Von Willebrand Disease

Von willebrand disease is the most common inherited bleeding disorder. Partial lack of VWF (von Willebrand factor) causes mild or moderate bleeding tendency. Patients typically present with menorrhagia, bruising, bleeding from gums or after surgery. It is typically autosomal dominant with variable penetrance. Laboratory investigation reveals defective platelet adherence (PFA-100) or long bleeding time, subnormal levels of von Willebrand antigen and factor VIII in plasma and low ristocetin cofactor activity or VWF activity.

Single very large molecules visualized by electron microscopy
Single very large molecules visualized by electron microscopy. Journal of Clinical Investigation, vol 76, October 1985
vWF unfolds under stress, the faster the blood flow, the stickier it gets. Blood, 1996; volume 88
vWF unfolds under stress, the faster the blood flow, the stickier it gets.
Blood, 1996; volume 88

Types of von Willebrand disease

  • Type 3: Patient has severe deficiency of vWF. Antigen, activity and factor VIII levels are all < 10%. Clinically patients have a hemophilia-like phenotype. It is inherited recessively.
  • Type 2: Patients have a qualitative defect (missense mutation) of the vWF. There are several different types. Usually there is a disproportionate decrease in vWF activity vs antigen.
  • Type 1: vWF antigen and activity are reduced proportionately. vWF levels range from < 20% to ~50%. Only 65% of cases are associated with VWF gene mutations. It has an autosomal dominant inheritance pattern with variable penetrance (affected by blood type, other factors).Defects in VWF processing, storage or secretion may account for cases lacking VWF gene mutation. Some cases are associated with accelerated VWF clearance.

Type-2 vWD

  • 2A: Deficiency of intermediate & large multimers due to either defective assembly (mutation in either of two domains involved in multimer formation), or increased susceptibility to proteolysis (mutation in domain cleaved by ADAMTS-13)
  • 2B: Largest multimers are missing. This is due to gain of function mutation in platelet Gp Ib binding domain of vWF.Largest multimers bind spontaneously to platelets and are cleared from blood. Rarely, a mutation in Gp Ib may have the same effect (“platelet-type” vWD).
  • 2M: Normal multimer pattern. There is loss of function mutation in GP Ib binding domain
American Society of Hematology.
Image: American Society of Hematology.

Laboratory analysis

Laboratory testing in vWD (Table 1)
Laboratory testing in vWD (Table 1)

Von Willebrand factor activity: Measures binding of patient VWF to latex beads coated with monoclonal Ab to GPIb binding site; sensitive to multimer size and platelet-binding ability

Platelet function screen (PFA): Measures time necessary for platelet plug to form in collagen coated tube under high shear conditions in the presence of ADP or epinephrine

Desmopressin (DDAVP) in VWD

DDAVP releases vWF from endothelial cells and can be given IV or intranasally ( 0.3 mcg/kg IV, or 150 mcg per nostril ). It typically causes 2-4 fold increase in blood levels of vWF (in type 1 vWD), with half-life of 8+ hours. Response to DDAVP varies considerably. Administration of a trial dose si necessary to ensure a given patient responds adequately.

vwd4

Indications for clotting factor concentrate administration in vWD include

  • Type 2 or 3 vWD with active bleeding, surgery or other invasive procedures or
  • Type 1 vWD with inadequate response to DDAVP.

Acquired von Willebrand Disease

This can happen in association with either monoclonal gammopathy ( vWF neutralized by paraprotein) , autoimmune disorders (autoantibody to vWF), myeloproliferative disorder (large multimers absorbed onto neoplastic cells), cardiovascular diseases (AS, VSD, etc, high shear stress causes unfolding/proteolysis of large multimers), or hypothyroidism (decreased release of vWF from endothelial cells). Treatment varies depending on the cause/mechanism in each case.

NEJM 2009;361:1887
NEJM 2009;361:1887

 

Vajpayee,Neerja2014_small

-Neerja Vajpayee, MD, is an Associate Professor of Pathology at the SUNY Upstate Medical University, Syracuse, NY. She enjoys teaching hematology to residents, fellows and laboratory technologists.

Five Things to Know … Granulocyte Transfusions

This is the first in series of “5 Things to Know” updates on various Transfusion Medicine topics, posted on Lablogatory and the Blood Bank Guy website. Today, we will cover a topic that is a mystery to many: Granulocyte transfusions!

