ANEMIA

Anemia – Overview

Approach to the anemic patient Definition Manifestations, symptoms, and signs Causes Acute management Peripheral smears

Transfusions Indications and when to transfuse What to transfuse Ordering and documentation Transfusion reactions

…so let’s get going.

Definition

What values define anemia? Values more than 2 standard deviations below the mean Hgb < 13.5 g/dL or Hct < 41% in men Hgb < 12.0 g/dL or Hct < 36% in women

Don’t forget…Hgb is a concentration! May be modified by its content May be modified by its dilutent (plasma) Assess the patient’s volume status!

Hemoconcentrated – dehydration Hemodiluted – after receiving significant IVF Falsely appearing normal – acute hemorrhage

Assess the patient History, Physical, Laboratory evaluation Stable vs. Unstable

Acute anemia due to hemorrhage Signs/Symptoms of intravascular volume depletion

•Pallor•Diaphoresis•Tachypnea•Cold, clammy extremities

•Hypotension•Tachycardia•Shock

Anemia that develops slowly May be recent, subacute, or lifelong Not usually accompanied by signs of intravascular

volume depletion, and symptoms subtle

Common Symptoms and Signs

Symptoms Fatigue Dyspnea Palpitations Worsening angina

symptoms or claudication GI disturbances –

anorexia, nausea, bowel irregularity

Abnormal menstrual patterns

Signs Pallor Tachypnea Tachycardia Wide pulse pressure Hyperdynamic precordium Jaundice or splenomegaly

Physical Exam

Sign HgbLoss of palmar creases 7 g/dL

Sublingual pallor of mucous membranes 8 g/dL

Conjuctival pallor 9 g/dL

Other Clues Glossitis – iron, folate, B12 deficiency Jaundice or Scleral icterus – hemolysis Splenomegaly – severe thalassemia, chronic hemolytic anemia,

leukemia/lymphoma, myeloproliferative syndrome Neurologic Abnormalities - paresthesias/ataxia B12 deficiency

Causes of Anemia

Kinetic ApproachBlood loss Inadequate production of RBCsHemolysis

Blood Loss

Obvious bleeding Trauma Melena Hematemesis Menometorrhagia

Occult bleeding Slowly bleeding ulcer or

carcinoma

Induced bleeding Repeated lab testing Hemodialysis losses

Post-surgical bleeding Retroperitoneal space Upper thigh

Most common cause of anemia

Blood Loss

Iron DeficiencyWith loss of RBCs, loss of iron will eventually

lead to iron deficiency anemia Iron Stores Depleted

1200 mL of blood loss – Males 600 mL of blood loss – Females

25% of menstruating females have no iron stores Any amount of blood loss could result in anemia

Decreased RBC Production

Rate of production < rate of destructionReticulocyte count < 2%Three morphologies

Microcytic (MCV < 80) Normocytic (MCV 80 – 99) Macrocytic (MCV ≥ 100)

Decreased RBC Production: Microcytic

Iron deficiency Anemia of chronic disease Copper deficiency Lead poisoning Congenital or acquired sideroblastic anemia

Decreased RBC Production: Normocytic

Early B12 or folate deficiency Dietary loss

Pernicious anemia, sprue, iron deficiency Anemia of chronic disease

Infection (ie. TB), Inflammation, Malignancy Bone marrow suppression

Aplastic anemia, acquired red cell aplasia, irradiation Chronic Renal Insufficiency Endocrine

hypothyroidism, hypopituitarism Meds

sulfa drugs, penicillins, anti-epileptics

Decreased RBC Production: Macrocytic

B12 or folate deficiency Myelodysplastic syndrome Aplastic Anemia or Pure Red Cell Aplasia MEDS: Hydroxyurea, zidovudine, ARA-C,

methotrexate, azathioprine, 6-MP Hypothyroidism EtOH abuse Multiple Myeloma or other plasma cell disorders Liver disease / Cirrhosis

Increased RBC Destruction

Hemolysis RBC life span < 100 days Occurs when bone marrow cannot keep up with

replacement of 5% RBC mass per day RBC survival ~ 20 days Reticulocyte count > 3% Elevated indirect bilirubin Elevated LDH Decreased haptoglobin

