Neutropenia: decreased in absolute numbers of neutrophils (normal neutrophil count = 2,500-7,000/mm³; serious infections may occur if << 500/mm³)

Lymphopenia

• Decrease in number of lymphocytes (normal = 1,000 – 4,000/mm³ in adults and up to 8,000/mm³ in kids [their immune systems are still developing])

• Causes: bacterial sepsis, active TB, uremia, lymphomas (especially Hodgkin’s disease), autoimmune syndromes, immunologic deficiency syndromes, chemo agents and glucocorticoids, and malnutrition

• Lymphopenia + neutrophilic leukocytosis + increased WBC = bacterial sepsis

Inadequate or ineffective granulopoiesis from

• Aplastic anemia

• Infiltrative marrow d/o like mets

• Myelosuppressive drugs (including chemo)

• Idiosyncratic drug reactions

• Megaloblastic anemia

• Myelodysplastic syndromes

• Congenital neutropenias such as Kostmann syndrome

Accelerated neutrophil removal and destruction

• Immunologic d/o such as Felty’s syndrome (rheumatoid arthritis with splenomegaly [due to sequestration of neutrophils in there], neutropenia, and leg ulcers)

• Hypersplenism with splenic sequestration

Decreased production and increased destruction

• Drug effects including sulfas and chloramphenicol

• Viral infections

• Overwhelming sepsis

Neutrophilia (granulocytic leukocytosis; > 8,000/mm³)

Eosinophilia (eosinophilic leukocytosis; > 500/mm³)

Basophilia (> 100/mm³)

Monocytosis (> 1,000/mm³)

Lymphocytosis (> 4,000/mm³ in adults and > 8,000/mm³ in kids)

Granulocytic leukocytosis (neutrophilia)

• Bacterial infection with left shift and reactive changes, including toxic granulation, cytoplasmic vacuolization, and Dohle bodies

  • A left shift indicates that there are neutrophils in circulation that are less mature than bands

  • Toxic granulation is the appearance of coarse, purple cytoplasmic granules; this is a sign of bacterial infection

  • Cytoplasmic (toxic) vacuolization appear as holes in the cytoplasm and are very associated with bacterial sepsis

  • Dohle bodies look like little blue lakes…they are patches of dilated ER

  • If there is neutrophilia without reactive changes there is not a bacterial infection; reactive changes are very often associated with bacterial infection

• Physiologic stress leukocytosis (NE leads to neutrophil demargination)

• Leukemoid reaction

  • Extreme leukocytosis with immature granulocytes stimulating leukemia

  • Differential includes overwhelming infection and chronic granulocytic leukemia

• Leukoerythroblastosis – circulating granulocyte precursors and nucleated RBCs

Eosinophilic leukocytosis (eosinophilia)

• Allergic d/o (including asthma and hay fever)

• Allergic drug reactions

• Parasitic infections

• Skin diseases including pemphigus, eczema, and dermatitis herpetiformis

• Eosinophilic enteropathies including eosinophilic gastritis

• Idiopathic hypereosinophilic syndromes including Loeffler’s

• CA of the lung, stomach, pancreas, ovaries, or uterus

• Collagen vascular disease (e.g., SLE)

Lymphocytosis

• Chronic inflammation

• Viral infections including hepatitis, CMV, and EBV (very common cause)

Monocytosis

• Chronic infections including TB, bacterial endocarditis, brucellosis, malaria, and rickettsiosis

• Chronic inflammation as seen with collagen vascular diseases and inflammatory bowel disease

• Myelodysplastic syndromes

Neutrophils

• Toxic granulations: coarse, purple cytoplasmic granules that are a sign of a bacterial infection

• Toxic vacuolization: holes in the cytoplasm associated with bacterial sepsis

• Dohle bodies: little blue lakes of dilated ER

• All are associated with bacterial infection

Lymphocytes – transformed variant/atypical lymphocytes

• See a lot of lymphocytes, but they look different than those of a leukemia because the cells are heterogenous, not homogenous

• Often associated with viral infection (e.g., EBV), but it’s really only a nonspecific reaction to antigenic stimulation as seen with drug hypersensitivity, TB, fungal infections, and stress

• If platelets are normal suspect infection; if they’re low it may be a malignancy

Monocytes – cytoplasmic basophilia and vacuolization

• Irregular nuclear contours and cytoplasmic vacuoles in a basophilic cytoplasm

• Lots of cytoplasmic vacuoles

Left shift means the appearance of granulocytes that are less mature than bands; this is associated with bacterial infection

Leukoerythroblastosis is the appearance of circulating granulocyte precursors and nucleated RBCs

CML is associated with splenomegaly

Basophilia is associated with CML

CML is associated with a decreased leukocyte alkaline phosphatase score, reactive processes should have an increased LAP score (LAP is associated with neutrophils ready to kill things)

CML is associated with Ph¹

Lymphadenitis is inflammation of lymph nodes

• See nodal enlargement with edema, follicular hyperplasia, and germinal center proliferation

• The follicular centers show lots of mitotic figures (virgin B cells undergoing lymphoid transformation), “tingible body macrophages” containing cellular debris (seen in cells eating Ag to present to differentiating B cells), and maybe necrotic abscess formation (acute necrotizing lymphadenitis)

• Neutrophils may be seen around the follicles and within the sinuses, especially with abscess formation

• Affected nodes become tender due to capsular distension (nodes will feel squishy and there will be local hyperemia if the process is from infection…this is not true with CA)

• Draining sinuses may form with fungal infections…these drain necrotic node debris out onto the skin

• Causes

  • Commonly seen in nodes draining areas of bacterial infection

  • Foreign body reactions

  • IV drug users may have lymphadenopathy in the limb they inject into (foreign bodies?)

