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

Interferon alfa (pregnant pt) or ³²P in refractory cases

3. Chronic Myeloid Leukemia

This malignant clonal disorder of hematopoietic stem cells is characterized by abnl proliferation and accumulation of immature granulocytes. Philadelphia chromosome, which is chromosome translocation t(9;22)(q34;q11.2), is present in >95% of pts.

Three Major Phases

Chronic Phase (Months to Years)

Asymptomatic after Rx

No features of accelerated phase or blast crisis

Accelerated Phase

Leukocyte count increasingly difficult to control w/standard Rx

↑ Blast %

• >10% in blood or bone marrow

• >20% blasts plus promyelocytes in blood or bone marrow

• >20% basophils plus eosinophils in blood

Progressive anemia or thrombocytopenia

New cytogenetic abnlities, especially a second Ph chromosome or trisomy 8

Worsening constitutional sx

Progressive splenomegaly

Development of myeloblastomas or myelofibrosis

Blast Crisis

>30% blasts plus promyelocytes in blood or bone marrow

Diagnosis

H&P

40% of pts are asymptomatic, and dx is based solely on an abnl blood count. Common complaints at the time of dx are weakness and discomfort secondary to an enlarged spleen (abd discomfort or pain). Splenomegaly is present in up to 40% of pts at time of dx.

Labs

WBC count (generally >100,000/mm³) w/broad spectrum of granulocytic forms, ↓ Hgb/Hct, ↑ Plt

Bone marrow: hypercellularity w/granulocytic hyperplasia, ratio of myeloid cells to erythroid cells, and number of megakaryocytes. Blasts and promyelocytes constitute <10% of all cells.

↑↑ LAP (can distinguish CML from other myeloproliferative disorders)

Treatment

BCR-ABL inhibitors: imatinib. Nilotinib or dasatinib can be used in pts resistant to or intolerant of imatinib.

Allogeneic HSCT in pts resistant to BCR-ABL inhibitors

4. Primary Myelofibrosis

This clonal hematopoietic stem cell disorder is characterized by abnl myeloid and megakaryocyte production.

Epidemiology and Presentation

Fatigue, night sweats, wt loss, abd pain, early satiety, gout, bone pain, pulmonary HTN

Hepatomegaly

Extramedullary hematopoiesis (vertebrae, lymph nodes)

Diagnosis

+JAK2 mutation (50% pts)

↑ LDH, uric acid, alk phos

Peripheral smear: leukoerythroblastic (L-shifted granulopoiesis, nucleated teardrop RBCs)

Treatment

If sx anemia: Transfuse.

Ruxolitinib (JAK inhibitor) Rx in high-risk pts

Androgen Rx (danazol) for anemia (30% response)

Hydroxyurea may help constitutional sx (hepatosplenomegaly, thrombocytosis).

Splenectomy in refractory cases

5. Acute Myeloid Leukemia (AML)

This malignant disease is characterized by uncontrolled proliferation of primitive myeloid cells (blasts).

Diagnosis

H&P

Pts come to medical attention because of the effects of the cytopenias:

• Anemia: weakness, fatigue

• Thrombocytopenia: bleeding, petechiae, ecchymosis

• Neutropenia: infections, fever

• Hyperleukocytosis: leukostasis with ocular and cerebrovascular dysfunction or bleeding

PE: skin pallor, bruises, petechiae, hepatosplenomegaly, peripheral lymphadenopathy

Labs

CBC: anemia, thrombocytopenia. Peripheral WBC count varies from <5000 to >100,000/mm³.

Dx requires >20% blast cells in blood or bone marrow.

Flow cytometry and (+) myeloperoxidase stains distinguish AML from ALL.

Treatment

Induction chemo: cytarabine + daunorubicin

Consolidation Rx: high-dose cytarabine in younger pts with favorable risk, intermediate-dose cytarabine in older pts; allogeneic HSCT in pts with high-risk disease

Sx hyperleukocytosis: leukapheresis, hydroxyurea

Clinical Pearl

Acute promyelocytic leukemia (APL) is a variant of AML (+ 15;17 gene translocation). APL is associated with DIC. Rx by adding all trans-retinoic acid (ATRA) to standard chemo = >75% cure. ATRA Rx may result in differentiation syndrome (fever, +/- pulmonary infiltrate, dyspnea hypotension, edema) which is treated with dexamethasone

6. Acute Lymphoblastic Leukemia (ALL)

Malignancy of B or T lymphoblasts

Diagnosis

H&P

Skin pallor, purpura, or easy bruising

Lymphadenopathy or hepatosplenomegaly

Fever, bone pain, oliguria, weakness, weight loss, change in MS, headaches, cranial nerve palsy

Labs

CBC: normochromic, normocytic anemia; thrombocytopenia

Peripheral smear: lymphoblasts

Dx requires >25% blast cells in bone marrow.

Flow cytometry and (−) myeloperoxidase stains distinguish ALL from AML.

Treatment

Intrathecal chemoprophylaxis w/w/o cranial irradiation (because of ↑ risk CNS involvement)

Prevention of urate nephropathy by vigorous hydration, rasburicase

Induction Rx: anthracycline, vincristine, L-asparaginase + corticosteroid

Maintenance chemoRx with multiple agents for 2 to 3 yr to maintain a state of remission

Allogeneic HSCT in first remission in pts with high-risk disease

Prognosis is generally poorer in adult disease compared w/childhood disease (30%-40% adult cure rate vs. 80% cure rate in children).

E. Multiple Myeloma and Related Disorders

1. Multiple Myeloma (MM)

This malignant neoplasm of plasma cells is characterized by overproduction of intact monoclonal immunoglobulin or free monoclonal κ or λ chains.

Diagnosis

Diagnostic criteria:

• Presence of >10% plasma cells in bone marrow (or bx of a tissue w/monoclonal plasma cells)

• Monoclonal protein in serum or urine

• Evidence of end-organ damage (Ca elevation, Renal insufficiency, Anemia, or Bone lesions [CRAB])

“Asymptomatic myeloma”: M protein ≥3 g/dL or ≥10% plasma cells on bone marrow but absence of myeloma-related end-organ damage

“Nonsecretory myeloma”: MM w/o detectable monoclonal protein

Staging (International Staging System)

• Stage I: serum β₂-microglobulin <3.5 mg/L, serum albumin ≥3.5 g/dL

• II: not stage I or III

• III: serum β₂-microglobulin >5.5 mg/L

H&P

Bone pain (58%) (back, thorax) or pathologic Fxs (30%) resulting from osteolytic lesions

Fatigue (32%) or weakness from anemia secondary to bone marrow infiltration w/plasma cells

Recurrent infections from impaired neutrophil function and deficiency of nl immunoglobulins

N/V related to constipation and uremia

Delirium resulting from hypercalcemia

Neurologic complications: spinal cord or nerve root compression, blurred vision from hyperviscosity

Purpura, epistaxis: from thrombocytopenia

Peripheral neuropathy: uncommon, seen with coexisting AL amyloidosis (POEMS syndrome [Polyneuropathy, organomegaly, Endocrinopathy, Monoclonal protein, Skin changes])

Labs

Normochromic, normocytic anemia; rouleaux formation on peripheral smear

Hypercalcemia (15% of pts at dx)

↑ BUN, Cr, uric acid, and total protein

Proteinuria secondary to overproduction and secretion of free monoclonal κ or λ chains (Bence Jones protein).

Tall homogeneous monoclonal spike (M spike) on protein IEP (75% of pts). ↑ immunoglobulins are generally IgG (75%) or IgA (15%).