Increased RBC Destruction

Inherited Hereditary spherocytosis Sickle cell disease Thalassemia major

Antibodies Viruses Drugs AI connective tissue

diseases cancer

(leukemia/lymphoma) AIHA

Acquired Coombs’ positive AIHA TTP/HUS DIC MAHA PNH Malaria Prosthetic heart valves Trauma Hypersplenism Liver disease

Management

Admitting patients overnight? What happens when you’re on call? The middle of the night phone call…

Think of differential diagnoses on your way Address for most serious life-threatening possibility first

Bedside assessment of patient Rapid visual assessment of patient’s condition Vitals Selective H&P, chart review Management Document

Why would they call you for anemia?

“Doctor, this patient is bleeding from…” “Doctor, this patient’s H/H came back and

it’s 6 and 18…”

What do you do?

Management: Hypovolemic patients Notify resident Two large-bore IVs (16 gauge) Type and crossmatch for packed RBCs

May take up to an hour

IV fluids (crystalloid) Normal Saline or Lactated Ringers

Wide open if in shock 500 mL to 1000 mL NS bolus if mild/moderate volume

depletion Serial exams are important! for volume status and cardiac exam Be careful not to put patient in pulmonary edema

Management: Hypovolemic patients Determine site of hemorrhage

Look for obvious signs of bleeding IV sites, skin lesions, hematemesis, menstruation

Occult blood loss? Rectal exam for melena Flank swelling, flank or periumbilical ecchymosis post-op Pelvic exam in reproductive age women Ruptured aneurysm?

Review chart – PMH, meds, recent labs Surgical consult when appropriate

Management: Normovolemic patients Exclude active hemorrhage

If Hgb <10 g/dL, consider repeat measurement to exclude lab error

Even if Hgb 10-12 g/dL and normal vitals patients may become unstable quickly if bleeding

What is the patient’s baseline? Check graphic in Easy-CHCS If Hgb is more than 0.1-0.2 g/dL less than baseline,

assume underlying cause has worsened or secondary factor

Has chronic anemia been evaluated in the past?

Management: Normovolemic patients

Patient is comfortable, normal cardiovascular exam, no suspicion of bleeding…

Baseline studies for further evaluationMCV (microcytic, normocytic, macrocytic)RDW - representation of anisocytosisReticulocyte countPeripheral smear

Laboratory Evaluation

Reticulocyte countHigh (>3-5)

Increased erythropoietic response to continued hemolysis or blood loss

Low (<2) Deficient production of RBCs (reduced marrow

response) Concurrent disorder that impairs production (infxn,

prior chemotherapy)

Peripheral Smear

Normal peripheral smearNormal RBC diameter ~ 8-9 microns

About the size of a nucleus of a small lymphocyte Central pallor ~ 1/3 the RBC diameter

Peripheral Smear Polychromatic macrocytes

Young reticulocytes with RNA and ribosomes

• Slightly larger than other RBCs by 1-2m

• Grayish-blue in color

• Lacks normal biconcave shape

Represent shift out of marrow into circulation Can be used to estimate adequacy of erythropoietin

response to anemia

He who would cross the Bridge of Death

Must answer me

These questions three

Ere the other side he see….

Peripheral Smear Microcytic anemia – Two examples

• Microcytic/Hypochromic

• Pronounced aniso- and poikilocytosis

• Presence of cigar-shaped RBCs

• Absence of target cells

• Microcytic/Hypochromic

• Prominent target cells

• Marked deficit of Hgb – flattened appearance

?

Peripheral Smear

Macrocytosis Larger than normal RBCs Often oval shaped and well

hemoglobinized

Hypersegmented neutrophils Larger than normal neutrophils Five or more nuclear lobes

Two commonly seen types of anemia ?

Peripheral Smear

Myelofibrosis - When would you see this

Tear drop cells Nucleated RBCs Leukoerythroblastic

smear Seen with immature

WBCs

?