1. We aren’t totally sure that granulocytes actually work! In the nearly half-century that granulocyte concentrates have been transfused, numerous retrospective articles, case reports, and small series about granulocytes have been published. If you ask Hematology-Oncology docs, you will likely find a general consensus that granulocytes can be effective (including a really cool, almost miraculous-sounding story!). Sadly, stories are not evidence. A study begun in 2008 called The “RING study” (Resolving Infection in people with Neutropenia with Granulocytes) was designed to gather evidence by randomizing recipients into either a group that received granulocytes or one that did not. Unfortunately, the study failed to gather enough participants before closing in 2013 to be truly meaningful (though the data that was gathered did not show a substantial beneficial effect, according to data presented at the 2014 American Society of Hematology Annual Meeting). PByoukeepusingthatword-Product-2

So, does this mean that granulocyte transfusions are stupid? Not from my perspective! Honestly, if the standard for producing a product is proof positive that the product is effective, we blood bankers would have NOTHING on our shelves! Some of my colleagues disagree with me, but from my perspective, granulocytes have value in some limited settings (outlined below).

2. Modern granulocyte collections are a multiple day process. Historically in the United States, granulocytes were collected by apheresis either from “walk-in” unstimulated donors (more common) or from donors given a single dose of oral steroids to increase their white blood cell count. The unstimulated collections resulted in a product with a total granulocyte count of about 1.0 x 1010 (that number is the minimum requirement in at least 75% of collections, according to AABB Standards, and is a GREAT number to remember if you are studying for an exam!). However, if we have learned anything about granulocytes, we know that 1.0 x 1010 just isn’t enough! A “modern” U.S. granulocyte collection is from an apheresis donor stimulated the day before collection with an injection of Granulocyte Colony Stimulating Factor (“G-CSF”), in many cases supplemented by an oral dose of steroids (typically dexamethasone); this regimen typically results in a yield of 4.0 x 1010 granulocytes or more (please note that G-CSF is not FDA-approved for use in stimulating donors, so donors should have a formal informed consent prior to undergoing stimulation). As an aside, granulocytes may be produced in different ways outside of the US. The United Kingdom, in particular, does not permit G-CSF or steroid stimulation of granulocyte donors that are not family or friends of the patient. As a result, non-family member UK granulocyte products are produced from pooled buffy coats from ten random donors, with a yield of approximately 1.0 x 1010 granulocytes. These collections require lots of extra effort by numerous people (including our donors!), which leads us to number three…

3. Granulocytes should only be ordered in specific clinical settings Granulocyte collections are not easy, and they should not be ordered carelessly. While there is no universally agreed-upon set of conditions, granulocytes are most commonly utilized in one of the following clinical situations:

  • Patients with hematologic malignancies and low neutrophil counts due to chemotherapy
  • Stem cell transplant recipients during pancytopenic phase
  • Neonates with sepsis
  • Patients with chronic granulomatous disease

This is not to say that everyone in one of those situations will or should receive granulocytes. Instead, we are looking for some specific clinical and laboratory findings before agreeing to start the granulocyte collection process, especially in the first three groups of patients on the list above. Here’s what we like to see:

  • Proven or highly probable bacterial or fungal infection (NOTE: Available data suggests granulocytes work better with bacterial infections)
  • No response to appropriate antimicrobial therapy
  • Absolute neutropenia (<500 granulocytes/microliter)
  • A reasonable expectation that the patient will begin producing granulocytes soon

Traditionally, blood bankers have strongly resisted “prophylactic” granulocyte transfusions (for immunosuppressed patients without current evidence of infection but at high risk of acquiring one) or use in fever of unknown origin. There has been some debate about this recently, but most still believe (as do I) that granulocytes should only be given for patients who have an infection.

