growth
factor-independent proliferation. However, they don't have much of an impact for cell differentiation.
Therefore, they progress over a longer period of time, and the cells neoplastic cells are morphologically
difficult to distinguish from normal cells. Acute myeloid leukemia and myelodysplastic syndromes (AML
and MDS) have an additional mutation that affects the activity of transcription factors responsible for the
proper maturation of the cell.
Acute myeloid leukemia (AML)
Acute myeloid leukemia (myeloblastic) is not one disease but a group of more than 20 diseases, consisting in
uncontrolled proliferation of a cell clone originating in the early stages of myelopoiesis. The disease is caused by
mutations in various genes, on the basis of which AML is then classified. When the mutation is unknown,
leukemia is classified based on the dominant cell type.
The most common acute leukemias among adults. They account for ~80% of acute leukemias in adults and
around 15-20% in children. It is the most common leukemia among newborns. Morbidity increases with age.
The median age at diagnosis is 65–70 years. According to recognition criteria: ≥ 20% blasts (cells with no signs of
cellular maturation) or specific mutations detected ( t(15;17), inv(16) i t(8;21)).
Acute myeloid leukemia (AML)
Signs and symptoms:
General - fever, weakness, night sweats, weight loss, bone pain;
Associated with bleeding disorders due to thrombocytopenia;
Associated with anemia (pallor, tachycardia, dyspnea etc.),
Associated with leukopenia (infections),
Associated with leukostasis (TIA, hypoxia, headaches, vision disturbances),
Associated with tissue infiltration (splenomegaly, gingival hyperplasia, nodular infiltrates on the skin).
 CML
Myeloproliferative disease caused by the clonal proliferation of a neoplastic stem cell, caused by the presence of the BCR-ABL1
fusion gene on the Philadelphia chromosome, due to translocation of chromosomes t(9;22). The product of the BCR-ABL1
gene is the bcr-abl protein, a tyrosine kinase with an increased activity that leads to uncontrolled cell proliferation. CML
accounts for approximately 15% of adult leukemias. The peak incidence falls on the 6th decade of life. The only known
etiological factor is exposure to ionizing radiation. Three phases can be distinguished in the course of the disease:
1) Chronic (CP - Chronic Phase).
2) Accelerated Phase (AP).
3) Blast Crisis (BC - Blast Crisis).

Signs and symptoms:

Weight loss, fatigue, excessive sweating, spleno/hepatomegaly abdominal pain/discomfort)/, symptoms of leukostasis (TIA,
hypoxia, vision disturbances, priapism, headaches and dizziness). Around 50% of cases is asymptomatic and diagnosed
accidentally during a routine blood test.
 Lymphoid neoplasms
Their origin is from a lymphocyte at any stage of differentiation or maturation. They can be divided into:
• Tumors derived from lymphoid precursors (e.g. lymphoblastic lymphoma/leukemia).
• Tumors of mature lymphocytes and plasma cells (further grouped by origin, e.g. CLL or multiple myeloma).
• Hodgkin lymphoma.

Lymphoma B signs – if these occure, the prognosis is worse:

1) Unexplained weight loss of ≥10% in the past 6 months.
2) Unexplained fever (temperature ≥38°C) in the last 2 weeks.
3) Unexplained recurring night sweats.
Lymphadenopathy in lymphomas
Lymphadenopathy is the most common and usually the first noticeable clinical manifestation
of lymphomas. Oncological vigilance should be aroused by the following nodes:

