CONTENTS

common issues in hospitalized/ICU patients

• Acute anemia
• Gradual anemia: the ICU drift
• Transfusion targets for stable patients
• Managing Jehovah's Witness patients

general approach to anemia

• [1] Gleaning information from the CBC
  • MCV
  • MCHC
  • RDW
• [2] Investigation
  • Reticulocyte count

selected diagnoses

• Iron deficiency anemia
• Anemia of chronic disease
• Anemia in alcoholism
• Hemolytic anemia
• Splenomegaly

blood smear

• Acanthocytes
• Basophilic stippling
• Bite cells & Heinz body hemolytic anemia
• Burr cells (aka ecchinocytes)
• Elliptocytes
• Howell-Jolley Bodies & hyposplenism
• MDS (myelodysplastic syndrome)
• Nucleated red cells
• Polychromatophilia
• Rouleaux formation
• Schistocytes
• Spherocytes
• Target cells
• Teardrop cells (“dacrocytes”)

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acute anemia

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causes of acute anemia 

Acutely falling hemoglobin indicates either hemolysis or hemorrhage. Erythrocytes normally have a half-life of 120 days, so even complete cessation of erythropoiesis cannot cause an acute fall in hemoglobin.  

hemorrhage (usually)

• External:
  • GI bleed.
  • Phlebotomy.
  • Trauma/surgery.
• Internal:
  • Hemoperitoneum.
  • Hemothorax.
  • Retroperitoneal hemorrhage, rectus sheath hematoma.
  • Bleeding into the thigh (common after hip fracture).

hemolysis

• Malfunctioning intravascular prosthesis:
  • Impella device.
  • Mechanical heart valve.
  • Vascular graft or shunt.
• Microangiopathic hemolytic anemia (e.g., DIC, TTP, HUS).
• Infection:
  • Clostridia.
  • Babesia or malaria.
• G6PD deficiency.
• Sickle cell crisis.
• Autoimmune hemolytic anemia (e.g., due to transfusion reaction or medications).

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evaluation of acute anemia

lab evaluation

• Repeat CBC to verify that hemoglobin is truly falling.
• Hemolysis screen: Haptoglobin, lactate dehydrogenase (LDH), blood smear.
• Labs to assist in the management of hemorrhage:
  • Type & screen.
  • Check coagulation factors and fibrinogen.

imaging evaluation of hemoglobin drop

• Bedside ultrasonography (including FAST scan) should allow for the exclusion of hemothorax or hemoperitoneum.
• CT abdomen/pelvis may be indicated to evaluate for retroperitoneal hematoma, particularly if there was a recent procedure that may have caused this.
  • If there is a high index of suspicion for retroperitoneal hematoma or hemoperitoneum, consider CT angiography as this may guide a subsequent procedure by interventional radiology.

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management 

general management

• Review anticoagulants; consider holding them if possible.
• If stress ulcer/erosion is probable, consider an empiric proton pump inhibitor.

transfusion 📖

• ⚠️ Relative contraindications to transfusion:
  • Uncontrolled hypervolemia.
  • Severe hyperkalemia.
• Target hemoglobin >7 (or >8 if active myocardial ischemia or cardiac surgery).
• Unless anemia is definitely severe, avoid ordering multiple units at a time.
• Consider a combination of blood with diuretics for patients who are hypervolemic.

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gradual anemia- the ICU hemoglobin drift

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defining ICU hemoglobin drift

• Most ICU patients experience a gradual decrease in hemoglobin over time. This is probably multifactorial, with the following contributory factors:
• [1] Suppression of hematopoiesis due to inflammation (similar to anemia of chronic disease).
• [2] Phlebotomy for laboratory studies.
• [3] Minor, subclinical stress ulceration in the GI tract.
• [4] Volume overload and fluid redistribution into the vascular space.

management of hemoglobin drift

• Minimize phlebotomy:
  • Avoid unnecessary labs.
  • Especially for patients at increased risk from anemia (e.g., ARDS patients with limited oxygen delivery), draw labs in pediatric tubes.
• Conservative transfusion strategy (more on this below).
• Discontinue unnecessary anticoagulants. For example, some patients are on chronic aspirin for primary prevention – this should be discontinued.
• Prevention/treatment of stress ulceration:
  • Preventing stress ulceration:
    • Enteral nutrition, if possible.
    • Proton pump inhibitor (more on this below).
  • For patients who consistently lose more hemoglobin than usual, initiating a proton pump inhibitor may be considered for empiric treatment of gastrointestinal erosions.
• (Erythrypoitein)
  • Erythropoietin has been trialed several times for this, with disappointing results. (17804841) For most patients, this isn't worth the expense and work involved. Erythropoietin should be considered, however, for the Jehovah's Witness patient.

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transfusion targets for patients not exsanguinating

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transfusion should be used carefully and judiciously

• Transfusion may cause numerous problems:
  • Transfusion-associated circulatory overload (TACO 🌮; a fancy name for volume overload).
  • Transfusion reactions include transfusion-related acute lung injury (TRALI) and anaphylaxis.
  • Immunosuppression.
  • Hyperkalemia, hypocalcemia.
• More liberal administration of blood products has been shown to be non-beneficial or harmful in most studies of critically ill patients.

contraindications to transfusion

• Transfusion may be especially problematic in:
  • Patients with increased blood viscosity (e.g., due to hyperleukocytosis in uncontrolled AML).
  • In patients with thrombotic thrombocytic purpura (TTP), transfusion may increase hemolysis.
  • Uncontrolled hypervolemia (especially in dialysis patients).
  • Hyperkalemia (potassium leaks out of RBCs in storage, potentially increasing serum potassium levels).
• In these contexts, it may be reasonable to hold transfusion in patients with hemoglobin <7 mg/dL without signs of organ hypoperfusion.
  • It is often wise to transfuse dialysis patients during hemodialysis to avoid volume overload or hyperkalemia.

transfusion target for the patient who is not acutely hemorrhaging

• The transfusion target for nearly all ICU patients is 7 mg/dL (70 g/L). However, a target of >8 mg/dL (80 g/L) is preferable for patients recovering from CABG surgery or patients with active myocardial ischemia (myocardial infarction or unstable angina). (28284299, 31449062)
• Blood should generally be transfused one unit at a time. (19773646, 32700082) Avoid transfusion of more than one unit of blood unless the patient is actively hemorrhaging or the hemoglobin is extremely low. This is done for two reasons:
  • 1) Hemoglobin bounces around a bit from day to day. Overreacting to a “low” hemoglobin with two units of blood transfusion will often over-correct the anemia.
  • 2) Blood transfusion tends to cause pulmonary edema (more so than crystalloid). Two units of blood is a significant volume bolus for a patient who may have euvolemic or hypervolemic anemia.

transfusion target for the patient with a gastrointestinal hemorrhage

• For patients who don't have a massively exsanguinating bleed, a conservative transfusion target (>7 mg/dL) was shown to improve mortality compared to a liberal transfusion target (>9 mg/dL). (23281973)
• If you're worried that the patient might suddenly open up, the safest approach is to order blood to be typed & crossed and placed on hold in the blood bank. Make sure the patient has good intravenous access. Then, if the patient starts exsanguinating, you're all set – just request that the blood be infused. Most of the time, the patients won't bleed, allowing you to avoid exposing them to the risk of excessive transfusion.
• The harms from over-transfusion are probably greatest for patients with variceal hemorrhage, where over-transfusion can push patients into a death spiral:📖