4. Granulocytes look funny, and have unusual storage, matching, and modification requirements. If you have never seen a granulocyte product, you might guess that granulocyte and platelet concentrates look alike, since both cells reside in the “buffy coat” and both are collected in the US primarily by apheresis technology. Your guess would be wrong! Apheresis granulocyte units typically contain between 30 and 50 mL of RBCs, because it is essentially impossible to get a good granulocyte yield without harvesting some RBCs as well (they are immediately adjacent to each other by density separation in the apheresis machine). 30-50 mL sounds like a small amount, but that quantity makes the granulocyte product look almost as “red” as a unit of RBCs! (see images below)

GrannieonhookGranniebag

Notice how the same 30 mL that makes the bottom of the bag look red during collection (on left) makes the whole bag look REALLY red after mixing!

Granulocytes have pretty much the shortest shelf life of any product that we collect directly from donors. They should be transfused “as soon as possible” after collection, but definitely within 24 hours of collection. They are stored at room temperature, like platelets, but they should not be continuously agitated, unlike platelets. This out-of-the-ordinary storage is really another reason that granulocytes are only collected on an “as-needed” basis. Granulocytes are also unusual in that they are almost always issued prior to the availability of the infectious disease screening results! For that reason, essentially all unrelated apheresis granulocyte donors will be recent apheresis platelet donors who have had negative results on a donation within the previous 30 days. We still perform the testing, of course, but the results just aren’t available before the product has to be transfused. Because there are so many RBCs in each granulocyte product, the donor must be ABO compatible with the recipient, and the unit must be crossmatch-compatible with the recipient. By AABB Standards, if more than 2 mL of RBCs are present in any product, those RBCs must be compatible with the recipient’s plasma antibodies. In addition, if the recipient has an unexpected RBC antibody (like anti-D, anti-K, or any others), the granulocyte unit must come from someone who is negative for that antigen, as well. To make matters even more challenging, if the patient has developed anti-HLA antibodies (most commonly in previously pregnant females), then the donor should be HLA matched or at least HLA compatible with the patient’s antibodies. Finally, to complete the weirdness, it is essential to remember which modifications CAN and CAN’T be done to granulocytes. First, granulocytes CAN (and must) be irradiated to prevent Transfusion-associated Graft vs Host Disease (TA-GVHD). This is an extremely fresh product, full of highly active T-lymphocytes in addition to the granulocytes, and the recipient is immunocompromised, by definition. As a result, irradiation is essential to deactivate those donor T-lymphocytes and protect the patient (see image below). Second, granulocytes CAN’T be leukocyte-reduced. Every now and then, people will ask me about leukoreducing granulocytes for prevention of Cytomegalovirus (CMV) transmission. Rather than make fun of them, I usually just sit quietly while they work it out themselves (“OK, let’s see: Granulocytes are WBCs, which some people call ‘leukocytes,’ so if I leukocyte-reduce a unit of a product that is primarily composed of leukocytes, I would be left with…nothing! OHHHH!”). As a result of our inability to make a granulocyte product “CMV-safe” by leukoreduction, CMV-seronegative donors will be recruited to provide products for CMV-seronegative patients whenever possible. Note that it is totally fine to run granulocyte concentrate through a “standard” transfusion filter, just not a leukoreduction or microaggregate filter.

IrradOKNoFilter

Irradiation is not only OK for granulocyte concentrate, it is essential! Leukocyte reduction, on the other hand, makes no sense for granulocytes, and shouldn’t be done.

5. Granulocytes very commonly cause reactions in recipients. Granulocytes are famous for causing transfusion reactions much more often than other components. The two issues that are seen most often are fever and chills (without hemolysis) and pulmonary reactions. I won’t discuss the self-explanatory fever and chills issue, but the pulmonary reactions are worth mentioning here. Considering that current thought suggests that neutrophils are the primary cell involved in the pathogenesis of Transfusion-related Acute Lung Injury (TRALI), it is not surprising that granulocyte transfusions are thought to cause pulmonary compromise quite often (5% in one study). Granulocytes LOVE the lungs, and they localize there very quickly (especially when the infection being treated is pneumonia). So, even if full-blown TRALI does not occur (which certainly CAN happen!), granulocyte transfusions are notorious for at least transient pulmonary compromise. Clinicians should be prepared to manage dypsnea and hypoxia during granulocyte transfusion. Note that the previously suggested “link” between more pulmonary reactions when granulocytes were given with the antifungal Amphotericin B seems to be disproven (though many still advise avoiding transfusing granulocytes within a few hours of administration of that medication). As mentioned in item 4, TA-GVHD is a risk for a fresh product, so irradiation is required. Further, HLA alloummunization can certainly occur as a result of granulocyte transfusion. Final thoughts: There is no question to me that granulocytes CAN, in some circumstances, appear to make a difference for patients. Unfortunately, there’s not a lot of objective proof that they are a predictably helpful treatment. However, given our current ability to collect granulocyte products with substantially higher yields than in years past, I expect that interest in this product will continue despite the lack of “proof” of its effectiveness.