• Enlarged for more than 3 weeks, without infection

• Painless
• Diameter >1cm in a shorter dimension
• Lymph node clusters
• Enlarged supra/infraclavicular lymph nodes
• Painful after drinking alcohol (in some patients with Hodgkin's lymphoma)
• Not movable relative
• Increasing, asymmetric, not diminished by the use of antibiotics
 Acute lymphoblastic leukemia (ALL)
The most common type of leukemia in children - 80%, and around 15-20% leukemias in adults.
Acute lymphoblastic leukemias (ALL) and lymphoblastic lymphomas (LBL) are collectively referred to as B or T
lymphocyte precursor cell neoplasms. According to the WHO classification, both forms are considered the same
disease entity, but they differ in the main location of the infiltrates:
1) ALL → mainly affects blood and marrow
(≥20% marrow blasts),
2) LBL → mainly affects lymph nodes and extranodal tissues
(<20% marrow blasts)
Signs and ymptoms:
1) enlarged lymph nodes and spleen in 50% of patients,
2) osteoarticular pain in 25% of patients,
3) less severe symptoms of anemia and thrombocytopenia, than in patients with AML
4) Very high leukocytosis with domination of lymphoid blasts in the blood smear.
30% of patients are Ph+. If the bone marrow is affected by malignant cells then we can observe
pancytopenia.
 Hodgkin Lymphoma
It is a B-cell cancer of the lymphatic system characterized by the presence of Reed-Sternberg and Hodgkin
cells. The highest incidence rates is among patients in the age of 20–40 years and ≥50 years. Risk factors
for developing Hodgkin's lymphoma include: EBV infection, exposure to ionizing radiation, genetic
predispositions, congenital and acquired immune disorders (including immunosuppression and HIV
infection). In most patients, the first symptom of Hodgkin's lymphoma is lymphadenopathy, including
nodes above the diaphragm (cervical, mediastinal and axillary are most often involved), less often below
the diaphragm (inguinal and retroperitoneal). Deviations in laboratory tests: Normocytic anemia (in 20-
50% of patients). Lymphocytopenia, thrombocytopenia, neutrophilia, eosinophilia (in 10-15% of
patients). Increase in serum LDH or alkaline phosphatase (ALP), increased ESR values.

The basic test is to collect the entire lymph node for histopathological examination. A biopsy is not
performed to obtain the diagnosis, because neoplastic cells account for about 1% of the cells of the node,
and the rest are reactive cells. Performing a biopsy is therefore associated with a high risk of
ommiting cancer cells and not diagnosing lymphoma.
 Non-Hodgkin Lymphomas
A group of neoplastic diseases characterized by clonal proliferation of lymphoid cells corresponding to
different stages of differentiation of normal B lymphocytes, rarely T lymphocytes or natural killer (NK)
cells. Risk factors: Environmental/work-related (exposure to chemicals and pesticides, benzene, asbestos,
ionizing radiation); Viral infections (HTLV-1, EBV, HIV, HHV-8, HCV), Bacterial infections (Helicobacter
pylori), Autoimmune diseases (ex. Sjogren syndrome, celiac disease, lupus), immunodeficiencies, obesity,
and previous chemotherapy, especially in combination with radiotherapy due to a different
neoplasm. Lymphomas can be located in almost any organ, but usually involve the lymphatic system
(lymph nodes, spleen) and bone marrow. NHL are more common in young children than HL. HL is more
common in adolescents. Over 80% of NHL accounts for B-cell lymphomas. Agressive, Diffuse large B-cell
lymphoma (DLBCL) is the most common type of NHL and the most common type of lymphoma in general.

In children, non Hodgkin's lymphomas are most often located in the abdominal cavityor chest. The most
common extranodal locations include the stomach, skin and CNS (typical in HIV+ patients).
 CLL
Chronic lymphocytic leukemia (CLL) / small B-cell lymphoma (SLL)
It is a type of leukemia which originates from a single clone
morphologically mature lymphoid cells with a characteristic immunophenotype - B-cell (CD19, CD20, CD23) and T-cell (CD5).
CLL is the most common type of leukemia in adults in Europe and North America (30-40% of all leukemias in this group). The
diseuse affects elderly, usually >70 years old.
Signs and symptoms:
- Generalized, painless lymphadenopathy.
- Hepato/splenomegaly.
- General symptoms and most patients are asymptomatic at the time of diagnosis, apart from lymphadenopathy
- High lymphocytosis in blood test with mature cells.