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managing Jehovah's Witness patients

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getting started: clarify goals

• Discuss with the patient and/or family whether they would accept a blood transfusion if necessary.
• Clarify whether some blood products may be acceptable (for example, some patients may accept coagulation factor concentrates).
• If possible, these discussions should occur early, when the patient is stable. Ethics consultation may be helpful when in doubt.

avoid blood loss

• Avoid hemoglobin drift: The major threat to these patients isn't necessarily an acute hemorrhage but rather gradual blood loss, which is commonly seen in ICU patients (see above: “hemoglobin drift”). Gradual blood loss can easily become a major problem over a 1-2 week ICU stay. The following measures may be used to avoid this:
  • Begin aggressively to conserve blood immediately upon arrival to the ICU (don't wait until the patient's hemoglobin has dropped to 5 mg/dL).
  • Draw labs in pediatric tubes.
  • Discontinue all scheduled blood draws (no “cycling” of labs). Every blood draw should represent a deliberate decision by the treatment team. Consider giving patients “lab holidays” (e.g., checking basic labs q48hr or q72hr).
  • Lab draws should be strictly limited to mission-critical tests, which are absolutely required for patient care.
• Adequate stress ulcer prophylaxis.
  • NSAIDs should be avoided to reduce the risk of peptic ulceration (as is the case for most critically ill patients).
  • Stress ulcer prophylaxis should be considered.
• Avoid coagulopathy
  • Whenever possible, avoid or minimize anticoagulation.
  • When anticoagulation is necessary, use the lowest dose possible of a reversible agent. Avoid direct-acting oral anticoagulants.
  • Be aware of coagulation labs and act accordingly – especially for patients with active bleeding or when prescribing an anticoagulant.
• Avoid unnecessary procedures that pose a risk of bleeding.
• Aggressive management of any acute hemorrhage
  • Early operative intervention (e.g., prompt endoscopy for GI hemorrhage)
  • The use of procoagulants (e.g., tranexamic acid) may be rational.

promote blood synthesis

• The use of erythropoietin hasn't been shown to be beneficial in most patients, but it may improve hemoglobin levels. Among Jehovah's Witness patients, this is a rational therapy. This may be achieved as follows:
• 1) sq erythropoietin 300 U/kg/day for two weeks if necessary, then three times per week.(19958881, 27526872)
• 2) IV iron sucrose as needed to maintain ferritin >> 100 ng/mL and transferin saturation >20%.(17804841) Erythropoietin won't work without adequate iron stores.
• 3) Give empiric folate and vitamin B12 to support hematopoiesis.

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summary: management of Jehovah's Witness patient in ICU 

• [1] Clarify which products may be used:
  • Discuss early & document well (e.g., some pts will accept PCC & cryoprecipitate).
  • Consult ethics if unclear.
• [2] Minimize blood loss proactively upon admission:
  • All labs should be drawn in pediatric tubes.
  • Discontinue scheduled labs and limit to mission-critical tests spaced at wide intervals.
• [3] Avoid coagulopathy:
  • Avoid anticoagulants as able (including aspirin and NSAIDs).
  • When anticoagulation is essential, use the lowest dose & most reversible agent.
  • Be aware of coagulation labs (periodically check platelets, INR, PTT).
• [4] Consider stress ulcer prophylaxis.
• [5] Promote blood synthesis pro-actively if anemic:
  • Erythropoietin 300 U/kg/day s.q. for two weeks.
  • Empiric folate and B12.
  • IV iron to maintain ferritin >100 ng/ml & transferrin saturation >20%.
• [6] Treat any bleeding aggressively:
  • Early procedural control of bleeding to prevent ongoing blood loss.
  • Aggressive use of hemostatic agents (e.g., tranexamic acid, desmopressin).

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approach to anemia: initial information from the CBC

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Every patient with an anemia diagnosis already has a CBC checked, so this information is immediately available early in the evaluation. The CBC provides some useful clues that can help guide further evaluation. 

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hemoglobin: confirming the presence of anemia 

• Rough benchmarks for defining anemia are:
  • <13 mg/dL for men.
  • <12 mg/dL for nonpregnant women.
  • <11 mg/dL for pregnant women.
• However, normal hemoglobin ranges may vary (e.g., depending on altitude).

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MCV (mean cell volume) & MCH (mean cell hemoglobin)

MCV and MCH are generally the most important indices since they allow for the classification of anemia as microcytic, normocytic, or macrocytic. They should generally correlate with each other. MCV has traditionally been utilized primarily, but MCH might be subject to fewer measurement artifacts. (27195903)

microcytic anemia (MCV <80 fL; MCH <27.6 pg)

• Iron-deficient state:
  • Iron deficiency.
  • Anemia of inflammation (late in disease evolution).
• Thalassemia may be suggested by:
  • Extremely chronic microcytic anemia.
  • Severely reduced MCV (MCV <70 Fl suggests thalassemia or iron deficiency).
  • Mentzer Index <13. This is calculated as (MCV in fl)/(RBC count in million/uL). 🧮
• Sideroblastic anemia (defects in porphyrin synthesis cause extra iron to be deposited in the mitochondria of the erythrocyte precursor, causing basophilic stippling ⚡️):
  • Congenital.
  • Lead poisoning.
  • Alcoholism.
  • Medications (e.g., isoniazid, chloramphenicol, cycloserine).
  • Myelodysplastic syndrome (idiopathic sideroblastic anemia is a preleukemic state).
• Copper deficiency (may be caused by bariatric surgery, anorexia, or excess zinc supplementation).

normocytic anemia (MCV 80-100 fL; MCH 27.6-33 pg)

• Early iron-deficient state:
  • Early iron deficiency.
  • Anemia of inflammation.
• Chronic renal insufficiency (GFR usually <30).
• Blood loss:
  • Hemorrhage.
  • Hemolysis.
• Combined microcytic and macrocytic anemia with pseudonormalization of the MCV (e.g., iron and B12 deficiencies). This might be suggested by an elevated RDW (see section below).
• Hypothyroidism.
• Many forms of bone marrow dysfunction:
  • Aplastic anemia.
  • Medication-induced (chemotherapy, azathioprine, methotrexate).
  • Bone marrow infiltration (e.g., metastatic malignancy).
  • Hematologic malignancy (e.g., leukemia, myeloma, lymphoma, myelofibrosis).

macrocytic anemia (MCV >100 fL; MCH >33 pg)