I hope that this quick “5 Things to Know” has been useful for you!

Chaffin

-Joe Chaffin, MD, is the new Vice President and Chief Medical Officer for LifeStream, a Southern California blood center headquartered in San Bernardino, CA. He has a long history of innovative educational efforts and is most widely known as the founder and chief author of “The Blood Bank Guy” website (www.bbguy.org).

You Never Know What You Might Find on Peripheral Smear Review

A 15 month patient was seen in the Pediatric Hematology-Oncology clinic in June 2014 for mild normocytic anemia.

Review of Systems

Negative 12 system review. No history of pallor, jaundice or high colored urine.

Ref. Range 6/14
WBC 6-17 K/uL 11.4
Hemoglobin 10.5-13.5 g/dL 8.9 (L)
Hematocrit 33-39 % 25.4 (L)
Platelets 150-400 K/uL 648 (H)
RBC 3.7-5.3 M/uL 3.57 (L)
MCV 70-86 fL 71.2
MCH 23-30 pg 24.9
MCHC 31-36 % 34.9
RDW 11.5-14.5 % 16.4 (H)

His serum iron profile was normal, serum lead levels were normal. Reticulocyte percentage and absolute reticulocyte count were also both not elevated.

Review of peripheral smear revealed moderate anisopoikilocytosis with presence of numerous elliptocytes.

he1

he2

Molecular studies demonstrated a heterozygous mutation in the EPB41 gene associated with HE.

Patient was diagnosed with Hereditary Elliptocytosis (HE).

He has been followed up at the hematology clinic for a year now. His follow up CBC results are as follows. He has reached his age appropriate milestones and continues to grow well.

Ref. Range 7/14 10/14 12/14 4/15
WBC 6-17 K/uL 10.3 11.3 7.4 10.0
Hemoglobin 10.5-13.5 g/dL 9.3 (L) 9.9 (L) 9.7 (L) 11.0
Hematocrit 33-39 % 26.5 (L) 28.7 (L) 28.1 (L) 33.6
Platelets 150-400 K/uL 599 (H) 570 (H) 403 (H) 447 (H)
RBC 3.7-5.3 M/uL 3.74 3.91 3.87 4.58
MCV 70-86 fL 70.8 73.3 72.6 73.5
MCH 23-30 pg 24.8 25.4 25.1 23.9
MCHC 31-36 % 35.0 34.7 34.5 32.6
RDW 11.5-14.5 % 16.9 (H) 17.7 (H) 18.2 (H) 18.0 (H)

Hereditary elliptocytosis (HE) is an inherited hemolytic anemia, secondary to red cell membrane defect more commonly assembly of spectrin, spectrin-ankyrin binding, protein 4.1 and glycophorin C with a clinical severity ranging from asymptomatic carriers to a severe hemolytic anemia. It is more common in individuals from African and Mediterranean decent – neither applies to our patient.It is inherited in an autosomal dominant pattern, typically individual who are heterozygous are asymptomatic while those who are homozygous or compound heterozygous have a mild to severe anemia. Occasional patients with more severe hemolysis may require splenectomy.

Regardless of the underlying molecular abnormality, most circulating red cells are elliptical or oval. They still have an area of central pallor, since there is no loss of the lipid bilayer (as seen in Hereditary spherocytosis).

Vajpayee,Neerja2014_small

-Neerja Vajpayee, MD, is an Associate Professor of Pathology at the SUNY Upstate Medical University, Syracuse, NY. She enjoys teaching hematology to residents, fellows and laboratory technologists. 

Hematology Case Study: 60-Year-Old Male with Hives

A 60-year-old male presents with hives, skin flushing, and headaches. After an appropriate preliminary work-up, a bone marrow biopsy is performed. A representative section from the bone marrow biopsy is shown here. What are the granulated cells at the center of this image?

mast

A. Megakaryocytes
B. Promyelocytes
C. Mast cells
D.Myeloma cells
E. Adenocarcinoma cells

The granulated cells in this image are mast cells, which are identified by their abundant, metachromatic granules. This patient was diagnosed with systemic mastocytosis, a clonal disorder of mast cells and their precursors.

