Symptomatic Anemia and Transfusion Medicine Case File

Symptomatic Anemia and Transfusion Medicine Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 55

A 62-year-old man presents to the emergency department with the sudden onset of abdominal discomfort and passage of several large, black, tarry stools. The patient states he has chest pain similar to that of his recent non–ST-segment elevation myocardial infarction (NSTEMI) 3 weeks ago, with coronary angiography performed prior to discharge revealing no significant coronary artery stenosis. He was discharged with aspirin, clopidogrel, atorvastatin, and metoprolol. On present examination, his temperature is 99 °F, blood pressure (BP) is 124/92 mm Hg lying down and 95/70 mm Hg upon standing, heart rate (HR) is 104 beats per minute (bpm), respiratory rate (RR) is 14 breaths per minute, and oxygen saturation is 96% on room air. On physical examination, he appears pale and diaphoretic. His neck veins are flat, his chest is clear to auscultation, and his heart rhythm is tachycardic but regular, with a soft systolic murmur at the right sternal border and an S4 gallop. His apical impulse is focal and nondisplaced. His abdominal examination is positive for mild epigastric tenderness. Rectal examination shows black, sticky stool and is positive for occult blood. His hemoglobin level is 5.9 g/dL. Prothrombin time (PT) and partial thromboplastin time (PTT) are both normal, as are his renal and liver function tests. An electrocardiogram (ECG) reveals sinus tachycardia with no ST-segment changes, T-wave inversion in the anterior precordial leads, and no ventricular ectopy. Creatine kinase (CK) is 127 U/L with a normal creatine kinase myocardial band (CK-MB) fraction, and troponin I levels are normal.

▶ What is the most likely diagnosis?

▶ What is the next step?

▶ What are some possible complications from the intervention?

ANSWERS TO CASE 55:

Symptomatic Anemia and Transfusion Medicine

Summary: A 62-year-old man presents with

• A recent NSTEMI without major blockage
• Angina at rest without electrocardiographic changes
• Tachycardia with orthostatic hypotension, which indicates major hypovolemia from blood loss
• Melena and hemoglobin 5.9 g/dL, suggesting upper gastrointestinal (GI) hemorrhage, possibly from antiplatelet agents

Most likely diagnosis: Unstable angina, which has been precipitated by anemia secondary to acute GI blood loss.

Next step: Transfusion with packed red blood cells (PRBCs).

Possible complications: There are a multitude of transfusion complications, ranging from transmission of infections (hepatitis C, hepatitis B, human immunodeficiency virus [HIV], etc) to reactions such as acute hemolytic transfusion reaction, febrile nonhemolytic transfusion reaction, transfusion-related acute lung injury (TRALI), and anaphylaxis.

ANALYSIS

Objectives

1. Understand the indications for transfusion of red blood cells. (EPA 1, 4)
2. Recognize the indications for transfusion of platelets and of fresh frozen plasma (FFP). (EPA 1, 4)
3. Describe the complications of transfusions. (EPA 10)
4. Be aware of alternatives to transfusion. (EPA 4, 12)

Considerations

This 62 year old patient has two urgent problems, the upper GI hemorrhage and acute coronary syndrome, which is most likely unstable angina. The first set of cardiac enzymes are negative, but another set is important to obtain to definitely rule out acute MI. The patient had a recent coronary angiography which did not show blockage; thus, the severe anemia likely is causing the chest pain and ECG findings, consistent with unstable angina. The unstable angina may be the result of decreased oxygen supply to the heart due to blood loss. Thus, replacing blood volume treats both problems. Importantly, restoration of oxygen delivery to the heart is critical to avoid myocardial necrosis. The hemoglobin level of 5.9 g/dL may not be reflective of the true severity of anemia. Acutely, because patients bleed whole blood, the ratio of red cells to plasma volume does not change. It is only after volume repletion and restoration of the intravascular volume that we may see the true hemoglobin level. Meanwhile, another consideration is that transfusion that is too rapid may lead to volume overload, if the patient has any degree of heart failure. Thus, this patient is very complex and fragile, and should be monitored carefully in the critical care area.

APPROACH TO:

Transfusion Medicine

DEFINITIONS

ACUTE HEMOLYTIC REACTION: Transfusion reaction due to antibody lysis of transfused red blood cells.