  • Mesenteric lymphadenitis (may mimic acute appendicitis; from Yersinia enteritis)

  • Generalized lymphadenopathy seen with viremia, septicemia

Antigenic stimulation of B cells

Germinal centers increase in their size and number and vary in their size and shape

Causes

• Chronic bacterial infection

• Rheumatoid arthritis

• Syphilis

• Early stages of HIV infection

From antigenic stimulation of T cells

Follicles may be pushed out of the way or may even become atrophic

Causes

• Viral infections such as Herpes zooster and EBV

• Vaccination reactions

• Skin disease (dermatopathic lymphadenopathy)

• Collagen vascular diseases

• Drug reactions

Distension and prominence of lymphatic sinusoids with proliferation of epithelioid histiocytes (hyperplasia of histiocytes in order to deal with large amounts of Ag entering the node)

Frequently found in regional nodes draining a site of CA

Toxoplasmosis

• Commonly seen in cervical lymph nodes

• See aggregates of epithelioid histiocytes in the interfollicular areas

Kawasaki’s disease

• Mucocutaneous/lymph node syndrome

• Affected children develop conjunctivitis, erythema of the oral mucosa, an erythematous desquamative rash on the palms and soles (only RMSF and Hand/Foot/Mouth disease also produce a rash on the palms and soles), inflammation and infarction of the coronary vessels, and cervical node enlargement

• Etiology unknown

• Nodes show microthrombi and multifocal necrosis

Caseating granulomas, think TB and brucellosis

Non-caseating granulomas, think fungi and sarcoidosis (the latter of which may be associated with Langerhans giant cells)

Stellate granulomata

• Clusters of histiocytes that have radiating spicules coming out of them

• Seen with cat scratch F, lymphogranuloma venereum, and tularemia

Patient may notice splenomegaly as a dragging sensation in the LUQ and may notice early satiety

Storage function of spleen may become exaggerated (hypersplenism), leading to anemia, leukopenia, and thrombocytopenia (can be corrected with a splenectomy)

Spleen pathology

• Nonspecific acute splenitis

  • May occur with any blood-borne infection

  • Parenchyma is soft and there is acute congestion (hyperemia) of the red pulp

  • Diffuse increase in neutrophils may lead to abscess formation

  • May have foci of necrosis

• Congestive splenomegaly

  • Blood isn’t leaving the spleen, leading to capsular and parenchymal fibrosis and hemorrhage

  • Causes

    • Systemic venous congestion from RSHF or cor pulmonal following LSHF (size usually < 500 grams)

    • Cirrhosis and resultant portal HTN (can lead to massive splenomegaly)

    • Thrombosis or compression of the extrahepatic portal vein which may be associated with intrahepatic obstructive disease, vascular inflammation, or neoplasms

• Splenic infarcts

  • From occlusion of splenic artery or its branches

  • Usually from cardiac emboli; septic infarcts may arise from infective endocarditis of left-sided heart valves

  • Also seen in early stages of sickle cell anemia, with progression to total infarction (autosplenectomy)

• Splenic neoplasms

  • Primary or secondary involvement by lymphoma or leukemia and metastatic carcinomas are most common

  • Primary neoplasms are rare and include fibromas, osteomas, chondromas, lymphangiomas, and hemangiomas

• Congenital anomalies (unusual that spleen is the only anomaly)

  • Hypoplasia

  • Asplenia (usually associated with situs inversus and cardiac malformations

  • Accessory spleens (spleniculi)

    • Common; come from splenic trauma seeding peritoneum with lymphoid tissue

    • Only significant if all splenic tissue needs to be removed for therapeutic reasons, such as in hereditary spherocytosis, refractory thrombocytopenic purpura, and some causes of hypersplenism

• Rupture

  • May be traumatic or spontaneous; usually necessitates splenectomy from massive intraperitoneal hemorrhage

  • Spontaneous rupture associated with mono, malaria, typhoid F, leukemia, and acute splenitis

Anatomy

• Maximum weight of 20-50g achieved at puberty; after that it begins atrophy (severe stress may hasten this)

• It is pyramidal, bilobed, and well encapsulated with fibrous extensions of the capsule dividing the lobes into lobules; each lobule has an outer cortical layer surrounding a central medulla

• T cells and thymic epithelial cells are most of the cells there

• Epithelial cell whorls with keratinized cores form the Hassall corpuscles

• Macrophages, eosinophils, dendritic cells, B cells, and the occasional neutrophil may be present

