7. Hemacology/Oncology

Decreased production/hypoproliferation

Ineffective erythropoiesis

Decreased red cell survival

Common Causes to Remember

Epidemiology

RBC lifespan ~120 days

Etiology of anemia in intensive care unit (ICU) patients is often multifactorial

Incidence in ICU patients between 29% and 37%

44% of ICU patients in the United States will receive one blood transfusion during their ICU stay

Key Pathophysiology

Hemodilution

Blood Loss

Phlebotomy

Hemorrhage

Reduced RBC survival and production

Iron Metabolism

B12/Folate Metabolism

Decreased Erythropoietin Concentration

Abnormal Red Cell Maturation

Anemia in the Critically Ill:

Critical Illness → Blood Loss and/or decreased production → Immune activation → Decreased Iron → Decreased erythropoiesis

Differential Diagnosis

Iron Deficiency Anemia

Most common cause of anemia

Patients with iron deficiency anemia have longer ICU stays

Hemolytic Anemia (RBC destruction)

Intrinsic defect of the RBC; usually inherited (sickle cell anemia, thalassemias)

Extrinsic (aka autoimmune hemolytic anemia)

Infectious—hepatitis, CMV, EBV, Escherichia coli

Medications—PCN, sulfa, anti-malarials

Diseases—SLE, rheumatoid arthritis, ulcerative colitis

Blood Loss

Management and Treatment

(see Transfusion Therapy, Section 18)

Blood Transfusions

Erythropoietin Therapy

SUGGESTED READINGS

Henry ML, Garner WL, Fabri PJ. Iatrogenic anemia. Am J Surg. 1986;151:362.

Shander A. Anemia in the critically ill. Crit Care Clin. 2004;159-170.

Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499-1507.

VonAhsen N, Muller C, Serke S, Frei U, Eckardt KU. Important role of nondiagnostic blood loss and blunted erythropoietic response in the anemia of medical intensive care patients. Crit Care Med. 1999;27: 2630-2639.

Walsh TS, Saleh E. Anemia during critical illness. BJA. 2006;97:278-291.

7.2

Thrombocytopenia

Sheri M. Berg

Disease of decreased number of platelets characterized by

Platelet count < 150,000

Petechiae

Purpura

Bruising

Frank bleeding

Common Causes to Remember

Epidemiology

Platelet lifespan ~10 days

Etiology of thrombocytopenia in intensive care unit (ICU) patients can be multifactorial

Most common causes in the ICU are drug exposure and sepsis

Incidence in ICU patients between 13% and 60%

Associated with increased length of stay, morbidity, and mortality

Key Pathophysiology

Dilutional—transfusion of crystalloid, packed cells, and/or FFP without replacing platelets

Distributional—splenic sequestration in those with splenomegaly

Destruction—(+ schistocytes on blood smear, as there is usually associated hemolysis)

Nonimmune

Mechanical devices that cause shearing of cells, such as an IABP or LVAD

Thrombotic thrombocytopenic purpura (TTP)

Hemolytic uremic syndrome (HUS)

Immune

Idiopathic thrombocytopenic purpura (ITP)

Heparin-induced thrombocytopenia (HIT)

Drug induced (can be immune mediated or nonimmune)

Differential Diagnosis

TTP

Microangiopathic process with thrombocytopenia and microvascular thrombosis being the most prominent features

Platelet aggregates contain vonWillebrand factor antigen

Classic “pentad”: thrombocytopenia, microangiopathic hemolytic anemia, fever, mental status changes, and renal insufficiency

“Triad” of thrombocytopenia, schistocytosis, and elevated lactate dehydrogenase levels suggests TTP

HUS

Hallmark = renal failure

Predominantly renal platelet-fibrin thrombi

Often preceded by a gastrointestinal illness with a gram-negative cytotoxin-producing bacteria (Escherichia coli, Shigella)

ITP

Autoimmune (platelets become coated with IgG antibodies)

Hallmark = low platelets and mucocutaneous bleeding

Often a diagnosis of exclusion

HIT

Autoimmune (IgG antibodies to the heparin–platelet factor IV complex)

Actually quite uncommon (0.3%–0.5%); often overdiagnosed

Requires recent exposure to heparin (more commonly seen with unfractionated heparin; however, can occur after exposure to the low molecular weight heparin (LMWH) as well)