Peripheral Smear Hemolytic anemia Inerent defects

Membrane structure, Hgb stability, metabolic fxn Environmental

trauma, infection, autoimmune

• Microspherocytes• Bite Cells• Fragmented RBCs• Abnormal inclusion bodies

Can you name 2 types of inclusion bodies ?

Peripheral Smear Membrane defects

• Uniform elliptical shape

• Normal cell indices

• Caused by deformation through capillary beds

• Cytoskeletal abnormality that prevents recovery of normal shape • Small, dense RBCs

• Lack central pallor of normal RBCs

• Lack of cell water Higher MCHC

• Hereditary spherocytosis

• Autoimmune hemolitic anemia

Blood Transfusions

Decision making in a bleeding patient…Rapid, acute hemorrhageEBL > 30 – 40%, symptomaticEBL < 25 – 30%, no uncontrolled hemorrhage

When do patients need PRBCs?Hgb < 7 g/dL ?Hgb < 10 g/dL ?

Blood Transfusions

Rapid, acute hemorrhage

EBL > 30 – 40%, symptomatic

EBL < 25 – 30%, no uncontrolled hemorrhage

Transfuse PRBC May require uncrossmatched

or type-specific blood

Transfuse PRBC May require uncrossmatched

or type-specific blood

Crystalloid/Colloid resuscitation Proceed to PRBC for recurrent

signs of hypovolemia

Blood Transfusions What is your transfusion threshold? How about some help from EBM?

Hebert, et al. (NEJM 1999) looked at critically ill euvolemic patients 418 transfused for Hgb < 7 g/dL, 420 transfused for Hgb < 10 g/dL 30-day mortality was similar These results suggest transfusing at Hgb < 7 g/dL is at least as effective as, and

possibly superior to, transfusing at Hgb < 10 g/dL in critically ill patients Possible exception for patients with AMI and UA

Hebert, et al. (Crit Care Med 2001) did a multi-center trial in critically ill pts with CV disease

357 pts were randomly assigned to be transfused for Hgb < 7 or < 10 g/dL There was no differences in overall mortality for the entire group There was a higher mortality in the subgroup of 257 patients with severe ischemic

heart disease who were transfused for Hgb < 7 g/dL (not statistically significant) Rao, et al. (JAMA 2004) – retrospective study of transfusion in pts ≥ 65 with AMI

30-day mortality reduced when pts received transfusions for Hct ≤ 30 percent Possible effectiveness in pts with a Hct ≤ 33 percent

Blood Transfusions

What about transfusing… Platelets

< 50,000 if acutely bleeding < 20,000 if not bleeding and febrile < 10,000 if not bleeding and afebrile

Cryoprecipitate If patient is in DIC and fibrinogen < 100 Some say 175 if acutely bleeding

FFP Emergency reversal of warfarin therapy in bleeding patient Factor replacement in DIC

Blood Transfusions

What to transfuse and expected increase PRBC’s:

1 unit raises Hct by 3 – 4% and Hgb by about 1 gm/dl unless there is continued bleeding

Platelets: 1 “six pack” should raise the platelet count by 25,000/mcL

FFP: Prepared from a single unit of whole blood, contains all coagulation

factors and proteins in 1 unit of blood Cryoprecipitate:

Concentrated preparation of FFP containing only Factors VIII (100 units), XIII, fibrinogen (200 mg) and vWF – final volume is 10-15 mL

Ten bags of cryo (2g fibrinogen) will raise fibrinogen level about 70 mg/dL

Blood Transfusions

Compatability testing Fully crossmatched RBCs (T&C)

Patients requiring elective transfusion of RBCs Type, antibody screen, major crossmatch of each unit

Indirect antiglobulin test for minor blood group antibodies Tests donor cells against patient serum for ABO compatibility

May take several hours

Type and Screen (T&S) Surgical procedures when blood is occasionally needed ABO and Rh type Serum tested for RBC antibodies

