Pathology of Hereditary Spherocytosis |Pathology|

Hereditary Spherocytosis is one type of hemolytic anemia. We are going to discuss on it in detail. We gonna cover on pathogenesis, clinical manifestation and few other things that might pass through my head along the way.

Pathogenesis

First of all, this is a genetic disease, which form the name itself implies it can be inherited. Ok, before we go any further, let us do some recap o Histology of erythrocytes.

Erythrocyte is biconcave in shape. Why? Because it has a complex cytoskeleton architecture that holds its plasma membrane into place.
1) Vertical filaments (anchor the plasma membrane)
+Ankyrin
+Band 4
+Band 3
2) Horizontal filaments
+Spectrin
3) Protein links between both vertical and horizontal filaments
+15 monomeres of actin

So, what turns wrong in spherocytosis?
Spherocytocis is an autosomal genetic disorder, in which:-
1) 85% autosomal dominant trait
+ Means the gene only needs a single allele (heterozygous) to express its abnormality
2) 25% autosomal recessive trait
+It requires two similar alleles (homozygous) to express its abnormality
Often, this kind of disorder leads to more severe spherocytosis

This abnormal genes somehow affect :-
1) Band 3
2) Ankyrin
3) Spectrin

In people with hereditary spherocytosis, these filaments are found absent and due to that, RBCs couldn’t maintain its original morphology of biconcavity. As the name implies, spherocytosis red cells appear spherical in shape thus loosing its distinctive central pallor area in blood smear.

It becomes spherical due to loss of membrane stability – some membrane with few cytoplasms are released. RBC which spgerical in shape is rigid and couldn’t pass through splenic sinusoid thus making it highly susceptible to be phagocytosed by splenic macrophage.

It has a high chance of getting splenomegaly in patient with spherocytosis (mechanism is the same to that of general pathogenesis of hemolytic anemias we already discussed before). There is profound  jaundice in spherocytosis. Due to the increased hemolysis, there will be compensatory mechanism of erythropoeisis which will eventually lead to erythroid (red marrow) hyperplasia and increase presence of reticulocytes at peripheral blood flow (reticulocytosis)

Due to its distinctive clinical manifestation to the spleen, it is found beneficial to do splenectomy (removal of the spleen) for this patient even though spherocytes still persist. Until now, there is still no profound treatment proposed for spherocytosis rather than splenectomy.

Morphology and Clinical Manifestations
1) Lack of central pallor region of RBCs on the blood smear
2) Increased presence of reticulocytes at the peripheral blood (reticulocytosis)
3) Splenomegaly – 500gm to 1000gm
4) Congestion in the cord of Bilroth of the spleen
5) Increased number of splenic macrophages

Next we will discuss on Sickle Cell Anemia.
Until then, thank you!! =)

Pathology of Hemolytic Anemias |Pathology|

Ok let us now talk about Pathology. Previously, we already discussed on the basic pathology of anemias, but today we gonna talk about specific pathology for Hemolytic Anemias.

There are several types of hemolytic anemias which we gonna discuss in detail in separate post, but for the time being let us take it as a whole.

Below is the list of the most commonly occurring hemolytic anemias with its causes:

1) Heriditary Spherocytosis
+Deformed structure of erythrocytes
+Lack of
-Band 3
      -Ankyrin
      -Spectrin
+Due to
-85% autosomal dominant trait
      -25% autosomal recessive (often severe case)

2) Sickle Cell Anemia
+Deformed structure of Beta globin chain
+Missense mutation (point mutation), SUBSTITUTION (glutamic acid to valine)
+Replacement of HBA1 to HBS
+Autosomal recessive
      -Homozygous leads to 100% of HBS replacement
      -Heterozygous leads to 50% of HBS replacement

3) Thalassemia
+Co-dominant autosomal genetic disorder
+Due to gene DELETION which leads to frameshift mutation
+Divided into
  -Beta thalassemia (chromosome 16)
+Homozygous – Major thalassemia
+Compound heterozygous – intermediate thalassemia
+Heterozygous – trait, asymptomatic
-Alpha thalassemia (chromosome 11)
a) –/– – Hydrops fetalis; fatal in utero
b) –/-a – moderately severe
c) –/aa – alpha thalassemia trait
d) –a/aa – silent carrier, asymptomatic
4) Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
+Defective in G6PD gene at the X chromosome
+Less activity of G6PD
+Red cells vulnerable towards oxidant/free radicals

Pathogenesis

Like we all agreed, this post will solely discuss on hemolytic anemias as whole. So, let us talk about the general pathogenesis of hemolytic anemias

Hemolytic anemias have 3 major fates that all of them will undergo along the course of the diseases, which are
1) Increased rate of hemolysis
2) Increased compensatory erythropoeisis leads to reticulocytosis (accumulation of reticulocytes in the peripheral blood)
3) Accumulation of by products of hemolysis especially iron

Due to its deformed structure, RBCs of hemolytic anemias are considered to be some kind of foreign bodies. Therefore, there are highly susceptible towards degradation by macrophage – specifically Kupffer cell of the liver and Splenic macrophage of the spleen.

