You Make the Diagnosis: a 32-Year-Old with Mild Jaundice

A 32-year-old male presents with mild jaundice and flank pain. He recently developed sinusitis, which was treated with trimethoprim-sulfamethoxazole, but is otherwise healthy. His hemoglobin is 10.2 g/dL (13.5-17.5), MCV is 90 μm3 (80-100), and total bilirubin is 3.4 mg/dL (0.2-1.5). A representative field from his blood smear is shown here. What is the most likely diagnosis?

g6pd1

  1. Aplastic anemia
  2. Iron-deficiency anemia
  3. Glucose-6-phosphate dehydrogenase deficiency
  4. Autoimmune hemolytic anemia
  5. Megaloblastic anemia

The answer is glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an X-linked recessive disorder in which patients produce decreased amounts of G6PD, a red blood cell enzyme involved in detoxifying free radicals.

When a patient with G6PD deficiency is exposed to an oxidant stress (which can be anything from an illness to ingestion of certain foods or drugs), the resulting reactive oxygen species attack structures within the red cell.

Globin chains are particularly vulnerable to oxidant damage. They become denatured and stick to the inside of the red cell membrane, forming inclusions called Heinz bodies, which are visible on crystal violet staining. Heinz bodies are removed by macrophages in the spleen, leaving visible “bites” in the red cells. Several bite cells are visible in this patient’s blood smear (arrows).

g6pd2

Most episodes of hemolysis in patients with G6PD deficiency resolve on their own after the offending substance is removed.

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.

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. 

Issues for Blood Management in Hematology/Oncology

Hematology/Oncology patients comprise a unique subpopulation for whom transfusion therapy is often necessary in both the acute care setting as well as for long-term support. Red blood cells (RBCs) and platelets are the most common components transfused particularly in patients undergoing high-dose chemotherapy, intensive radiation therapy and human hematopoietic stem cell transplantation (HSCT).

Restrictive transfusion practice has become the “new world order” particularly for general medical and surgical patients. Those with hematologic malignancies or solid tumors have not frequently been a large part of many of the randomized controlled trials that speak to this approach. Literature is available, however, that provides evidence that judicious use of blood components via restrictive transfusion and single unit transfusions for inpatients and outpatients can be clinically effective, safe, and will decrease the potential for transfusion-associated adverse events.

Feasibility studies of restrictive RBC transfusion in the Hematology/Oncology population have been reported. These studies provide compelling evidence that lower transfusion triggers, targets and single unit use are not associated with increased bleeding episodes and will reduce overall transfusion exposure.¹ ² ³ The American Society of Hematology (ASH), as part of their Choosing Wisely Campaign, advises against liberal transfusion of RBCs with hemoglobin (Hgb) targets of 7- 8 g/dL, along with implementation of single-unit transfusions when possible.4

Recent RCTs and consensus from the AABB point to similar restrictive practice for platelet transfusion with a trigger of 10,000/µL for prophylactic transfusion in most patients.⁵ Subgroups of patients, such as those with autologous HSCTs, may not require prophylactic transfusion at this level, but can be effectively transfused using a therapeutic-only strategy.⁶ The use of lower doses of platelets has been shown to be safe and effective.⁷ Similar strategies may also be applicable for outpatients.⁸

Pursuant to those patients receiving radiation therapy, historically, there have been reports in the literature that found loco-regional control to be improved in patients whose Hgb is maintained at a higher level, typically > 10 g/dL. Many, if not most of these studies had significant confounding and have not adjusted for comorbidities. A publication in 2012, however, concluded “…that hypoxia is a well-established cause of radio-resistance, but modification of this cannot be achieved by correcting low Hgb levels by…transfusion and/or [ESAs[.”⁹ Similarly, a recent study covering over 30 years of experience with cervical cancer patients undergoing radiation therapy (the original target population from a historical perspective) adjusted for confounders and found no evidence that anemia represented an independent predictor of outcomes associated with diagnosis or treatment. ¹° Transfusion, in and of itself, has significant negative immunomodulatory effects via cell-to-cell interactions and cytokines.   Thus, maintenance of Hgb levels for these patients should not be considered an absolute necessity.