Located in the anterior mediastinum

Thymic hypoplasia/aplasia

• DiGeorge syndrome

  • Comes from maldevelopment of the 3^rd and 4^th pharyngeal pouches

  • May be accompanied with

    • Hypoparathyroidism – developmental failure

    • Immunosuppression – deficient CMI with poor defense against viruses and fungi

    • Cardiac and other malformations

• SCIDS – deficient CMI and humoral immunities

Thymic cysts – incidental finding

Thymomas are tumors of thymic epithelial cells with a variable component of reactive thymic T cells

Benign: encapsulated with no significant cytologic atypia

Malignant: invasive and/or cytologically malignant; capable of local invasion and/or metastasis

Paraneoplastic syndromes

• These are how the thymomas will present

• Myasthenia gravis – weakness

• Grave’s disease – thyroid enlargement and exophthalmos

• Acquired hypogammaglobulinemia – T cell response causes decrease of Ig production

• Pure RBC aplasia

• Pernicious anemia

• Dermatomyositis/polymyositis

• Cushing syndrome

These are all pretty rare

Malignant lymphoma

Hodgkin’s disease

Germ cell tumors

Carcinoids

Thrombocytopenia = decreased platelet numbers

• Normal = 150,000 – 450,000/mm³

• Spontaneous bleeding if platelet count <>3

Thrombocytopenic bleeding usually seen with petechiae of skin and mucus membranes

Most common cause in the face of normal bone marrow is idiopathic thrombocytopenic purpura

Thrombocytopenia is quite often a sign of early leukemia

Decreased platelet production

• Generalized bone marrow disease

  • Aplastic anemia

  • Marrow infiltration (myelophthisic)

• Selective impairment of platelet production

  • Drug-induced (EtOH, thiazides, cytotoxic drugs, etc)

  • Infections (childhood rubella, HIV)

• Ineffective megakaryopoiesis

  • Megaloblastic anemias

  • Myelodysplastic syndromes (similar to megaloblastic anemias but they are due to an acquired DNA abnormality)

  • Paroxysmal nocturnal hemoglobinuria

  • Inherited d/o (Wiskott-Aldrich syndrome, hereditary immunodeficiency with thrombocytopenia, eczema, and recurrent infections)

Decreased platelet survival

• Immunologic destruction

  • Autoimmune (ITP, SLE)

  • Isoimmune (alloimmune): post-transfusion (because platelets have Ags on them other than ABO) and neonatal

  • Drug-associated (quinine, quinidine, heparin, penicillins, sulfa compounds, thiazides, methyl dopa, heparin)

  • Infections (EBV, HIV, CMV)

• Increased consumption

  • DIC

  • Thrombotic microangiopathies (TTP, HUS)

  • Vascular abnormalities (giant hemangiomas, arteritis, etc)

  • Microangiopathic hemolysis

Sequestration (hypersplenism)

Dilutional thrombocytopenia with massive transfusion (should give 1 platelet transfusion for every 10 units of blood cells)

These diseases are also called nonthrombocytopenic purpuras because they aren’t associated with platelet abnormalities; they make petechial and purpuric hemorrhages on the skin and mucus membranes without a lot of bleeding

Platelet count, bleeding time, and other coagulation tests are usually normal unless DIC complicates the issue

Microbiological damage to the vessels (vasculitis)

• From bacteria: menigococcemia, sepsis from other bacteria, typhoid F, scarlet F, leptospirosis, diphtheria, TB

• Viruses like measles and small pox

• Rickettsial diseases like RMSF and typhus

• Protozoal diseases like malaria and toxoplasmosis

Drug reactions

• Often from Abs made to drugs and vascular deposition of immune complexes with production of hypersensitivity (leukocytoclastic = necrotic neutrophils around the blood vessels) vasculitis

• Examples

  • Atropine

  • Quinine

  • Phenacetin

  • Aspirin

  • Coumarin

D/o of collagen production lead to decreased vessel support

• Inherited

  • Ehlers-Danlos syndrome

  • Osteogenesis imperfecta

  • Pseudoxanthoma elasticum

• Acquired

  • Scurvy

  • Corticosteroid purpura (protein wasting)

  • Cushing’s syndrome (protein wasting)

  • Senile purpura (atrophy of collagen)

Henoch-Schonlein purpura

• Systemic hypersensitivity reaction of unknown cause with vascular deposition of immune complexes

• The purpuric rash is seen with colicky pain, polyarthralgia, and acute GN

• A barium enema will show a “thumbprint” sign from filling defects of the colon due to bleeding into and edema of the bowel (impinges on lumen)

Hereditary hemorrhagic telangiectasis

• AD d/o

• Associated with dilated, tortuous, thin walled blood vessels

Amyloidosis

• Primary or secondary lymphoproliferative syndrome

• Amyloid infiltration of blood vessel walls weaken them and cause mucocutaneous petechiae

Abs are against platelet membrane glycoproteins; their binding encourages phagocytic destruction

Spleen is thought to make Abs and be place where the platelets are destroyed, but splenomegaly and lymphadeopathy are rarely seen

In the marrow, megakaryocytic hyperplasia is seen, and this is reflected in the blood by larger than normal platelets