<20% of pts have flat level of immunoglobulins but light chains in the urine by electrophoresis.

<3% of pts have nonsecreting myeloma (no ↑ in immunoglobulins and no light chains in the urine) but have other evidence of the disease (e.g., bone marrow exam).

↓ AG from the + charge of the M proteins and the frequent presence of hyponatremia in pts w/myeloma

Hyponatremia, serum hyperviscosity

Imaging

X-ray films of painful areas: punched-out lytic lesions

MRI: for suspected spinal compression or soft tissue plasmacytomas

Bone scans not useful because lesions are not blastic

Treatment

Treatment strategy is mainly related to age and comorbidities.

Initiation of induction Rx with thalidomide, lenalidomide, or bortezomib plus HSCT is indicated for pts <65 yr old who do not have substantial heart, lung, renal, or liver dysfunction.

Autologous stem-cell transplantation with a reduced-intensity conditioning regimen should be considered in older pts or those with coexisting conditions.

Rx of pts who are not candidates for HSCT (because of age or comorbidities) is with melphalan + prednisone + thalidomide or bortezomib.

Prompt dx and Rx of infections. Common bacterial agents are Streptococcus pneumoniae and Haemophilus influenzae. Prophylaxis against Pneumocystis w/TMP-SMZ is indicated in pts receiving chemoRx and high-dose corticosteroid regimens.

Vaccinate against S. pneumoniae, influenza, and H. influenzae.

Rx hypercalcemia w/IV fluids, corticosteroids, bisphosphonates (pamidronate, zoledronate).

Pain management w/analgesics. RT for painful bone lesions or spinal cord compression. Surgical stabilization of pathologic Fx. Consider vertebroplasty or kyphoplasty for selected vertebral lesions.

ESAs are given for severe anemia.

2. Monoclonal Gammopathy of Undetermined Significance (MGUS)

Diagnostic Criteria

Serum M protein concentration <3 g/dL

<10% plasma cells in the bone marrow

Absence of anemia/renal insufficiency/hypercalcemia/bone lesions

Treatment

Rx not indicated. Risk of progression of MGUS to MM is 1%/yr and is related to the level of M protein values and to the type of protein (↑ risk w/higher M protein values and in pts w/IgM and IgA M proteins).

Monitor serum M protein. If serum M protein is >2 g/dL, repeat electrophoresis every 6 mo.

3. Waldenstrom’s Macroglobulinemia

This plasma cell dyscrasia is characterized by production of monoclonal IgM Ab.

Diagnosis

H&P

Weakness, fatigue, weight loss, fever, night sweats

Mucosal bleeding, bruising

Headache, dizziness, vertigo, deafness, and seizures (hyperviscosity syndrome)

Fever, night sweats

Exam: ecchymoses, purpura, hepatomegaly, splenomegaly, lymphadenopathy, symmetric peripheral neuropathy

Diagnostic Criteria

Presence of lymphoplasmacytic lymphoma ≥10% of bone marrow cellularity + presence of an IgM M protein

Labs

CBC w/diff: anemia; WBC count usually nl. Thrombocytopenia may occur.

Peripheral smear may reveal “stacked coin” rouleaux formations.

SPEP: homogeneous M spike (monoclonal gammopathy). IEP confirms IgM responsible for the M spike.

Urine IEP: Monoclonal light chains are usually κ chains.

Serum viscosity: Sx usually occur when the serum viscosity is 4× nl; this is a classic feature, although present in only 15% of cases.

Treatment

Plasmapheresis if sx of hyperviscosity

Rx rituximab ± nucleoside analogues (fludarabine, cladribine) or alkylating agent (chlorambucil, cyclophosphamide)

4. AL Amyloidosis

Primary amyloidosis (AL) is associated with an underlying clonal plasma cell disorder making an abnormal light chain protein with deposition in multiple organ systems.

Diagnosis

Histologic confirmation is necessary with a fat pad and bone marrow bx with Congo red staining to establish a diagnosis.

If a noninvasive fat pad bx does not establish a diagnosis, then bx of the affected organ may be needed.

H&P

Findings depend on organ system involvement: edema, fatigue, dyspnea, abd pain, dizziness, bleeding.

Macroglossia, periorbital ecchymoses (raccoon eyes), peripheral neuropathy, tendinopathy

Treatment

Melphalan and prednisone

F. Lymphoid Malignancies

1. Non-Hodgkin’s Lymphoma

This comprises a heterogeneous group of malignant neoplasms of the lymphoreticular system.

Diagnosis

H&P

Asymptomatic lymphadenopathy

Pruritus, fever, night sweats, wt loss less common than in Hodgkin’s disease

Hepatomegaly and splenomegaly

One third of NHL originates extranodally. Involvement of extranodal sites can result in unusual presentations (e.g., GI tract involvement can simulate PUD).

NHL cases associated w/HIV infection occur predominantly in the brain.

Labs

Labs: CBC, ESR, U/A, LDH, BUN, Cr, serum Ca, uric acid, LFTs, SPEP, HIV, Hep C and Hep B screen. β₂-microglobulin levels should be obtained initially (prognostic value) and serially in pts w/low-grade lymphomas (useful to monitor therapeutic response of the tumor).

Bone marrow (aspirate and full bone core bx)

Imaging

CXR (PA and lateral)

CT scan of abd and pelvis; CT scan of chest if CXR abnl

PET scan

Bone scan (particularly in pts w/histiocytic lymphoma)

Classification and staging

The WHO classification is described in Table 7-3. NHLs are also subdivided in 3 major groups: low grade (indolent), intermediate (aggressive), and high grade (highly aggressive).

Staging: The Ann Arbor classification is used to stage NHLs (Table 7-4). Histopathology has greater therapeutic implications in NHL than in Hodgkin’s disease.

TABLE 7-3

WHO Classification of Non-Hodgkin’s Lymphoma

B-Cell Lymphomas
Precursor B-cell lymphoma	Precursor B lymphoblastic lymphoma/leukemia
Mature B-cell lymphoma	Chronic lymphocytic leukemia/small lymphocytic lymphoma Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Burkitt’s lymphoma/leukemia
T/NK-Cell Lymphomas
Precursor T-cell lymphoma	Precursor T-cell lymphoblastic leukemia/lymphoma Blastic NK-cell lymphoma
Mature T/NK-cell lymphoma	Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary’s syndrome Primary cutaneous anaplastic large-cell lymphoma Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma

Adapted from Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization Classification of Tumors: Pathology and Genetics. Tumors of Hematopoietic and Lymphoid Tissues. Lyons, France, IARC Press, 2001.

Treatment and Prognosis

Table 7-5 describes combination chemoRx regimens for NHL. Prognostic indicators are described in Table 7-6.

2. Chronic Lymphocytic Leukemia (CLL)

Definition

Lymphoproliferative disorder characterized by proliferation and accumulation of mature-appearing neoplastic lymphocytes

TABLE 7-4

Ann Arbor Staging System for Lymphomas

Stage^∗	Cotswold Modification of Ann Arbor Classification
I	Involvement of a single lymph node region or lymphoid structure
II	Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is considered a single site, whereas the hilar lymph nodes are considered bilaterally); the number of anatomic sites should be indicated by a subscript (e.g., II₃)
III	Involvement of lymph node regions on both sides of the diaphragm: III₁ (with or without involvement of splenic hilar, celiac, or portal nodes) and III₂ (with involvement of para-aortic, iliac, and mesenteric nodes)
IV	Involvement of one or more extranodal sites in addition to a site for which the designation E has been used

^∗ All cases are subclassified to indicate the absence (A) or presence (B) of the systemic symptoms of significant fever (>38.0° C [100.4° F]), night sweats, and unexplained weight loss exceeding 10% of normal body weight within the previous 6 mo. The clinical stage (CS) denotes the stage as determined by all diagnostic examinations and a single diagnostic bx only. In the Ann Arbor classification, the term pathologic stage (PS) is used if a second bx of any kind has been obtained, whether negative or positive. In the Cotswold modification, the PS is determined by laparotomy; X designates bulky disease (widening of the mediastinum by more than one third or the presence of a nodal mass >10 cm), and E designates involvement of a single extranodal site that is contiguous or proximal to the known nodal site.

