Ingenious Immune System

Hello friends, today let's take a moment to appreciate how amazing is our immune system.

In our immune system, just like any regular car, there are brakes in place to regulate its working. Removing brakes can certainly enhance its function which underlies the concept of immune checkpoint blockade.

Two such molecules on the surface of T-cells are CTLA-4(Cytotoxic T-lymphocyte associated protein 4) and PD-1(Programmed cell death protein 1).

When CTLA-4 binds to its ligands B7-1 and B7-2 which are often expressed in increased numbers on tumor cells it results in inhibition of T-cells and hence allowing tumor cells to evade apoptosis and survive.

Similarly when PD-1 binds to PD-L1on tumor cells inhibitory signals are relayed to T-cells.

In macrophages signal, regulatory protein alpha mediates inhibitory signals on interacting with CD47 on tumor cells.

In NK-cells KIR2DL1(killer cell immunoglobulin-like receptor 2DL1) mediates inhibitory signals.

So blocking these inhibitory signals by monoclonal antibodies can remove "brakes" on the immune system ultimately enhancing their ability to kill tumor cells.

Approved antibodies include:

Anti CTLA-4-Ipilimumab

Anti PD-1-Nivolumab, Pembrolizumab

Anti PD-L1-Avelumab,Durvalumab

Kirtan Patolia

Cryptic conundrum in ET: Thrombosis or bleeding?

In essential thrombocytosis, contrary to what might be surmised, bleeding is more of threat than thrombosis.

This is because high platelet count especially above 1 million/mm3 cause acquired von willebrand disease, much like type 2b von willebrand disease, where excessive affinity of vWF for platelet Gpib result in excessive removal of platelet-vWF complex by spleen results in  thrombocytopenia and loss of high molecular weight vWF multimers.

However, incidence of erythromelalgia , transient ischemic attack and other microvascular events are also high in patients with essential thrombocytosis.

Pretty complex and contradictory, right?

- Kirtan Patolia ( BJ medical college).

Zebra series: Stauffer syndrome

Hello,

I'll be talking about Stauffer syndrome today!

Why is the level of Vitamin B12 increased in CML?

Why is the level of Vitamin B12 increased in Chronic Myeloid Leukemia (CML)?

Pathophysiology: The transport of vitamin B12 in the blood as well as hepatic uptake require the presence of transcobalamins (TCBs).

TCB types I (TCB I) and III (TCB III) ensure the binding of ∼80% of circulating vitamin B12.

Warfarin and Newer Oral Anticoagulants (NOACs) notes

Hey guys!
These are my notes from Harrison on Warfarin and Newer Oral Anticoagulants (NOACs).

Complications of massive blood transfusion

Hii everyone! 

Massive blood transfusion is defined as

Complications from massive transfusion include :
1) Hypothermia
2) Hypocalcemia - because citrate present in transfused blood is a calcium chelator, it decreases the available calcium.
3) Acidosis - as citrate is acidic in nature.
4) Hyperkalemia - as Hydrogen ions are present in excess due to acidosis, it is compensated by H+ loss in urine and K+ is regained back into blood. So this causes hyperkalemia.
5) Hypokalemia - in stored blood, the Na+-K+ pump is less functioning,  so there is decrease in intracellular K+ in stored blood.  But after blood transfusion, the Na+ K+  pump again starts functioning and increases intracellular K+, this leads to decrease in the available K+ outside the cell causing hypokalemia.
6) Dilutional coagulopathy - massive blood transfusion leads to dilution of clotting factors . It later manifests as DIC-like leading to multiorgan failure and death.

Thanks for reading.

Madhuri.

Complications of blood transfusion

Hii everyone!
This post is about the complications from a single blood transfusion.