Bleeding tendency and prolongation of bleeding time <> (platelet count usually < 5,000/mm³)

Acute: self-limited, abrupt onset in kids following viral infections (give steroids in severe cases)

Chronic

• Thrombocytopenia there for > 6 months

• Platelet-bound Ig (direct anti-platelet Ab) present in 90% of patients

• Mostly seen in adults (mostly repro age women; babies born to a woman with ITP will be transiently thrombocytopenic)

• May occur with another autoimmune d/o or lymphoproliferative syndrome (such as lymphocytic leukemias or lymphomas)

• Treatment includes immunosuppression, plasmapheresis, and splenectomy if refractory

Mediated by Abs against a specific platelet Ag (e.g., Duzo, PL, Bak)

Neonatal

• Mom exposed to a fetal platelet Ag she doesn’t have

• IgG anti-fetal platelet Abs cross the placenta and destroy the fetus’ platelets

Post-transfusional

• This is an anamnestic response to previous sensitization (maybe from transfusion, maybe from pregnancy) to certain platelet Ags that the patient doesn’t have

• When given a transfusion, platelets that have said Ag will be coated with Ab and their survival will greatly decrease

Seen in 5% of adults getting unfractioned heparin; rare in those on LMWH

Associated with 2 kinds of thrombocytopenia

• Type I

  • More common variant; onset rapidly after starting heparin therapy

  • This is modest in severity and is clinically insignificant

  • This is a result of the direct platelet aggregating effects of heparin

• Type II

  • Much more severe; typically starts 5-14 days after starting heparin therapy

  • This is due to the production of circulating Abs to a heparin/platelet factor 4 complex

    • Abs bind to those complexes on platelets and endothelial cells resulting in platelet activation and endothelial damage

    • Systemic platelet aggregation leads to life-threatening venous and arterial thrombosis and infarction

People getting heparin therapy should always be watch for thrombocytopenia

Treatment involves stopping the unfractioned heparin and using LMWH or another anticoagulant

See impaired production and increased destruction

HIV kills megakaryocytes

Anti-HIV gp120 Abs cross-react with platelet membrane glycoprotein Ib-IIIa

TTP

• Characterized by thrombocytopenia, microangiopathic hemolytic anemia, F, transient neurological defects, and renal failure

• May be seen with a prodromal viral illness or HIV

• Systemic formation of hyaline microthrombi (platelets and fibrin) in arterioles and capillaries with widespread organ dysfunction; activation of clotting proteins not important, and the PT and aPTT are usually normal

• More common in women, incidence peaks in 4^th decade

• Treatment with corticosteroids, platelet aggregation inhibitors, and intense plasmapheresis or exchange transfusion

• Some people with this have an abnormally nonfunctioning, deficient, or Abs to vonWillebrand cleaving protease, which normally cleaves large vWF multimers to limit their platelet aggregating abilities

  • This is thought to be responsible for chronic, relapsing TTP

  • Cryoprecipitate-poor products should be used for plasmapheresis; these don’t contain the large vonWillebrand products, but do supply the cleaving proteases

HUS

• Like TTP, but without neurological c/s; the pathology is mainly in the kidneys

• Most common in kids; associated with E. coli O157H7 or Streptococcus pneumoniae infection in kids, pregnant women, those with autoimmune d/o, and those who are immunosuppressed (including HIV)

• Carries a better prognosis in kids than in adults (except with E. coli infection)

Congenital

• Bernard-Soulier syndrome

  • AR deficiency of a platelet membrane glycoprotein that’s required for vWF-mediated platelet adhesion to collagen (the membrane protein is Ib-IX)

  • Associated with the presence of “giant” platelets and a mild thrombocytopenia with a disproportionate bleeding tendency

• Glanzmann’s thrombasthenia

  • AR deficiency of membrane glycoprotein IIb-IIIa, which is required for platelet aggregation by binding to fibrinogen

  • There may e a severe bleeding tendency

• Storage pool diseases

  • Normal initial aggregation with collagen or ADP cannot be maintained due to abnormalities of the release reaction

  • Platelet dense granules have decreased levels of ADP, ATP, prostaglandins, and serotonin

  • Examples: Hermansky-Pudlak, Chediak-Higashi, thrombocytopenia with absent radii (TAR syndrome), and Wiskott-Aldrich

• Grey platelet syndrome

  • Alpha granules are deficient (a-SPD)

  • Variable thrombocytopenia and platelets look gray

Acquired

• Aspirin and other NSAIDS

  • Inhibit COX and thus synthesis of the platelet prostaglandins prostacyclin and thromboxane, which are involved with platelet aggregation and the subsequent release reaction

  • It’s a permanent inhibition, so bleeding time may be prolonged for up to 2 weeks post ingestion

  • Platelet dysfunction may be reversed with a transfusion of small numbers of platelets or with DDAVP

• Uremia

  • Not really well understood why this causes problems

  • This may also be treated with DDAVP, but correction of underlying kidney d/o is very important

• Acquired storage pool defect – seen in chronic liver disease

All of these will show bleeding (not petechial bleeding as is seen with platelet defects, but as large ecchymoses or hematomas after a minor injury) with normal platelet number and function

