This chapter will discuss anemia, thrombocytopenia, coagulation disorders, and oncologic emergencies that are seen in the critical care setting.

Two-thirds of patients admitted to the intensive care unit (ICU) will have a hemoglobin level less than 12 g/dL, and 97% will have anemia by day 8.^1-4 The lifespan of a red blood cell (RBC) is 120 days, and normal aging leads to increased oxygen hemoglobin affinity, decreased repair of oxidant injury, and decreased ability to membrane deformability during transit.^1,5 Red blood cell formation begins at 20 mL/d and can increase to 200 mL/d in hemolysis and heavy blood loss in a healthy patient.⁶ Increasing levels of erythropoietin stimulate red cell production, inhibit erythroid precursor apoptosis, and enhance the removal of senescent RBCS. In addition to erythropoietin, healthy RBC production requires iron, zinc, folate, vitamin B₁₂, thyroxine, androgens, cortisol, and catecholamines.¹

Anemia in the ICU is due to blood loss and decreased production.¹ Insensible blood loss occurs from phlebotomy, especially for patients with arterial catheters; stress gastritis exacerbated by mechanical ventilation, nutritional deficiencies, antithrombotic medication, and renal failure; and invasive procedures and surgical interventions.^1,7-12 Decreased production may be secondary to nutritional deficiencies, anemia of inflammation (AI), and medications. In AI, cytokines such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-6 increase hepatic hepcidin synthesis, which inhibits iron absorption and delivery to the bone marrow compartment and blocks iron release from bone marrow macrophages to the erythron.^1,13-16 Medications such as norepinephrine and phenylephrine inhibit hematopoietic maturation and angiotensin-converting enzyme inhibitors (ACEI), calcium channel blockers, theophylline, and β-adrenergic blockers suppress the secretion of erythropoietin by the kidney in response to anemia-induced hypoxemia.^17-20

Anemia has been shown to be associated with adverse effects and poor outcomes in patients with normal renal function, chronic renal failure, chronic obstructive pulmonary disease (COPD), congestive heart failure, and acute myocardial infarction.^21-31 Anemia can persist up to 6 months after ICU stay.³²

Evaluation

Anemias are classified based on the mean corpuscular volume (MCV) and the reticulocyte count (Table 23-1). The next step in the diagnosis of anemia is examining the leukocyte count and differential, the platelet count, and the blood smear (Table 23-2). Anemias are normocytic, microcytic, and macrocytic, and within each category, they are subdivided into normoproliferative, hypoproliferative, and hyperproliferative, if the reticulocyte count is normal, decreased, or increased, respectively. Healthy reticulocyte production should increase 1.5-fold for a hematocrit (Hct) of 30% to 40%, should double with Hct of 20% to 30%, and should triple with Hct of 15% or less; these increases are designated maturation factors. The reticulocyte production index (RPI) is used to determine proliferation status:

For example, the RPI for a patient with a Hct of 20% and a reticulocyte count of 10% can be calculated as (10 × 20/45)/2 = 2.2, which is normal. An RPI less than 2 suggests a hypoproliferative anemia and an RPI of greater than 4 suggests a hyperproliferative anemia.

Hemolytic Anemia

Hemolytic anemia is the premature destruction of red blood cells. It can occur intravascularly or extravascularly within the spleen.^33,34 Extravascular hemolysis is usually due to an immunoglobulin G (IgG)-mediated process, designated as warm antibody autoimmune hemolytic anemia (AIHA). Investigation begins with careful history and physical examination that includes review of any infectious process and medications. Laboratory findings that indicate hemolysis include an elevated or rising mean corpuscular volume, increased reticulocytes, increased lactate dehydrogenase (LDH), increased indirect bilirubin, low haptoglobin, and the presence of microspherocytes (small red cells without any central pallor) on blood smear. The diagnosis is confirmed by indirect and direct antiglobulin test (DAT) also referred to as Coombs testing. The indirect Coombs test looks for an autoantibody in the patient’s serum. The direct Coombs test looks for an autoantibody on the patient’s red cells. Table 23-3 lists the pattern of Coombs testing for IgG-mediated AIHA (antibodies that bind to red cells at body temperature), IgM-mediated AIHA (antibodies that bind to red cells only at lower temperatures, the so-called cold agglutinins) and hapten-mediated AIHA (an antibody that binds to the red cell modified by the presence of a membrane-bound substance such as penicillin).