RBCs that already been degraded by macrophage will be change into Heme (iron) and globin (protein, in this case). Heme will eventually turn into bilirubin which will be excreted through bile meanwhile protein will be recycled back.

Due to extensive extravascular hemolysis, bile excretion couldn’t take pace and due to that, bilirubin starts to accumulate in tissues. Increased level of bilirubin (hyperbilirubinemia) will eventually lead to jaundice and it is most prominently seen at the sclera (scleral jaundice).

At the same time, iron is also retained in the body, but when the rate of hemolysis is progressively high, erythropoeisis couldn’t take pace and due to that iron starts to overload. Accumulation of iron (hemosiderosis) will eventually lead to tissue damage (hemochromatosis). The most severely affected organs are the heart and pancreas.

Now, we can see that hemolytic anemias always lead to increased of hemolysis. But the body must do something to it, isn’t it? So, the body starts to release more erythropoietin from the peritubular capillary endothelial cells of the kidney in order to increase the rate of erythropoeisis.

Increased in erythropoeisis will lead to hyperplasia of the erythroid tissue in the red marrow. Therefore, red marrow starts to expand, and eventually compresses the bone and lead to bone deformity. But, it must be clear, compensatory mechanism has its own limit; once it has reached its limit, extramedullary (outside the bone) erythropoeisis will take part.

Extramedullary erythropoeisis involves the reticuloendothelial system – liver and spleen. Those two organs start to increase its activity. We can see that the liver and spleen already do two tasks; hemolysis and erythropoeisis simultaneously. What will happen then? Both organs will start to enlarge. This is called hepatosplenomegaly.

That is pretty much about the general ideas on hemolytic anemias. In next posts, we will discuss in more detail about different types of hemolytic anemia individually.
With that, thank you =)

Histology of Agranulocytes |Histology|

Ok this will be the last post on Histology for Heamopoeitic and Lymphatic System.
This post will concentrate in discussing on histology of agranulocyes; Monocyte and Lymphocyte
I will discuss separately for both cell so it would be easy for us to understand their characteristics

Lymphocytes

Introduction
1) Contained a very huge nucleus located at the center of the cell
2) Due to the huge size of nucleus, the cytoplasm is somehow pushed to the periphery giving its distinctive shape of a blue rim
3) The nucleus has a dense heterochromatin
4) Some evident of azurophilic granule presence
5) Its not functional in bloodstream, but elicit its response in connective tissue
6) Produced in red marrow, mature at connective tissue
7) Once it is competent enough, it will undergo mitosis to produce identical progeny cells
8) All members of a particular clone will only act on the same antigen the mother cell responded before
9) Appear in small number in connective tissue but rather increase during chronic inflammation

Types of Lymphocytes
1) T-lymphocytes
+80% of total lymphocytes
+Lifespan of few months
+Function primarily in CELLULAR IMMUNITY
+Migrate from red marrow and mature at THYMUS
+Subtypes of T-lymphocytes
-T-killer cells/cytotoxic cells
+destroy viral infected cells or cancer cells
+T-helper cells
-Initiate response and development of response
+T-suppressor
-Suppressed immune response
2) B-lymphocytes
+15% of total lymphocytes
+Lifespan of at most 5years
+Function primarily in HUMORAL IMMUNITY
+Migrate from red marrow and mature at BURSAE FIBRICIOUS (not at bone marrow like most of us think off)
+Differentiated into PLASMA CELLs to produce antibodies to fight against antigens
3) Null cells
+5% of total lymphocytes
+It is a type of circulating stem cell
+Give rise to
-Formed elements
-Natural killer (NK) cells
4) Memory cells
+Do not involve in any immunological response
+Use to keep memory so that it will mount immediate response during future exposure

Formation
Lymphocytes always follow the Lymphoid Heamotopoeisis pathway. There is a slightly different in the development of lymphocyte in regard to other cells in which the progenitor cell gives rise to precursor cell which name with “cyte” at the compared to other cell which normally having “blast” at its end. Belo is the diagram of lymphocyte development :-

Pluripotent Heamapoeitic Stem Cell –> CFU-Lymphocyte –> CFU-Lymphocyte T/Lymphocyte B –> T/B lymphocyte –> T/B lymphoblast –> T/B Lymphocyte