• Round (RBC membrane defects):
  • Reticulocytosis (MCV of a reticulocyte is 160 fL). Further discussion of reticulocytosis: ⚡️
  • Hypothyroidism.
  • Alcoholism.
  • Liver disease (may be associated with macrocytic target cells). (24716235)
  • Renal disease.
  • Aplastic anemia.
• Oval (macroovalocytes; DNA synthesis defects):
  • Megaloblastic anemias (hypersegmented neutrophils may be seen on peripheral smear)
    • B12 deficiency.
    • Folate deficiency.
  • Drugs that impair DNA synthesis:
    • Folate antagonists (methotrexate).
    • Purine antagonists (6-mercaptopurine, azathioprine, acyclovir).
    • Pyrimidine antagonists (fluorouracil, zidovudine).
    • Ribonucleotide reductase inhibitors (cytosine arabinoside, hydroxyurea).
    • Alkylating agents (cyclophosphamide).
  • MDS (myelodysplastic syndrome) – blood smear may show various abnormalities as discussed below: ⚡️

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MCHC (mean cell hemoglobin concentration)

• Normal: 32.8-36.4 g/dL.
• Low MCHC indicates hypochromic anemia, with the same differential as low MCV (see above).
• High MCHC indicates hyperchromic anemia, which suggests a relative cell membrane deficiency:
  • Hereditary spherocytosis.
  • Autoimmune hemolytic anemia.
  • Cold agglutinin disease (agglutination of RBCs causes spurious elevation of MCHC). (29304902)
  • Dehydration with subsequent concentration of the erythrocytes.

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RDW (red cell distribution width)

• RDW is a measurement of anisocytosis (variation in erythrocyte size). Unfortunately, its significance is limited, so it should be interpreted cautiously.
• RDW-CV (more commonly utilized):
  • RDW-CV is the standard deviation divided by the mean cell size.
  • Normal is <14%.
  • RDW-CV magnifies variation in size among patients with microcytosis.
  • RDW-CV may be insensitive to mild or early macrocytosis.
• RDW-SD:
  • RDW-SD measures the range in size that encompasses 80% of erythrocytes.
  • Normal is <47 fL.
  • RDW-SD is sensitive to small populations of microcytic or macrocytic cells.
• Elevated RDW is relatively nonspecific, with some causes listed below. This may be an indication to evaluate further (e.g., by obtaining a blood smear).
  • Deficiency of iron, B12, and/or folate.
  • Sideroblastic anemia.
  • Chronic liver disease.
  • Myelodysplastic syndrome.
  • Reticulocytosis (e.g., due to hemolysis or blood loss). (29304902)

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approach to anemia: evaluation

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history

• Acute or chronic? (data review)
• Any obvious source of blood loss?
  • Hematemesis.
  • Hematochezia or melena?
  • Red or brown urine? (may indicate hemolysis)
  • Menses?
  • Recent trauma, especially with external hemorrhage?
• Family history of anemia?
• Medication review, focusing on:
  • Medications that can cause anemia.
  • Anticoagulants and antiplatelet agents.

examination

• ? Icterus (may suggest hemolysis).
• ? Conjunctival pallor.
• ? Splenomegaly (exam techniques here: ⚡️)

initial basic lab panel for anemia of unclear etiology (all comers)

• Complete blood count with indices (already done, but it is reasonable to repeat this).
• Blood smear.
• Reticulocyte count.
• Iron evaluation:
  • Ferritin, at a minimum.
  • +/- Iron profile (Serum iron, total iron binding capacity, iron saturation).
• Methylmalonic acid level (superior to B12 level). (28189170)

additional labs to obtain selectively

• Hemolysis testing (if MCV is normal or elevated, especially with reticulocytosis):
  • Basic:
    • Haptoglobin.
    • LDH (lactate dehydrogenase).
  • More advanced:
    • Liver function tests, including direct and indirect bilirubin.
    • Urinalysis with sediment evaluation.
    • Plasma-free hemoglobin or an equivalent laboratory test.
• TSH (if MCV is normal or elevated, other evidence of hypothyroidism).
• Homocysteine level to evaluate for folate deficiency if the MCV is elevated or nutritional deficiency is suspected (homocysteine may be elevated in folate and/or B12 deficiency). (28189170)

further discussion of anemia diagnostics:

1. Discussion of the reticulocyte count: below👇.
2. Evaluation for iron deficiency: 📖
3. Evaluation for hemolysis: 📖
4. Blood smear evaluation: 📖

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using the reticulocyte count 

metrics for reticulocyte count

• Absolute reticulocyte count:
  • Normally ~30,000-100,000/uL (i.e., 30-100 b/L). (27195903)
  • <100,000/uL in the context of anemia suggests inadequate erythropoiesis.
  • The absolute reticulocyte count has the advantage that it doesn't require correction for other factors (e.g., hematocrit). (27195903)
• Reticulocyte index:
  • This is calculated based on the percent of reticulocytes and the hematocrit. 🧮
  • A reticulocyte index <2 in the context of anemia suggests inadequate erythropoiesis.

anemia with inadequate reticulocyte count (e.g., index <2)

• This is usually the case for most patients with anemia, especially hospitalized patients.
• Causes of anemia with inadequate reticulocyte index:
  • [1] Erythrocyte production problem.
  • [2] Combined disorder (e.g., hemolytic anemias can present with an inadequate reticulocyte count due to folate deficiency and/or immune destruction of erythrocyte precursors).
  • [3] Acute anemia or hemolysis (the bone marrow requires up to 1-2 weeks to increase reticulocyte number). (37823455)
• So, finding an inadequate reticulocyte count usually doesn't change things much. However, if the reticulocyte count is extremely low (<0.1%), this strongly suggests bone marrow failure and should suggest the potential need for a bone marrow biopsy.

anemia with an adequate reticulocyte count (e.g., index >2)

• This is a highly significant finding that should help substantially redirect the evaluation of anemia.
• Causes of adequate reticulocyte count include the following:
  • [1] Blood loss.
  • [2] Hemolysis.
  • [3] Recovery phase from anemia (due to any etiology).
• The approach to this finding is as follows:
  • [1] Has the patient recently been treated for some form of anemia (e.g., with iron/folate/B12 supplementation)?  If so, reticulocytosis probably reflects recovery from a prior anemia.
  • [2] Test for hemolysis. If detected, evaluate further as appropriate (discussed below ⚡️).
  • [3] If no hemolysis is detected, evaluate for a source of occult blood loss (e.g., gastrointestinal bleeding).

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iron deficiency anemia

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epidemiology: common causes of iron deficiency

• Blood loss, e.g.:
  • Gastrointestinal tract (e.g., colitis, polyps, cancer, peptic ulcer disease).
  • Menstrual blood loss.
  • Chronic epistaxis.
• Impaired iron absorption, e.g.:
  • Status post bariatric surgery.
  • Celiac disease.
  • Helicobacter pylori infection; achlorhydria due to anti-parietal cell antibodies.

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laboratory markers of iron store adequacy

[1/4] RBC morphologic clues

• An MCV <70 fL suggests either iron deficiency or thalassemia. This isn't sensitive, but may occasionally be helpful.
• Some findings on blood smears may support iron deficiency (e.g., elliptocytes, pencil forms).

