William Aird
@WilliamAird4
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Professor of Medicine at Harvard Medical School #Hematology #MedEd Founder of @TheBloodProjec1
Boston, MA
Joined August 2021
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Camels are able to survive 10-15 days in extreme heat without H2O, losing up to 40% of body weight in water.
They then rehydrate by drinking up to 50 L in a few minutes (!), which is rapidly absorbed into the vascular compartment. How do their RBCs avoid osmotic rupture?
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If blood is red, why do veins appear blue? It's an optical illusion! Blood is normally red because Hb preferentially reflects red light (oxyHb more so than deoxyHb). Blood in veins, by contrast, appears blue because skin scatters and returns more blue light than red to the eye.
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Hb vs. Hct - PART 1
I recently asked a series of questions about Hb vs Hct.
I will address some of the answers here and others in a follow-up thread.
QUESTION: If I give you the Hb of a patient can you predict their Hct?
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What is the difference between ERYTHROCYTOSIS and POLYCYTHEMIA?
Although the terms are often used interchangeably, they have slightly different meanings.
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Hey hematology enthusiasts, what do you know about HbA1c (A1c)? I was recently asked to see a patient with an elevated A1c whose serum fructosamine - another marker of long-term glycemic control - was normal. Hemoglobinopathy? I confess that I had to brush up a little😉
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EXAMPLE OF Hb-Hct DISCORDANCE
Take a look at the values in the graphic. Without looking ahead in the thread, can you make a diagnosis?
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TOILET PAPER BEZOAR
One of the most remarkable cases I have seen is that of a 55 yo F who presented to the ED of an outside (academic) hospital with difficulty swallowing. She denied having eaten or swallowed anything unusual.
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DVT - PHYSICAL EXAM
I am on a physical exam kick, reliving nightmares from my dreaded Canadian oral exam in medicine.
"Dr. Aird, will you please examine this patient for possible DVT, and tell us [white-coated, bow-tied examiners] what you are thinking as you proceed."
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SERUM FERRITIN
Ferritin serves to store/sequester iron inside cells. Small amounts of ferritin are found in the serum and their levels are used clinically in the ddx of anemia and as an indicator of iron overload or inflammation.
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ORAL IRON IN IRON DEFICIENCY ANEMIA (IDA)
I tweeted a poll asking how you would treat a case of uncomplicated IDA with oral iron. The options and responses are shown below:
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Food for thought:
The hematocrit (Hct) is IMPERVIOUS to the hemoglobin (Hb). The ONLY determinants of Hct are RBC count and MCV. So, it is theoretically possible to have a normal Hct with Hb 0.0.
***Only Hb is a marker of oxygen carrying capacity of blood***
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ERYTHROCYTE SEDIMENTATION RATE (ESR)
I tweeted - seems like ages ago - about 4 cases of ESR-CRP discordance. Before addressing these cases, I wanted to give a bit of background about the ESR and CRP, beginning with the ESR.
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CLASSIFICATION SCHEME FOR HEMOLYTIC ANEMIA
1. Immune vs. non-immune
2. Immune - autoimmune vs. alloimmune
3. Non-immune - intra vs extracorpuscular
4. Intracorpuscular - Hb, membrane, enzymes
5. Extracorpuscular - TMA, MAHA, liver, infection
6. Mimics - B12, hematoma, HLH
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Hb vs. MCHC
Mean corpuscular hemoglobin concentration (MCHC) and Hb concentration are both expressed as g Hb/dL. So, what’s the difference?
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OVERVIEW OF RBC PARAMETERS
Here is a fun graphic that ties together the relationships between RBC parameters:
1. RBC count gives us no information about Hct or Hb, but it can be used to help distinguish between thal minor and iron deficiency anemia (e.g., Mentzer index).
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Hct or Hb?
Don't be lazy, TAKE A SIDE! 😀
Consider:
1. O2 delivery (DO2) = CO x O2 content of blood
2. O2 content correlates positively with Hb
3. CO correlates negatively with Hct (through its effect on blood viscosity)
4. DO2 as function of Hb/Hct = bell-shape curve
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Sudden Drop in Hb
I saw a patient in the ICU (diagnosis doesn't matter for purposes of this discussion) whose Hb suddenly dropped over a 5 h period from 9.3 to 5.7 g/dL (see graphic).