1) The most common complication is febrile nonhemolytic tranfusion reaction(FNHTR). -- this occurs due to anti-HLA antibodies in the recipient which kills WBCs leading to release of interleukins and cytokines which are pyrogens. So the treatment is antipyretics.
2) Urticaria - it is due to IgE antibodies in plasma. So we give antihistamines to control it.
3) Hemolytic transfusion reaction - due to antibodies against RBCs. This is rare.  It may occasionally occur due to clinical errors in pretranfusion tests.
4) Infections - bacterial infection due to faulty storage, hepatitis, HIV, malaria.
5) Air embolism
6) Thrombophlebitis
7) Transfusion- related acute lung injury - usually occurs within 6 hrs after transfusion.

Hope this helps.

Madhuri

Hematology Diagrams

Hello Awesomites! :D

I made these diagrams during my exams.
I kept in mind the details of cells.
Hope it will help.

-Upasana Y. :)

AML and ALL differentiating features.

Hello awesomeites !

Today let us find out the difference between AML and ALL on the basis of cell morphology, cytochemistry and immunophenotyping.

So, Acute Leukemia is the presence of blasts >=20% either in peripheral blood or bone marrow.

Myeloblasts in AML and Lymphoblasts in ALL are the two main types. 

Cell morphology:

Myeloblasts:  The characteristic feature is the presence of Auer rods with moderate amount of cytoplasm and cytoplasmic granules and multiple nucleoli

Lymphoblasts:  They have a scanty cytoplasm no granules and nucleoli are not present

Many a times differentiating the two on morphological basis isn’t feasible. So we take the help of cytochemistry.

Cytochemistry:

Myeloblasts:  are myeloperoxidase(MPO) and Sudan black B (SBB) positive

                         Monoblasts which are a part of the myeloid lineage are nonspecific esterase (NSE) positive

Lymphoblasts:  are periodic acid Schiff (PAS) positive

MPO stains the enzyme within the azurophilic granules and is the most specific while SBB stains the lipid membrane of the azurophilic granules and is most sensitive for myeloid differentiation .

Even after this if we aren’t able to differentiate then we take the help of immunophenotyping

 
Immunophenotyping:

It is performed by flow cytometry.

The sample either bone marrow or peripheral blood is stained with antibodies and the cells are allowed to fall freely in a single file across a beam of laser (this is the over simplified version of it :P).

The laser used is Blue laser of wavelength 488nm. When the laser beam hits the cells some of it gets scattered to the sides and is known as the side scatter which is a measure if the granularity of the cells. While the rest of the beams travel in the same line without deviation and is called as the forward scatter and is a measure of the size of the cells.

Neutrophils are the cells with the highest side scatter.

Staining of the cells with antibodies helps in subtyping acute leukemias on the basis of CD markers.

Here is a list of CD markers on varies cells of myeloid and lymphoid lineage

B cell markers:

CD19: present on all B cells

CD10: immature B cells

CD20: mature B cells

T cell markers:

CD3: present on all T cells

CD4 CD8 CD2 CD5 CD7 are some of the other markers present on various T cells

Myeloid markers: CD13 CD33 CD117

Stem cell markers: CD34

Monocyte markers: CD14 CD64

NK cell markers: CD16 CD56

CD45 is present on all leucocytes a.k.a pan leucocyte marker 

That’s all for now, hope this helps in better understanding of AML and ALL!

Keep calm and keep studying!

Stay awesome!

-          Ashish G. Gokhale

Tumor lysis syndrome and rhabdomyolysis: Why does calcium decrease?

Doubt in response to you post on tumor lysis syndrome: What is the mechanism behind hyperphosphatemia causing hypocalcemia in tumor lysis syndrome? Wouldn’t the tumor cells also release calcium, thus leading to hypercalcemia? Asked via email

Lymphoma and Leukemia Translocations Mnemonic

Hello everyone!

Here's an intuitive way to remember the chromosomal translocations involved in various lymphomas and leukemias.
































Hope this helps. Happy studying!

-- Ashish Singh

Cryoprecipitate constituents mnemonic

Hello!