From Hoffman R, Benz EJ, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice, 5th ed. New York, Churchill Livingstone, 2009.

TABLE 7-5

Combination Chemotherapy Regimens for Non-Hodgkin’s Lymphoma

Regimen	Dose	Days of Administration	Frequency
CHOP-R			Every 21 days
Cyclophosphamide	750 mg/m² IV	1
Doxorubicin	50 mg/m² IV	1
Vincristine	1.4 mg/m² IV^∗	1
Prednisone, fixed dose	100 mg PO	1-5
Rituximab	375 mg/m² IV	1
CVP-R			Every 21 days
Cyclophosphamide	1,000 mg/m² IV	1
Vincristine	1.4 mg/m² IV^∗	1
Prednisone, fixed dose	100 mg PO	1-5
Rituximab	375 mg/m² IV	1
FCR			Every 28 days
Fludarabine	25 mg/m² IV	1-3
Cyclophosphamide	250 mg/m² IV	1-3
Rituximab	375 mg/m²	1

^∗ Vincristine dose often capped at 2 mg total.

From Goldman L, Schafer AI (eds): Goldman’s Cecil Medicine, 24th ed. Philadelphia, Saunders, 2012.

TABLE 7-6

International Prognostic Index for Aggressive Lymphomas^∗

Risk Group	IPI Score	CR Rate (%)	5-Yr Overall Survival (%)
Low	0, 1	87	73
Low intermediate	2	67	51
High intermediate	3	55	43
High	4, 5	44	26

CR, Complete response; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index.

^∗ One point is given for the presence of each of the following characteristics: age >60 yr, elevated serum LDH level, ECOG performance status ≥2, Ann Arbor stage III or IV, and >2 extranodal sites.

From Hoffman R, Benz EJ, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice, 5th ed. New York, Churchill Livingstone, 2009.

Diagnosis

H&P

Clinical presentation varies according to stage of the disease. Some pts come to medical attention because of weakness and fatigue (secondary to anemia) or lymphadenopathy. Many cases are diagnosed on the basis of lab results obtained after routine PE.

Labs

Proliferative lymphocytosis (>15,000/dL) of well-differentiated lymphocytes is the hallmark of CLL.

There is monotonous replacement of the bone marrow by small lymphocytes (marrow contains >30% of well-differentiated lymphocytes).

Staging (Table 7-7)

The pt’s prognosis is related to the clinical stage (e.g., the average survival in pts in Rai stage 0 is >120 mo; whereas for Rai stage 4 it is approx 30 mo) and several other adverse factors such as high serum β₂-microglobulin levels (>3.5 mg/L),+ ZAP 70, cytogenetic studies unmutated heavy gene), lymphocyte doubling time (<12 mo), and mutational gene assessment (presence del [17p13][p53]). Overall 5-yr survival is 60%.

TABLE 7-7

Rai Staging Systems in Chronic Lymphocytic Leukemia

Lymphocytosis		Lymphadenopathy	Hepatomegaly or Splenomegaly	Hemoglobin (g/dL)	Platelets × 10³/μL
Rai Stage
0	+	−	−	≥11	≥100
I	+	+	−	≥11	≥100
II	+	±	+	≥11	≥100
III	+	±	±	<11	≥100
IV	+	±	±	Any	<100

From Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia, Saunders, 2000.

Treatment

Rai stage 0: observation

Symptomatic pts in Rai stages I and II: fludarabine; local irradiation for isolated symptomatic lymphadenopathy and lymph nodes that interfere w/vital organs

Rai stages III and IV: rituximab + combination chemo

3. Hairy Cell Leukemia

Definition

Lymphoid neoplasm characterized by the proliferation of mature B cells w/prominent cytoplasmic projections (hairs)

Diagnosis

H&P

PE: splenomegaly (>90% of cases) secondary to tumor cell infiltration

Labs

CBC: pancytopenia involving erythrocytes, neutrophils, and Plts

Peripheral smear: hairy cells (5%-80% of cells in the peripheral blood). The cytoplasmic projections on the cells are redundant plasma membranes.

Leukemic cells stain + for tartrate-resistant acid phosphatase (TRAP)

Bone marrow may result in a “dry tap” (because of marrow reticulin).

Treatment

Cladribine

4. Hodgkin’s Lymphoma

This malignant disorder of lymphoreticular origin is characterized histologically by the presence of multinucleated giant cells (Reed-Sternberg cells) usually originating from B lymphocytes in germinal centers of lymphoid tissue.

Diagnosis

H&P

Palpable lymphadenopathy, generally painless, is the most common presenting sx.

The most common site of involvement is the neck region.

Fever and night sweats: Fever in a cyclical pattern (days or weeks of fever alternating w/afebrile periods) is known as Pel-Epstein fever.

Wt loss, generalized malaise

Persistent, nonproductive cough

Pruritus

Labs

Dx is confirmed w/lymph node bx.

Staging and Prognostic Risk Factors

Detailed H&P (w/documentation of “B sx”)

Surgical bx

Labs (CBC, ESR, BUN, Cr, alk phos, LFTs, alb, LDH, uric acid)

CT scan of chest, abd, pelvis, neck

18-FDG PET scan

Staging for Hodgkin’s disease follows the Ann Arbor staging classification (see Table 7-4).

Prognostic risk factors are male sex, age >45 yr, leukocyte count >15,000/μL, serum albumin <4 g/dL, Hgb <10.5 g/dL.

Treatment

Rx is determined by disease stage and not histology (same Rx for all cell types).

Stage I and II: radiation Rx alone unless a large mediastinal mass is present (mediastinal-to-thoracic ratio ≥1.3); in the latter case, a combination of chemoRx (doxorubicin + bleomycin + vincristine + dacarbazine [ABVD]) and RT may be used.

Stage IB or IIB: RT is often used, although ABVD chemo is performed in many centers.

Stage IIIA: Rx is controversial. It varies w/the anatomic substage after splenectomy.

III₁A and minimum splenic involvement: RT alone may be adequate.

III₂ or III₁A w/extensive splenic involvement: There is disagreement whether ABVD chemo alone or a combination of chemo and RT is the preferred Rx modality.

IIIB and IVB: chemoRx w/ or w/o adjuvant RT

BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated by some as the new standard for treatment of advanced Hodgkin’s lymphoma in place of ABVD, but the long-term clinical outcome did not differ significantly between the two regimens. In addition, with the use of the escalated BEACOPP regimen, the rate of complications is higher (3% treatment-related death, 20% rate of hospitalization, and 3% rate of secondary leukemia). Thus, if the goal is cure with the least overall toxic effects, it is best to favor ABVD Rx, reserving rescue Rx with high-dose chemoRx and autologous HSCT for pts in whom the primary treatment fails.