Not knowing anything about the patient, what are possible explanations?
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I don't know about you, but I LOVE flow charts in hematology. Below is a graphic showing ddx of microcytosis (MCV < 90 fL).
NOTES:
1. Microcytosis may occur +/- anemia
2. MCHC (represented by white:red ratio in the schematized RBCs) provides helpful clues
3. Remember HbC & HbE
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ERYTHROCYTE SEDIMENTATION RATE (ESR)
1. The ESR measures the rate (mm/h) at which RBCs form aggregates (or rouleaux) that sediment when anticoagulated fresh blood is left in a vertical tube.
2. Thus, ESR is not a measure of an analyte but of a physical phenomenon.
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Are the Hb and Hct interchangeable?
If I you give the Hb of a patient, can you predict their Hct?
If they are interchangeable, then why bother reporting both (the "H&H")?
If they are not interchangeable, then what different information are you imparting by reporting both?
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I have to refresh my memory from time to time about the relationship between creatine (Cr), creatine kinase (CK) and creatinine. As a hematologist, I traffic in all the above (e.g. differentiating rhabdo from hemolysis, diagnosing anemia of CKD), but only peripherally.
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The red cell distribution width (RDW) measures variation in RBC size around the mean (MCV).
An elevated RDW indicates increased variation in cell size and is called anisocytosis.
A "decreased" RDW is clinically meaningless.
There are 2 ways to report the RDW (see graphic).
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Hb or Hct?
I prefer using Hb in patients with anemia because oxygen carrying capacity is limiting, and Hct in patients with polycythemia because blood viscosity is limiting.
For those at equipoise, it's dealer's choice, though I like to think positively and use Hb. 😉
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SPLENOMEGALY
Q: What is it?
A: An abnormal enlargement of the spleen
Q: How is it defined?
A: Typically by a craniocaudal dimension of >13 cm
Q: How common is it?
A: Reported in 2%-5.6% of unselected medical outpatients
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IRON ABSORPTION
It's easy to forget what's what in iron oxidation states during iron absorption.
Bottom line:
1. Foods contain heme and non-heme iron.
2. Heme iron is in ferrous state (Fe2+) and is readily absorbed.
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Did you know that red blood cells are only found in vertebrates and that they are nucleated in all classes (fish, amphibians, reptiles, birds) except mammals?
It is safe to say that the loss of the erythrocyte nucleus in the ancestral mammal provided a survival advantage.
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Patients w:h SLE can present with a staggering array of hematologic abnormalities. Virtually no component of the blood is spared... everything is fair game:
1. Blood cells - cytopenia and cytoses
2. Hemostasis - thrombosis, TMA
3. Lymphadenopathy/splenomegaly
4. Lymphoma
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Serum albumin is considered by many to be a surrogate for an individual’s nutrition status. As shown in an SR (Am J Med. 2015;128:1023), serum albumin levels are "USELESS AS MARKERS OF NUTRITIONAL STATUS"
Low albumin = inflammation, liver disease or protein losing 'opathies'
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#thyroid
#endocrine
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THYROID AND HEME
1. Thyroid and RBCs
We often order a TSH as part of the w/u for anemia. But do we really understand the connection between thyroid disorders and anemia? Is there a causal relationship? If so, how common a cause are they?
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METHEMOGLOBINEMIA
1. MetHb refers to the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+) within the Hb molecule.
2. Methemoglobinemia occurs when the concentration of methemoglobin in RBCs is >5%.
3. MetHb competes for O2 binding and causes left shift of ODC.
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PLATELET COUNT THRESHOLDS
Note that natural selection has provided us with a very generous cushion so that counts must typically fall from 150 to <10-20 before increased risk of bleeding.
It is cultural evolution (e.g. surgery) that has led to higher PLT count thresholds.
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DILUTIONAL ANEMIA
What is the fastest and surest way to induce anemia?
Not blood loss, since it takes time for fluid to shift from the extravascular to intravascular space.
Instead, it is the administration of crystalloid or colloid fluids.
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TREATMENT OF SEVERE IDA
I tweeted a poll yesterday asking how you would treat a 31 yo F with chronic iron deficiency anemia and a Hb 5.9 g/dL. The options included transfusion alone, iron alone or transfusion followed by iron.