The intrinsic pathway is measured by aPTT, the extrinsic by the PT; both measure the formation of fibrin (thus, problems with the common pathway will show prolongation of both PT and aPTT)

Factor XIII polymerizes fibrin, thus problems with factor XIII will show lots of bleeding, with normal platelet number and function, PT, aPTT, and thrombin time

Bleeding into GI and GU tracts and into weight-bearing joints is common

Quantitative or functional deficiency of factor IX

X-linked recessive and is clinically similar to (but less common than) hemophilia A

The aPTT is prolonged

Quantitative or functional deficiency of factor VIII

X-linked recessive; bleeding has been seen in heterozygous women, most likely it’s due to unfavorable mosaicism

About 30% of patients have no family history and get the d/o through a new mutation

Bleeding characteristics

• May have life-threatening spontaneous, post-traumatic, or post-surgical bleeding

• Often see hemarthroses and joints may be crippled if recurrent

• Minor cuts don’t bleed too much because platelets are normal; petechiae are usually absent

• The aPTT is prolonged, and bleeding time, PT time, and platelet counts are normal

Factor VIII transfusions carried HIV risk until recently

Severity relates to amount of functional factor VIII

• Severe = < 1% of normal factor VIII levels

• Moderate = 1% to 5% of normal

• Mild = 6% to 50% of normal

About 15% of patients develop Abs to factor VIII

Quantitative or qualitative decrease in vWF (which is produced by endothelial cells and megakaryocytes; the most active forms of vWF are intermediate to large sized multimers)

AD, but may be AR

C/S variable but include spontaneous bleeding from mucus membranes, excessive bleeding from wounds, menorrhagia, and prolonged bleeding time in the presence of a normal platelet count

vWF causes adhesion of platelets to exposed subendothelial collagen and promotes platelet aggregation; it also acts as a cofactor in activation of factor X (when bound to factor VIII) and protects the bound factor VIII from degradation…because of this, the aPTT may be prolonged and levels of factor VIII decreased

Bleeding time is prolonged and PT and platelet counts are normal

Treatment involves replacing vWF and factor VIII through transfusion of cryoprecipitated plasma; factor VIII levels and correction of bleeding time are used to monitor adequacy

2 major categories

• Types I & III

  • Can make vWF, but release of multimers impaired

  • Type I

    • AD, 70% of cases

    • Relatively mild

  • Type III

    • AR, more severe

    • DDAVP may be helpful with cryoprecipitate therapy because it stimulates the release of vWF from endothelial cells

• Type II

  • Can’t make vWF multimers

  • AD, accounts for 25% of cases

  • Mild to moderate bleeding

  • DDAVP may not be helpful since multimers are bad (may even be harmful due to the production of systemic platelet aggregation and resultant thrombosis)

May be associated with factor X and other factor deficiency (-ies) and is thought to come from increased clearance

LP syndromes may make monoclonal Abs that react with specific coagulation factors; acquired von Willebrand’s disease may be from Abs directed against vWF

Vitamin K deficiency leads to decreased synthesis of factors II, VII, IX, and X, and protein C

Coumarin therapy inhibits synthesis of vitamin K-dependant procoagulant factors and protein C (physiologic inhibitor of activated factors V and VIII)

Both PT and aPTT may be prolonged, but PT is more sensitive and is used to monitor coumarin therapy (PT should be 1.5-2.5 X > normal)

In people with a protein C deficiency, coumarin therapy can lead to thrombotic skin necrosis (especially on the breast and penis) if they aren’t heparinized first

O/D of coumarin-like anticoagulants can lead to bleeding complications (no shit?)

Liver disease will look like coumarin/vitamin K deficiency, but there will also be low factor V, and there may also be production of functionally abnormal fibrinogen (dysfibrinogenemia) and a platelet defect (acquired storage pool d/o); the bleeding tendency may be further aggravated by activation of fibrinolysis

DIC is an acute or subacute thrombohemorrhagic d/o that is ALWAYS secondary to something else

There is systemic activation of coagulation and formation of microthrombi, which uses up all of the platelets, fibrin, and coagulation factors; there is also systemic activation of fibrinolysis

Clinical findings

• Patients may present with signs of tissue hypoxia and infarction or with those of a hemorrhagic d/o

• Spherocytes, schizocytes, and other fragmented RBCs can be seen on peripheral smear because fibrin is being deposited in the microvasculature, leading to microangiopathic hemolysis of RBCs

Lab findings

• Variable

• May include combinations of prolongations of PT, aPTT, bleeding time, and thrombin time, thrombocytopenia, decreased fibrinogen, and elevated fibrin degradation products

• D-dimer will be elevated

  • D-dimer is elevated when pre-formed clots are busted (i.e., active clotting + clot lysis)

  • D-dimer is elevated in DIC, pathologic thrombosis, and embolism

• Fibrin monomers

  • These will also be elevated (evidence of active clotting)

  • Monomers are normally polymerized by factor XIII; with systemic or localized clotting, some of the monomers are carried to the bloodstream before polymerization can occur

Treatment mostly involves correcting the underlying d/o, replacement of clotting factors and platelets, and/or anticoagulant therapy; prognosis is variable and largely depends on the underlying d/o