NON–ST-ELEVATION MYOCARDIAL INFARCTION: Clinical features of unstable angina, but with evidence of myocardial necrosis such as elevated cardiac biomarkers.

TRANSFUSION-RELATED ACUTE LUNG INJURY: Immune-mediated lung injury in reaction to any blood product. Characterized by acute respiratory distress occurring during or within 6 hours of the transfusion.

UNSTABLE ANGINA: Angina pectoris or equivalent ischemic discomfort occurring at rest, or severe and new onset, or in a crescendo pattern. Unstable angina, unlike NSTEMI or STEMI (ST-segment elevation myocardial infarction), does not cause elevated levels of cardiac biomarkers or ST-segment elevation on ECG.

CLINICAL APPROACH

Anemia

Anemia occurs when the hemoglobin level is less than 12 g/dL in women or less than 13 g/dL in men. Symptoms attributable to anemia are manifold and depend primarily on the patient’s underlying cardiopulmonary status and the chronicity with which the anemia developed. For a slowly developing, chronic anemia in patients with good cardiopulmonary reserve, symptoms may not present until hemoglobin levels are as low as 3 or 4 g/dL. Patients with serious underlying cardiopulmonary disease who depend on adequate oxygen-carrying capacity may become symptomatic with smaller drops in hemoglobin.

Packed Red Blood Cells

Indications for transfusion of PRBCs are acute surgical or nonsurgical blood loss; anemia with end-organ effects (eg, syncope, angina pectoris) or hemodynamic compromise; and critical illness to improve oxygen-carrying capacity or delivery to tissues. There are no absolute guidelines or thresholds for transfusion. Many believe that a hemoglobin level of 7 g/dL is adequate in the absence of a clearly defined increased need, such as cardiac ischemia, for which a hematocrit level of at least 30% may be desired. In the absence of ongoing bleeding or destruction of red cells, we typically expect that each unit of PRBCs will result in an increase of 1 g/dL in the hemoglobin level or 3% in the hematocrit level. In addition to PRBCs, there are other components of whole blood, including platelets, FFP, cryoprecipitate, and intravenous immunoglobulin (IVIg).

Platelets and Fresh Frozen Plasma

Thrombocytopenia can frequently be treated with platelet transfusion. When a patient has a platelet count of less than 50,000/mm3 and has significant bleeding, or when a patient is at risk for spontaneous bleeding with a level of less than 10,000/mm3, platelets can be transfused. Each unit increases the platelet count from 5000 to 10,000/mm3. Transfusion is generally not helpful in cases of platelet destruction, such as immune thrombocytopenic purpura (ITP), unless active, severe bleeding occurs. Platelet transfusion is contraindicated in patients with thrombotic thrombocytopenic purpura (TTP), as it may worsen microvascular thrombosis and cause worsening neurologic symptoms or renal failure.

Fresh Frozen Plasma. FFP replaces clotting factors and is often given to reverse warfarin (Coumadin) anticoagulation. Cryoprecipitate from FFP replaces fibrinogen and some clotting factors, making it useful in patients with hemophilia A and von Willebrand disease.

Alternatives to Transfusions

Erythropoietin, a hormone that promotes red cell production, is often used in the treatment of renal failure–related anemia or in patients who are banking a presurgical autologous transfusion to encourage quicker recovery of their hemoglobin levels prior to surgery. Cell savers salvage some intraoperative blood losses, which are then transfused back into the patient. Some patients may not wish to have foreign blood products transfused. In these cases, we can increase the baseline hemoglobin level by using erythropoietin and iron before planned surgery, minimize phlebotomy for laboratory testing, and use cell savers during surgery.

Complications

Infection. Viruses that are screened for but can still be transmitted include hepatitis C virus (1 in 103,000 units), human T-cell lymphocyte virus types I and II, HIV (1 in 700,000), hepatitis B virus (1 in 66,000), and parvovirus B19. Rarely, bacterial contamination (eg, Yersinia enterocolitica) causes fevers, sepsis, and even death during or soon after transfusion. Parasites (eg, malaria) are screened for by questioning a donor’s medical and travel history.