Mastocytosis is actually a spectrum of rare disorders, all of which are characterized by an increase in mast cells. Most patients have disease that is localized to the skin, but about 10% of patients have systemic involvement, like the patient in this case. There is a localized, cutaneous form of mastocytosis called urticaria pigmentosum that happens mostly in children and accounts for over half of all cases of mastocytosis.

Clinically, the skin lesions of mastocytosis vary in appearance. In urticaria pigmentosum, the lesions are small, round, red-brown plaques and papules. Other cases of mastocytosis show solitary pink-tan nodules that may be itchy or show blister formation. The itchiness is due to the release of mast cell granules (which contain histamine and other vasoactive substances).

In systemic mastocytosis, patients have skin lesions similar to those of urticaria pigmentosum – but there is also mast cell infiltration of the bone marrow, lymph nodes, spleen and liver. Patients often suffer itchiness and flushing triggered by certain foods, temperature changes, alcohol and certain drugs (like aspirin).

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Peripheral Smear Review: Inexpensive Test to Establish Diagnosis of a Rare Disease

29-year-old woman with a history of ITP (immune mediated thrombocytopenia) diagnosed in 2008. She had previously been treated with steroids, IVIG (intravenous immunoglobulin) and splenectomy. She also received Romiplostim for 1 year prior to its discontinuation. She had also been diagnosed with lupus one year previous.

Follow up visit after having her platelets evaluated in the office 2 weeks ago revealed a platelet count of 9 K/uL on CBC which was flagged by the instrument due to platelet clumping.

  • WBC: 7.5 K/ul
  • HGB: 12.2 g/dl
  • HCT: 37.3 %
  • PLT: 9 K/ul *

*On manual count the platelet count was deemed to be 74 K/uL.

Peripheral smear review:

Numerous large and some giant platelets, platelet clumping and basophilic Dohle body like inclusions in nearly all neutrophils.

mayheg1

Characteristic giant platelet with poorly defined granulation. Normal-sized platelet is also present. Neutrophil contains large, well-defined, basophilic, peripherally placed cytoplasmic inclusion body (resembling Döhle body).

mayheg2

The value of peripheral smear review is very well highlighted by this case. As the smear was never reviewed earlier in the disease course, diagnosis of MHA was not made and the patient was diagnosed as ITP entirely based on clinical presentation. Perhaps earlier review of peripheral smear would have significantly altered the clinical management of the case.

After discussion with pathologist who reviewed the peripheral blood smear, diagnosis of May-Hegglin anomaly was confirmed and appropriately documented in the patient’s chart.

May-Hegglin anomaly (MHA):

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by various degrees of thrombocytopenia that may be associated with purpura and bleeding; giant platelets containing few granules; and large (2-5 um), well-defined, basophilic, cytoplasmic inclusion bodies in granulocytes that resemble Döhle bodies.

MHA is one of a family of macrothrombocytopenias characterized by mutations in the MYH9 gene present in chromosomal region 22q12-13. The mutation results in disordered production of nonmuscle myosin heavy-chain type IIA, which leads to invariable macrothrombocytopenia secondary to defective megakaryocyte maturation.

Clinical features:

The rarity of MHA has led to conflicting literature regarding the risk for bleeding. Asymptomatic patients have been described however, abnormal bleeding has also been documented. The bleeding risk is increased by taking drugs that decrease platelet function. The risk for excess bleeding with surgical procedures is unclear. Rare reports have described arterial thrombotic events associated with May-Hegglin anomaly, though the risk remains unclear. Patients are often asymptomatic. The bleeding tendency associated with MHA is generally mild and is thought to mainly depend on the degree of thrombocytopenia.