Obstetric complications such as abruptio placentae, retained dead fetus, septic abortion, amniotic fluid embolism, and toxemia of pregnancy (placental microthrombi)

Infections like G(-) sepsis, menigococcemia (Waterhouse-Friderichsen syndrome; acute adrenal hemorrhage/necrosis), RMSF, histoplasmosis, aspergillosis, and malaria

Neoplasms like mucinous adenocarcinomas of the pancreas, prostate, ovary, lungs, and stomach, or acute promyelocytic leukemia

Massive tissue injuries such as trauma, burns, and extensive surgery

Miscellaneous conditions

• Acute intravascular hemolysis (as in transfusion reaction)

• Snakebite

• Giant hemangioma

• Shock

• Heat stroke

• Vasculitis

• Aortic aneurysm

• Liver disease

Mostly in kids and young adults; 80% of childhood leukemia

Almost twice as common in whites and more common in boys

Lymphadenopathy (from leukemic infiltration), hepatosplenomegaly (also leukemic infiltration), and infiltration of other organs (especially the brain and testicles) is common

May have a mediastinal mass reflecting thymic involvement with T cell ALL

Morphologic classification (FAB)

• ALL L1

  • Homogenous population of small lymphoblasts (lymphoblasts = precursor B or T cells) with scant cytoplasm and variable basophilia

  • Nuclei are round and clefted with homogenous chromatin; inconspicuous or absent nucleoli

  • 85% of all childhood ALL

  • Often have PAS “block” positivity

• ALL L2

  • Heterogeneously sized population of relatively large lymphoblasts with moderately abundant cytoplasm and variable basophilia

  • Multiply cleaved nuclei with prominent nucleoli and clumped chromatin

  • 15% of childhood ALL; most frequent adult ALL

  • PAS 

• ALL L3

  • Homogenous population of intermediate sized cells (L1 <>

  • Cytoplasm is abundant, deeply basophilic, and vacuolated (vacuoles are oil red O (+))

  • Nuclei are round to oval with 1+ prominent nucleoli

  • This is a leukemic manifestation of Burkitt’s lymphoma

    • If it’s first and most prominently manifested in the blood it’s leukemia

    • If it’s first and most prominently manifested in the nodes it’s lymphoma

  • 1-2% of childhood ALL

Immunologic classification

• 80% are of B cell origin; those that are of T cell origin are arrested in the early intrathymic stages

• Prognosis related to immunophenotype

  • Best with early precursor B cell ALL

  • Intermediate with immature T cell and pre-B cell ALL

  • Poorest with mature B cell ALL (ALL L3; leukemic Burkitt’s)

  • ALL in kids 2-10 YOA with early pre-B phenotype and hyperdiploidy carries the best prognosis

  • Adults (no matter phenotype) and kids with mature B phenotype have a very poor prognosis

Leukemia is malignant neoplasms of the hematopoietic stem cells; the peripheral blood may or may not be involved, but the marrow is always involved (must have > 30% blasts in smear or marrow)

Acute leukemia

• Characterized by immature hematopoietic cells (blasts) and a rapidly fatal course if untreated

• Often associated with anemia, thrombocytopenia, infection (from decreased neutrophil count), and/or bleeding – all manifestations are a result of the accumulation of neoplastic blast cells in the bone marrow that suppress normal hematopoiesis by crowding

• Abrupt onset, fatigue (due to anemia), F (due to infection), and bleeding (petechiae, ecchymoses, epistaxis, and gingival bleeding) due to thrombocytopenia or DIC (most frequent with AML M3)

• Bone pain and tenderness due to marrow expansion, bone resorption, and subperiosteal infiltration

• CNS manifestations from meningeal involvement: H/A, N, V, papilledema, CN palsies, seizure, and even coma; intracerebral or subarachnoid hemorrhages may come form thrombocytopenia and leukostasis and are most often associated with AML

• WBC count may be decreased, normal, or increased

Chronic leukemia

• Mature, yet atypical appearing cells

• Clinical course often prolonged even without treatment

• Associated cytopenias appear late in disease

Mostly in adults 15-39 YOA; only 20% of childhood leukemia

Chloromas may be seen and they represent tumorous masses of leukemic cells in soft tissues

Infiltration of the gums is characteristic of M4 and M5

Morphological and cytochemical classification (FAB)

• M0: minimally differentiated

  • 2-3% of AML

  • Blasts like cytologic and cytochemical markers or myeloblasts, but express myeloid lineage Ags

• M1: AML without differentiation

  • ~20% of AML

  • Myeloblasts predominate

  • Distinct nucleoli, few granules or Auer rods

  • Myeloperoxidase and/or Sudan black +

• M2: AML with differentiation

  • 30-40% of AML

  • Myeloblasts and promyelocytes (type II blasts) predominate

  • Auer rods are often present

  • SB and/or MP ++

  • Better prognosis if t(8;21) is present

• M3a: acute promyelocytic leukemia

  • 5-10% of AML; more common in Hispanics

  • Hypergranular promyelocytes, often with many Auer rods per cell

  • May have reniform or bilobed nucleus

  • SB and MP +++

  • Often develop DIC

  • The t(15;17) is characteristic

• M3b: microgranular variant

  • Similar to M3a, but greater risk for DIC

  • Also associated with t(15;17)