If none, typed blood set aside, but not crossmatched If patient requires transfusion, crossmatched RBC can be made

available quickly If emergency, type-specific blood transfused, crossmatch after

Blood Transfusions

Compatability testing Emergency crossmatch

Urgently needed blood Type and crossmatch of RBCs in 15-30 min once pt’s blood is

received If pt has already been transfused, they usually have a sample

already

Uncrossmatched/type-specific RBCs If pt cannot wait 15-30 min for crossmatched or type-specific blood

or if pt’s blood type is unknown Type O-(Rh)negative

Once O-negative is exhausted, O-positive may be substituted with little risk

Conversion to type-specific, crossmatched blood should occur as soon as possible

Risk of inducing antibody only important in women of childbearing age

Blood Transfusions

Leukoreduced RBCs HLA alloimmunization against class I antigens does not occur Leukoreduced RBCs do not transmit CMV Indicated for chronically transfused patients, potential transplant

recipients, patients with previous febrile nonhemolytic reactions and CMV negative patients at risk

Irradiated RBCs Eliminates immunologically competent lymphocytes Prevents the occurrence of GVHD in patients who have

hereditary immune deficiency states Washed RBCs

Should be considered in patients in whom plasma proteins may cause a serious reaction

IgA deficiency, anaphylaxis with previous transfusions

X

XX

ANEMIA

The Black Knight20/123-45-6789

Document, document, document!

You must write a note regarding the indication of transfusion or at least comment on it in your daily progress note

20/123-45-6789The Black Knight

KJ

KJ

WARD STAFF

KJ KJ

KJ

The end of this lecture is not far….

Transfusion Reactions Acute Hemolytic Transfusion Reaction Due to ABO incompatibility Incidence 1:250,000-1:1,000,000 with mortality

17-60% Sx include: fever, chills, vomiting, flank pain,

dyspnea, hypotension, tachycardia Pink plasma and red urine due to intravascular

hemolysis May lead to DIC, shock, and acute renal failure

due to ATN

Transfusion ReactionsDelayed Hemolytic Transfusion Reaction Caused by anamnestic antibody response to specific transfused

RBC antigens previously encountered by transfusion, transplantation, or pregnancy

Clinical presentation Usually asymptomatic Hct slight fever unconjugated bilirubin spherocytosis on peripheral smear

Hemolysis is usually extravascular, gradual, and less severe than with acute reactions

Rapid hemolysis can occur Incidence 1:1000

Transfusion Reactions Febrile nonhemolytic transfusion reaction

Most common transfusion reaction Occur within 1 – 6 hrs after transfusion RBCs or

platelets Fever, with or without chills or dyspnea Sx may mimic AHTR or infection – don’t ignore Incidence: 1% of PRBC transfusions and 30%

of platelet transfusions

Transfusion Reactions Transfusion-related Acute Lung Injury TRALI is a pulmonary agglutinin reaction

Pathogenesis – 2 stimuli needed primes neutrophils and activates endothelial cells, leading to increased

expression of adhesion molecules Ex. recent surgery, cytokine administration, massive blood transfusion, or active

infection activates neutrophils causing release of toxic mediators, endothelial

damage, and increased capillary permeability lipid-soluble species that is formed during the storage of banked blood

Causes acute respiratory distress, hypoxemia, hypotension, fever, and pulmonary edema, initially without signs of left ventricular failure

Occurs within 2 – 4 hrs of beginning the transfusion Incidence 1:2000 More favorable prognosis than ARDS

Mortality in ≤ 10% of cases of TRALI Recovery is generally complete within 96 hrs of onset

Transfusion ReactionsAnaphylaxis and Allergy

Allergic reactions Common – typically see urticarial rash Only transfusion rxn in which the blood product can be continued

Anaphylaxis Abrupt onset of hypotension, respiratory distress, angioedema,

nausea, abdominal cramping, diarrhea Incidence 1:20,000 – 50,000

Transfusion-associated GVHD Immunocompromised patients Sx include rash, elevated LFTs, and pancytopenia Mortality of 80% Prevent by irradiation of blood

Transfusion Reactions Septic Reactions

Secondary to asymptomatic donor bacteremia or skin “plugs”

Confined to blood products stored at room temp (platelets)

Incidence 1:12,000 platelet transfusions, 25% fatal Incidence 1:500,000 PRBC transfusions, 71 % fatal Most commonly implicated in bacterial contamination of

red cells is Yersinia enterocolitica

Management

Important things to find out on the phone What symptoms does the patient have?