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As a benign hematologist, sometimes I wish we were partnered with hepatology instead of oncology. We have similar mind sets and skill sets, and besides, the overlap between the two disciplines is greater.
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INPATIENT THROMBOCYTOPENIA
One of the more straightforward consults is the inpatient with de novo thrombocytopenia.
Why?
Because the VAST majority of cases are due to infection or medications.
Those that are not can make things interesting!
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When considering the ddx of thrombocytopenia, the time honored MECHANISTIC classification has poor discriminatory power because the vast majority of causes fall under destruction/consumption.
A much more useful approach is according to CLINICAL CONTEXT (see graphic).
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FERRITIN THRESHOLDS FOR TREATING DIFFERENT PATIENT POPULATIONS WITH IRON
Practice guideline recommendations for Fe therapy vary between disease states. The ferritin threshold is increased in patients with cancer, CHF, CKD and inflammatory bowel disease (100-500 ng/ml).
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RENAL VEIN THROMBOSIS IN NEPHROTIC SYNDROME
Nephrotic syndrome is associated with an acquired hypercoagulopathy that is associated with an increased risk of renal vein thrombosis (and VTE).
What are the mechanisms underlying this propensity?
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CHAIN OF INFORMATION
RBC count is a poor indicator of red cell mass, which is why we normally ignore it altogether. What we need is the MCV to convert the RBC count into a meaningful value, namely the Hct.
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CAUSES OF HYPERFERRITINEMIA
(1) Inflammation
(2) Iron overload
(3) Ferritin leak
(4) Congenital hyperferritinemia
(5) Tumor secretion (malignancy-associated inflammation a more common cause)
(6) Reduced clearance (theoretically)
See PMID: 29672840
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The ABCs of acute phase proteins (APPs):
1. APPs are a component of the acute phase response, an evolutionarily conserved response to injury or infection.
... other components include fever, leukocytosis, anemia of inflammation, thrombocytosis, negative nitrogen balance...
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Camels survive up to 15 days in extreme heat without water, losing up to 40% of their body weight in H2O.
They then rehydrate by drinking up to 50 L in a few minutes (!), which is rapidly absorbed into the vascular compartment.
How do their RBCs avoid osmotic rupture?
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Did you know that HEYDE SYNDROME, which today is defined by a triad of 1) aortic stenosis, 2) recurrent bleeding from GI angiodysplasia, and 3) acquired type IIA von Willebrand syndrome was first described by Edward Heyde in a 1958 correspondence to the NEJM?
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CRP-ESR DISCORDANCE
CRP and ESR are widely used tests of inflammation that sometimes give discordant results. When discrepancies exist, they may give a clue to the underlying diagnosis.
Check out the 4 cases in the two graphics...
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ISOLATED NEUTROPENIA IN ADULT OUTPATIENT
A common referral to our clinic!
Most often labeled BEN/DANC (in individuals of certain ethnic groups) or chronic idiopathic neutropenia on basis of exclusion. Neither has any clinical consequences.
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Did you know that there is an exception to the rule that all vertebrates have RBCs?
Yup, the Antarctic ice fish! All of its oxygen is dissolved in plasma.
It helps that it lives in cold water, where oxygen is more soluble. Can you predict its cardiovascular adaptations?
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ALCOHOL (ETOH) AND IRON
Alcohol is often included in the differential diagnosis of elevated ferritin.
What are the mechanisms? See * in graphic.
1. ETOH --> reduced hepcidin --> increased iron absorption.
2. Direct (Fe-independent) induction of ferritin expression.
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FERRITIN IN IRON DEFICIENCY AND/OR INFLAMMATION
ID represses ferritin TRANSLATION
Inflammation induces ferritin TRANSCRIPTION
When both ID and inflammation are present, the inhibitory effects of ID win out, and ferritin RARELY exceeds 100 ng/ml (exception = patient with CKD).
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FOCUS ON MCHC, NOT MCH
When choosing between mean corpuscular Hb (MCH; weight of RBC in Hb) and mean MCHC (the concentration of Hb inside the cell; think central pallor), it is the latter that provides discriminatory power in the ddx of anemia.
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THROMBOCYTOPENIA (TP) IN SEPSIS
1. Thrombocytopenia occurs in about 50% of patients in the ICU.
2. Sepsis accounts for approximately 50% of all thrombocytopenia in the severely ill.
3. Platelet count is included in the SOFA score.
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SERUM FERRITIN THRESHOLDS
Clinically useful thresholds for serum ferritin.