[2/4] ferritin

• Normal ferritin level is ~30-300 ng/ml.
• Ferritin is the best single index of iron stores.
• Limitation of ferritin:
  • [1] Ferritin is elevated in the context of inflammation and liver diseases (including nonalcoholic fatty liver disease). (39011129)
  • [2] Ferritin might be less reliable among patients recently receiving iron therapy or blood transfusion. However, 97% of patients with iron deficiency may still have a reduced ferritin and transferrin saturation within 48-72 hours of blood transfusion. (36573406)
• ____FERRITIN INTERPREATATION____
• Ferritin <30 ng/mL indicates total body iron deficiency with high specificity.
• Ferritin 30-100 ng/mL is a grey zone. This could be normal, or it could represent a combination of iron deficiency plus anemia of chronic inflammation. Higher cutoffs are more appropriate for patients with increasing age, comorbidity, and/or systemic inflammation:
  • <45 ng/mL cutoff to define iron deficiency:
    • The American Gastroenterology Association recommends using ferritin <45 ng/mL in all patients as a cutoff to define iron deficiency. This cutoff yields a sensitivity of 85% and a specificity of 92%. (32828801)
    • Ferritin levels normally increase with age. Consequently, patients >65 years old with a ferritin <45 ng/mL are especially likely to have iron deficiency (specificity >92%).
  • <100 ng/mL cutoff to define iron deficiency:
    • Older patients tend to have higher ferritin levels (similar to D-dimer levels), so they may have iron deficiency with ferritin in the ~50-100 ng/mL range.
    • Ferritin <100 ng/mL should be interpreted to indicate iron deficiency in the context of an obvert etiology of chronic inflammation (36573406, EHA guidelines 39011129) or chronic kidney disease (GFR <60 ml/min). (37823455) However, if the transferrin saturation is >20% then the diagnosis of iron deficiency must be questioned. (37823455)
• Ferritin >100 ng/mL essentially rules out iron deficiency. (28189170)

[3/4] transferrin or TIBC (total iron binding capacity)

• Transferrin (normal 200-350 ug/mL): This directly measures the transferrin level (the glycoprotein that binds and transports iron in the blood). This is slightly more accurate, but it may have increased turnaround time.
• TIBC (total iron binding capacity)(normal 240-450 ug/mL): This indirectly measures the iron-binding capacity of proteins in the blood by adding iron and evaluating the amount of iron that remains unbound. This approach may slightly overestimate the iron-binding capacity due to iron binding to other proteins in the blood (e.g., albumin).
• Interpretation of transferrin/TIBC:
  • Low levels:
    • Anemia of chronic disease (transferrin is a negative acute phase reactant, so the most common cause of a low level is inflammation or malignancy). (29304902)
    • Malnutrition.
    • Liver disease.
    • Nephrotic syndrome.
    • Protein-losing enteropathies.
  • Normal levels:
    • Combined iron deficiency anemia plus anemia of chronic disease may cancel each other out to generate normal levels.
  • Elevated levels:
    • Iron deficiency: Elevated TIBC is insensitive but specific for iron deficiency. (28189170)
    • Pregnancy, oral contraceptives.

[4/4] transferrin saturation

• Normal range: 15-45%.
• Low transferrin saturation (<20%) may occur in either iron deficiency anemia or anemia of chronic inflammation.
• High transferrin saturation: >50% indicates a toxic state of iron overload (e.g., hemochromatosis).

(serum iron isn't very helpful)

• Normal is ~37-170 ug/mdL.
• Marked diurnal and day-to-day variation (higher in the morning).
• In isolation, the serum iron doesn't seem to be very useful. The serum iron level is predominantly utilized to calculate the transferrin saturation.
• Low serum iron:
  • Inflammation, physiological stress.
  • Iron deficiency.
• High serum iron:
  • Liver disease (e.g., hepatitis may release iron stores from the liver).
  • Hemolysis.
  • Oral iron supplementation.
  • Oral contraceptives (causing elevated transferrin level).
  • Iron overload states (e.g., hemochromatosis).

(other indices are less useful for hospitalized patients)

• Serum transferrin receptor is elevated in iron deficiency or elevated erythropoiesis (e.g., autoimmune hemolytic anemia). It is not elevated in inflammation or liver disease. The transferrin receptor level may be useful in sorting out iron deficiency versus combined iron deficiency plus anemia of chronic disease. Unfortunately, this isn't widely available, nor is it available for rapid turnaround.
• Reticulocyte hemoglobin (RET-He) can be obtained alongside a CBC using modern blood analyzers (without requiring additional phlebotomy or technology). RET-He reflects the iron available for erythropoiesis in the preceding 2-3 days.  RET-He may be elevated by inflammation, so it can't be utilized as a simple test to differentiate iron deficiency versus anemia of chronic inflammation.  A normal RET-He is 31.2-39.9 pg. RET-He <30 indicates iron deficiency anemia, anemia of chronic inflammation, or beta-thalassemia. RET-He >30 pg excludes iron deficiency anemia.

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treatment of iron deficiency with oral iron

dosing

• Every-other-day dosing is equivalent and better tolerated than daily therapy.
• Various formulations of iron have similar efficacy.
• Coadministration with vitamin C improves absorption.

expected results

• Hemoglobin should increase by 1 g/dL within two weeks.
• Ferritin levels should increase within a month.
• If these parameters aren't met, consider IV iron. (38864796)
• 💡 Oral iron usually won't work within the time frame of hospital admission, but initiation of oral iron may at least start this therapy and determine if it is tolerated.

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treatment of iron deficiency with IV iron

indications for IV iron: iron deficiency + one of the following: 

• Failure of oral iron:
  • Inability to tolerate oral iron.
  • Refractory to oral iron (see above; note that this also requires further diagnostic evaluation).
• Condition in which oral iron is unlikely to be absorbed, e.g.:
  • Active inflammatory bowel disease.
  • Status post bariatric surgery.
  • Systemic inflammation impairs enteral iron absorption. (36573406)
• Severe iron deficiency (IV iron accelerates recovery and avoids clinical deterioration).
• Need for rapid replacement of iron stores (e.g., preoperative optimization prior to pending major surgery).
• Heart failure with reduced ejection fraction.
• Pregnancy beyond 13 weeks gestation. (38282557)

contraindications to IV iron

• Serious infection (especially bacteremia).
• Tenuous IV access (extravasation may generate a permanent tattoo).
• Untreated hypophosphatemia (IV iron may exacerbate this).

dosing & estimation of iron deficit

• The Ganzoni equation may be utilized to estimate the iron deficit (use 14 mg/dL as a target hemoglobin). 🧮
• Dosing based on the Ganzoni equation results in slightly improved hemoglobin levels and less need for subsequent treatment. (36573406)
• One unit of PRBCs contains ~200 mg of iron. If the patient has received a PRBC transfusion, this should be subtracted from the iron deficit.

selection of iron formulation

• Current formulations of IV iron are extremely safe.  Different formulations have similar risks. (38864796) 
• The selection of the form of IV iron depends largely on logistical considerations.
• Ideally, a form of IV iron that allows for complete repletion in a single infusion (total dose infusion) should be utilized.

low molecular-weight iron dextran (INFeD™️)