Clinical Features of MYH9 -Related Thrombocytopenias

Condition Macrothrombocytopenia Granulocyte inclusions Nephritis and Deafness Cataracts
MHA Yes Döhlelike No No
Epstein syndrome Yes Absent or faint Yes No
Fechtner syndrome Yes Spherical granules Yes Yes
Sebastian syndrome Yes Spherical granules No No

Differential diagnosis:

In addition to acute immune thrombocytic purpura, the differential diagnosis for thrombocytopenia associated with large platelets (elevated mean platelet volume) includes Bernard-Soulier syndrome, Montreal platelet syndrome, gray-platelet syndrome, and Alport syndrome.

The differential diagnosis for thrombocytopenia due to ineffective thrombopoiesis includes Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, Greaves syndrome, thrombopoietin deficiency, and megaloblastic anemia.

The differential diagnosis for leukocytic inclusions, sometimes called Döhle bodies, includes septicemia, myeloproliferative disorders, and pregnancy.

Laboratory investigation:

  • The complete blood count (CBC) is essential in assessing MHA. The platelet count is decreased (usually in the range of 40-80 ´ 109/L), but the degree of thrombocytopenia varies.
  • The disorder is also characterized by giant platelets. Platelets are enlarged (>15 µm in diameter), and the mean volume of MHA platelets can be as high as 30 fL. Platelet morphology is otherwise normal.
  • On electron microscopy, platelets are seen to contain normal organelles (alpha granules, dense granules, lysosomes, and mitochondria). The most conspicuous ultrastructural feature of the platelets is an increased amount of disorganized microtubules.
  • Cytoplasmic inclusion bodies particularly in the neutrophils but also in monocytes, eosinophils, and basophils. The inclusions are large (>5 µm), spindle-shaped, pale, blue-staining bodies that consist of ribosomes, segments of endoplasmic reticulum, and microfilaments. They are located in the periphery of the cytoplasm and resemble Döhle bodies.
  • Ultrastructural studies reveal that these bodies consist of clusters of ribosomes oriented along parallel myosin heavy-chain filaments 7–10 nm in diameter. Neutrophil function is considered to be normal, and patients have no increased susceptibility to infections.
  • Immunocytochemistry can detect NMMHCIIA complexes within the leukocytes and is a useful confirmatory test.
  • The bleeding time is prolonged in concordance with the degree of thrombocytopenia.
  • Platelets usually aggregate normally in response to various agonists. The glycoprotein composition of the platelet surface is normal.

Management

Most patients with MHA do not appear to have clinically significant bleeding problems, and specific treatment is not required.

  • Corticosteroids and splenectomy are ineffective
  • In rare patients with severe bleeding, platelet transfusion may be required
  • Bleeding risk is not significantly increased by normal vaginal delivery
  • For patients scheduled to undergo surgery, intravenous desmopressin acetate (DDAVP) may be valuable; routine prophylactic platelet transfusions are not usually indicated, but platelets should be kept available
  • Depending on circumstances, refraining from participation in contact or collision sports may be prudent.

Vajpayee,Neerja2014_small

-Neerja Vajpayee, MD, is an Associate Professor of Pathology at the SUNY Upstate Medical University, Syracuse, NY. She enjoys teaching hematology to residents, fellows and laboratory technologists. 

Pancytopenia in a 67-Year-Old Female

A 67-year-old female presents with pancytopenia, a markedly enlarged spleen, and extramedullary hematopoiesis. Her blood smear is shown here. She is found to have a JAK-2 mutation. What is the diagnosis?

myeloprolif

  1. Chronic myelofibrosis
  2. Chronic myeloid leukemia
  3. Hairy cell leukemia
  4. Metastatic breast carcinoma
  5. Renal cell carcinoma

The diagnosis in this case is chronic myelofibrosis. Chronic myelofibrosis is one of the four main chronic myeloproliferative disorders (the others are chronic myeloid leukemia, essential thrombocythemia, and polycythemia vera). In this disorder, the bone marrow is initially hypercellular, with proliferation of all of the myeloid cell lines (neutrophils, red cells, and megakaryoblasts). Over time, however, the marrow becomes progressively fibrotic. Eventually, there is not enough room for normal hematopoiesis, and the body starts making hematopoietic cells elsewhere (most notably in the spleen, which becomes markedly enlarged).

In these later stages of chronic myelofibrosis, the blood is characterized by pancytopenia (a decrease in white cells, red cells and platelets). Teardrop-shaped red cells (dacryocytes) may also be seen as a result of the red cells wending their way through a fibrotic marrow. Red cell precursors, such as the normoblast present in this image, are also commonly present, as there is less and less room for red cells to mature fully before leaving the marrow.