Monoclonal Ab Rx: SGN-30 and MDX-060 and rituximab have shown promising results.

G. Bleeding Disorders

1. Evaluation of Suspected Bleeding Disorder

See Figure 7-4.

2. Hemophilia

This hereditary bleeding disorder is caused by low factor VIII coagulant activity (hemophilia A) or low levels of factor IX coagulant activity (hemophilia B). Spontaneous acquisition of factor VIII inhibitors (acquired hemophilia) is rare.

Diagnosis

↑ PTT

↓ Factor VIII: C level distinguishes hemophilia A from other causes of ↑ PTT.

Nl factor VIII antigen, PT, fibrinogen level, and bleeding time

↓ Factor IX coagulant activity levels in pts w/hemophilia B

Coagulation factor activity measurement is useful to correlate w/disease severity: The nl range is 50 to 150 U/dL; 5 to 20 U/dL indicates mild disease, 2 to 5 U/dL indicates moderate disease, and <2 U/dL indicates severe disease w/spontaneous bleeding episodes.

Treatment

Hemophilia A

Plasma derived and recombinant factor VIII concentrates are effective in controlling spontaneous and traumatic hemorrhage in severe hemophilia. Recombinant factor VIII is w/o added human serum alb (↑ risk of transmission of infectious agents).

Desmopressin (causes release of factor VIII:C) may be used in preparation for minor surgical procedures in pts w/mild hemophilia.

Aminocaproic acid is used for persistent bleeding that is unresponsive to factor VIII concentrate or desmopressin.

Hemophilia B

Factor IX concentrates

3. Von Willebrand’s Disease (vWD)

This most common autosomal bleeding disorder (mild form: codominant, severe form: recessive) results from deficiency of vWF (type I, 85% of cases) or qualitative protein abnormality (type II, 15% cases). Type III is a rare autosomal recessive (severe deficiency of vWF) disorder.

FIGURE 7-4 Differential diagnosis of bleeding disorders. ∗In many labs, “bleeding time” is no longer available and has been replaced with PFA-100. (From Cluster JW, Rau, RE: The Harriet Lane Handbook, 18th ed. St. Louis, Mosby, 2009.)

Diagnosis

H&P

Hx mucocutaneous bleeding

Women (menorrhagia, postpartum hemorrhage)

Labs

↑ Bleeding time, PFA-100 assay

↓ vWF Ag <30 IU/dL (“low” vWF 30-50 IU/dL), ↓ vWF activity (measured by ristocetin cofactor assay)

↓ Factor VIII:C

vWF Type II A (absent ristocetin cofactor)

vWF Type II B (↑ ristocetin agglutination)

Treatment

Type 1 (mild) vWD: DDAVP

Types 2, 3 vWD: infusion vWF-containing factor VIII concentrate

4. Coagulopathy of Liver Disease

Liver disease = ↑ PT, APTT (TCT may also ↑) → coagulopathy, hypofibrinogenemia, dysfibrinogenemia, thrombocytopenia

Splenomegaly → thrombocytopenia (may be refractory to transfusion)

D-dimer clearance impaired, ↑ Plt consumption (analogous to DIC)

↑ INR but pt not autocoagulated and has ↑ risk of DVT

Rx: FFP + vitamin K (correct coagulopathy)

5. Disseminated Intravascular Coagulation (DIC)

This acquired thromboembolic disorder is characterized by generalized activation of the clotting mechanism → microangiopathic hemolysis and intravascular formation of fibrin → thrombotic occlusion of small and midsize vessels.

Etiology

Infections (e.g., gram(−) sepsis, RMSF, malaria, viral or fungal infection)

Obstetric complications (e.g., dead fetus, amniotic fluid embolism, toxemia, abruptio placentae, septic abortion, eclampsia)

Tissue trauma (e.g., burns, hypothermia-rewarming)

Neoplasms (e.g., adenocarcinomas [GI, prostate, lung, breast], acute promyelocytic leukemia)

Quinine, cocaine-induced rhabdo

Liver failure

Acute pancreatitis

Transfusion reactions

Respiratory distress syndrome

Other: SLE, vasculitis, aneurysms, polyarteritis, cavernous hemangiomas

Diagnosis

Peripheral blood smear generally shows RBC fragments (schistocytes) and ↓ Plt count.

Coagulation factors are consumed at a rate in excess of the capacity of the liver to synthesize them, and Plts are consumed in excess of the capacity of the bone marrow megakaryocytes to release them.

Diagnostic characteristics of DIC are ↑ PT, PTT, TT, fibrin split products, D-dimer; ↓ fibrinogen level, thrombocytopenia.

Coagulopathy secondary to DIC must be differentiated from that secondary to liver disease or vitamin K deficiency.

Vitamin K deficiency: ↑ PT and nl PTT, TT, Plt count, and fibrinogen level; PTT may be ↑ in severe cases.

Liver disease: ↑ PT and PTT; TT and fibrinogen are usually nl unless severe disease is present; Plts are usually nl unless splenomegaly is present.

Factors V and VIII are ↓ in DIC, but they are nl in liver disease w/coagulopathy.

Treatment

Correct and eliminate underlying cause (e.g., antimicrobial Rx for infection).

Replacement Rx w/FFP and Plt in pts w/significant hemorrhage:

• FFP 10 to 15 mL/kg can be given w/goal of normalizing INR.

• Plt transfusions are given when Plt count is <10,000 (or higher if major bleeding is present).

Cryoprecipitate 1 U/5 kg is reserved for hypofibrinogen states.

Antithrombin III Rx may be considered as a supportive therapeutic option in pts w/severe DIC. Its modest results and substantial cost are limiting factors.

Heparin Rx at a dose lower than that used in venous thrombosis (300-500 U/hr) may be useful in selected cases to neutralize thrombin (e.g., DIC associated w/acute promyelocytic leukemia, purpura fulminans, acral ischemia).

6. Vitamin K Deficiency

Vitamin K is required for generation of active factors II, VII, IX, and X.

Etiology

Malabsorption syndromes, liver disease, poor dietary intake, and hereditary combined deficiencies of the vitamin K–dependent proteins, including prothrombin, factor VII, factor IX, and factor X

Lab

↑ PT (INR) that corrects after a 1:1 mix w/nl pooled plasma

Treatment

Mild deficiency: PO vitamin K₁ 100 to 150 mg qd. INR begins to normalize after 12 hr and should normalize completely in 48 hr. Vitamin K can also be given SC (poorly absorbed in edematous pts) and IV (risk of anaphylaxis).

Severe deficiency and active bleeding or requiring invasive procedures: The administration of vitamin K should be preceded by the infusion of FFP.

H. Platelet Disorders

1. Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

In this autoimmune disorder, Ab-coated or immune complex–coated Plts are destroyed prematurely by the reticuloendothelial system, resulting in peripheral thrombocytopenia.

Etiology

Drugs commonly implicated: quinidine, heparin, abx (linezolid, vancomycin, sulfonamides, rifampin), Plt inhibitors (tirofiban, abciximab, eptifibatide), cimetidine, NSAIDs, thiazide diuretics, antirheumatic agents (gold salts, penicillamine), acetaminophen, and chemotherapeutic agents (cyclosporine, fludarabine, oxaliplatin)

Diagnosis

H&P

Children: generally present w/sudden onset of bruising and petechiae from severe thrombocytopenia

Adults: insidious presentation; dx often made on incidental routine labs

Petechiae, purpura, epistaxis, or heme(+) stool from GI bleeding in pts w/severe thrombocytopenia

Labs

CBC, Plt count, and peripheral smear: Plts are ↓ but nl or larger in size.