• This is often a preferred formulation for inpatients. It is one of three formulations recommended as an optimal formulation of IV iron in expert consensus guidelines (alongside ferumoxytol and ferric derisomaltose). (38282557)
• The major advantage of low molecular weight iron dextran is that a total dose can be given as a single infusion.
• The maximal single dose used for iron deficiency anemia may be as high as 2,000 mg. However, 1,000 mg is a more typical dose (and this dose is listed as an optimal dose in recent guidelines). (38864796, 38282557) 
• 💡Avoid infusion reactions by running the IV iron slowly. Low molecular-weight iron dextran is administered to outpatients at 1,000 mg over an hour. However, stretching this out among inpatients over several hours can avoid infusion reactions.
• A test dose is used at some institutions prior to administration of the therapeutic dose. The therapeutic dose may be ordered >30 minutes after the patient receives the test dose.
  • The concept of a test dose is a historical holdover from older generations of high molecular-weight iron dextran that had substantial toxicity. Currently, this is likely unnecessary. The rate of transfusion-related adverse events is slightly lower with iron dextran than with iron sucrose. (36573406) 

iron sucrose (Venofer™️)

• Iron sucrose is often perceived as being safer than other formulations, but this isn't evidence-based. Indeed, the iron molecule is held less tightly to the carbohydrate in iron sucrose as compared to other IV iron formulations. Consequently, at higher doses (>200 mg per infusion), iron sucrose may have a higher rate of infusion reactions than other forms of iron. This is why iron sucrose doses are capped to <400-500 mg. (38282557)
• The maximal single dose is 400-500 mg, so full repletion will usually require multiple infusions. For this reason, recent expert consensus guidelines state that iron sucrose is a suboptimal form of IV iron. (38282557) However, if iron sucrose is the only form available to you, it is safe and effective.

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understanding & managing reactions to IV iron

background

• Reactions to IV iron almost invariably reflect CARPA (complement activation-related pseudoallergy, aka Fishbane reaction). (38864796) CARPA is not life-threatening. Symptoms of CARPA may include flushing, arthralgia, myalgias, back pain, and chest pressure. This is usually managed by pausing the infusion and resuming the infusion at a slower rate.
• It's unclear whether current IV iron formulations can cause true anaphylaxis. The reported rate of anaphylaxis from IV iron is <1 in 200,000 infusions. (38282557) Most reports of “anaphylaxis” due to modern IV iron formulations were probably CARPA that was misdiagnosed by practitioners who aren't familiar with this reaction. Guidelines recommend that a patient with an infusion reaction can be rechallenged with the same form of iron, substantiating the concept that these are not allergic (IgE-mediated) events. (38282557)

prevention of infusion reactions

• 💡For hospitalized patients, infusion reactions may be avoided by running the infusion extremely slowly. Fast infusions are needed for outpatients in the infusion suite, but inpatients are stuck in the hospital anyway, so there is no benefit in running the infusion rapidly.
• Premedication is controversial and not generally indicated.  Antihistamines have been reported to be associated with an increased risk of adverse reactions, so these should be avoided. (38282557)

diagnosis of CARPA

• CARPA often causes flushing, arthralgia, myalgias, back pain, and chest pressure. It usually occurs during the beginning of an iron infusion. 
• CARPA should not cause hypotension, wheezing, periorbital edema, stridor, or gastrointestinal pain. (38282557)

management of CARPA

• ⚠️ First-generation antihistamines (e.g., diphenhydramine) should be avoided since they may worsen symptoms. (38864796)
• Steroids can be utilized for more severe reactions (e.g., 100-200 mg IV hydrocortisone), but this is rarely needed.
• Following an infusion reaction, the patient can be rechallenged with the same form of iron. (38282557)
• Further details regarding the management of reactions are below:

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anemia of chronic disease

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causes may include

• Rheumatologic disorders, e.g.:
  • Rheumatoid arthritis.
  • Inflammatory bowel disease.
• Malignancy.
• Infection.
• Congestive heart failure.
• COPD.
• Diabetes.
• Renal disease.

diagnosis

• Anemia of chronic disease is usually normochronic and normocytic, but microcytic anemia may also occur.
• Hemoglobin is rarely <8 mg/dL, so this doesn't generally cause severe symptomatic anemia.
• Differentiation from iron deficiency anemia is discussed in the section above.
• Anemia of chronic disease is a diagnosis of exclusion.

management

• Inpatient management focuses on the evaluation and treatment of underlying causes.

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anemia in alcoholism

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mechanisms whereby alcoholism may cause anemia

• Folate deficiency.
• Blood loss:
  • Variceal hemorrhage.
  • Esophagitis and/or gastritis due to alcohol.
  • Traumatic blood loss.
• Alcohol has a direct toxic effect on the bone marrow (including sideroblastic anemia due to interference with vitamin B6 functioning).
• Hypersplenism due to cirrhosis.

laboratory findings

• Laboratory studies may be complex due to superimposed abnormalities.
• MCV can be anything (microcytic, normocytic, or macrocytic). Overall, the MCV is often elevated.

management

• Vitamin administration, including at least:
  • Folate supplementation.
  • Thiamine supplementation (to prevent Wernicke encephalopathy).
  • Vitamin B6 supplementation (especially if there is evidence of sideroblastic anemia, this may be helpful).
• Treat any sources of blood loss (e.g., gastrointestinal bleeding).
• Replace iron if deficient (e.g., based on ferritin levels).
• Promote abstinence from alcohol and ideally repeat blood count after alcohol discontinuation.

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hemolysis

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[1/3] initial considerations when approaching possible hemolysis 

clinical clues to support hemolysis may include:

• Anemia.
• Jaundice (e.g., scleral icterus).
• Brown or red urine (suggests intravascular hemolysis).
• Severe, acute intravascular hemolysis may be clinically overt with features that can include:
  • Acute kidney injury.
  • Hypotension.
  • Abdominal and back pain.
  • Altered mental status.
  • Disseminated intravascular coagulation. (24716235)
• Splenomegaly suggests extravascular hemolysis. ⚡️

tests to order

• Basic evaluation with screening for hemolysis:
  • Reticulocyte count.
  • LDH.
  • Haptoglobin.
• If there is high suspicion of hemolysis, also obtain the following:
  • Liver function tests, including indirect and direct bilirubin.
  • Plasma-free hemoglobin (either order directly or by checking an electrolyte panel, depending on your hospital's laboratory availability).
  • Urinalysis with sediment evaluation.
  • Blood smear.

historical elements of note

• Immediately after transfusion?
• Transfusion within the prior month?
• Medication review, looking for:
  • Drug-induced autoimmune hemolytic anemia.
  • Drugs that may exacerbate G6PD deficiency.
  • Drug-induced thrombotic microangiopathy.
• Aortic stenosis, mechanical heart failure, Impella, ECMO, or LVAD?
• Family history of anemia? (Causes include sickle cell disease, hereditary spherocytosis, thalassemias, and G6PD deficiency.) (30215915)