Immune-Mediated Complications. With respect to immune mechanisms, it is possible that a recipient has preformed natural antibodies that lyse foreign donor erythrocytes, which can be associated with the major A and/or B or O blood types or with other antigens (eg, D, Duffy, Kidd). To avoid hemolysis, a “type and cross” is first performed, in which blood samples are tested for compatibility prior to transfusion.

An acute hemolytic transfusion reaction, which is caused by ABO incompatibility due to clerical error, typically occurs within 1 hour of the transfusion being started. It may be associated with hypotension, fever, chills, hemoglobinuria, flank pain, disseminated intravascular coagulation (DIC), and renal failure. This is a medical emergency, so transfusion must be halted immediately, and fluids, specifically normal saline, should be started urgently to prevent progression into renal failure. Lactated Ringer’s solution and fluids with dextrose should be avoided; the calcium content in lactated Ringer’s may cause clotting of blood in the intravenous line, and dextrose can cause hemolysis of red blood cells in the intravenous line. Diuretics may be used in those with volume overload if the patient is not hypotensive; in severe cases, dialysis may be initiated to protect from kidney failure via immune-complex deposits. Laboratory tests for intravascular hemolysis should be checked (lactate dehydrogenase [LDH], indirect bilirubin, haptoglobin), as well as coagulation tests for DIC.

Delayed hemolytic reactions are less predictable and usually milder; these reactions involve amnestic responses from the recipient. They range from urticaria treated with diphenhydramine and transfusion interruption to anaphylaxis, in which case the transfusion must be stopped and epinephrine and steroids given. Febrile nonhemolytic transfusion reactions, thought to result from production of leukocyte cytokines during storage, can be treated by antipyretics and prevented by leukoreduction. Sometimes TRALI occurs, in which case the appearance of bilateral interstitial infiltrates in the lung represents noncardiogenic pulmonary edema.

Nonimmune Complications. Considering nonimmune consequences, the transfusion itself supplies 300 mL of fluid per unit of PRBCs intravascularly, so patients can easily become volume overloaded. Adjusting the volume and rate and using diuretics will prevent this complication. Each unit of blood also provides 250 mg of iron. Multiple and frequent transfusions can cause iron overload and deposition (hemosiderosis), leading to cirrhosis, cardiac problems (eg, arrhythmia, heart failure), or diabetes.

CASE CORRELATION

• See also Case 3 (Acute Coronary Syndrome), Case 54 (Iron-Deficiency Anemia), Case 56 (Immune Thrombocytopenia Purpura/Abnormal Bleeding), and Case 58 (Sickle Cell Crisis).

COMPREHENSION QUESTIONS

55.1 A 32-year-old man with no significant past medical history is brought into the emergency department after a motor vehicle accident. On examination, he is actively bleeding from a femur fracture. He is found to be in hypovolemic shock with a BP of 60/40 mm Hg, HR of 120 bpm, and RR of 20 breaths/min. Laboratory tests show a hemoglobin level of 6 g/dL. His wife is absolutely sure that the patient’s blood type is A positive. Which of the following is the most appropriate type of blood to be transfused?

A. Await crossmatched A-positive blood.

B. Give AB-positive blood, uncrossmatched.

C. Give O-negative blood, uncrossmatched.

D. Give type-specific A-positive blood, uncrossmatched.

55.2 A 45-year-old woman presents to the emergency department for 6 months of severe menorrhagia. Initial vital signs reveal a temperature of 98.2 °F, BP of 105/82 mm Hg, HR of 102 bpm, RR of 14 breaths/min, and oxygen saturation 95% on room air. Laboratory tests showed a hemoglobin level of 6 g/dL. She feels dizzy, weak, and fatigued. She receives 3 units of packed erythrocytes intravenously. Two hours into the transfusion, she develops fever to 103 °F and shaking chills. Which of the following laboratory tests would most likely confirm an acute transfusion reaction?

A. Direct bilirubin level

B. Glucose level

C. LDH level

D. Leukocyte count

55.3 A 57-year-old man on warfarin with a past medical history of hypertension and aortic stenosis with prosthetic aortic valve replacement is brought to the emergency department by his wife. He is noted to have an international normalized ratio (INR) of 7 and is actively bleeding large clots from his gums and rectum and when urinating. Which of the following is the best next step in management?