Direct assay for Plt-bound Ab (+ predictive value 80%-83%)

Additional labs: HIV, ANA, TSH, LFTs, bone marrow exam

Imaging

CT of abd in pts w/splenomegaly (r/o lymphoma)

Treatment

Asymptomatic pts w/Plts >30,000/mm³: observation

Pts w/neurologic sx, internal bleeding, or those undergoing emergency surgery: methylprednisolone 30 mg/kg/day IV plus IVIG (1 g/kg/day for 2-3 days) and infusion of Plts

Adults w/Plts <20,000/mm³ and those who have counts <50,000/mm³ and significant mucous membrane bleeding: prednisone 1 to 2 mg/kg qd, continued until the Plt count is normalized, then slowly tapered off

Adults w/severe thrombocytopenia or bleeding: high-dose Ig (IgG 0.4 g/kg/day IV, infused on 3-5 consecutive days) or high-dose parenteral glucocorticoids (methylprednisolone 30 mg/kg/day)

Rituximab: useful in ITP resistant to conventional Rx

Splenectomy: Consider in adults w/Plts <30,000/mm³ after 6 wk of medical Rx or after 6 mo if >20 mg of prednisone/day is required to maintain Plts >30,000/mm³.

Plt transfusion: only in case of life-threatening hemorrhage

Eltrombopag and romiplostim: Rx of chronic ITP refractory to corticosteroids, immunoglobulins, or splenectomy

2. Heparin-Induced Thrombocytopenia (HIT)

Immunologic drug reaction caused by Plt-activating IgG Abs that recognize complexes of Plt factor 4 (PF4) and heparin. It is associated w/venous or arterial thrombosis.

Diagnosis and Treatment

HIT usually develops within 5 to 10 days after heparin exposure. It may develop earlier (within 2 days) in pts w/previous exposure. It may also occur up to 3 wk after exposure to heparin secondary to high titers of Plt-activating IgG induced by heparin (delayed-onset HIT). Risk of HIT > with UFH then LMWH.

This dx should be differentiated from early, benign, transient thrombocytopenia that can occur w/heparin Rx. Factors favoring immune thrombocytopenia are as follows:

• ↓ in Plt count to <100,000/mm³ or >50% of baseline value

• The falling Plt count generally occurs after 5 days of heparin Rx or earlier if the pt had recent exposure to heparin.

• Screening can be performed w/ELISA HIT test, which detects the presence of all Ig classes (IgA, IgG, IgM) w/specificity for antigens present on a complex of PF4/heparin. The dx can be confirmed w/ELISA IgG-HIT test, which is more specific for type II HIT. The “4T score” in Table 7-8 can be used to determine probability of HIT and the treatment approach.

TABLE 7-8

A Diagnostic and Treatment Approach to Heparin-Induced Thrombocytopenia

Suspicion of HIT Based upon the “4 Ts”	Score	Pretest Probability Score Criteria
Suspicion of HIT Based upon the “4 Ts”	Score	2	1	0
Thrombocytopenia		Nadir 20-100, or >50% platelet fall	Nadir 10-19, or 30%-50% platelet fall	Nadir <10, or <30% platelet fall
Timing of onset of platelet fall		Day 5-10, or ≤ day 1 with recent heparin^∗	> Day 10 or timing unclear (but fits with HIT)	≤ Day 1 (no recent heparin)
Thrombosis or other sequelae		Proven thrombosis, skin necrosis, or ASR^†	Progressive, recurrent, or silent thrombosis; erythematous skin lesions	None
OTher cause of platelet fall		None evident	Possible	Definite
Total Pretest Probability Score		Periodic reassessment as new information can change pretest probability (e.g., positive blood cultures)

Total Pretest Probability Score
High	Moderate	Low
8 \| 7 \| 6	5 \|4	3 \| 2 \| 1 \| 0
Stop heparin^‡, give alternative nonheparin anticoagulant argatroban^¶ or lepirudin^# or danaparoid^∗∗ (or bivalirudin^†† or fondaparinux^‡‡)	Physician judgment	Continue (LMW) heparin
Positive test for HIT antibodies: continue nonheparin anticoagulant until platelet count recovery	HIT test	Negative test for HIT antibodies: consider continuing or switching back to (LMW) heparin^##
Thrombosis^∗∗∗ If HIT, continue nonheparin anticoagulant until platelet count recovery, then cautious coumarin overlap^¶¶	Imaging studies for lower limb DVT^†††	No thrombosis If HIT, consider anticoagulating until platelet count recovery, even if no thrombosis apparent (± coumarin^¶¶)

^∗ Recent heparin indicates exposure within the past 30 days (2 points) or past 30-100 days (1 point).

^† ASR, acute systemic reaction following IV heparin bolus (see Table 7-4).

^‡ Stop all heparin, including catheter “flushes” and possibly heparin-coated catheters.

^¶ Argatroban: approved (U.S., Canada) for isolated HIT and HIT complicated by thrombosis (2 μg/kg/min IV, adjusted to 1.5-3.0× patient’s baseline APTT or the mean of the laboratory normal range); reduce dose for hepatobiliary compromise: may increase INR more than the other direct thrombin inhibitors, thus requiring care in managing coumarin overlap (see footnote ^¶¶).

^# Lepirudin: approved (United States, Canada, European Union, elsewhere) for treatment of thrombosis complicating HIT (±0.4 mg/kg IV bolus, then 0.15 mg/kg/hr adjusted to 1.5-2.5× patient’s baseline APTT or mean of the laboratory normal range); used (off-label) also to treat isolated HIT (0.1 mg/kg/hr, adjusted by APTT); to avoid overdosing and anaphylaxis, it may be preferable to omit the bolus, and begin as IV infusion (except when facing life- or limb-threatening thrombosis); reduce dose for renal insufficiency.

^∗∗ Danaparoid: usual IV bolus, 2250 U (body weight 60-75 kg) followed by infusion (400 U/hr for 4 hr, then 300 U/hr for 4 hr, then 200 U/hr, adjusted by anti–factor Xa levels); this therapeutic-dose regimen is appropriate both for isolated HIT and for HIT complicated by thrombosis (although the dose is higher than approved in some jurisdictions); withdrawn from U.S. market (2002).

^†† Bivalirudin: no bolus, IV infusion 0.15 mg/kg/hr adjusted by APTT; limited experience (off-label).

^‡‡ Fondaparinux: dosing for HIT not established; limited experience (off-label).

^¶¶ Delay coumarin pending substantial platelet count recovery (at least >100, preferably >150); begin coumarin in low doses, with at least 4-5 day overlap, stopping alternative anticoagulant when INR therapeutic for 2 days and platelets recovered.

^## Depending on physician confidence in the laboratory’s ability to rule out HIT antibodies (usually, negative PF4-dependent enzyme immunoassay and/or washed platelet activation assay performed by an experienced laboratory).

^∗∗∗ Some thrombi may require special treatment (e.g., thrombectomy for large limb artery thrombosis).

^††† Routine ultrasound of lower limb veins recommended because many pts w/HIT have subclinical DVT.

Adapted from Warkentin TE, Aird WC, Rand JH: Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 497-519, 2003.

3. Thrombotic Thrombocytopenic Purpura (TTP)

Rare disorder characterized by thrombocytopenia (often accompanied by purpura) and microangiopathic hemolytic anemia; neurologic impairment, renal dysfunction, and fever may also be present.

Etiology

It is caused in some pts by an acquired deficiency of a circulating metalloproteinase and can also be caused in very rare cases by a hereditary deficiency of ADAMTS13.