Feel free to weigh in!
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THROMBIN TIME (TT)
Such a simple clotting test that bypasses most of the clotting cascade and focuses on the final step (thrombin-mediated cleavage of fibrinogen to fibrin). A prolonged TT has a nice tight differential diagnosis!
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MICROCYTIC ANEMIA AND SYSTEM 2 THINKING
The 2 most common causes of microcytic anemia are IDA and thalassemia trait. According to the morphological classification of anemia, microcytic anemia is divided into normochromic and hypochromic subtypes.
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BASOPHILIA
Talk about a neglected cell type.
A search for basophilia in UpToDate sends you to a topic on the evaluation of the peripheral blood smear. Hardly helpful!
The only useful review is:
For representative cases, see:
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SMOKING AND LEUKOCYTOSIS
I frequently get referred patients with mild leukocytosis who are smokers. When is it safe to ascribe the leukocytosis to smoking?
There are no reviews on this topic. So, I did a deep dive in the literature. This is what I found:
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Elevated serum ferritin?
Easy! Must be one or more of:
1. Inflammation (check acute phase reactants, e.g. CRP)
2. Iron excess (check TSAT)
3. Congenital hyperferritinemia (history of cataracts; mutation analysis)
3. Leak from damaged cells (alcohol abuse, check LFTs)
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MICROCYTIC ANEMIA
The ddx of microcytic anemia may be incorporated into the time-honored morphological classification of anemia.
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APPROACH TO NORMOCYTIC ANEMIA
This is the most common type of anemia, and its differential diagnosis can sometimes feel overwhelming, and 'all over the place'.
The following is organizational scheme with simple diagnostic buckets that covers virtually all causes:
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APPROACH TO PATIENT WITH HYPERFERRITINEMIA
Based on British Society of Hematology guideline on "Investigation and management of a raised serum ferritin" (PMID: 29672840).
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Reticulocytosis is a cause of macrocytosis.
Retics are about 20% larger than mature RBCs.
Retic count roughly correlates with the MCV (graphic, left).
However, even 100% retics does not increase the MCV above 115 fL (graphic, right).
If MCV > 115 fL look for another cause!
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RELATIONSHIPS BETWEEN RBC INDICES
RBC count
a. Used to calculate the Hct (Hct = MCV x RBC count)
b. Used by some to predict iron deficiency vs. thalassemia (e.g., Meltzer index)
b. Largely ignored because it says nothing about the size/Hbization of RBCs
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Macrocytosis = MCV > 100 fL
FACTOIDS:
1. Present in 3% of population
2. Only about 50% of cases have anemia
3. 20-30% of macrocytosis is unexplained
3. MCV>125 fL likely = B12 deficiency or meds
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DEFINITION OF ANEMIA
Yesterday, I posted a poll showing Hb 10.4 and Hct 41 and asked whether or not the patient had anemia.
About 62% of respondents answered YES.
That is the CORRECT answer.
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H PYLORI AND IRON DEFICIENCY
Saw a young previously healthy 36 yo male who presented with 2 month history of lower abdominal cramping and was found to have iron deficiency anemia with secondary thrombocytosis (CBCs shown in graphic, ferritin < 5).
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Diagnostic flow chart for hemolysis (see graphic)
NOTES:
1. Immune (DAT+) or non-immune (DAT-)?
2. If immune (DAT is positive), allo or auto? What is the identify of the antibody?
3. If non-immune (DAT is negative), is it extracorpuscular or intracorpuscular?
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APPROACH TO MICROCYTOSIS
For more information, see infographic:
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NORMOCYTIC, NORMOCHROMIC ANEMIA
There are many causes of normocytic, normochromic anemia. It helps to use an organizing framework that sorts causes into big, then smaller buckets:
1. Hypo- vs. hyperproliferative
2. Hyperproliferative: bleeding vs hemolysis
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IRON IN RESTLESS LEG SYNDROME (RLS)
The use of iron supplementation in a patient with normal peripheral iron stores is anathema to the hematologist.
But there is increasing data pointing to a role of LOCAL BRAIN iron deficiency in patients with RLS...