Hallmark = low platelets and thrombosis

Discontinue heparin if the platelet count falls to <50,000 or drops >50% of the patients baseline values or if thrombosis occurs (venous>arterial, except in cardiovascular patients)

Decrease in platelet count does not always precede thrombosis

ELISA test: anti-PF4 antibodies; sensitive but specificity is low

Drug induced

Clinical diagnosis made after fall in platelets after at least a week of exposure to a possible offending agent, with a return to normal levels after a week of discontinuing the drug

Platelet counts < 20,000 are more commonly drug induced.

Common offenders

Anticonvulsants (valproic acid, phenytoin)

Cinchona alkaloids (quinine, quinidine)

H2 antagonists (cimetidine)

Antibiotics (vancomycin, linezolid, rifampin, sulfonamides)

Platelet inhibitors (abciximab, eptifibatide)

Antirheumatics (gold salts)

Analgesics (naproxen, diclofenac, acetaminophen)

Management and Treatment

TTP: plasmapheresis

Give FFP to supply metalloproteases (until plasmapheresis can be initiated)

Do not give platelets (which can worsen microvascular thrombosis) unless there is severe hemorrhage or intracranial bleed.

Steroids have been tried for patients who have a relapse.

Other immunosuppressive agents (cyclophosphamide, cyclosporine, vincristine, rituximab) have also been used (although clinical trials guiding their use are lacking).

HUS: supportive therapy with fluids if oliguria persists for <24 hours; can progress to requiring renal replacement therapy

Platelet transfusions are unnecessary (as the thrombocytopenia is not often severe).

Plasmapheresis results are equivocal.

ITP: IV Immunoglobulin

Steroids can be used as an adjunct

Splenectomy (for refractory cases).

Do not give platelets (as the “new” platelets will be subjected to the same autoimmune destruction as native platelets) unless there is severe hemorrhage or intracranial bleed.

HIT: remove all heparin exposure (including heparin catheters and flushes)

Need to substitute with another anti-coagulating agent (Argatroban, Lepirudin)

Do not give platelets, as they can initiate a thrombotic event.

Drug induced

Remove offending agent

Most patients do not require specific treatment; however, those with severe thrombocytopenia should receive platelet transfusions.

Can try steroids, although there is no evidence that it helps

IVIg and plasmapheresis have been used as well; however, there is no supporting evidence for their efficacy.

SUGGESTED READINGS

Cawley MJ, Wittbrodt ET, Boyce EG, et al. Potential risk factors associated with thrombocytopenia in a surgical intensive care unit. Pharmacotherapy. 1999;19:108-113.

Hanes SD, Quarled DA, Boucher BA. Incidence and risk factors of thrombocytopenia in critically ill trauma patients. Ann Pharmacother. 1997;31:285-289.

Hui P, Cook DJ, Lim W, et al. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest. 2011;139:271-278.

Priziola JL, Smythe MA, Dager WE. Drug-induced thrombocytopenia in critically ill patients. Crit Care Med. 2010;38(6 Suppl):S145-S154.

Strauss R, Wehler M, Mehler K, et al. Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements and outcome. Crit Care Med. 2002;30:1765-1771.

7.3

Thrombocytosis

Sheri M. Berg

Disease of increased number of platelets characterized by

Platelet count > 450,000

Often symptomless but can predispose to thrombosis

Common Causes to Remember

Epidemiology

Most often reactive/secondary

Key Pathophysiology

Reactive thrombocytosis: increased levels of thrombopoietin, interleukin-6, cytokines (all may be produced in response to increased “stress”—inflammation, infections, and cancer)

Myeloproliferative: increased levels of thrombopoietin secondary to mutations in the thrombopoietin gene

Differential Diagnosis

Reactive/secondary thrombocytosis

Patients will have a clinically apparent systemic disease process that can explain the elevated platelet count.

Megakaryocytes appear normal.

Platelet function is usually normal.

Myeloproliferative

Patients are more likely to have complications (bleeding, thrombosis).

Splenomegaly is more common.

“Giant” platelets are more often seen on a peripheral blood smear.

Megakaryocytes appear abnormal (giant, dysplastic, increased ploidy).