Many drugs, including clopidogrel, PCN, antineoplastic agents, OCPs, quinine, and ticlopidine, have been associated w/TTP.

Other precipitating causes include infectious agents, pregnancy, malignant neoplasms, allogeneic bone marrow transplantation, and neurologic disorders.

Diagnosis

H&P

Most pts present w/nonspecific constitutional sx (weakness, nausea, abd pain, vomiting).

Purpura (secondary to thrombocytopenia), jaundice, pallor (secondary to hemolysis), mucosal bleeding, fever

Fluctuating levels of consciousness (secondary to thrombotic occlusion of the cerebral vessels)

Renal failure and neurologic events are usually end-stage features.

Labs

Severe anemia and thrombocytopenia (Plt count <50,000 or >50% ↓ from previous count)

↑ BUN and Cr, ↑ reticulocyte count, indirect bili, LDH, ↓ haptoglobin

U/A: hematuria (red cells and red cell casts in urine sediment), proteinuria

Peripheral smear: severely fragmented RBCs (schistocytes); >4% RBC fragments in the peripheral blood

No laboratory evidence of DIC (nl FDP, fibrinogen)

The ADAMTS13 level is not necessary, and metalloproteinase deficiency need not be proved for dx of TTP.

Treatment

Discontinue potential offending agents.

Daily plasma exchange w/replacement of 1.0 to 1.5× the predicted plasma volume of the pt continued for ≥2 days after the Plt count returns to >150,000/cm³.

4. Hemolytic-Uremic Syndrome (HUS)

Definition

Syndrome characterized by nonimmune hemolytic anemia, thrombocytopenia, and severe renal failure secondary to endothelial damage by Shiga toxin–producing Escherichia coli serotype O157:H7 or Shigella species.

Diagnosis

H&P

Usually preceded by bloody diarrhea (90% of cases)

Labs

Anemia, thrombocytopenia, ↑ BUN, and creat

Peripheral smear: schistocytes, burr cells, and helmet cells

Stool cultures for E. coli O157:H7 + in >90% of cases

Treatment

Plasma exchange or infusion started within 24 hr after dx

Abx should be avoided

5. HELLP Syndrome

This variant of preeclampsia is the most frequently encountered microangiopathy of pregnancy. HELLP is an acronym for Hemolysis, Elevated Liver enzymes, and Low Platelet count. There are 3 classes:

Class 1: Plt 50,000/mm³

Class 2: Plt >50,000 to 100,000/mm³

Class 3: Plt >100,000/mm³

Diagnosis

H&P

RUQ pain, edema

Labs

Abnl peripheral smear w/schistocytes

↑ LFTs (ALT, AST), nl PT, PTT, low Plts

Treatment

Mg sulfate, BP control (hydralazine, labetalol)

Pregnancies 34 wk or class 1 HELLP → delivery, either vaginal or abd, within 24 hr is the goal.

Preterm fetus → corticosteroid Rx to enhance fetal lung maturation

I. Thrombotic Disorders

1. Hypercoagulable State

This inherited or acquired condition is associated w/risk of thrombosis.

Etiology (Table 7-9)

Inherited

Factor V Leiden (FVL) mutation

• Autosomal dominant mutation w/low penetrance

• Causes activated protein C resistance (APCR); 90% of APCR is caused by FVL mutation

• Most common genetic risk factor for venous thrombosis; accounts for thrombosis in 40%-50% of inherited cases

• OCP use in heterozygous carriers is associated w/an 8-fold ↑ risk of thrombosis compared w/noncarriers and a 35-fold ↑ risk of thrombosis compared w/noncarriers not using OCP.

• Probably low risk of recurrent thrombotic events

• May be associated w/CVD in select high-risk subgroups

Prothrombin G20210A mutation (PGM)

• Autosomal dominant mutation w/↓ penetrance

• OCP use in heterozygous carriers is associated w/a 1 × 6↑ risk of thrombosis compared w/noncarriers not using OCP.

• Probably low risk of recurrent thrombotic events

• May be associated w/CVD in select high-risk subgroups and young pts w/ischemic strokes

Protein C, protein S, antithrombin deficiency

• Autosomal dominant inheritance; many mutations identified for each of these conditions

• ↓ Level or abnl function

• First episode of thrombosis usually in young adults

• ↑ Risk of recurrent thrombosis

Protein C and protein S

• Lifetime risk of thromboembolic event up to 50%

• Homozygous condition very rare, usually associated w/lethal thrombosis in infancy

• Associated w/warfarin-induced skin necrosis, which occurs secondary to depletion of vitamin K–dependent anticoagulant factors sooner than procoagulant factors in the first few days of Rx

Antithrombin deficiency (ATD)

• Most thrombogenic of the identified inherited factors; lifetime risk of thromboembolic event up to 70%

• Homozygous condition very rare, probably not compatible w/nl fetal development

TABLE 7-9

Hypercoagulable Conditions

	Prevalence in General Population (%)	Prevalence in Population with Thrombosis (%)	A/V Events	Relative Risk of Thrombosis
FVL mutation	5% of whites; rare in nonwhites	12%-40%	V	Heterozygous: 3-7 Homozygous: 80
Prothrombin G20210A mutation	3% of whites; rare in nonwhites	6%-18%	V	3
AT deficiency	0.02%	1%-3%	V	20-50
PC deficiency	0.2%-0.4%	3%-5%	V	7-15
PS deficiency	0.03%-0.1%	1%-5%	V	5-11
Antiphospholipid antibody syndrome	1%-2%	5%-21%	V + A	2-11
Hyperhomocysteinemia	5%-7%	10%	V + A	3
Elevated factor VIII level	11%	25%		5

A, Arterial; AT, antithrombin; FVL, factor V Leiden; PC, protein C; PS, protein; V, venous.

From Ferri F: Ferri’s Clinical Advisor 2010. Philadelphia, Mosby, 2010.

• Rarely, arterial thrombosis can occur.

• Recurrent thrombotic events reported in up to 60% of pts

• Can cause heparin resistance

↑ Factor VIII level

• May be an important risk factor for thrombosis in African American populations

• Risk of recurrent thrombosis

• Genetic etiology suspected but not yet identified

Other possible causes: dysfibrinogenemias, thrombin activatable fibrinolysis inhibitor, plasminogen deficiency, factor IX and factor XI levels

Acquired

APS

• Most common cause of acquired thrombophilia

• Can manifest as arterial or venous thrombosis, recurrent pregnancy loss, and adverse pregnancy outcomes

• Thromboembolic events in up to 30% of pts; high risk of recurrent thrombosis (up to 70% reported)

• See the next section, “Antiphospholipid Syndrome,” for more information.

Hyperhomocysteinemia

• Can be inherited (most commonly an autosomal recessive mutation in methylene tetrahydrofolate reductase gene) but more often secondary to poor dietary intake. Deficiency of folate, vitamin B₆, or vitamin B₁₂ accounts for two thirds of cases.