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PHYSICAL EXAM IN MACROCYTIC ANEMIA
When I sat my oral exam for internal medicine in Canada, my short case started with:
"Dr. Aird, please examine this patient for an MCV of 120 fL. Tell us what you are thinking as you move from head to toe".
... I still have nightmares!
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CASE STUDY
1/11
74 yo F presents with CBC shown in graphic below. You will note she has macrocytic anemia, which has a wide differential diagnosis (also shown in graphic).
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POLYCLONAL GAMMOPATHY
I was recently referred a patient for evaluation of polyclonal gammopathy.
I have to admit that beyond liver disease and general inflammation, I was drawing blanks! OK, Castleman's and IgG4-related disease, but these are pretty rare.
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RBC INCLUSIONS
My approach to RBC morphology on a peripheral smear is to assess:
1. RBC size
1a. Average size
1b. Variation in size
2. RBC staining
2a. Central pallor
2b. Polychromatophilic cells
3. RBC shape (poikilocytes)
4. Inclusions (see graphic)
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COLD SENSITIVITY IN IRON DEFICIENCY (ID)
I am struck by how common patients with ID (with or without anemia) complain of cold sensitivity. Like other symptoms of ID, the patient must be directly questioned about this feature.
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DIC LAB MARKERS
I tweeted a poll yesterday asking which of 4 markers is least sensitive for diagnosing DIC.
Over 4,300 responses ... awesome participation! ❤️
The correct answer is fibrinogen. Interestingly, it was the least favored choice (just 18% voted for it).
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CORTICOSTEROIDS IN ITP
I tweeted a poll asking whether you would treat a patient with newly diagnosed ITP with high-dose dexamethasone (HD-DXM) or prednisone (PRED).
57% chose HD-DXM.
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LYMPHOCYTOPENIA
You are asked to see a patient with incidental finding of lymphocytopenia (also known as lymphopenia) (see graphic).
What do you do?
HIV test?
ANA?
Warn against risk of infection?
Watch and wait?
There is LITTLE guidance out there!
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CASE
QUESTION: Describe the CBC shown in the graphic in the fewest words possible.
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To those who insist on using Hct over Hb to describe a patient with anemia (I hope they are few in number), does this patient have anemia or not?
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CEREBRAL VEIN THROMBOSIS (CVT)
Saw a 34 yo F who presented with acute headache and word finding difficulties and was found to have large left temporal intraparenchymal hemorrhage secondary to transverse & sigmoid sinus thrombosis.
Got me thinking/reading about CVT.
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SYMPTOMS OF NON-ANEMIC IRON DEFICIENCY (ID)
I just love this study from
@TobyRichardsUCL
- on many levels.
To begin with, the title ("The misogyny of iron deficiency") is a classic, and a topic for another day.
But check out the shear diversity of symptoms from ID. Awesome!
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ANEMIA + THROMBOCYTOPENIA
1. Hypersplenism (any combo of cytopenias)
2. Babesiosis
3. Evans syndrome (ITP + AIHA)
4. B12 deficiency (+/- leukopenia)
5. TMAs (e.g. TTP)
6. HLH (+/- leukopenia)
7. PNH (+/- leukopenia)
8. Alcohol (+/- leukopenia)
9. Other primary BM process
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CASE STUDY
67 yo M with background history of HTN and mild CKD presents with recent onset orthostatic hypotension, worsening renal function and proteinuria.
In preparation for a renal biopsy, a PT/aPTT are sent and they come back elevated.
Question: What is the ddx?
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HEPARIN-INDUCED THROMBOCYTOPENIA (HIT) - PHYSICAL EXAM
This is my check list when approaching a patient with HIT.
What would you add?
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EPONYMS IN HEMATOLOGY
Yesterday, I tweeted about the eponymous Evans syndrome, named after Dr. Robert Evans.
Today, I'd like to highlight Eric von Willebrand (VW), whose last name refers to both a disease and a factor.
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DILUTIONAL ANEMIA
I recently tweeted about how easy it would be to make you (temporarily) anemic with a bolus of fluid 😀
I asked 2 questions:
1. What would happen to your oxygen carrying capacity?
ANSWER: Decreased
2. What about oxygen delivery
ANSWER: Probably no change
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CASE
QUESTION: Take a look at the CBC below and describe it in the fewest words possible.
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