Hematology/Oncology

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Look at reticulocyte count and MCV.

The reticulocyte count can help distinguish excess RBC destruction or blood loss (↑ reticulocyte count) from ↓ production (↓ reticulocyte count).

The mean MCV classifies anemia as normocytic, microcytic, or macrocytic.

A diagnostic algorithm for anemia based on MCV and reticulocyte count is described in Figure 7-1.

1. Anemia Secondary to Maturation Defects or Underproduction

a. Iron Deficiency Anemia

Etiology

Blood loss from GI or menstrual bleeding (GU blood loss less often the cause)

Dietary iron deficiency (rare in adults)

Poor iron absorption in pts w/gastric or small bowel surgery

Repeated phlebotomy

↑ Requirements (e.g., pregnancy)

Other: traumatic hemolysis (abnlly functioning cardiac valves), idiopathic pulmonary hemosiderosis (iron sequestration in pulmonary macrophages), PNH (intravascular hemolysis)

Diagnosis

H&P

Fatigue, dizziness, exertional dyspnea, pagophagia (ice eating), pica. Pt’s hx may also suggest GI blood loss (melena, hematochezia, hemoptysis).

Labs

Vary w/the stage of deficiency: absent iron marrow stores and ↓ serum ferritin → ↓ serum iron, ↑ TIBC → ↓ MCV

Peripheral smear: microcytic hypochromic RBCs w/a wide area of central pallor, anisocytosis, poikilocytosis

↑ RDW (usually <15), ↓ MCV, ↓ serum ferritin level, ↑ TIBC, ↓ serum iron

Treatment

Ferrous sulfate 325 mg PO qd, parenteral iron, transfusion of PRBCs depending on severity

b. Cobalamin (Vitamin B₁₂) Deficiency

Etiology

Pernicious anemia (PA): gastric anti–parietal cell Abs in 90% of pts, anti–intrinsic factor Abs in >70% of pts

Malabsorption, atrophic gastric mucosa, bacterial overgrowth, IBD, meds (PPIs, metformin)

Diagnosis

H&P

Impaired memory, gait disturbances, paresthesias, and complaints of generalized weakness in advanced stages

Labs

CBC: macrocytic anemia and leukopenia w/hypersegmented neutrophils

↑ MCV, ↓/nl reticulocyte count

Plasma MMA (P-MMA) (↑) and urinary MMA (↑), total homocysteine level (↑): used for detecting cobalamin deficiency in pts w/nl vitamin B₁₂ levels

Treatment

Traditional Rx of severe cobalamin deficiency consists of IM injections of vitamin B₁₂ 1000 μg/wk for 4 wk followed by 1000 μg/mo IM indefinitely.

PO cobalamin (1000-2000 μg/day) is effective for dietary deficiency and in mild cases of PA because about 1% of PO dose is absorbed by passive diffusion, a pathway that does not require intrinsic factor.

Clinical Pearl

Anemia is absent in 20% of pts w/cobalamin deficiency, and macrocytosis is absent in >30% of pts at the time of dx.

c. Folate Deficiency

Etiology

Malnutrition (alcoholism), ↑ needs (pregnancy), ↑ cell turnover (sickle cell, psoriasis)

Diagnosis

RBC folate more accurate (serum folate may be nl after just 1 folate-containing meal)

↑ Homocysteine (>90% sensitivity/specificity) in dx despite nl folate level

FIGURE 7-1 Algorithm for diagnosis of anemia. (From Goldman L, Schafer AI [eds]: Goldman’s Cecil Medicine, 24th ed. Philadelphia, Saunders, 2012.)

Treatment

Folate 1 to 5 mg/day PO

R/o vitamin B₁₂ deficiency before Rx as folate Rx can improve anemia but not B₁₂ neuro sx

If folate deficiency or pregnancy

d. Inflammatory Anemia (Anemia of Chronic Disease [ACD])

Etiology

Chronic infections (TB, SBE)

Chronic inflammation (connective tissue disorders, burns)

Malignant disease (carcinomas, lymphomas)

Endocrine (hypothyroidism, hypogonadism, hypopituitarism)

CKD, Chronic liver disease, IBD

Mechanism: ↓ erythrocyte survival, ↑ uptake and retention of iron within cells of the RES, limited availability of iron for erythroid progenitor cells, iron-restricted erythropoiesis

Diagnosis

Labs

Normochromic, normocytic, or microcytic anemia

↓ Iron and transferrin saturation, ↓ TIBC, and N/↑ ferritin level

Table 7-1 compares various causes of microcytic anemia.