• May be associated w/VTE, atherosclerotic disease (CV, cerebrovascular, and peripheral vascular), and possibly adverse pregnancy outcomes

Conditions associated w/ risk of thrombosis

• Prior thrombosis

• Trauma

• Chronic medical illness: CHF, DM, obesity, nephrotic syndrome, IBD, PNH, HUS/TTP, DIC, sickle cell anemia

• Pregnancy (6× risk of thrombosis compared w/nonpregnant women), post partum, OCP (3-5× risk of thrombosis w/use, risk w/third-generation OCP), HRT (2× risk of thrombosis w/use), tamoxifen, raloxifene

• Immobilization, travel

• Surgery (especially orthopedic), central venous catheters

• Hyperviscosity syndromes

• Myeloproliferative disorders

• Malignancy: disease or Rx related

• HIT and thrombosis

• Cigarette smoking

• IV drug use

Thrombophilia testing

• AT, protein C, protein S, and fibrinogen levels are not accurate during acute thrombotic event and should be obtained later than 4 wk post anticoagulation Rx discontinuation.

• Screening for FVL and PGM can be performed anytime.

• Testing criteria should target the following higher risk groups: age ≤40 yr, idiopathic thromboembolism, + family hx (first-degree relative), thromboembolism of unusual sites, pts with warfarin skin necrosis (↑ risk protein C deficiency), pts planning future pregnancies, very young pts with purpura fulminans.

2. Antiphospholipid Syndrome

This syndrome is characterized by arterial or venous thrombosis or pregnancy loss and the presence of antiphospholipid Abs (APL).

The syndrome is referred to as “primary APS” when it occurs alone and as “secondary APS” in association w/SLE, other rheumatic disorders, or certain infections or medications. “Catastrophic APS” is APS + disseminated microvascular thrombosis + multiorgan failure.

Diagnosis

APS Abs can be detected transiently in up to 5% of asymptomatic adults. Diagnostic criteria of APS include at least one of the following clinical criteria and at least one of the following lab criteria:

Clinical Features

Venous, arterial, or small-vessel thrombosis or

Morbidity w/pregnancy (fetal death at >10 wk gestation; or premature births before 34 wk gestation secondary to eclampsia, preeclampsia, or severe placental insufficiency; or three or more unexplained consecutive spontaneous abortions <10 wk gestation)

Labs

Anticardiolipin Ab (IgG or IgM ACL in medium or high titers) or

β2-glycoprotein I Ab (IgG or IgM ACL in high titers) or lupus anticoagulant found on >2 occasions, at least 12 wk apart

Treatment

+ APL w/ venous thrombosis: initial anticoagulation w/heparin, then lifelong warfarin Rx, INR 2.0 to 3.0. Consider higher target INR (3-4) in pts with recurrent thromboembolism on warfarin.

+ APL w/arterial thrombosis

• Cerebral arterial thrombosis: ASA 325 mg qd or warfarin

• Noncerebral arterial thrombosis: warfarin

Catastrophic APS: Combination of anticoagulation, corticosteroids, and IVIG or plasma exchange

Prophylaxis for asymptomatic pts w/+ APL w/o previous thrombosis:

• No routine prophylaxis is recommended.

• Questionable whether ASA 81 mg qd is effective

• Antithrombotic prophylaxis for major surgery, prolonged immobilization, and pregnancy

Note on warfarin or UFH monitoring:

• In pts with APS Ab that artificially ↑ PT/INR, when using warfarin, monitor INR by measuring chromogenic factor X levels.

• In pts with APS ab that ↑ APTT, when using UFH, use anti-Xa assay to monitor UFH or change over to LMWH.

3. Venous Thromboembolism (DVT)

Presence of thrombi in the deep veins of the extremities or pelvis

Diagnosis

H&P

Pain and swelling of the affected extremity

In LE DVT: leg pain on dorsiflexion of the foot (Homans’ sign)

Exam may be unremarkable in early DVT.

Clinical prediction rules can be used to establish pretest probability of DVT. The Wells’ prediction rules for DVT are described in Table 7-10. These rules perform better in younger pts w/o h/o DVT and in those w/o comorbidities. In younger pts w/o associated comorbidities and a low pretest probability by Wells’ criteria and a (−) high-sensitivity D-dimer test result, the dx of DVT can be reasonably excluded.

Labs

Baseline PT (INR), APTT, and Plt count should be obtained on all pts before anticoagulation is started.

D-dimer assay by ELISA: DVT can be ruled out in pts who are clinically unlikely to have DVT and have a (−) D-dimer test result. D-dimer can also be combined w/U/S. The combination of a nl D-dimer w/a nl compression venous U/S is useful to exclude DVT and to eliminate the need for repeated U/S at 5 to 7 days. Figure 7-5 describes an algorithm for the Dx of DVT.

TABLE 7-10

Wells’ Clinical Assessment Model for the Pretest Probability of Lower Extremity DVT

	Score
Active cancer (treatment ongoing or within previous 6 mo or palliative)	1
Paralysis, paresis, or recent plaster immobilization of the lower extremities	1
Recently bedridden >3 days or major surgery within 4 wk	1
Localized tenderness along the distribution of the deep venous system	1
Entire leg swollen	1
Calf swelling >3 cm asymptomatic side (measured 10 cm below tibial tuberosity)	1
Pitting edema confined to the symptomatic leg	1
Collateral superficial veins (nonvaricose)	1
Alternative diagnosis as likely as or greater than that of DVT	−2

In patients with symptoms in both legs, the more symptomatic leg is used. Pretest probability is calculated as the total score: high, >3; moderate, 1-2; low, <0.

From Crawford MH, DiMarco JP, Paulus WJ (eds): Cardiology, 2nd ed. St. Louis, Mosby, 2004.

Imaging

Compression U/S (see Figure 7-5)

FIGURE 7-5 Integrated strategy for diagnosis of DVT by using clinical probability assessment, measurement of D-dimer, and ultrasonography of legs as primary diagnostic tests. If clinical probability is low (i.e., DVT unlikely and D-dimer negative), no further investigations are required. If D-dimer is positive, proceed to ultrasonography of legs; then either treat or stop investigations. If clinical probability is high (i.e., DVT likely), D-dimer measurement need not be carried out; proceed directly to ultrasonography of legs. If negative, options are to repeat ultrasound in 1 week or in some cased to perform an ascending venogram. (From Vincent JL, Abraham E, Moore FA, et al [eds]: Textbook of Critical Care, 6th ed. Philadelphia, Saunders, 2011.)

Treatment

Rapidly acting anticoagulants (LMWH, fondaparinux, or UFH) followed by warfarin Rx ≥5 days and until therapeutic INR (2-3) has been achieved with warfarin. Discontinue parenteral Rx after INR ≥2 has been achieved for at least 24 hr. Alternatives to warfarin may include dabigatran (direct oral thrombin inhibitor) and rivaroxaban (oral factor Xa inhibitor).

Outpt treatment of DVT is appropriate for pts without prior DVT, thrombophilic conditions, or substantial comorbidity, but not for those who are pregnant or are likely not to adhere to Rx.

Exclusions from outpt treatment of DVT include pts with potential high complication risk (e.g., hemoglobin <7, Plt count <75,000, guaiac(+) stool, recent CVA or noncutaneous surgery, noncompliance).

Insertion of an IVC filter to prevent PE is recommended in pts with contraindications to anticoagulation (e.g., hemorrhagic stroke, active internal bleeding, pregnancy), HIT in a pt with an active VTT/PE, recurrent PE despite adequate anticoagulant Rx, emergency surgery in a pt with DVT, presence of free-floating ileofemoral, lower IVC thrombosis (incipient embolization), and chronic pulmonary (thromboembolic) HTN with limited pulmonary reserve.

Thrombolytic Rx (streptokinase) can be used in rare cases in pts with extensive iliofemoral venous thrombosis and a low risk of bleeding. There are concerns about hemorrhagic complications related to the large doses of thrombolytics required in systemic thrombolysis for DVT (2%-10% risk of major hemorrhagic complications).

