Blood cookies!

I’ve been really busy teaching this fall, so I haven’t been posting nearly as much as I’d like. I will be back to normal (ha) soon – but until then, I thought I’d share what we did in class yesterday. We’ve been learning about hematopathology (my favorite) – so I made cookies depicting some of the diseases we covered.

It’s super geeky, but I’m okay with that. It’s really fun to combine path knowledge with something that’s actually creative and pretty. And it’s sort of educational for my class…at the very least, they get a well-deserved break from the HOURS of lecture they have to sit through. Here are the end results (with a few high-yield things about each cell).

Sickle cells

Sickle cells are seen, of course, in sickle cell anemia. They’re abnormally shaped because when sickle hemoglobin deoxygenates, it polymerizes, contorting the red cell into a sickle shape.

Reed-Sternberg cell

Reed-Sternberg cells are the malignant cells in Hodgkin lymphoma. They’re gigantic, and typically they have two nuclei with prominent nucleoli, giving the cell an “owl’s-eye” appearance.

Neutrophil with Dohle body

In some cases of bacterial infection, neutrophils develop little blue cytoplasmic inclusions, called Döhle bodies, which are chunks of revved-up rough endoplasmic reticulum.

Butt cell

No, I didn’t make this up! Follicular lymphoma is made up, in part, of small cleaved cells – and when these get out into the blood, their nuclei totally look like butts. Adorable.

Faggot cell

Faggot cells contain TONS of Auer rods (faggot means bundle of sticks). They’re pathognomonic of acute promyelocytic leukemia, which has a t(15;17) that you should stick in your head somewhere.

Blast with Auer rod

Auer rods are only seen in malignant myeloblasts. So if you see one, you know you’re dealing with acute myeloid leukemia. Not all AMLs have Auer rods, though – so the absence of Auer rods doesn’t rule out AML.

Platelets

These could be normal platelets…but since we’re talking about diseases, let’s say they’re platelets from essential thrombocythemia, which is one of the four chronic myeloproliferative disorders (it’s the one in which the blood has an extremely high platelet count).

Do all leukemias arise from hematopoietic stem cells?


Q. I have a quick question on the cell of origin in leukemia. In our pharmacology class, we went through a section on cancer. There was a slide that said leukemia is a tumor of hematopoietic stem cells. But leukemia involves more than just hematopoietic stem cells, right? (more…)

What the H is HLH?

Hemophagocytic lymphohistiocytosis is not easy to pronounce. That’s why it is often abbreviated HLH, which is a lot kinder on both the tongue and the keyboard.

The “hemophagocytic” part of the name, which means “blood + eat + cell,” comes from the observation that the immune activation in HLH often results in hemophagocytosis, in which blood cells are engulfed by histiocytes (macrophages in the tissue) in a very cannibalistic way. Check out the histiocyte in the center of this image (can you see the red cells inside?).

This activation of macrophages is why the disease has also been called macrophage activation syndrome in the setting of juvenile rheumatoid arthritis. The “lympho” part comes from the increase in lymphocytes that happens in HLH. Even though this disease has a complicated name and several different triggers, the symptoms have one common cause: Cytokine Storm.

What causes HLH? Cytokines and hit men.

Cytokines are important molecules in inflammatory signaling in the body, and when not properly regulated they can cause a lot of destruction. if you want a mini-review on cytokines check out all about cytokines in less than 400 words.   

HLH happens when something triggers an over-activation of cytotoxic T and natural killer (NK) cells, which are cells responsible for quickly recognizing and destroying cells which have been infected, usually by viruses. Cytotoxic T cells and NK cells are specialized lymphocytes which are kind of the hit men of the immune system. When they detect cells presenting viral antigens via major histocompatibility complexes, they release perforins to punch holes in the cells and cytokines to signal other inflammatory cells to rush in and finish the job.

This immune over-activation turns on lots and lots of cytokine-producing macrophages. The massive cytokine release causes fever. The huge numbers of activated macrophages end up “eating” or destroying the patient’s own blood cells as well as doing damage to many organs, such as the bone marrow, lungs, and liver. The damaged blood cells get trapped in the spleen, causing splenomegaly. HLH can also kick off other problems in blood regulation, such as disseminated intravascular coagulation (DIC).

Primary vs. Secondary HLH

HLH can be genetic (“primary”) or acquired (“secondary”). Genetic cases usually appear in early childhood and are associated with a mutation affecting cytotoxic cell function, or with an immunodeficiency state such as Chediak-Higashi syndrome. Acquired forms of HLH can occur at any age – but often affect adults (although some adults are later found to have a predisposing mutation). Adult cases are hard to recognize, because they happen in the setting of other serious illnesses and can present with non-specific symptoms.

Acquired HLH can be triggered by any event provoking an immune response. Usually, though, it occurs in the setting of infection or malignancy, when the immune system is already compromised. Infectious triggers are usually viral, most commonly Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Exactly why adult HLH happens in these settings is still poorly understood, although it is thought that underlying genetic susceptibility could play a role in some cases.

Diagnosis

Despite the name of the disease, hemophagocytosis is not necessary to diagnose HLH. It can be helpful  – but it isn’t specific for HLH, and can be found in a lot of other inflammatory conditions. So to diagnose HLH, you need either an established molecular abnormality consistent with an HLH mutation, or 5 of the following clinical criteria:

  1. Fever
  2. Splenomegaly
  3. Cytopenias in at least 2 blood cell lineages (indicating that the blood cells are being eaten up)
  4. High triglycerides and/or low fibrinogen (the latter is involved in the clotting cascade)
  5. Hemophagocytosis
  6. Low or absent NK-cell activity
  7. High ferritin (which transports iron and is also a marker of acute stress in the body)
  8. Elevated soluble CD25 (also called soluble IL-2 receptor alpha. Remember, IL-2 tells lymphocytes to proliferate and differentiate)

Treatment

It is very important to recognize HLH quickly so treatment can be started – but diagnosis can be tricky since many of the symptoms overlap with sepsis or malignancy. Treatment includes chemotherapy, immunosuppression, supportive care, and sometimes bone marrow transplant (mostly in genetic cases). Untreated, HLH is nearly universally fatal.

Bottom Line

The lesson here? Never underestimate the power of cytokines…and think about the possibility of HLH in a very sick patient with the appropriate clinical warning signs.

For more about HLH, read Robbins 9e., pages 585-586

Reference:
Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. & McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. Blood 118, 4041–4052 (2011).

A huge thanks to Michelle Stoffel, MD PhD, PGY3 Pathology Resident at the University of Wisconsin, for yet another informative and fun post! Check out her other awesome posts here , here and here

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Blood cookies!

Okay, that was disturbing. But it was a lot of fun making cookies in the shape of different blood cells for our lectures on anemia and leukemia this week! (more…)