A. Administer IVIg.

B. Administer vitamin D.

C. Discontinue the warfarin and observe.

D. Transfuse FFP.

55.4 A 34-year-old woman presents to the emergency department complaining of weakness, dizziness, and fatigue. Her menstrual period started 4 days ago, and she has been having heavier than normal bleeding, soaking through four or five pads a day. She appears pale on physical examination. On initial vitals, she is afebrile and hemodynamically stable. Hemoglobin level is 6.6 g/dL. One unit of red blood cells is ordered. One hour into the transfusion, she complains of chills and flank pain. Vitals reveal a temperature of 101.5 °F, BP of 95/70 mm Hg, HR of 110 bpm, RR of 18 breaths/min, and O2 saturation of 95% on room air. The blood transfusion is immediately stopped. Which of the following is the best next step in management?

A. Antibiotics

B. Furosemide

C. Methylprednisolone

D. Normal saline

ANSWERS

55.1 C. This patient needs a blood transfusion immediately, as evidenced by his dangerously low BP. He does not have the 45 minutes required for crossmatching his blood (answer A). Even though the patient’s wife is “absolutely sure” about the blood type being type A (answer D), history is not completely reliable. In an emergent situation such that uncrossmatched blood must be given, O-negative blood (universal donor) (answer C) usually is administered. Giving AB-positive blood, uncrossmatched (answer B), is not the best treatment for this patient in any circumstance.

55.2 C. This patient is suffering from acute hemolytic transfusion reaction characterized by fever, hypotension, and hemolysis. Elevated LDH and indirect bilirubin levels or decreased haptoglobin levels would be consistent with hemolysis. Glucose (answer B), direct bilirubin (answer A), and leukocyte count (answer D) are not direct markers of hemolysis.

55.3 D. This patient has active bleeding, so watching and observing (answer C) is not an option. When life-threatening acute bleeding occurs in the face of coagulopathy due to warfarin use, the treatment is FFP. The INR is extremely high, consistent with a severe coagulopathy. IVIg (answer A) is not treatment for bleeding secondary to supratherapeutic INR; IVIg is used in the treatment of immune thrombocytopenia. Vitamin D (answer B) does not have a primary role in coagulation, whereas vitamin K does have a primary role.

55.4 D. This patient is likely experiencing an acute hemolytic transfusion reaction, as evidenced by his fever, hypotension, and flank pain an hour after red blood cell transfusion. Treatment includes immediately stopping the transfusion and starting normal saline to prevent the progression to renal failure. Diuretics (answer B) can be used to prevent oliguric renal failure, but this patient is hypotensive, so that would not be the next step. This patient spiked a fever, but this is likely a result of a transfusion reaction rather than sepsis at this point. Therefore, antibiotics (answer A) are not yet warranted. Methylprednisolone (answer C), which is a potent corticosteroid, has not been shown to be effective in treating acute transfusion reactions but is sometimes used as an adjunct medication for anaphylactic reactions following transfusions.

CLINICAL PEARLS

▶ The symptoms of anemia are related to the onset time with which the anemia developed as well as the patients’ underlying cardiopulmonary status.

▶ Myocardial ischemia or infarction may be precipitated by factors related to loss of oxygen-carrying capacity.

▶ Transfusion of blood carries certain risks, such as hemolytic reaction, infection (ie, HIV and hepatitis C), and transfusion-related lung injury.

▶ Platelet transfusions are indicated for severe thrombocytopenia with bleeding symptoms, but they have limited benefit in ITP and are definitely contraindicated in TTP.

▶ Fresh frozen plasma is used to correct coagulopathy by providing clot-ting factors.

REFERENCES

Cannon CP, Braunwald E. Unstable angina and non–ST-elevation myocardial infarction. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw Hill; 2012:2015-2021. 

Dzieczkowski JS, Anderson KC. Transfusion biology and therapy. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw Hill; 2012:951-957. 

Goodnough LT, Brecher ME, Kanter MH, et al. Transfusion medicine (part 1). N Engl J Med. 1999;340:438-447. 

Silvergleid AJ. Approach to the patient with a suspected acute transfusion reaction. Tirnauer JS, ed. UpToDate. Waltham, MA: UpToDate; 2019. https://www.uptodate.com/contents/approach-to-the-patient-with-a-suspected-acute-transfusion-reaction. Accessed June 10, 2019.

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