Other treatment modalities for DVT include surgical thrombectomy and catheter-directed thrombolysis (CDT). Thromboreduction by surgical thrombectomy is effective but invasive and expensive. CDT is also invasive, carries a bleeding risk, and requires ICU admission.

Duration of Anticoagulant Rx

Rx duration varies w/the cause of DVT and risk factors.

Rx for 3 mo: pts w/reversible risk factors (low-risk group). ↑ D-dimer level measured after 3 mo of anticoagulation in pts w/unprovoked DVT or persistent thrombosis on duplex imaging should favor a longer duration of Rx.

Anticoagulation for 3 to 6 mo: pts w/idiopathic venous thrombosis or medical risk factors for DVT (intermediate-risk group)

Indefinite anticoagulation: pts w/DVT associated w/active cancer; pts w/inherited thrombophilia (e.g., deficiency of protein C or S Ab), APS, and recurrent episodes of idiopathic DVT (high-risk group)

Anticoagulation Monitoring

Warfarin: INR should be obtained daily when warfarin is initially administered concomitantly with rapidly acting anticoagulants. Its mean half-life is 32 to 40 hr; therefore, full impact of a dose change will take several days. Metabolism is also influenced by meds that affect cytochrome P-450 and dietary vitamin K content.

UFH: A heparin dosage regimen is described in Box 7-1.

BOX 7-1 Heparin Dosage Regimens

1. Weight-Based Nomogram

The initial dose is a bolus of 80 U/kg body weight, followed by an infusion starting at a rate of 18 U/kg/hr. The APTT is measured every 6 hr, and the heparin dose is adjusted as follows.

Measured Value	Adjustment
PTT <35 sec (<1.2 × control value)	80 U/kg as bolus, then infusion rate by 4 U/kg/hr
APTT 35-45 sec (1.2-1.5 × control value)	40 U/kg as bolus, then infusion rate by 2 U/kg/hr
APTT 46-70 sec (>1.5-2.3 × control value)	No change
APTT 71-90 sec (>2.3-3 × control value)	↓ Infusion rate by 2 U/kg/hr
APTT >90 sec (>3 × control value)	Stop infusion for 1 hr, then ↓ infusion rate by 3 U/kg/hr

2. 5,000-U Bolus Dose, Followed by 1,280 U/hr

APTT (sec)	Bolus (U)	Stop Infusion (min)	Rate of Change (mL/hr)	Repeat APTT
<50^∗	5,000	0	+3	In 6 hr
50-59	0	0	+3	In 6 hr
60-85	0	0	0	Next morning
85-95	0	0	−2	Next morning
96-120	0	30	−2	In 6 hr
>120	0	60	−4	In 6 hr

^∗ If the APTT is subtherapeutic despite a heparin dose of at least 1,440 U/hr (36 mL/hr) at any time during the first 48 hours of therapy, the response to an APTT of <50 sec is a bolus of 5,000 U and a rate increase of 5 mL/hr.

3. Intravenous Dose-Titration Nomogram for APTT

The starting dose is a 5,000-U bolus, followed by 40,000 U/24 hr (if the patient has a low risk of bleeding) or 30,000 U/24 hr (if there is a high risk of bleeding).

APTT (sec)	Intravenous Infusion^†		Additional Action
APTT (sec)	Rate of Change (mL/hr)	Change in Dose (U/24 hr)	Additional Action
≤45	+6	+5,760	Repeat APTT in 4-6 hr
46-54	+3	+2,880	Repeat APTT in 4-6 hr
55-85	0	0	None^‡
86-110	−3	−2,880	Stop heparin for 1 hr; repeat APTT 4-6 hr after restarting heparin Rx
>110	−6	−5,760	Stop heparin for 1 hr; repeat APTT 4-6 hr after restarting heparin Rx

^† A heparin sodium concentration of 20,000 U in 500 mL is equal to 40 U/mL.

^‡ During the first 24 hours, repeat the APTT in 4 to 6 hr. Thereafter, the APTT is determined once daily, unless the value is in the therapeutic range.

Note: 1 mL/hr = 40 U/hr.

Reprinted with permission from Ginsberg IS: Management of venous thromboembolism. N Engl J Med 335:1821, 1996.

LMWH/fondaparinux: No monitoring is needed but it is renally excreted; therefore, ↓ dose in renal insufficiency.

Dabigatran, rivaroxaban: No monitoring is necessary.

Anticoagulation Reversal

Warfarin: vitamin K, 10 mg IV over 1 hour

• Prothrombin complex concentrate 25 to 50 units/kg IV

• Recombinant human factor VIIa, 25 to 90 μg/kg IV

UFH: protamine 1 mg/100 U UFH, infused slowly (<5 mg/min)

LMWH: protamine 0.5 to 1 mg/1 mg enoxaparin or 100 IU dalteparin

Direct Thrombin Inhibitors

Activated prothrombin complex concentrates, 50 to 100 U/kg IV

Oral activated charcoal or hemodialysis for dabigatran

J. Oncologic Urgencies and Emergencies

1. Tumor Lysis Syndrome

Syndrome characterized by rapid development of ↑ uric acid, ↑ K⁺, ↑ PO⁻₄, and ↓ Ca²⁺ due to leukemic cell death secondary to chemoRx (often seen w/high-grade lymphoma, ALL, AML chemoRx)

Treatment

IV hydration with normal saline and administration of allopurinol to lower uric acid level

Pts w/ ↑↑ serum uric acid level may be treated w/recombinant urate oxidase (rasburicase) which converts uric acid to soluble allantoin with faster onset than allopurinol.

2. Superior Vena Cava Syndrome

Definition

This set of sx results when a mediastinal mass (lung cancer [80% of all cases] lymphoma [15%]) compresses the SVC or the veins that drain into it.

The pathophysiologic mechanism of the syndrome involves the pressure in the venous system draining into the SVC, thus producing edema of the head, neck, and UEs. Sx develop during a period of 2 wk in 30% of pts.

Diagnosis

H&P

Clinical presentation: dyspnea, chest pain, cough, dysphagia, syncope

PE: chest wall vein distention, neck vein distention, facial edema, UE swelling, cyanosis

Imaging

CXR

Chest CT scan or MRI

Venography: warranted only when an intervention (e.g., stent or surgery) is planned

Treatment

Management is guided by severity of sx and the underlying etiology.

Emergency RT is indicated in critical situations, such as respiratory failure or CNS signs associated w/ICP.

Rx of the underlying malignant disease: RadioRx, systemic/chemoRx

Percutaneous self-expandable stents can be placed under local anesthesia w/radiologic manipulation in selected pts to bypass the obstruction.

3. Brain Metastases

Epidemiology and Physical Findings

>50% of adult intracranial tumors

Headache 40%-50% (if posterior fossa mets, may result in obstructive hydrocephalus)

• Cognitive dysfunction (30%-45%)

• Seizures/hemiparesis (30%-40%)

• Acute CVA (5%-10%)

20% brain mets dx synchronously or before primary tumor found

Imaging and Labs

LP contraindicated because of ↑ ICP

Brain bx necessary if unknown primary tumor

MRI with/without contrast = imaging study of choice

MRI spectroscopy and PET used to delineate tumor, nontumor, radiation necrosis

Treatment

Steroids used to ↓ peritumoral edema and ↑ ICP

Pts with no hx seizure, prophylaxis not necessary

Anticoagulants to prevent venous thromboembolic disease

Whole brain radiation and stereotactic radiosurgery (SRS) for chronic cases

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