Treatment of AIHA begins with identifying and treating the underlying disease. For idiopathic warm AIHA, corticosteroid treatment is first-line therapy. Second-line treatment for patients with refractory AIHA from corticosteroids includes splenectomy or rituximab.³⁴ Patients with AIHA after splenectomy are high risk for venous thromboembolism. Although transfusion therapy of patients with AIHA is complicated by difficulties with patient blood typing and cross-matching, it is imperative that life-threatening anemia be treated with transfusion, often using the least incompatible blood, such as O negative.

Transfusion Therapy

It has been hypothesized that euvolemic resting patients with an acute drop of hemoglobin of 5 g/dL can have elevated cardiac index and oxygen extractions with no tissue hypoxia.³⁵ Chronicity allows the body to tolerate even lower values.³⁶ The 2016 American Association of Blood Bank (AABB) Guidelines recommend a restrictive transfusion threshold of 7 g/dL over a liberal transfusion threshold of 10 g/dL because the 30-day critical care outcome has 3 fewer deaths per 1000 with the restrictive transfusion threshold, shows no evidence of harm, and does not affect length of stay, functional status, and fatigue.³⁷ A transfusion threshold of 8 g/dL is sometimes recommended for orthopedic surgery, cardiac surgery, or known cardiovascular disease because that was the threshold used for the randomized control trials.³⁷ The restrictive threshold has not been advocated for patients with acute coronary syndrome because the liberal threshold was associated with a trend toward decreased mortality.^38,39 According to AABB, it also has not been advocated for patients with hematologic and oncologic disorders, severe thrombocytopenia at risk for bleeding, and transfusion-dependent anemia.³⁷ The Society of Critical Care Medicine (SCCM) and the Eastern Association for the Surgery of Trauma (EAST) still recommend an individualized approach to transfusion threshold.⁴⁰ It takes 15 minutes for the blood to equilibrate after blood transfusion.^41,42 However, in certain scenarios, such as trauma or active bleed, a follow-up complete blood count (CBC) should not be used to direct further transfusion. Worsening hemodynamic instability or ongoing bleeding should prompt further transfusion.

One unit of packed red blood cells is 450 to 500 mL and can increase the hemoglobin by 1 g/dL or hematocrit by 3% to 4%.⁴³ Donor blood must be serologically compatible with the recipient’s blood prior to administration, except in cases of life-threatening hemorrhage or anemia. Blood type O negative is the universal donor. Blood type AB can receive blood from any other blood type. Although rare, transfusions are associated with infections. These include human immunodeficiency virus (HIV) (1 in 1,467,000), hepatitis C (1 in 1,149,000), hepatitis B (1 in 282,000), West Nile virus, cytomegalovirus (CMV), bacteria (1 in 2000–3000), and parasites such as Trypanosoma cruzi, which causes Chagas disease.⁴³ There are also noninfectious adverse effects such as those listed in Table 23-4.

Transfusion is the most important cause of clinically significant immunization against blood group antigens. In addition, there are naturally occurring antibodies to A, B, P, and other antigens in children and nontransfused adults due to their production by gut microbes. The antigens responsible for major hemolytic transfusion reactions are in descending order: ABO system > anti-D (part of the Rh system) > anti-K (Kell system) > anti-E (Rh system). Blood typing and screening will establish the patient’s ABO and Rh type and examine for any antibodies against minor antigens, such as the Kell antigens or other systems that could cause minor or delayed hemolytic transfusion reactions (eg, the Lutheran, Lewis, Duffy, and Kidd systems). Cross-matching will provide red blood cells that are ABO and Rh compatible and that lack any antigens identified as targets in the antibody screen (the purpose of which is to identify alloantibodies).