These blood smear findings are not specific for chronic myelofibrosis. Teardrop-shaped red cells may be seen when the marrow is fibrotic for other reasons, such as metastatic cancer, and pancytopenia and normoblasts may be seen in many other conditions. The JAK-2 mutation, however, is seen most frequently in three of the four chronic myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and chronic myelofibrosis.

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

A Rare Myeloproliferative Disorder

hypereosinophilic

A 59-year-old male presents with skin lesions, hepatosplenomegaly and cardiomyopathy. A representative field of his blood smear is shown here. Of the following, what is the most likely diagnosis?

  • A. Chronic myeloid leukemia
  • B. Multiple myeloma
  • C. Metastatic prostate carcinoma
  • D. Hypereosinophilic syndrome
  • E. Bacterial sepsis

The diagnosis in this case is hypereosinophilic syndrome, a rare myeloproliferative disorder characterized by a marked and persistent elevation in the eosinophil count. Although this disease is primarily a hematopoietic disorder, it usually affects many other organ systems, such as the cardiovascular, nervous, respiratory, and gastrointestinal systems. Typical presenting symptoms include cardiomyopathy, skin lesions, thromboembolic disease, neuropathy, hepatosplenomegaly, and pulmonary disease. The pathophysiology behind the damage in these organs isn’t well understood, but it probably has something to do with the release of eosinophil granules in those tissues.

You need to have three things in order to make the diagnosis:
1. Persistent eosinophilia (absolute eosinophil count >1500/μL)
2. No other cause for the eosinophilia
3. Signs and symptoms of organ involvement

Other more common causes of eosinophilia, such as drug reactions, allergic reactions and autoimmune disease, must be ruled out before making the diagnosis.

Usually, patients aren’t treated unless or until they have symptoms (because the treatment itself has its risks). These patients are monitored closely with serum troponin levels (to monitor for MI), echocardiograms and pulmonary function tests.

Some patients with hypereosinophilic syndrome have a tiny deletion in 4q12, which ends up producing a fusion transcript called FIP1LI-PDGFRA (which is also present in some cases of systemic mastocytosis). Imatinib works very well in the majority of these patients.

Patients who have symptoms (but not FIP1LI-PDGFRA) are generally treated with steroids first. If those don’t work, interferon alpha and hydroxyurea are used. If those don’t work either, then imatinib is the treatment of choice (it doesn’t work as well as it does in patients withFIP1LI-PDGFRA, but it does seem to work in at least some of these patients).

Here are the reasons the other answers are incorrect.

  1. Myeloma is a monoclonal disease of plasma cells which manifests mainly in the bone marrow. In the blood, the main thing you see is rouleaux (red cells stacking up on top of each other). This blood smear just has a lot of eosinophils – so it’s not consistent at all with myeloma. The clinical history also doesn’t fit. In myeloma, patients usually have bone pain, signs of anemia (fatigue, palpitations), and maybe signs of renal failure. Hepatosplenomegaly, skin lesions, and cardiomyopathy aren’t generally seen in myeloma.
  2. In CML, you see a massive leukocytosis which is composed of neutrophils and precursors. There is a big left shift and a basophilia. This smear just has a ton of eosinophils, which is not consistent with CML. The patient’s hepatosplenomegaly would be consistent with CML (especially the splenomegaly part) – but the skin lesions and cardiomyopathy don’t go along with that diagnosis.
  3. In metastatic prostate cancer, it’s possible that you might see a rare tumor cell in the blood; you might also see a monocytosis (you occasionally can see that with solid tumors). Eosinophilia, however, is not consistent with prostate cancer. The history is also unsupportive. Patients with advanced prostate cancer may have urinary symptoms (trouble urinating, blood in the urine), abdominal or pelvic pain, or signs of metastasis (bone pain, particularly in the spine).
  4. The characteristic blood finding in bacterial sepsis is a neutrophilia, with or without a left shift. You may also see toxic changes in the neutrophils: toxic granulation, Döhle bodies, and/or cytoplasmic vacuolization. Bacterial infections generally don’t produce an eosinophilia – but some parasitic infections can.

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.