TABLE 7-1

Lab Differentiation of Microcytic Anemias

Abnormality	Ferritin	Serum iron	TIBC	RDW
Iron deficiency	↓	↓	↑	↑
Inflammatory anemia	N/↑	↓	↓	N
Sideroblastic anemia	N/↑	↑	N	N
Thalassemia	N/↑	N/↑	N/↓	N/↑

Treatment

Rx is aimed at identification and Rx of underlying disease.

Erythropoiesis-stimulating agents (ESAs) (epoetin alfa, epoetin β, and darbepoetin) can be used in pts w/CKD (to ↑ Hgb to max of 11-12 g/dL), in HIV pts undergoing myelosuppressive Rx, and in pts w/cancer who are undergoing chemoRx.

e. Sideroblastic Anemia

Iron-loading anemia secondary to defective heme synthesis

Etiology

Primary hereditary sideroblastic anemia: inherited as a sex-linked recessive disease

Secondary acquired sideroblastic anemia: caused by alcohol, isoniazid, pyrazinamide, cycloserine, chloramphenicol, copper deficiency, lead poisoning

Diagnosis

Labs

Hypochromic anemia (↓ MCV, ↑ RDW)

Peripheral smear: dimorphic large and small cells revealing “Pappenheimer bodies” or siderocytes when stained for iron

Bone marrow: ringed sideroblasts, which represent iron storage in the mitochondria of normoblasts

Treatment

ESAs

Avoid alcohol

Sideroblastic anemia secondary to isoniazid, pyrazinamide, and cycloserine: vitamin B₆ (50-200 mg/day)

2. Acquired Hemolytic Anemia

a. Autoimmune Hemolytic Anemia (AIHA)

Premature destruction of RBCs caused by the binding of auto-Abs (IgG [80%], IgM [20%]) or complement to RBCs. AIHA may be idiopathic or associated with other disorders.

Etiology

Warm AIHA (WAIHA): IgG (often idiopathic or associated w/leukemia, lymphoma, thymoma, myeloma, viral infections, and collagen-vascular disease)

Cold agglutinin disease (CAD): IgM and complement in majority of cases (often idiopathic, at times associated w/infections [EBV], lymphoma)

Drug-induced: three major mechanisms:

• Ab directed against Rh complex (e.g., methyldopa)

• Ab directed against RBC drug complex (hapten-induced, e.g., PCN)

• Ab directed against complex formed by drug and plasma proteins; the drug–plasma protein–Ab complex causes destruction of RBCs (innocent bystander, e.g., quinidine)

Diagnosis

H&P

Pallor, jaundice

Tachycardia w/flow murmur if anemia is pronounced

Dyspnea and fatigue: most common presentation

Pts w/intravascular hemolysis may present w/dark urine and back pain.

Presence of hepatomegaly or lymphadenopathy suggests an underlying lymphoproliferative disorder or malignant neoplasm.

Splenomegaly may indicate hypersplenism as a cause of hemolysis.

Labs

Initial labs: ↑ reticulocyte count, ↑ LFTs (indirect bili, LDH), Coombs’ test (+ direct Coombs’ = Abs or complement on the surface of RBC; + indirect Coombs’ = anti-RBC Abs freely circulating in the pt’s serum), ↓ haptoglobin level

RBC clumping in CAD, falsely ↑ MCV

Imaging

CXR

CT of chest and abd: r/o lymphoma

Treatment

WAIHA: Prednisone 1 mg/kg/day. Consider rituximab, splenectomy, danazol, cyclophosphamide in resistant cases.

CAD: Avoid cold exposure in pts w/cold Ab.