Blood products are also modified to decrease the risk of adverse effects. These modifications include leukocyte reduction, washing, irradiation, and volume reduction. Leukocyte reduction is achieved by differential centrifugation or filtration where 99.9% of leukocytes are removed to reduce the incidence of nonfebrile hemolytic transfusion reactions (NFTR); CMV transmission, particularly in neonates, pregnancy patients, patients with HIV, organ transplant recipients and other immunocompromised patients, and fetuses receiving intrauterine transfusions; human leukocyte antigen (HLA) alloimmunization; and transfusion-related immunomodulation (TRIM).^49,50 Washing consists of instilling normal saline with or without dextrose to remove residual plasma. This will decrease the risk of anaphylaxis from an IgA-deficient recipient with anti-IgA antibodies, severe allergies, sensitivity to hyperkalemia, and paroxysmal nocturnal hemoglobinuria. Twenty percent of the RBC may be lost.⁴³ Shelf-life of the washed product is 24 hours if stored at 1°C to 6°C, and 4 hours if stored at 20°C to 24°C.⁴³ Irradiation is used to prevent transfusion-associated graft-versus-host disease (GVHD), which is almost always fatal in the following circumstances: (1) the donor is family member, an HLA-selected donor, or a donor with a relationship that has not been established; (2) the patient has acute leukemia with HLA-matched or family-donated products; (3) the patient is an allogenic hematopoietic progenitor cell (HPC) transplant recipient; (4) the patient was an allogenic HPC donor 7 days prior to or during harvest; (5) the patient is an autologous HPC recipient; (6) the patient has Hodgkin disease; (7) the patient has a history of purine analogs and related drugs such as fludarabine; (6) the patient has a history of alemtuzumab use; and (7) the patient had aplastic anemia treated with cyclosporine A and antithymocyte globulin.⁴³

Packed RBC transfusion alternatives such as erythropoietin, blood substitutes, and iron supplementation have been investigated. Administration of high-dose erythropoietin can produce the equivalent of 1 unit of packed RBCs after 7 days, but its use in the critically ill has been controversial since it has not been shown to improve survival and can increase thrombotic events in patients.^51,52 Blood substitutes such as hemoglobin-based oxygen carriers and perfluorocarbons are not available. Iron absorption may be limited due to the effect of critical illness on hepcidin secretion, and IV administration is preferred.¹ These alternatives may be contemplated in severely anemic symptomatic patients who refuse blood transfusions.

Polycythemia is defined as increased red blood cells with increased hemoglobin or hematocrit (hemoglobin [Hgb] > 16.5 g/dL or Hematocrit(Hct) ≥ 49% in men and Hgb >16 g/dL or ≥ Hct 48% in women). Relative polycythemia has elevated hemoglobin, hematocrit, and RBC count but no increase in red cell mass. This can be from Gaisbock disease or stress erythrocytosis, or it can be spurious. If there is an associated increase with red cell mass, this is called absolute polycythemia, which comes in primary and secondary forms. Symptoms due to increased blood viscosity include headaches, chest pain, abdominal pain, and shortness of breath. Treatment should include treatment of the underlying cause. Primary polycythemia (polycythemia vera) is treated immediately with phlebotomy, aiming to achieve a hematocrit less than 45%. Patients with secondary polycythemia from hypoxia often do not require phlebotomy, but if phlebotomy is done, the target hematocrit is 55%.^53,54

Thrombocytopenia is defined as a platelet count of less than 150 × 10³/μL (150,000/µL), although less than 100 × 10³/μL (100,000/µL) is considered the threshold for bleeding risk.^55-57 Thrombocytopenia has been used as a prognostic marker, and its magnitude is correlated with length of ICU stay and mortality.^57-66 About 150 billion platelets are produced daily, and they circulate for 10 days.⁵⁸ A decrease in platelet count causes increased soluble thrombopoietin, which stimulates megakaryocytopoiesis. The timeframe of thrombocytopenia onset offers clues to its etiology. Rapidly developing thrombocytopenia can be the result of bacteremia, disseminated intravascular coagulation (DIC), or immune clearance by platelet autoantibodies or alloantibodies. Slowly progressive thrombocytopenia suggests medication- or chemotherapy-induced thrombocytopenia, or a primary or secondary bone marrow disorder affecting thrombopoiesis.⁵⁸ Heparin-induced thrombocytopenia (HIT) almost never occurs before day 4 of heparin therapy in patients not exposed during the previous 3 months and will not develop among patients who have been treated continuously for 2 weeks or longer (Table 23-5).