• M4: acute myelomonocytic leukemia

  • 15-20% of AML

  • Seen myeloblasts (resemble M2) and monoblasts (bidifferentiation)

  • MP and nonspecific esterase ++

  • M4eo

    • This is marrow eosinophilia and abnormalities of chromosome 16

    • Associated with good prognosis, but frequent CNS involvement

• M5a: acute monoblastic leukemia

  • ~10% of AML

  • Undifferentiated blasts that look like M1 predominate

  • MP , NSE +/++

• M5b: acute promonocytic variant

  • See mostly cells that look like monocytes (promonocytes)

  • MP , NSE ++/+++

• M6: acute erythroleukemia (diGuglielmo’s disease)

  • ~5% AML

  • Multinucleated, megaloblastoid erythroblasts predominate; also some myeloblasts

  • Myeloblasts MP+, erythroblasts PAS+

• M7: acute megakaryocytic leukemia

  • ~1% of AML

  • See pleomorphic undifferentiated blasts that may have cytoplasmic budding

  • Marrow is often fibrotic

  • Megakaryoblasts react with platelet-associated Abs and platelet peroxidase; vWF (+)

• Rare variants: mixed lineage AML (myeloid + lymphoid) – eosinophilic/basophilic

ALL

• 90% have chromosome abnormalities

• Hyperdiploidy (> 50 chromosomes) is associated with a good prognosis and is fairly common in early precursor B cell ALL and in about 25-30% of all cases of ALL

• All translocations are associated with a poor prognosis

  • 20-25% of pre-B cell ALL have a t(1;19) translocation

  • B cell ALL (ALL L3) is almost always associated with the t(8;14) translocation of Burkitt’s

AML

• t(9;22), the Philadelphia (Ph¹) chromosome

  • 10-15% of M1

  • Poor prognosis because of Bcr-c-abl fusion

• t(8;21) – 20-25% M2, favorable prognosis, more in young males

• t(15;17) – 100% M3 only; intermediate prognosis

• Inv 16 or del 16q

  • 20-25% of M4

  • Favorable prognosis (worry about CNS involvement)

• Del 11q or t(11,V*)

  • 30-40% of M5 (some M4)

  • Very poor prognosis

• Trisomy 8

  • Seen in M1, M2, M4, M5, and M6

  • No prognostic value

  • Most common abnormality in a wide variety of hematopoietic neoplasms

• Monosomy 7 or del 7q; monosomy 5 or del 5q

  • Most often in secondary leukemias, usually in people > 60YOA

  • Associated with exposure to environmental carcinogens; poor prognosis

Auer rods

• Red toothpick looking things in the cytoplasm

• They are abnormal azurophilic granules

• Intensely peroxidase (+)

• Say for sure that you are looking at myeloid differentiation

Telling ALL from AML

• It’s important to tell them apart because they are treated very differently

• Myeloblasts tend to have more delicate chromatin, prominent or multiple nucleoli, and fine azurophilic granules in the cytoplasm…Auer rods are a sure thing

• TdT

  • Terminal deoxynucleotidyl transferase, a DNA polymerase

  • Seen in 95% of ALL and <>

• Myeloid monoclonal antibodies (CD33, CD13, CD11, etc) are reactive in most (80%) of AML; they are rare in ALL and when they are there it’s not good

• Special stains

  • PAS: “block” positivity in lymphoblasts, diffuse positivity in erythroblasts

  • MP: myeloblasts

  • SB: myeloblasts

  • NSE: monoblasts

CML is associated with splenomegaly

Basophilia is associated with CML

CML is associated with a decreased leukocyte alkaline phosphatase score, reactive processes should have an increased LAP score (LAP is associated with neutrophils ready to kill things)

CML is associated with Ph¹

Clonal proliferation of multipotential stem cells; no block in maturation

Seen in people 25-60 YOA, slightly more in males

15-20% of all cases of leukemia

Insidious onset and vague C/S

WBC often > 100,000/mm³

• Circulating cells are mostly neutrophils and metamyelocytes, but less mature neutrophilic precursors may be present, including a small number of myeloblasts, and some nucleated RBCs (leukoerythroblastosis)

• Since it is a stem cell disease, eosinophilia, basophilia, and thrombocytosis may be seen

Blast crisis

• Accelerated phase with development of resistance to therapy, development of anemia and/or thrombocytopenia, acquisition of more chromosomal abnormalities, and may even begin to look like an acute leukemia

  • 70% of patients have leukemic blasts with myeloid features

  • Blasts in other 30% are lymphoid origin

• Pretty much all treatments (save Gleevec) are worthless

CLL is the most indolent of the leukemias

25% of leukemias, seen in people > 50 YOA, males 2X more

Most are of B cell type and express small amounts of IgM or IgD with restriction to  or  light chains (they are monoclonal)

They are mature B cells and as such will express pan-B cell Ags like CD19 and CD20 but not the early-B cell Ags like CD10 (common ALL Ag, CALLA) or TdT