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[2/3] laboratory evaluation for hemolysis

indicators of any type of hemolysis

• [1] Reticulocytosis: discussed above ⚡️
• [2] Haptoglobin:
  • Haptoglobin level <25 mg/dL is 83% sensitive and 96% specific for hemolysis. (7365971)
  • Low haptoglobin isn't completely specific for hemolysis (other causes of reduced haptoglobin include liver disease, PRBC transfusion, malnutrition, and rarely congenital absence of haptoglobin). (28189170) However, an undetectable haptoglobin level is strongly supportive of hemolysis.
  • Elevated haptoglobin levels may reflect systemic inflammation (it is an acute phase reactant).
• [3] LDH (lactate dehydrogenase):
  • LDH is sensitive for hemolysis but nonspecific.
  • Markedly elevated LDH may suggest intravascular hemolysis.
• [4] Indirect bilirubin:
  • Elevated indirect bilirubin only supports the presence of hemolysis if direct bilirubin is normal.
  • Indirect bilirubin >4 mg/dL generally indicates hemolysis. (28189170)
  • Other causes of elevated indirect bilirubin:
    • [1] Liver disease (which may be implied by elevated direct bilirubin).
    • [2] Gilbert syndrome (a benign condition wherein indirect bilirubin levels become elevated in the context of physiological stress).

indicators of intravascular hemolysis

• [1] Plasma-free hemoglobin is an indicator of active intravascular hemolysis. Measurement of free hemoglobin may be achieved in various ways:
  • [1] Direct measurement of plasma-free hemoglobin (available in some labs).
  • [2] Chemistry analyzers will often automatically evaluate for free hemoglobin (to exclude hemolysis as a cause of hyperkalemia). Thus, simply ordering a set of electrolytes may be a screen for intravascular hemolysis. 📖
• [2] Hemoglobinuria:
  • Profound hemoglobinuria may cause urine to appear grossly pink or brown (oxidation of heme generates brown methemoglobin).
  • Urinalysis may show positive hemoglobin without, but urine sediment doesn't show erythrocytes.

blood smear may reveal specific causes of hemolysis:

• Spherocytes suggest immune hemolysis (microspherocytes) due to IgG antibodies (warm autoimmune hemolysis).
• Erythrocyte clumps suggest hemolysis due to IgM or IgG antibodies that bind in the cold (cold autoimmune hemolysis).
• Schistocytes reflect angiopathic hemolysis.
  • Mechanical valve: evaluate for valve leak.
  • ECMO circuit or impella: evaluate for malposition or other causes of hemolysis.
  • No obvious cause: evaluate for microangiopathic hemolytic anemia (here ***)
• Sickle cells suggest sickle cell anemia.
• Spur cells (acanthocytes) imply spur cell anemia. ⚡️
• Bite cells reflect oxidant injury (generally G6PD deficiency).
• Erythrocyte ghosts reveal intravascular hemolysis, especially due to clostridial bacteremia.
• Visible organisms may reveal malaria, babesia, or Bartonella. (37823455)
• (Further discussion on blood smear: ⚡️)

DAT (direct antiglobulin test, aka direct Coombs test)

• DAT tests whether erythrocytes are coated with IgG and/or complement (by incubating erythrocytes with anti-IgG and anti-C3d antibodies). If a DAT is positive, it may be followed by a differential DAT, which incubates erythrocytes with anti-IgG or anti-C3d separately to determine which is present.
• DAT(+) with precipitation caused by anti-IgG antibodies suggests warm antibody autoimmune hemolytic anemia. This is often associated with spherocytes on the blood smear. Warm autoimmune hemolytic anemia is discussed further in the section below on extravascular hemolysis.
• DAT(+) with precipitation caused by anti-C3D antibodies suggests cold antibody autoimmune hemolytic anemia.  This is often associated with erythrocyte agglutination in the blood smear. Causes to consider include:
  • Cold agglutinin disease (discussed below in the section on extravascular hemolysis).
  • Paroxysmal cold hemoglobinuria (discussed below in the section on intravascular hemolysis). PCH is caused by IgG, but this antibody only binds to erythrocytes at cold temperatures and then falls off at warmer temperatures.
• Performance of DAT:
  • False-positive DAT may occur following administration of antithymocyte globulin, RhD immune globulin, IVIG (intravenous immunoglobulin), or daratumumab.
  • False-negative DAT may occur in ~10% of patients with autoimmune hemolytic anemia.

other laboratory studies that may help

• Thin and thick blood smears for Babesiosis or malaria.
• Evaluation for Wilson disease.
• G6PD levels to evaluate for G6PD deficiency.
• Flow cytometry for paroxysmal nocturnal hemoglobinuria.

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[3/3] causes of hemolysis

The distinction between intravascular versus extravascular hemolysis isn't cut and dry. For example, severe warm autoimmune hemolytic anemia may saturate the reticuloendothelial system and spill over into causing intravascular hemolysis. However, in some cases, hemolysis is clearly either intravascular or extravascular, so this may provide some focus for the initial evaluation: 

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[1/2] intravascular hemolysis

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angiopathic hemolytic anemia

• MAHA (microangiopathic hemolytic anemia) – Discussed further in the chapter on thrombotic microangiopathy here: 📖
• Macroangiopathic hemolytic anemia:
  • Severe aortic stenosis.
  • Mechanical valve leak.
  • ECMO circuits.
  • LVADs (left ventricular assist devices).
  • Impella pumps.
  • Arterial graft.
  • Hemangioma (Kasabach-Merritt syndrome: high flow and shear rates in giant hemangiomas).
• Prolonged marching.

infection

• Clostridia perfringens bacteremia may cause severe intravascular hemolysis with marked microspherocytosis.
• Malaria.
• Babesia.
• Bartonella henselae.

G6PD deficiency

• G6PD deficiency is a sex-linked recessive disorder that primarily affects males.
• Hemolysis may be provoked by infection or oxidative drugs (e.g., benzocaine, dapsone, fluoroquinolones, methylene blue, nitrofurantoin, primaquine, pyridium, rasburicase,  sulfonylureas).

complement activation with membrane attack complex

• PNH (paroxysmal nocturnal hemoglobinuria):
  • Acquired deficiency of complement regulatory proteins.
  • Clinically, it causes chronic intravascular hemolysis, hypercoagulability, and sometimes pancytopenia.
• Paroxysmal cold hemoglobinuria:
  • Usually seen in children following viral infections.
  • Most often triggered by infection (e.g., EBV, CMV, mycoplasma, influenza, or chlamydia). However, less often, this may be caused by hematologic malignancy such as non-Hodgkin lymphoma.
  • IgG antibody (Donath-Landsteiner antibody) targets the P-antigen on erythrocytes. It binds at cold temperatures and causes hemolysis when blood is warmed to body temperature, causing intravascular hemolysis.
• Occasional drug-induced autoimmune hemolytic anemias (for example, quinidine, phenacetin).

other

• Acute hemolytic transfusion reaction.
• Wilson's disease hemolytic crisis.
• Specific exposures:
  • Hypotonic infusions.
  • Severe burn injuries.
  • Snake venom.