Monocyte

Introduction
1) The largest blood cell in the circulating bloodstream
2) Has considerable amount of azurophilic granules which stained blue
3) No specific granules
Nucleus is accentric, kidney shaped, and having coarse chromatin network
4) Once enter the tissue it will form MACROPHAGE
5) Circulate the blood only for few days, then migrate to tissue

Formation
Monocyte shares the same progenitor cell with neutrophil which is CFU-GM. Below is the diagram for monocyte development:-

Pluripotent Heamopoeitic Stem Cell –> CFU-S –> CFU-GM –> CFU-Monocyte –> Promonocyte –> Monocyte

This is the last Histology post on Heamopoeitic and Lymphatic System.
I do hope it helps you even a bit.
Goodluck!
Thanks again =)

Histology of Basophil |Histology|

Ok, now, we will talk about Basophils.

Introduction
1) Basophil is the rarest leukocytes found in a normal blood smear
2) Large amount of granules, they even compressed against its cell membrane giving its angular appearance
3) The granules are stained by hematoxylin – acidic in nature
4) Have numerous receptors including IgE receptors
5) Involved in hypersensitivity response (in contrast with eosinophil)
6) Have almost  similar activity like mast cells but they are considered as different cause having different progenitor cell

Basophilic Granules
1) Its granules are stained by basic dye (hemotoxylin) due to the presence of heparin (acidic in nature)
2) Specific granules of basophil are less and irregular in shape
3) Basophilic granules contained
+Heparin
+Histamine
+Leukotriene
+Serotonin

Formation
Basophil formation is more or less the same like other grabulocytes as it shares same progenitor cells of CFU-S. It is also controlled by cytokine like Colony Stimulating Factor (CSF). Following is diagram of basophil formation

Pluripotent Heamopoeitic Stem Cell –> CFU-S –> CFS-basophil –> Myeloblast –> Promyelocyte –> Basophil myelocyte –> Basophil metamyelocyte –> Stab cell –> Basophil

Those are all about basophil.
Thank you =))

Histology of Eosinophil |Histology|

We will now talk about another type of Granulocytes called Eosinophils.

Introduction
1) Eosinophil is one of rarest leukocytes found in the normal blood smear
2) Contained numerous pinkish or reddish-orange granules
3) Azurophilic granules also present
4) Bilobed nucleus, makes it looks like a sausage with nuclear projection linking the two lobes

Eosinophilic Granules
1) Numerous specific granules stained by Eosin dye – basic in nature
+Specific eosinophilic granules
      -Crystalline core or internum  containing large number of arginine
+These proteins function in killing parasitic worm especially shistosomes
-Surrounds the internum is the externum
+Azurophilic granules
-Contained lysosomal enzymes to digest parasitic worms

Clinical importance of Eosinophils
1) Eosinophil contains IgE, one type of immunoglobulin important for parasitic infection
2) Eosinophil DEACTIVATES inflammatory (anti-allergic reaction) activity by inactivating
+Histamine
+Leukotriene
3) It also phagocytoses antigen – antibody complex
4) Increased in number indicates parasitic infection
5) Corticosteroid tends to decrease its number

Formation of Eosinophil
Like neutrophil, eosinophil production is control by cytokine especially Colony Stimulating Factor (CSF). Below is the diagram

Pluripotent Heamopoeitic Stem Cell –> CFU-S –> CFU-Eosinophil –> Myeloblast –> Promyelocyte –> Eosinophil myelocyte –> Eosinophil metamyelocyte –> Stab cell –> Eosinophil

That is all about Eosinophil. Simple and easy, isn’t it? I hope so =)

Thank you guys =)

Histology of Neutrophil |Histology|

Now it is time for us to discuss on immunocytes.
I will try to simplify the characteristics of all types of immunocytes but rather in this post I will be concentrating in Neutrophils.
Below is the simplification of immunocytes

1) Neutrophils
+Granular cytoplasm, neither being stained by eosin nor hemotoxylin – reflects its name ‘neutrophils’ – neutral
+Multi-lobulated nuclei
2) Eosinophils
+Large pink granules – stained by eosin; acidophilic
+Sausage-like nucleus
-Nuclear projection links between the two lobes
3) Basophils
+Dense dark blue granules – stained by hemotoxylin; basophilic
+Nucleus is somehow hidden behind the dense cytoplasmic granules
4) Monocytes
+Largest of all leukocytes
+Accentric kidney-like nucleus
+Lack of granule, thus agranulocyte
5) Lymphocytes
+Single, large, centrally located nucleus
+With narrow rim of cytoplasm

Those are few general ideas on leukocytes. Now let us concentrate on the Neutrophils.