Platelet function may be abnormal.

Management and Treatment

Reactive/Secondary

Do not usually require treatment, but the underlying disease process needs to be identified and treated accordingly.

Myeloproliferative

May require platelet lowering therapy (cytoreduction)

If symptomatic (signs of cerebrovascular or digital ischemia), treat with hydroxyurea.

Anagrelide (po quinolzalone derivative) reduces platelet counts via inhibition of megakaryocyte proliferation and differentiation.

Interferon alpha

Aspirin

SUGGESTED READINGS

Harrison CN. Current trends in essential thrombocythemia. Br J Haematol. 2002;117:796-808.

Pearson TC. The risk of thrombosis in essential thrombocythemia and polycythemia vera. Semin Oncol. 2002;29(Suppl 10):16-21.

Shafer AI. Thrombocytosis and thrombocythemia. Blood Rev. 2001;15: 159-166.

Shafer AI. Thrombocytosis. N Engl J Med. 2004;350:2122-2129.

7.4

Neutropenia

Sheri M. Berg

Definition

Disease of decreased number of neutrophils characterized by

Absolute neutrophil count (ANC) < 1,500/mm³

Classified as mild, moderate, or severe

Risk of infection increases as ANC decreases

Common features include fevers and infections

Severe neutropenia and increased risk of severe infections occur when the ANC < 500/mm^3.

Common Causes to Remember

Epidemiology

Females > males

Elderly > young

African Americans > whites

Key Pathophysiology

Neutrophils are an imperative component of the host defense system.

Oral mucosal ulceration and gingivitis are common problems, as bacteria overwhelm the oral pharynx in those who are neutropenic.

Neutropenia secondary to chemotherapy drugs tends to result in the most severe infections.

Infections can be severe, necessitating intensive care unit (ICU) admission.

Usually secondary to “neutropenic fever”

Oral pharynx and gastrointestinal tract can be severely affected.

Chronic neutropenics tend to have functional monocytes and intact immune function.

Infections tend to be less severe as compared to those with neutropenia caused by chemotherapy.

It is important to note that normal, systemic signs of infection may be blunted in neutropenics, but they will present with fever, possibly as their only marker of inflammation and infection.

Differential Diagnosis

Any neutropenic patient must be thoroughly worked up, as they often simply present with a fever.

Fever of unknown origin

Drug induced

Infection: bacterial, viral, fungal

CBC with differential and evaluation of a peripheral blood smear

Shock and respiratory failure are the leading causes for neutropenic admissions to the ICU.

Macrophage activation syndrome (aka lymphohistiocytic activation syndrome)

Can be seen in a patient who is neutropenic

Can cause neutropenia

Vasoplegic shock and multisystem organ failure can ensue

Three key features are fever, hepatosplenomegaly, and thrombocytopenia

Treated with steroids and etoposide (chemotherapy drug)

Management and Treatment

If a specific drug is the assumed offending agent, remove it immediately.

If a neutropenic patient presents with a fever, antibiotic therapy should be initiated and provide coverage against

Gram-positive cocci (staph and strep)

Gram-negative rods (pseudomonas)

Antifungals (if a patient has not improved within a week of what should be adequate antibacterial coverage, antifungal coverage should be added)

Hematopoietic growth factors

Granulocyte colony-stimulating factor—increases neutrophil count and function

Isolation rooms

SUGGESTED READINGS

Bhatt V, Saleem A. Review: drug induced neutropenia- pathophysiology, clinical features, and management. Ann Clin Lab Sci. 2004;34(2):131-137.

Boxer L, Dale DC. Neutropenia: causes and consequences. Semin Hematol. 2002;39(2):75-81.

Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutropenia in the US population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007;146(7):486-492.

Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730-751.

7.5

Hemoglobinopathies

Jarone Lee

Introduction

Hemoglobinopathies include a group of disorders of globin chain synthesis, which include the sickle cell syndromes, thalassemias, sickle cell and thalassemia combinations, unstable hemoglobins, and toxic exposures, such as methemoglobinemia.

The theory is that the hereditary forms developed over time as a way for the body to resist blood-born infectious diseases, mostly malaria.

Epidemiology

Hereditary hemoglobinopathies are clustered in areas where malaria is endemic, affecting around 200 million individuals worldwide.