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[2/2] extravascular hemolysis

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autoimmune hemolytic anemia (AIHA)

• Cold agglutinin disease:
  • Usually occurs in older patients with chronic lymphoproliferative disorders (e.g., IgM gammopathy, Waldenstrom macroglobulinemia, lymphomas).
  • IgM antibodies are often generated by a clonal B-cell population (usually older patients with lymphoproliferative disorders).
  • IgM binds to erythrocytes at cold temperatures, leading to complement activation and predominantly extravascular hemolysis.
  • Symptoms may include Raynaud phenomena and chronic hemolytic anemia exacerbated by cold exposure.
• Warm antibody hemolytic anemia (IgG-mediated).
  • [1] Primary (idiopathic) warm autoimmune hemolytic anemia.
  • [2] Secondary warm autoimmune hemolytic anemia.
    • Most cases of drug-induced hemolytic anemia:
      • Drug-induced hemolytic anemia may be caused by a variety of medications, so the medication list should be specifically queried. Below are the most common offenders:
      • Antibiotics: Penicillins, cephalosporins, rifampin, trimethoprim/sulfamethoxazole, isoniazid.
      • Others: carboplatin, checkpoint inhibitors, diclofenac, erythromycin, fludarabine, hydrochlorothiazide, interferon-alpha, NSAIDs, oxaliplatin, probenecid, procainamide, quinidine, and quinine.
    • Rheumatologic disorders (e.g., SLE, RA).
    • Viral infections (e.g., hepatitis, CMV, EBV).
    • Lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, non-Hodgkin lymphoma) and various solid tumors.
  • [3] Delayed hemolytic transfusion reaction (may occur within a month following blood transfusion due to antibody generation against the transfused erythrocytes).
  • [4] Post-transplantation: Rarely, allogeneic stem cell transplantation or organ transplantation leads to “passenger lymphocyte syndrome” – donor lymphocytes produce antibodies against recipient erythrocytes.

miscellaneous

• Hypersplenism.
• HLH (Hemophagocytic lymphohistiocytosis).
• Hereditary, chronic RBC abnormalities:
  • Sickle cell anemia.
  • Thalassemia.
  • Hereditary spherocytosis.
  • Elliptocytosis.
• Chemical poisoning (e.g., lead, chlorate, arsenic).

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splenomegaly

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diagnosis of splenomegaly

ultrasound

• Spleen length (from upper pole to lower pole) >12 cm in adults is regarded as consistent with splenomegaly. However, the sensitivity (~45%) and specificity (~70%) of this measurement are limited.
• Multiplying spleen length by thickness may be more accurate (with an upper limit of >46 cm2). One study found this to have a sensitivity and specificity of ~95% for cirrhosis with stage 3-4 fibrosis. (32447741)

CT scan

• Maximal length >12 cm on the coronal oblique is sensitive (~80%) but not highly specific (~90%).
• Multiplying spleen length by thickness yields a calculation similar to that seen with ultrasonography, as discussed above. One study found that using a cutoff of 47 cm2, this had a sensitivity of 69% and specificity of 91% for splenomegaly. (29460042) Lower sensitivity on CT scans might relate to the inability to capture the maximal spleen length on the fixed orthogonal windows of the CT scan.
• Multiplying maximal length (Hmax above) by vertical height (Hvert above) yielded a sensitivity and specificity of ~93%, using a cutoff value of >115 cm2. (29460042)

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causes of splenomegaly include:

[1/5] congestive splenomegaly

• Right ventricular failure.
• Budd-Chiari syndrome (hepatic vein thrombosis).
• Cirrhosis with portal hypertension (of any etiology).
• Portal vein thrombosis.
• Splenic vein thrombosis.

[2/5] hematologic/oncologic

• Hemolytic anemias:
  • Sickel cell anemia.
  • Thalassemia.
  • Congenital spherocytosis.
  • Paroxysmal nocturnal hemoglobinuria.
  • B12 deficiency.
  • Autoimmune hemolytic anemia 🤯.
• Immune thrombocytopenia or neutropenia.
• Oncologic:
  • Lymphoma 🤯 (the most common malignancy involving the spleen is nonhodgkin lymphoma).
  • Leukemia (including chronic myeloid leukemia 🤯, hairy cell leukemia 🤯, chronic lymphocytic leukemia 🤯).
  • Metastatic tumors (rare; causes include breast, lung, ovarian, colorectal, gastric, and especially melanoma). (30115442)
  • Mastocytosis.
• Myeloproliferative:
  • Polycythemia vera 🤯.
  • Essential thrombocytosis.
• Extramedullary hematopoiesis:
  • Myelofibrosis 🤯.
  • Bone marrow failure due to toxins, radiation, or marrow infiltration.

[3/5] infection

• Viral infection:
  • EBV.
  • CMV.
  • HIV/AIDS (usually due to another coexisting infection, e.g., HCV).
• Bacterial infection:
  • Subacute bacteremia, including endocarditis.
  • Splenic abscess.
  • Rocky Mountain Spotted Fever.
  • Syphilis.
• Babesiosis.
• Actinomycosis (may cause multiple microabscesses).
• Tuberculosis.
• Histoplasmosis.
• Toxoplasmosis.
• Candidemia (may cause splenic microabscesses).
• Tropical/parasitic infections:
  • Schistosomiasis.
  • Leishmaniasis 🤯.
  • Typhoid.
  • Brucellosis.
  • Malaria 🤯.

[4/5] inflammatory

• SLE.
• Sarcoidosis 🤯.
• CVID (combined variable immunodeficiency syndrome).
• GPA (granulomatosis with polyangiitis).
• Rheumatoid arthritis (Felty syndrome incorporates neutropenia as well).
• HLH (hemophagocytic lymphohistiocytosis).

[5/5] other

• Amyloidosis.
• Infiltrative disorders (e.g., Gaucher disease 🤯).
• Diffuse splenic hemangiomatosis 🤯.
• Drug reaction to phenytoin, oxaliplatin-based chemotherapy, or serum sickness.

(🤯 indicates an etiology which may cause massive splenomegaly.)

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investigation of splenomegaly: tests to consider

The most common causes are liver disease, hematologic malignancy, or infection. (30115442)

laboratory studies

• CBC with differential.
• Blood smear.
• Haptoglobin and LDH levels.
• Liver tests (may include indirect/direct bilirubin to evaluate for hemolysis).
• Ferritin level.
• Blood cultures.
• Thick and thin smear for malaria or Babesiosis.
• BNP level.
• ANA and RF levels.

imaging studies

• Review old records to see if splenomegaly is chronic.
• Abdominal ultrasound with vascular studies of the hepatic, portal, and splenic veins.
• Contrasted CT scan (May provide superior imaging of surrounding lymph nodes, bony lesions, splenic texture).

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blood smear

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alphabetized listing

• Acanthocytes
• Basophilic stippling
• Bite cells & Heinz body hemolytic anemia
• Burr cells (aka ecchinocytes)
• Elliptocytes
• Howell-Jolley Bodies & hyposplenism
• MDS (myelodysplastic syndrome)
• Nucleated red cells
• Polychromatophilia
• Rouleaux formation
• Schistocytes
• Spherocytes
• Target cells
• Teardrop cells (“dacrocytes”)

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acanthocytes (spur cells) 

• Finding: RBCs have spiky projections with a rounded end.
• Mechanism: increased cholesterol in the erythrocyte membrane.
• Causes include:
  • Most commonly seen in severe liver disease (“spur cell anemia”). Severe hemolysis may occur in advanced liver disease with poor prognosis.
  • Malnutrition.
  • Abetalipoproteinemia.
  • Hyposplenism.
  • Neuroacanthocytosis syndrome (e.g., Chorea-Acanthocytosis, McLeod syndrome).