Introduction
1) The most abundant leukocytes in blood
2) Light pink cytoplasm
3) Lots of azurophilic granules (a dye used to stain neutrophilic granules, since they can’t be stained by either eosin or hemotoxylin)
4) Dark blue, coarse nucleus
5) Multi-lobulated nucleus, having 2 to 3 lobes
6) Upon activation, becomes highly motile and phagocytic
7) Once phagocytosed foreign materials, it will die and form the main constituent of pus

Maturation of Neutrophils
1) Nascent neutrophils do not have lobule in their nucleus, thus called as STAB CELLS
2) Increased in the number of stab cells in circulation indicates increased in the production of neutrophils, perhaps due to bacterial infection.
3) Below is supposed to be the normal range of neutrophils in the peripheral blood.

1) Neutrophilic metamyelocyte – 0-0.5%
2) Neutrophilic stab cell – 3-5%
3) Neutrophil – 40-70%

Neutrophilic Granules
1) Primary granules called azurophilic granules
+The same to that of lysosome of other cells
+First granules to appear
+Upon maturation, their numbers drop
+Dense dark
2) Secondary Granules
+Specific granules to neutrophils
+Two time numerous compared to primary granules
+Very light in color
+Contained
-Collagenase type IV
-Lysozyme
-Phogocytin

Formation

Neutrophil shares the same progenitor cell with Monocyte which is CFU-GM. The formation of neutrophil is controlled by numerous cytokines especially Colony Stimulating Factor (CSF). Below is the diagram of Leukocytopoeisis:-

Pluripotent Heamopoeitic Stem Cell –> CFU-S –> CFU-GM –> CFU-G –> Myeloblast –> Promyelocyte –> Neutromyelocyte –> Stab cells –> Neutrophils

Function

Neutrophil is a polymorphonuclear phagocyting cell. Once activated, it can survive in anaerobic condition due to its abundant content of glycogen granules for anaerobic respiration.
Below is the process on how neutrophil engulfs foreign particles

1) On the surface there are receptors which used to bind to antigens.
2) Once an antigen binds to the receptor, neutrophil creates pseudopodia thru assembly and disassembly of actin.
3) The pseudopodia fuse and surrounds the particle.
4) The foreign particle will fuse into a vesicle call phagosome.
5) Phagosome will fuse with primary granule containing lysosomal enzymes.
6) Enzyme will then degrade the particle
7) The degraded particle will form residual body

That is all about neutrophils. You can further on it, it would be very nice to know in detail.
Until then, thanks!!

Histology of Platelets |Histology|

Hello there! =)
Ok, I do realize it has been a lot of Histology thingy going on recently, but hey guys, Histology is the basis of medicine – we don’t have choice but to understand it in detail.
Right, enough with the talk, lets us get this thing done. Today we gonna discuss on Histology of Platelets.

Introdution

1) Smooth disk in shape
2) Plasmalemma containing complex receptors and thick glycocalyx (sticky material) for adhesion
3) They are fragments of giant cells called Megakaryocytes
4) Anuclear
5)Contained:-
+Mitochondria
+Mircotubules
+Complex cytoskeletons
+Glycogen granules
+Golgi elements
+Numerous numbers of enzymes for
-Aerobic respiration
-Anaerobic respiration
6) Has 2 distinctive regions of:-
+Dense central region called Granulomere, containing :-
– 4 types of granules :-
+Alpha granule
-Coagulation factors
+Gamma/dense granule
-Serotonin
+Lambda granule/Lysosome
-Lysosomal enzyme such as acid hydrolase
+Peroxisomes
-Peroxidase
+Light peripheral region of Hyalomere, containing
-Bundles of marginal microtubule – maintain platelet morphology
7) Function in hemostasis

Megakaryocytes
1) Huge polyploidy cells
2) Located at the red marrow
3) Dispersed chromatin
4) No nucleoli
5) Having basophilic granules, stained blue by hematoxylin
6) Its cytoplasmic blebs give rise to platelets

Formation
Thrombocytes/platelets formation is called as Thrombocytopoeisis. It takes place at the red marrow and control by hormone called Thrombopoeitin released by the liver. Below is the simplified diagram on how Platelet is produced :-

Pluripotent Heamopoeitic Stem Cell –> CFU-S –>CFU-Meg–> Megakaryoblast –> Promegakaryocyte –> Metamegakaryocyte –> Megakaryocyte –> Platelets

Those are pretty much about thrombocytes/platelets.
Later we will go in detail for Leukocytes.

Till then, thanks!! =)