Drug-induced AHA: Remove drug, and consider fludarabine.

b. Microangiopathic Hemolytic Anemia

Erythrocyte lysis during travel through the vascular system results in schistocytes or helmet cells on peripheral blood smear.

Differential Diagnosis

TTP

HUS

DIC

Intravascular foreign devices

Labs

↓ Haptoglobin, ↑ LDH

Hemoglobinuria

Treatment

Rx varies depending on etiology.

Plasma exchange may be lifesaving in pts with TTP or HUS.

c. Paroxysmal Nocturnal Hemoglobinuria (PNH)

Acquired clonal stem cell disorder (mutation in PIG-A gene) → episodes of intravascular hemolysis and hemoglobinuria, usually occurring at night

Diagnosis

CBC (anemia, leukopenia, thrombocytopenia, reticulocytosis)

↓ Serum iron saturation, ↓ ferritin

RBC smear: spherocytes

(−) Coombs test, (+) Ham test

↓ LAP, ↓ haptoglobin, ↑ LDH

↑ Urine hemoglobin, urobilinogen, hemosiderin

Flow cytometry for detection of CD55 and CD59 deficiency on surface of peripheral erythrocytes/leukocytes

Normoblastic hyperplasia on marrow aspirate or bx

H&P

First morning urinary void reveals hemoglobinuria with progressive clearing throughout day (25%), bleeding/anemia (30%), and thrombosis (40%).

Treatment

Anticoagulation in acute thrombotic event: Consider prophylaxis if >50% CD55− or CD59−deficient.

Eculizumab has shown ↓ transfusion requirements, ↑ quality of life.

Consider corticosteroids.

d. Hemolytic Transfusion Reaction

Acute Hemolytic Transfusion Reaction (AHTR)

Almost always caused by ABO incompatibility between donor and recipient (clerical error)

Physical Exam and Clinical Findings

Hypotension, fever, kidney failure, pain at transfusion site, DIC

Treatment

Stop transfusion immediately, recheck specimen for incompatibility, and provide supportive care (fluid resuscitation, vasopressor support, mannitol).

Delayed Hemolytic Transfusion Reaction (DHTR)

Via amnestic response of preformed erythrocyte alloantibody after repeat exposure to erythrocyte antigen outside the ABO system

Physical Exam and Clinical Findings

5-10 days s/p transfusion: anemia, jaundice, fever

Treatment

Supportive care

3. Congenital Hemolytic Anemias

a. Sickle Cell Syndrome

Substitution of the amino acid valine for glutamic acid in the sixth position of the γ-globin chain = Hgb S → exposed to low Po₂ → RBC sickling → stasis of RBCs in capillaries → obstruction of blood flow

Diagnosis

H&P

PE is variable, depending on the degree of anemia and presence of acute vaso-occlusive syndromes or neurologic, CV, GU, and musculoskeletal complications.

Bones are the most common site of pain. Dactylitis, or hand-foot syndrome (acute, painful swelling of the hands and feet), is the first manifestation of sickle cell disease in many infants.

Pneumonia develops during the course of 20% of painful events and can manifest as chest and abd pain. In adults, chest pain may be a result of vaso-occlusion in the ribs and often precedes a pulmonary event. The lower back is also a frequent site of painful crisis in adults.

The acute chest syndrome manifests w/chest pain, fever, wheezing, tachypnea, and cough. CXR reveals pulmonary infiltrates. Common causes include infection (mycoplasma, chlamydia, viruses), infarction, and fat embolism.

Musculoskeletal and skin abnlities: leg ulcers (particularly on the malleoli) and limb-girdle deformities caused by avascular necrosis of the femoral and humeral heads

Endocrine abnlities: delayed sexual maturation and late physical maturation, especially evident in boys

Neurologic abnlities: seizures and MS changes

Infections: Salmonella, Mycoplasma, and Streptococcus are common.

Severe splenomegaly secondary to sequestration often occurs in children before splenic atrophy.

Labs

Hgb electrophoresis confirms the dx and can identify Hgb variants, such as fetal Hgb and Hgb A₂.