This is a post on the constituents of Cryoprecipitate :)

Mentzer index mnemonic

Hello everyone!

Factors increasing iron absorption in the intestine mnemonic

Hello! Long time, no see!

Did you know a number of dietary factors influence iron absorption?

Ascorbate (vitamin C) and citrate increase iron uptake in part by acting as weak chelators to help solubilize it in the duodenum.

Megaloblastic Anemia

1. Why do we get " Megaloblasts" in Megaloblastic anaemia?
2. Why we get anaemia in Megaloblastic anaemia?
Megaloblastic anaemia is called so due to presence of " Megaloblasts" in bone marrow.
What are " Megaloblasts" They're gigantic, abnormally BIG RBC-precursors seen in bone marrow. WHY do we see them ?
It needs some conceptual understanding.                           
Normally, RBC-precursors are big cells which divide rapidly as they mature & become progressively smaller as they divide while maturing towards mature-form of RBCs.  Now, the problem begins in Megaloblastic anaemia that this cell-division is impaired due to lack of nutrients ( Folate & Vitamin B12).  Vit B12 & Folate are critical for normal DNA synthesis & cell maturation.                                                             It's also described by a complex -term called " Nuclear-Cytoplasmic Asynchrony".
As DNA-synthesis is impaired, nuclear maturation of RBC-precursors get slowed up & could not match with the pace of cytoplasmic maturity/development. This DEFECTIVE NUCLEAR MATURATION halts cell-division & those big "MEGA" RBC-precursors remain as Big, MEGA, gigantic " Megaloblasts" in bone marrow giving the name as " Megaloblastic anaemia". Moreover, these " Megaloblasts" do NOT mature enough to get released into the peripheral blood & most RBC-precursors undergo " apoptosis " or apoptotic-death in bone marrow ..this  causes anaemia in Megaloblastic anaemia.

Hope this helps some of you to understand the basic concepts.

-Md Mobarak Hussain (Maahii)

Poikilocytosis

Red blood cells

Also known as erythrocytes, is the most common type of blood cell and the principal means of oxygen transport in the body.

The normal biconcave shape is the essential feature of its biological function.
Through various stages of development and maturation, RBC loses its nucleus and most organelles in order to accommodate maximum space for haemoglobin.
This feature of RBC is critically affected by genetic and acquired pathological conditions.

Poikilocytosis is the term used to denote the variation in the shape of red blood cells.
Let's look at the major abnormalities in the shape of RBCs and the conditions in which they are seen:

1. Spherocyte - hereditary spherocytosis, autoimmune haemolytic anaemia, ABO haemolytic disease of the new born

2. Schistocyte - thalassemia, hereditary elliptocytosis, megaloblastic anaemia, iron deficiency anaemia and severe burns

3. Irregular contracted red cells - drug and chemical induced haemolytic anaemia, unstable haemoglobinopathies

4. Target cell (a type of leptocytosis)- iron deficiency anaemia, thalassemia, chronic liver disease and after splenectomy

5. Sickle cell (drepanocyte)- sickle cell anaemia

6. Tear drop cell - myelofibrosis, underlying marrow infiltrate

7. Crenated red cell - in blood films due to alkaline pH, presence of traces of fatty sustances on the slides or film allowed to stand over night

8. Acanthocyte - post splenectomy, chronic liver disease, Abetalipoproteinemia, McLeod blood group phenotype

9. Burr cell - uremia, liver disease, artifact

10. Stomatocyte - hereditary stomatocytosis, chronic alcoholism

11. Ovalocyte - hereditary ovalocytosis, hereditary elliptocytosis, severe iron deficiency anaemia

The diagram given represents the corresponding cells





Credits to: Shivani Mangalgi.

Pathophysiology of laboratory findings in tumor lysis syndrome

Which of the following electrolysi abnormalities will you see in tumor lysis syndrome?
Answer either high, normal or low for each of these - calcium, phosphate, potassium, uric acid.