Fever, chills, dyspnea, back pain, diaphoresis What are the vital signs? Which blood product is being transfused? How long ago did the transfusion start? Why was the patient admitted to the hospital?

Orders Stop the transfusion for the following symptoms

Sudden hypotension, chest pain, back pain, tachypnea Any symptom starting within minutes of the start of the transfusion Fever in a pt who has never been transfused or never been pregnant

If the transfusion has been stopped keep IV open with NS

Management

Always consider the major threats to life first Acute hemolytic reaction Anaphylaxis

Quick look at the patient Comfortable, distressed, or critical?

Assess airway and vital signs Check that the patient’s wristband and

identification tag on the blood match

Management

Selective Physical Exam HEENT

Flushed face Facial Edema

Lungs Wheezes

Neuro Decreased consciousness

Skin Heat along vein being used Oozing from IV sites

Urine color Red/Brown

Selective History Any new symptoms since the

initial phone call? Fever/chills HA, CP, back pain,

diaphoresis Shortness of breath

Has the patient had previous transfusion reactions?

Chills and fever are common

ManagementAnaphylaxis Stop transfusion Epinephrine

1:10,000 – profound anaphylactic shock 0.2 mL/min IV up to total dose of 3 mL in 15 min May repeat q15 min

1:1000 – less severe situations 0.5 mL IM, may repeat q5 min

Hydrocortisone 500mg slow IV or IM, then 100mg IV or IM q6 hrs

Albuterol nebs Benadryl 50-75 mg slow IV or IM Intubation if necessary

ManagementAcute Hemolytic Reaction Stop transfusion Replace IV tubing NS 500mL bolus, goal UOP > 100mL/hr Lasix 40mg IV (4 mg/min) or Mannitol 25g IV over 5 min

Labs• Repeat crossmatch• Coombs’ test• Free Hgb• CBC, RBC morphology• Coags, FDP• Urea, Creatinine• Unclotted blood for stat spin demonstrates hemolysis when plasma remains pink

Urine dipstick• Hemoglobinuria

Labs on donor blood• Repeat crossmatch• Coombs’ test

ManagementUrticaria Do not stop the transfusion

Hives alone are rarely serious Hives with hypotension is anaphylactic rxn until

proven otherwise

Benadryl 50mg PO or IV Premedicate prior to future transfusions If that fails to prevent urticarial rxns, transfuse

with washed RBCs

ManagementFever Do not stop the transfusion unless hemolytic rxn

is suspected Ex. Fever developing within minutes of start

Tylenol 650mg PO if needed Premedicate with tylenol prior to subsequent

transfusions If that fails to prevent fever, transfuse with

washed RBCs

Management Pulmonary Edema Stop transfusion or slow rate unless

patient urgently needs blood Lasix 40mg IV with transfusion

Blood Transfusions

Risks of infection:Hep B ~ 1:63,000Hep C < 1:2,000,000HIV 1 & 2 < 1:2,000,000HTLV 1 ~ 1:250,000-2,000,000Parvovirus B19 ~1:10,000

References On Call Principles & Protocols, 4th Ed. Elsevier Saunders, Philadelphia 2004. Hematology in Clinical Practice, McGraw-Hill, New York 2001. Hebert, PC, et al. Is a low transfusion threshold safe in critically ill patients with

cardiovascular diseases? Crit Care Med 2001; 29:227 Hebert, PC, et al. A multicenter, randomized, controlled clinical trial of transfusion

requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409

Rao, SV, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555

Valeri, CR, et al. Limitations of the hematocrit level to assess the need for red blood cell transfusion in hypovolemic anemic patients. Transfusion 2006; 46:365.

Dodd, RY, et al. Current prevalence and incidence of infectious disease markers and estimated window period risk in the American Red Cross blood donor population. Transfusion 2002; 42:975.

Stramer, SL, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004; 351:760

Any Questions?