↑ Bili and LDH ↓ haptoglobin

Peripheral blood smear: sickle cells, target cells, poikilocytosis, hypochromia

↑ BUN and Cr: in pts w/progressive renal insufficiency

U/A: hematuria, proteinuria

Imaging

CXR

Bone scan or MRI scan in suspected osteomyelitis

CT or MRI of brain: in pts w/TIA, CVA, seizures, or MS changes

Transcranial Doppler study: in pts at risk for stroke

Doppler echocardiography: r/o pulmonary HTN

Treatment

Avoidance of conditions that may precipitate sickling crisis, such as hypoxia, infections, acidosis, and dehydration

Maintain adequate hydration (PO or IV).

Correct hypoxia.

Ceph and azithromycin + incentive spirometry and bronchodilators in pts w/acute chest syndrome

Pain relief during the vaso-occlusive crisis

• Narcotics (e.g., morphine 0.1 mg/kg IV q3-4h or 0.3 mg/kg PO q4h) should be given on a fixed schedule (not PRN for pain), w/rescue dosing for breakthrough pain as needed.

• Except when contraindications exist, concomitant use of NSAIDs should be standard Rx.

Indications for transfusion include aplastic crises, severe hemolytic crises (particularly during third trimester of pregnancy), acute chest syndrome, and high risk of stroke.

Hydroxyurea is indicated for severe disease, typically in pts w/> 3 acute painful crises or episodes of the acute chest syndrome in the previous year.

Replace folic acid (1 mg PO qd).

Exchange transfusions: Consider for pts w/acute neurologic signs, in aplastic crisis, or undergoing surgery.

Allogeneic SCT can be curative in young pts w/symptomatic sickle cell disease; however, the death rate from the procedure is nearly 10%.

PCN V 125 mg PO bid should be administered by age 2 mo and to 250 mg bid by age 3 yr. PCN prophylaxis can be discontinued after age 5 yr except in children who have had splenectomy.

b. Thalassemia

β-Thalassemia

β (+)-Thalassemia (suboptimal β-globin synthesis)

β (0)-Thalassemia (total absence of β-globin synthesis)

δ-β-Thalassemia (total absence of both δ-globin and β-globin synthesis)

Lepore hemoglobin (synthesis of small amounts of fused δ-β-globin and total absence of δ- and β-globin)

Hereditary persistence of fetal hemoglobin (HPHF) (increased hemoglobin F synthesis and reduced or absence of δ- and β-globin)

α-Thalassemia

Silent carrier (three α-globin genes present)

α-Thalassemia trait (two α-globin genes present)

Hemoglobin H disease (one α-globin gene present)

Hydrops fetalis (no α-globin gene)

Hemoglobin constant sprint (elongated α-globin chain)

H&P

β-Thalassemia

Heterozygous β-thalassemia (thalassemia minor): no or mild anemia, microcytosis and hypochromia, mild hemolysis manifested by slight reticulocytosis and splenomegaly

Homozygous β-thalassemia (thalassemia major): intense hemolytic anemia; transfusion dependency; bone deformities (skull and long bones); hepatomegaly; splenomegaly; iron overload leading to cardiomyopathy, diabetes mellitus, and hypogonadism; growth retardation; pigment gallstones; susceptibility to infection

Thalassemia intermedia caused by combination of β- and α-thalassemia or β-thalassemia and Hgb Lepore: resembles thalassemia major but is milder

α-Thalassemia

Silent carrier: no symptoms

α-Thalassemia trait: microcytosis only

Hemoglobin H disease: moderately severe hemolysis with microcytosis and splenomegaly

The loss of all four α-globin genes is incompatible with life (stillbirth of hydropic fetus).

Diagnosis

Labs: β-Thalassemia

Microcytosis (MCV: 55 to 80 fL)

Smear: nucleated RBCs, anisocytosis, poikilocytosis, polychromatophilia, Pappenheimer and Howell-Jolly bodies

Hemoglobin electrophoresis: ↓ hemoglobin A, increased fetal hemoglobin, variable increase in the amount of hemoglobin A₂

Markers of hemolysis: elevated indirect bilirubin and lactate dehydrogenase, decreased haptoglobin

Labs: α-Thalassemia

Microcytosis

Hemoglobin electrophoresis: normal except for the presence of hemoglobin H in hemoglobin H disease

Treatment

Thalassemia minor: No treatment is indicated, but avoid iron administration for incorrect diagnosis of iron deficiency.

