Thread by @DanielRicottaMD

After long overdue, I am hopping on the #tweetorial bandwagon @tony_breu @AdamRodmanMD. So here goes nothing! #FOAMed #MedEd #Physiology

I’ve often been told not to order an ESR because it is a nonspecific test. In fact, our hospital doesn’t even run it anymore, it's a send-out!

So, what are the factors that influence ESR to make it non-specific?

(written alongside @AndyHale33 @FreedoBaggins)

In 1897, Polish pathologist Edmund Biernacki noticed that buckets of blood separated into the red blood cell (RBC) and plasma components at different rates in different disease states.

ncbi.nlm.nih.gov/pubmed/?term=K…

The ESR describes the rate (mm/hr) at which RBCs settle in a standard column (Westergren tube) and has been correlated with inflammatory states such as infection, rheumatologic, inflammatory conditions, and malignancy

So we know many things increase ESR, but it is still helpful to detect underlying inflammation...isn’t it? Consider:

A 23yo M with OUD p/w fever, petechial rash, new murmur, and shock. Labs with thrombocytopenia and GPC BCx. TTE with AV Vedge. ESR checked and was 5mm/hour

How could this patient with septic shock have a low ESR?

Let’s consider first what happens in the Westergren tube.

When blood is allowed to sit uninterrupted RBCs will naturally settle to the bottom of a tube. Because of the column of plasma, factors that influence the plasma composition such as viscosity will impact RBC sedimentation

RBCs also interact with each other, mechanically and electrically. The RBC cell membrane has a slight negative charge and cells will naturally repel each other which reduces the rate of sedimentation.

More simply, imagine RBCs as cars on a highway. ↓cars (anemia)→traffic will move faster (↑ESR). Cars in organized lanes (rouleaux formation)→traffic will move faster (↑ESR). Plasma viscosity is the smoothness of the road. Graded pavement (↑viscosity) → ↓ESR

So, to state it succinctly ESR is readily explained by three variables:
1. spatial interference within the column of blood
2. electrical charge of RBCs
3. viscosity of the plasma

1. Spatial interference – defined as factors that physically disrupt falling RBCs such as extreme leukocytosis. RBC downward flow is physically impeded by the numerous leukocytes (traffic cones on the highway) and the ESR decreases.

academic.oup.com/cid/article/33…

2. Electrical charge - RBCs have a slight (-) surface charge which causes each cell to repel each other and ↓ESR. If the plasma is enriched with + charge proteins, like Ig or fibrinogen, this electrical interference is blunted and RBC agglutination occurs, extreme is rouleaux

3. Plasma viscosity – increased viscosity slows erythrocyte sedimentation and concordantly decreases the ESR.

bloodjournal.org/cgi/pmidlookup…

OK, but you are telling me that extreme leukocytosis can reduce ESR and I know that infection increases ESR. These two factors often occur together and each's impact on ESR seem counter to each other. How do you reconcile this?

Turns out that of the 3 factors, the one that most strongly influences ESR is the electrical charge. Positively charged proteins create RBC cross-bridges, resulting in organization and promotes sedimentation which results in an increased ESR.

**Fibrinogen** in particular, is the primary reason ESR is elevated in inflammatory states because it is the main acute phase reactant by concentration.

academic.oup.com/ofid/article/2…

In the below experiment, we first eliminated fibrinogen in a sample of blood. We then added increasing concentrations of fibrinogen to the same sample and measured ESR. As you can see, in the same exact blood sample, over same time period ↑concentrations of fibrinogen ↑ESR

Oh by the way….
- Age related increase in ESR? → Fibrinogen increases with age
- Pregnancy related increase in ESR? → Fibrinogen increases in pregnancy

Interim summary:

ESR is readily explained by three variables:
1. spatial interference within the column of blood
2. electrical charge of RBCs
3. viscosity of the plasma

!!But electrical charge is the most important and fibrinogen specifically has the largest impact

So how do we explain the presented case scenario of a patient with septic shock and a low ESR?

The patient was in septic shock with resulting DIC and critically low Fibrinogen levels. Without fibrinogen, there was minimal counter-balance to the negative charges on RBC membranes and the outcome is reduced sedimentation.

Summary:
ESR is non-specific because it is influenced by many factors that influence three variables:
1. spatial interference
2. electrical charge of RBCs
3. viscosity of the plasma

!Electrical charge is the most important and *fibrinogen specifically has the largest impact

And before you go - the obligatory self-promotion. If you are interested in learning more check out our @FreedoBaggins @AndyHale33 paper in @JAMA_current

jamanetwork.com/journals/jama/…