If primarly asymptomatic patient with CLL acquires new symptoms in, such as as weight loss, fever, rapidly increasing
lymphadenopathy or the presence of an extranodal tumor can indicate a Richter's syndrome, i.e. transformation into another
cancer of the lymphatic system, which is diagnosed in 2-15% of patients with CLL/SLL.
 Multiple myeloma
Multiple myeloma is a rare neoplasm, mainly affecting people >70 years old, with characteristic proliferation of
monoclonal plasma cells in the bone marrow, producing a monoclonal protein called M protein (mainly IgG
class), leading to organ damage due to amyloidosis. The M protein can be detected in a urinalysis as Bence-
Jones protein. The accumulating protein leads to kidney failure, consequent renal amyloidosis which can lead
to nephrotic sydrome with hypoalbuminemia, as well as more aggresive myeloma can produce IL-6, which
inhibits liver albumin production. Albumin/globulin (A/G) ratio is low. And plasma cells infiltrates cause
osteolitic changes in the bones with subsequent hypercalcemia. Bone marrow infiltrates impede erythropoiesis
and cause anemia.
These symptoms are called CRAB: CRAB - ↑Calcium, Renal failure, Anemia, and Bones (osteolysis).
Other signs/symptoms are back/lumbar pain, vertebral compression fractures, thrombocytopenia, leukopenia,
infections, a high total protein level in plasma with low albumin concentration, very high (three-digit)
erythrocyte sedimentation rate (ESR), high plasma M protein levels in lead to hyperviscosity syndrome (HVS)
 Primary myelofibrosis (PMF)
Myeloproliferative neoplasm in which malignant megakaryocytes produce cytokines that stimulate fibroblast
proliferation and angiogenesis, leading to myelofibrosis and impaired hematopoiesis in the marrow.
The increase in the amount of collagen in the marrow displaces normal hematopoietic cells and impaires the normal
production of erythrocytes, leukocytes and platelets.

Signs and symptoms:

- weakness/fatigue,
-splenomegaly/hepatomegaly due to extramedullary hematopoiesis, abdominal pain
- weight loss
- anemia
- fever, night sweats
- infections
- bone and joint pains,
- bleeding and petechiae
 Essential Thrombocytosis (ET)
Essential thrombocythemia is a Philadelphia-negative myeloproliferative neoplasm characterized by markedly increased platelet
counts and increased proliferation of megakaryocytes in the bone marrow. Typical mutations include: V617F JAK2(60%); CALR(20-
25%); MPL(3-4%).

Signs and symptoms include:

1) Thrombosis of large vessels - arterial: TIA, strokes, and coronary arteries - acute coronary syndromes
(less often venous: e.g. deep vein thrombosis of the lower limbs, Budd-Chiari syndrome, portal vein thrombosis).
2) Thrombosis in the microcirculation - paresthesias, amaurosis fugax,
erythromelalgia, headaches and dizziness,
3) Bleeding (If the number of platelets is very high, >1 000 000/μL, due to acquired platelet dysfunction or acquired von Willebrand
syndrome).
4) Splenomegaly.

In differential diagnosis there should be excluded other states with high platelet levels, such as inflammatory states or iron
deficiency.
DIC
DIC is an acquired syndrome characterized by the intravascular activation of coagulation without a
specific localization and arising from different causes. It can originate from and cause damage to the
microvasculature, which if sufficiently severe, can produce organ dysfunction. underlying disease
stimulates such a strong procoagulant activity that it results in an excess of thrombin, which then
overcomes the anticoagulant control mechanisms of protein C (PrC), antithrombin (AT), and the tissue
factor pathway inhibitor (TFPI), allowing thrombosis to freely take place throughout the vasculature. DIC,
there is a battle between the excess thrombin state, which clinically manifests itself as thrombosis,
embolism, and microvascular occlusion by fibrin thrombi, leading to multiorgan dysfunction syndrome
(MODS) from tissue ischemia, and a hemorrhagic disorder from depletion of platelets, consumption of
coagulation factors, and/or accelerated plasmin formation
 Read at home!
IV. Bleeding disorders - pathogenesis, symptoms
- vascular disorders
- platelet disorders
- plasma coagulation disorders
- Disseminated intravascular coagulation (DIC)
V. Thrombophilias - pathogenesis, symptoms
The graphs used in this presentation are from the Calgary Guide,
which I highly recommend.
www.thecalgaryguide.com
Thank you :)