β-Thalassemia major (and hemoglobin H disease)

• Transfusion as required together with chelation of iron with desferrioxamine. Deferiprone, an oral chelating agent, can be used as a second-line treatment.

• Splenectomy for hypersplenism if present

• Bone marrow transplantation

• Hydroxyurea may increase the level of hemoglobin F.

c. Glucose-6 Phosphate Dehydrogenase (G6PD) Deficiency

Etiology

Mutation on X chromosome

Most common RBC enzyme defect → inability to generate NADPH = hemolysis when exposed to oxidant stress

Diagnosis

H&P

Episodic hemolysis following exposure to fava beans (Mediterranean G6PD variant) or drugs (nitrofurantoin, dapsone, trimethoprim-sulfamethoxazole) in African variant form

Labs

Peripheral smear: “bite” cells, denturated oxidized hemoglobin (Heinz bodies)

G6PD levels not helpful during acute hemolysis (may be falsely normal because of ↑ G6PD in young reticulocytes)

Treatment

Removal of offending agent, supportive care

d. Hereditary Spherocytosis

Etiology

Autosomal dominant

Most common RBC membrane disorder → spectrin deficiency = loss of erythrocyte surface area → spherocytic shape → trapping and destruction in spleen

Diagnosis

H&P

Neonatal jaundice, hx anemia, gallstones, splenomegaly

Labs

Osmotic fragility test with 24-hr incubation = ↑ fragility

Direct Coombs (−)

Peripheral smear: spherocytes

Treatment

Vaccination against meningococcus, pneumococcus, Hib followed by splenectomy in symptomatic pts

B. Bone Marrow Failure Syndromes

1. Aplastic Anemia

Bone marrow failure is characterized by stem cell destruction or suppression leading to pancytopenia.

Diagnosis

Labs

CBC: pancytopenia. Macrocytosis and toxic granulation of neutrophils may also be present. Isolated cytopenias may occur in the early stages, ↓ reticulocyte count.

Additional initial labs: vitamin B₁₂ level, RBC folate, HIV, Ham test (r/o PNH) hepatitis serology

Bone marrow examination: paucity or absence of erythropoietic and myelopoietic precursor cells. Pts w/pure red cell aplasia demonstrate only absence of RBC precursors in the marrow.

Chromosomal breakpoint analysis to r/o Fanconi anemia in pts <50 yr old

Treatment

Transplantation of allogeneic marrow (HSCT) or peripheral blood SCT from a histocompatible sibling is preferred initial Rx (cure rate >80%) in pts <40 yr old.

Immunosuppressive Rx with ATG and cyclophosphamide is indicated in pts who are not candidates for allogeneic bone marrow (long-term survival >60%).

2. Pure Red Cell Aplasia (PRCA)

Bone marrow failure affects erythroblasts (leukocyte and Plt production is normal).

Etiology

Idiopathic or secondary (thymoma, parvovirus B19, meds [chloramphenicol, phenytoin, INH]), collagen vascular and lymphoproliferative disorders, pregnancy)

PE: splenomegaly, signs of RA (33% of pts)

Diagnosis

Flow cytometry: CD57+ T-cells, clonality T-cell receptor gene rearrangement

Normocytic anemia

Presence of large granular lymphocytes when PRCA results from large granular lymphocytosis

Treatment

Removal of offending drugs/Rx secondary condition (IV Ig if parvovirus B19 infection)

Refractory cases: prednisone, ATG, cyclosporine, cyclophosphamide (first-line agents with response 3-12 wk)