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basophilic stippling

• Finding: abnormal ribosomes appear as blue dots within the erythrocyte. This reflects impaired hemoglobin synthesis.
• Causes:
  • Sideroblastic anemias (e.g., lead poisoning or other heavy metal poisoning).
  • Bone marrow stress (e.g., increased erythrocyte turnover).
  • Some thalassemias.

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bite cells & Heinz body hemolytic anemia

• Findings:
  • Heinz body = hemoglobin precipitates due to denaturation.
  • Bite cells = erythrocytes from which Heinz bodies have been “bitten” out by the reticuloendothelial system.
  • Blister cells may also be seen.
• Caused by oxidative hemolytic anemia:
  • G6PD deficiency.
  • Other oxidant-induced hemolysis (e.g., methemoglobinemia).
  • Unstable hemoglobins.

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burr cells (aka echinocytes)

• Finding: Short, evenly spaced spines over the cell surface.
• Etiology: Membrane alteration related to increased lipids and calcium. (28189170)
• Common causes:
  • Common in vitro artifact.
  • Uremia.
  • Liver disease.
  • Hyperosmolar solution.
  • Hyperlipidemia.

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elliptocytes (aka ovalocytes)

• Potential causes:
  • Hereditary elliptocytosis.
  • Iron deficiency (elliptocytes are microcytic and more elongated, termed “pencil cells”). (28189170)
  • Myelodysplasia.

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Howell-Jolley Bodies & hyposplenism

Howell-Jolley bodies

• Finding: Small, round nuclear remnants.
• Causes: Generally indicates hyposplenism (either surgical splenectomy or functional hyposplenism).

blood smear findings in hyposplenism

• Howell-Jolley bodies are the signature finding.
• Nucleated erythrocytes.
• Target cells may be seen.
• Acanthocytes.
• Thrombocytosis, monocytosis, and lymphocytosis.

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myelodysplastic syndrome (MDS) features on peripheral smear

blood film findings

• Dysplastic neutrophils, e.g.:
  • Abnormal nuclear shapes, e.g., pseudo-Pelger-Huet abnormality (bilobed or unilobed nuclei).
  • Hypogranular cytoplasm.
• Dysplastic erythrocytes, e.g.:
  • Basophilic stippling
  • Howell-Jolly bodies.
  • Macrocytosis is common, including macroovalocytes.
• Dysplastic platelets:
  • Large or giant platelets.
  • Hypogranular platelets.
• Atypical monocytes (e.g., enlarged and with irregular nuclear shapes).
• Blasts may be seen (but usually <20%).

laboratory findings

• Anemia +/- leukopenia and/or thrombocytopenia may be seen.
• Anemia is typically macrocytic with an inappropriately low reticulocyte count.

epidemiology of MDS

• Usually seen in older patients.
• It may occur in younger patients status post-chemotherapy.

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nucleated red cells

causes of nucleated erythrocytes include:

• Severe global disease, e.g.:
  • Sepsis.
  • Trauma.
  • ARDS.
• Bone marrow stress:
  • Elevated erythropoietin levels.
  • Systemic response to hypoxemia.
• Hematological disorders:
  • Myeloproliferative neoplasms.
  • Myelodysplastic syndromes.
  • Myelopthesis.
• Hyposplenism (which is usually accompanied by other abnormal erythrocytes such as Howell-Jolly body formation).

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polychromatophilia (aka polychromasia)

• Mechanism: Reveals the presence of immature erythrocytes in circulation (residual rRNA alters the staining properties).
• Causes:
  • [1] Generally, this is simply a reflection of reticulocytosis.
  • [2] It may result from infiltration of the bone marrow, resulting in the pathological release of immature cells.

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rouleaux formation

• Mechanism: Erythrocyte clumping generates stacks of erythrocytes that resemble a stack of coins. This reflects elevated levels of proteins that negate the zeta potential on the erythrocyte surface, which usually causes erythrocytes to repel each other. (28189170)
• Causes:
  • Paraprotein formation (Multiple myeloma, Waldenstrom macroglobulinemia).
  • Inflammatory states with elevated levels of acute phase reactants, especially fibrinogen (this may correlate roughly with elevated ESR).

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schistocytes

Schistocytes are fragmented erythrocytes that result from erythrocytes being damaged and lysed within the bloodstream.

pathological level of schistocytes?

• Schistocytes can occasionally be seen in normal patients but at very low concentrations (<<0.5% of erythrocytes).
• The presence of >0.5% schistocytes suggests angiopathic hemolytic anemia.

causes of pathological elevation of schistocytes

• [1] MAHA (microangiopathic hemolytic anemia):
  • This involves hemolysis as erythrocytes pass through small blood vessels.
  • MAHA is often associated with thrombotic microangiopathy (thrombosis of small blood vessels, causing tissue damage).
  • Further discussion of thrombotic microangiopathy here: 📖
• [2] Macroangiopathic hemolytic anemia reflecting hemolysis that occurs within larger blood vessels or devices:
  • Severe aortic stenosis.
  • Mechanical valve leak.
  • ECMO circuits.
  • LVADs (left ventricular assist devices).
  • Impella pumps.
  • Arterial graft.
  • Hemangioma (Kasabach-Merritt syndrome: high flow and shear rates in giant hemangiomas).

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spherocytes

• Mechanism: Loss of RBC membrane.
• Causes:
  • Autoimmune hemolytic anemia.
  • Hemolytic transfusion reaction.
  • Hereditary spherocytosis.
  • Infection (bartonellosis, Clostridia perfringens).
  • Anemia due to thermal injury (major burns).
  • Microangiopathic hemolytic anemia due to snakebite or insect bite. (28189170, 37823455)

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target cells

• Mechanism: Excessive RBC membrane cholesterol as compared to the amount of hemoglobin. (28189170)
• Causes:
  • Hemoglobinopathies:
    • Thalassemia.
    • Hemoglobin C and E disease.
    • Sickle cell disease.
  • Iron deficiency.
  • Liver disease (especially obstructive jaundice).
  • Status post splenectomy.

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teardrop cells (“dacrocytes”)

• Mechanism: extension of RBC cytoplasm.
• Causes:
  • Generally suggests extramedullary hematopoiesis, bone marrow fibrosis, or bone marrow infiltration (myelophthisis).
  • It may be seen in severe iron deficiency. (28189170)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Ordering iron studies on ICU patients to evaluate the etiology of acute-onset anemia. As discussed above, acute anemia can never be due to iron deficiency.
• Over-transfusion of blood remains a considerable problem in the ICU, despite repeated studies showing that this is dangerous. When in doubt, it's generally better to err on the side of not transfusing blood.
• A transfusion target of 7 mg/dL means that you don't transfuse unless the hemoglobin is actually below seven.
• Trying to transfuse blood to improve a patient's dyspnea is generally ineffective or harmful, unless the patient is severely anemic.

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