Other interventions may prove successful for Hematology/Oncology patients as part of a Blood Management Program. Identification and treatment of concomitant iron deficiency anemia or other nutritional deficiencies can potentially decrease or eliminate the need for transfusion. Drugs that might increase the risk for bleeding or hemolysis should be eliminated if possible as these cause or potentiate anemia. Use of new targeted drugs such as lenalidomide in patients with 5q deletion-associated MDS may prevent the need for long-term transfusion dependence. The use of antifibrinolytics in patients who have become refractory to platelet transfusions can enable platelet function even at low levels and prevent the unnecessary use of limited platelet resources.

Outpatient transfusion in the Hematology/Oncology arena comes with some unique circumstances. Many outpatients remain stable and will be capable of lower transfusion thresholds and longer intervals for both RBCs and platelets. Evidence-based restrictive transfusion can and should be a part of outpatient treatment strategy, just as with inpatients if the accessibility to post-transfusion care is adequate. No national guidelines are available for outpatient transfusion and each patient scenario must be considered on an individual basis, but certainly the absolute need for “standing” transfusions and obligatory 2-unit transfusions should be discouraged. Consider, as well, that patients often have their own view of the “need” for transfusion when symptoms and signs do not necessarily make it requisite. Discussion with our patients is essential to allow them to understand transfusion decisions.

The risks of transfusion are both immediate and delayed, particularly for those with chronic transfusion needs. Febrile non-hemolytic, allergic, hemolytic reactions, TRALI and TACO may occur as in other patient populations and should be recognized and treated as appropriate. Alloimmunization and transfusion-related iron overload are more common in the Hem/Onc arena given the potential for increased component exposure during the acute care setting and the high percentage of those that necessitate chronic transfusion support. The potential for transfusion-associated graft vs. host disease is also more worrisome given the degree of immunosuppression in these patients. Specialized products are often necessary including leukoreduced, antigen negative, irradiated or HLA-matched components. These specialized products may not be available on a STAT basis and add significantly to the overall transfusion cost. Careful consideration is warranted and inclusion of the Transfusion Service is key.

In the end, transfusion practice for Hematology/Oncology patients should include restrictive transfusion practices with assessment of the risks and benefits at the time of each potential transfusion episode. Each patient, whether inpatient or outpatient, should be evaluated based on their current state of stability, clinical course and availability and access to care. Nutritional assessments and subsequent interventions along with pharmaceutical agents may provide additional ways by which transfusion exposure can be decreased. Special products are often necessary and needs should be discussed with the Transfusion Service. Limiting transfusion ultimately avoids unpleasant, potentially severe acute and delayed adverse events as well as preserving resources within our communities.

References:

  1. Jansen et al. Transfus Med 2004; 14: 33
  2. Berger et al. Haematologica 2012; 97: 116
  3. Webert et al. Transfus 2008; 48: 81
  4. choosingwisely.com
  5. Kaufman et al. Ann Intern Med 2014; doi: 10.7326/M14-1589
  6. Stanworth et al. Transfus 2014; 54: 2385
  7. Slichter et al. N Engl J Med 2010; 362: 600
  8. Sagmeister et al. Blood 1999; 93: 3124
  9. Hoff Acta Oncologica 2012; doi: 10.3109/0284186X.2011.653438
  10. Bishop et al. Int J Radiat Oncol Biol Phys 2014; doi: 10.1016/j.ijrobp.2014.09.023

Burns

-Dr. Burns was a private practice pathologist, and Medical Director for the Jewish Hospital Healthcare System in Louisville, KY. for 20 years. She has practiced both surgical and clinical pathology and has been an Assistant Clinical Professor at the University of Louisville. She is currently available for consulting in Patient Blood Management and Transfusion Medicine. You can reach her at cburnspbm@gmail.com.