If sx anemia: erythrocyte transfusion

3. Thrombocytopenia

Etiology

↑ Destruction

• Immunologic

• Drugs: quinine, quinidine, digitalis, procainamide, thiazide diuretics, sulfonamides, phenytoin, ASA, PCN, heparin, gold, meprobamate, sulfa drugs, phenylbutazone, NSAIDs, methyldopa, cimetidine, furosemide, INH, cephs, chlorpropamide, organic arsenicals, chloroquine, Plt glycoprotein IIb/IIIa receptor inhibitors, ranitidine, indomethacin, carboplatin, ticlopidine, clopidogrel

• ITP

• Transfusion reaction: transfusion of Plts w/plasminogen activator (PLA) in recipients w/o PLA-1

• Fetal/maternal incompatibility

• Collagen-vascular diseases (e.g., SLE)

• AIHA

• Lymphoreticular disorders (e.g., CLL)

• Nonimmunologic

• Prosthetic heart valves

• TTP

• Sepsis

• DIC

• HUS

• Giant cavernous hemangioma

↓ Production

• Abnl marrow

• Marrow infiltration (e.g., leukemia, lymphoma, fibrosis)

• Marrow suppression (e.g., chemoRx, alcohol, irradiation)

• Vitamin deficiencies (B₁₂, folate)

• Hereditary disorders

• Wiskott-Aldrich syndrome: X-linked disorder characterized by thrombocytopenia, eczema, and repeated infections

• May-Hegglin anomaly: megakaryocytes but ineffective thrombopoiesis

Splenic sequestration

Hypersplenism

Dilutional (massive transfusion)

Diagnosis

Diagnostic Approach (Fig. 7-2)

Thorough hx (particularly drug hx)

PE: Evaluate for presence of splenomegaly (hypersplenism, leukemia, lymphoma).

Labs

CBC, Coombs, LDH, INR, PTT, Plt Ab, D-dimer, fibrinogen level

Peripheral blood smear; note Plt size and other abnlities (e.g., fragmented RBCs may indicate TTP or DIC; ↑ Plt size suggests accelerated destruction and release of large young Plt into the circulation, normal smear and ↑ platelet size = ITP).

Bone marrow: ↑ megakaryocytes suggest accelerated Plt destruction.

4. Neutropenia

Etiology

Congenital: mild forms not associated with ↑ infection risk; Rx not necessary

FIGURE 7-2 Evaluation of thrombocytopenia. (From Goldman L, Schafer AI [eds]: Goldman’s Cecil Medicine, 24th ed. Philadelphia, Saunders, 2012.)

Acquired: drugs (chemotherapeutic agents, antibiotics [trimethoprim/sulfamethoxazole, cephs, chloramphenicol], anticonvulsants [phenytoin, carbamazepine], NSAIDs, antiarrhythmics [procainamide, amiodarone]), SLE, RA (Felty syndrome if splenomegaly present), viral infections (CMV, EBV, HIV), bacterial infections (S. pneumoniae, N. meningitidis), rickettsia, vitamin B₁₂ and folate deficiencies, myelodysplasia, large granular lymphocytosis, and other malignant disorders

PE: splenomegaly, signs of RA (Felty syndrome)

Diagnosis

Antineutrophil Ab (if test available)

Bone marrow exam if suspecting stem cell disorder

Treatment

Removal of offending drugs/Rx of secondary condition

Consider G-CSF Rx in severe neutropenia.

C. Myelodysplastic Syndromes

This group of acquired clonal disorders affecting the hematopoietic stem cells is characterized by cytopenias w/hypercellular bone marrow and various morphologic abnlities in the hematopoietic cell lines. Myelodysplastic syndrome cells show abnl (dysplastic) hematopoietic maturation. Marrow cellularity is ↑, reflecting an effective hematopoiesis, but inadequate maturation results in peripheral cytopenias.

Classification

The French-American-British (FAB) classification is described in Table 7-2.

The WHO classification includes the following disease subtypes: refractory anemia, refractory anemia w/ringed sideroblasts, refractory cytopenia w/multilineage dysplasia, refractory cytopenia w/multilineage dysplasia and ringed sideroblasts, refractory anemia w/excessive blasts (1, 2), unclassified myelodysplastic syndrome, and myelodysplastic syndrome associated w/isolated deletion (5q).