8% of American blacks are heterozygous for sickle cell disease

1 in 400 American blacks are homozygous for sickle cell disease.

Acute Chest Syndrome

Highest in homozygous sickle cell disease

2 to 4 years of age: 25.3 per 100 patient-years

> 20 years of age: 8.8 per 100 patient-years

15% of American blacks are alpha-thalassemia carriers.

10%–15% of people from the Mediterranean and Southeast Asia have beta-thalassemia.

Key Pathophysiology

Hemoglobin is made of globin polypeptide chains arranged in a tetramer.

The tetramer typically divided into two alpha chains and two beta chains.

Each hemoglobin polypeptide chain interacts with one heme moiety and an iron atom in the ferrous state.

Each heme-ferrous complex can bind one oxygen molecule.

Therefore, each hemoglobin tetramer can bind four oxygen molecules.

Mutations in the amino acid sequences of the alpha or beta chains can cause disease and clinical symptoms.

The alpha chain is 141 amino acids encoded on chromosome 16, and the beta chain is 146 amino acids encoded on chromosome 11.

Known areas of mutations that cause clinical symptoms include: (1) a key histidine in the F helix; (2) connections between the Alpha1 and Beta 1 subunits; and (3) connections between the Alpha1 and Beta2 subunits.

Types of hemoglobin

During the first trimester, the fetus has primarily embryonic hemoglobins: Gower 1; Gower 2; and Portland 1.

By 34 to 36 week gestation, Fetal hemoglobin (Hb F) comprises 90% to 95%, with the rest represented by adult hemoglobin (Hb A).

At term, Hb F comprises 53% to 95%, with Hb A comprising around 20% to 30% of total hemoglobin.

Persistently elevated Hb F is seen in hemoglobinopathies, but can also be seen in the following infants:

Small for gestational age

Chronic hypoxia

Trisomy 13

Hb F levels stays elevated during the neonatal period, and decreases to <3% by 6 months of life.

At birth, the infant starts producing hemoglobin A2 (Hb A2) and reaches adult levels by 6 months.

Because of the predominance of alpha chain hemoglobins in infancy, typically alpha chain hemoglobinopathies present in the neonatal period, whereas beta chain abnormalities present after 3 months of age.

Common pathway for hereditary hemoglobinopathies

Chromosomal mutations in the amino acids associated with the alpha or beta chains will produce clinical syndromes if they alter solubility and/or oxygen-binding affinity.

This leads to an inadequate supply of hemoglobin, which leads to the destruction of red cells and associated precursors.

Depending on the number and location of mutations, clinical severity can range from inutero death (e.g., hydropsfetalis) to asymptomatic carriers with mild anemia.

Specific hereditary hemoglobinopathies

Sickle Cell Syndromes: caused by mutation in beta-chain that changes the sixth amino acid from glutamic acid to valine (Hb S)

When deoxygenated, Hb S will polymerize, which leads to red-cell hardening and the characteristic ‘sickle cell’.

Occluded capillary vessels from the polymers leads to microinfarction of organs and pain.

Furthermore, hemolysis occurs as the body attempts to digest the polymers.

Unstable Hemoglobins: mutations that decrease solubility, typically form inclusion bodies in red cells called Heinz bodies

The spleen removes these Heinz bodies, leaving defective red blood cells, which are subsequently destroyed by the body at a rapid rate.

As a result, even patients that are heterozygous are symptomatic.

Thalassemia: inherited disorder of alpha and beta subunits of hemoglobin

A reduced supply of the affect hemoglobin will cause decreased production and accumulation of the other subunits.

Heterozygous individuals typically only manifest with mild anemia.

Homozygous individuals typically are more severe, since the red cell precursors are destroyed in the bone marrow, with the few red cells that survive ultimately destroyed by the spleen.

This leads to a profound hemolytic anemia.

The body adapts by hypertrophy of the bone marrow.

This causes characteristic bone abnormalities in patients, such as ‘chipmunk’ facies.

Acquired hemoglobinopathies

Patients with acquired hemoglobinopathies typically have normal genetic hemoglobin structures but are either poisoned by toxins (e.g., methemoglobinemia) or have a myeloproliferative disorder.