Answers:
Labs in tumor lysis syndrome -
Hypocalcemia 
Hyperuricemia
Hyperphosphatemia
Hyperkalemia

Why?

When cancer cells lyse, they release potassium, phosphorus, and nucleic acids, which are metabolized into hypoxanthine, then xanthine, and finally uric acid. 

This leads to:

Hyperkalemia can cause serious — and occasionally fatal — dysrhythmias.

Hyperphosphatemia can cause secondary hypocalcemia, leading to neuromuscular irritability (tetany), dysrhythmia, and seizure, and can also precipitate as calcium phosphate crystals in various organs (e.g., the kidneys, where these crystals can cause acute kidney injury).

Uric acid can induce acute kidney injury not only by intrarenal crystallization but also by crystal-independent mechanisms, such as renal vaso-constriction, impaired autoregulation, decreased renal blood flow, oxidation, and inflammation.

Crystal-induced tissue injury occurs in the tumor lysis syndrome when calcium phosphate, uric acid, and xanthine precipitate in renal tubules and cause inflammation and obstruction.

That's all!

-IkaN

Causes of microcytic erythrocytosis

A high RBC count combined with a low mean volume is seen in:

1. Thalassemia minor, either alpha or beta
2. Polycythemia vera with iron deficiency
3. Secondary polycythemia (hypoxia) with incidental iron deficiency.

Differentiating thalassemia minor from polycythemia vera:

The RBC size distribution curves reliably distinguish between thalassemia minor and polycythemia with iron deficiency.

RDW is elevated in iron deficiency. It is normal in thalassemia minor.

That's all!

-IkaN

No cyanosis in cyanide poisoning. Why?

I was reading about cyanide poisoning today and saw "Cherry red skin" in the clinical manifestations. I know that carbon monoxide poisoning causes a cherry red color to blood. But why cyanide?

The curiosity lead to this post.

In normal cellular metabolism, most adenosine triphosphate (ATP) is generated from oxidative phosphorylation. .

Cyanide avidly binds to the ferric ion (Fe3+) of cytochrome oxidase a3, inhibiting this final enzyme in the mitochondrial cytochrome complex. When this enzyme's activity is blocked, oxidative phosphorylation ceases. The cell must then switch to anaerobic metabolism of glucose to generate ATP.

Anaerobic metabolism leads to the formation of lactic acid and the development of metabolic acidosis. Hydrogen ions produced by ATP hydrolysis are no longer consumed in aerobic ATP production, exacerbating this acidosis. Serum bicarbonate decreases as it buffers excess acid, leading to an increased anion gap.

Despite an ample oxygen supply, cells cannot utilize oxygen because of their poisoned electron transport chain. This functional (or "histotoxic”) hypoxia is particularly deleterious to the cardiovascular and central nervous systems (especially the basal ganglia).

Because of the decreased utilization of oxygen by tissues, the venous oxyhemoglobin concentration will be high, making venous blood appear bright red.

Therefore, despite hypotension, apnea, and/or bradycardia, the patient does not usually appear cyanotic in the setting of cyanide poisoning.

Clinical features:
Central nervous system toxicity is the most prominent in cyanide toxicity – Headache, anxiety, confusion, vertigo, coma, seizures.

Which should you suspect cyanide poisoning?
Victims of fires
Reported ingestions
Treatment with sodium nitroprusside

Antidote:
Hydroxocobalamin
Sodium thiosulfate
Nitrites (to induce methemoglobinemia)

That's all!
-IkaN

Cortisol and eosinophils

Today, I forgot the relationship between cortisol and esosinophils. Completely screwed up a practice question because I couldn't remember it.

Now I made a mnemonic to remember this :D

Mnemonic: In hypERcortisolism, Eosinophils Reduce.

Why do corticosteroids cause eosionopenia? Why does hypocortisolism cause an increase in eosinophil count?