TABLE 7-2

French-American-British Classification Chart

Subtype	Abbreviation	Peripheral Blood	Bone Marrow
Refractory anemia	RA	Blasts <1%	Blasts <5%
Refractory anemia with ringed sideroblasts	RARS	Blasts <1%	Blasts <5%, and >15% ringed sideroblasts
Refractory anemia with excess blasts	RAEB	Blasts <5%	Blasts 5%-20%
Refractory anemia with excess blasts in transformation	RAEB-T	Blasts >5%	Blasts 20%-30% or Auer rods
Chronic myelomonocytic leukemia	CMML	Monocytes >1 × 10⁹/L	Any of the above
Acute myelogenous leukemia	AML	Blasts >30%

From Hoffman R et al: Hematology, basic principles and practice, ed 5, Philadelphia 2009, Churchill Livingston.

Diagnosis

H&P

Splenomegaly, skin pallor, mucosal bleeding, and ecchymosis may be present.

Fatigue, fever, dyspnea

Labs

CBC w/diff, HIV, RBC folate, vitamin B₁₂ level, bone marrow exam, cytogenetic analysis

Treatment

• ESAs in sx anemia

• Lenalidomide

• Azacitidine

• Decitabine

• Allogeneic stem cell transplantation should be considered in pts <60 yr old.

Prognosis

Risk of transformation to AML varies w/% of blasts in bone marrow.

Advanced age, male sex, and deletion of chromosomes 5 and 7 are associated w/poor prognosis.

The most important variables in disease outcome are the specific cytogenetic abnlities, the % of blasts in bone marrow, and the number of hematopoietic lineages involved in the cytopenias.

D. Myeloproliferative Disorders

1. Polycythemia Vera

This myeloproliferative disorder is characterized mainly by erythrocytosis.

Diagnosis (Fig. 7-3)

Clinical Presentation

Sx associated w/ ↑ blood volume and viscosity or impaired Plt function

• Impaired cerebral circulation: headache, vertigo, blurred vision, dizziness, TIA, CVA

• Fatigue, poor exercise tolerance

FIGURE 7-3 Diagnostic algorithm for polycythemia vera (P. vera). (From Goldberger E: Treatment of Cardiac Emergencies, 5th ed. St. Louis, Mosby, 1990.)

• Pruritus, particularly after bathing (caused by overproduction of histamine)

• Bleeding: epistaxis, UGI bleeding (incidence of PUD)

Abd discomfort secondary to splenomegaly, hepatomegaly

Nephrolithiasis and gouty arthritis from hyperuricemia

PE

Facial plethora, congestion of oral mucosa, ruddy complexion

Enlargement and tortuosity of retinal vein

Splenomegaly (>75% of pts)

Labs

↑ RBC count, ↑ Hgb/Hct

↑ WBC (often w/basophilia), ↑ Plts (majority of pts)

↑ LAP, serum vitamin B₁₂, and uric acid levels

↓ Serum erythropoietin level

+ JAK2 V617F mutation (>95% of pts)

N_l O₂ sat

Bone marrow exam: RBC hyperplasia and absent iron stores

Treatment

ASA 81 mg/day

Phlebotomy to keep Hct <45%

Additional options: hydroxyurea, interferon alfa-2b

Prognosis

The median survival time w/o Rx is 6 to 18 mo after dx; phlebotomy extends the average survival time to 12 yr.

Prognosis worse in pts >60 yr of age and those who have h/o thrombosis.

2. Essential Thrombocythemia

↑ Plt count w/o conditions causing secondary thrombocytosis

Epidemiology and Presentation

<1% of pts progress to AML.

20%-30% arterial/venous thrombosis. Leukocytosis predicts severity.

If + JAK2 V617F mutation (50% pts) is present, then the course is more aggressive.

Hemorrhagic sx (40%)

Diagnosis

Plt count >600,000/μL on 2 separate occasions 1 mo apart

R/o secondary causes (iron deficiency, cancer, infection) in the absence of Philadelphia chromosome (t9:22).

Treatment

Plt-lowering agents in pt >65 yr old w/hx/↑ risk thrombosis

Hydroxyurea + low-dose ASA = ↓ risk thrombosis

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