CD5 (a T-cell Ag) is expressed on some B cells

T cell CLL is rare (<>

Associated with bcl-1 and bcl-2 mutations (sometimes)

Nonspecific C/S; generalized lymphadenopathy and hepatosplenomegaly in 50-60% of cases

Evan’s syndrome

• Formation of Abs against RBCs and platelets in 10-15% of CLL patients

• Get an autoimmune hemolytic anemia and/or thrombocytopenia

Survival depends on how long disease went undiagnosed; worst prognosis with anemia or thrombocytopenia

Transformation to acute leukemia with blast crisis rare; more common to progress to prolymphocytic leukemia (more aggressive than CLL but not as aggressive as an acute leukemia)

Myelodysplastic syndromes are stem cell d/o characterized by maturational defects resulting in ineffective hematopoiesis and risk of transformation into AML (called “preleukemia” syndromes)

Clinical features

• There may be cytopenias and dysmorphic changes in the peripheral smear with normal or hypercellular marrow

• If there is anemia it’s usually macrocytic and there may be monocytosis

• Most often in males 60-70 YOA

• May be asymptomatic or present with weakness, hemorrhage, and/or infection

• Chromosomal abnormalities are in up to 2/3 of patients and indicate a poor prognosis and increased risk of progressing to AML

• Median survival depends on form of myelodysplasia and presence of karyotypic abnormalities

Peripheral smear changes affect all 3 lineages (erythroid, myeloid, and megakaryocytic)

• Erythroid

  • Ringed sideroblasts (erythroblasts with iron-laden mitochondria that can be seen as perinuclear granules with a Prussian-blue stain

  • Megaloblastoid maturation like that seen with B₁₂ or folate deficiency

  • Nuclear budding abnormalities (nuclei with misshapen, often polypoid outlines)

• Myeloid

  • Neutrophils may contain decreased number of secondary granules or contain toxic granulations and Dohle bodies

  • Pseudo-Pelger-Huet cells (neutrophils with a nucleus with only 2 lobes) are often seen

  • Neutrophils may appear to completely lack nuclear segmentation

  • Myeloblasts may be increased but are <>

• Megakaryocytes – may have single nuclear lobes or multiple nuclei (pawn ball megakaryocytes) instead of a single multilobed nucleus

Classification

• RA (refractory anemia)

  • <>

  • Good prognosis

• RARS (refractory anemia with ringed sideroblasts)

  • Differs from RA only in that there are more ringed sideroblasts (> 15%)

  • Good prognosis

• RAEB (refractory anemia with excess blasts)

  • <5%>

  • Median survival only 11 months (tends to progress to leukemia)

• RAEB-T (refractory anemia with excess blasts in transformation)

  • Lots (21-29%) of blasts in marrow and blood

  • Very poor prognosis

• CMML (chronic myelomonocytic leukemia)

  • <>

  • Same prognosis as RAEB not because of transformation to leukemia but because these people tend to die of infection

  • See monocytosis (this is how you tell this apart from CML; CML has basophila, CMML has monocytosis)

• CMML-T (chronic myelomonocytic leukemia in transformation)

  • 21-29% blasts in marrow and blood

  • Will see monocytosis

  • Generally, the more blasts the worse the prognosis (more likely to go onto leukemia)

Other processes that cause dysmyelopoietic maturation

• Megaloblastic anemia of B₁₂/folate deficiency

• Chemotherapeutic drugs

• Alcohol

• Heavy metal intoxication

• AIDS and autoimmune d/o

• Paroxysmal nocturnal hemoglobinuria

CLL is the peripheral blood manifestation of non-Hodgkin’s lymphoma small cell type

Named for where it’s discovered

• If the patient presents with lymphadenopathy and a biopsy is done, the diagnosis will be malignant lymphoma of the small lymphocytic type (i.e., non-Hodgkin’s)

• If a peripheral smear is examined, it’ll be CLL

• If CBC picks up an abnormality and a node biopsy is done it’ll be NHL

Erythroid proliferation predominates

Usually in middle age and more in males

Must be separated from relative (spurious) polycythemia from hemoconcentration and from secondary polycythemia from increased EPO secretion

• This is best done by radiolabeling RBCs

• In Lubbock, done by HCT

Diagnostic criteria (diagnosis needs either all 3 major, or 2 major and 2 minor in the absence of splenomegaly)

• Major

  • Absolute increase in RBC mass

  • Normal arterial O₂ saturation (rules out chronic hypoxia as a cause of erythrocytosis)

  • Splenomegaly (not seen in other causes of erythrocytosis…this comes from extramedullary hematopoiesis that’s going on the spleen because of the neoplastic stem cells that are there undergoing hematopoiesis)

• Minor

  • Thrombocytosis

  • Leukocytosis (should see elevated neutrophils)

  • Elevated leukocyte alkaline phosphatase (LAP) score (this is how we can tell this apart from CML, which would have a decreased LAP score)

  • Elevated B₁₂ level or B₁₂ binding capacity (neutrophils are responsible for B₁₂ transport…if they are elevated, more B₁₂ can be bound)

Clinical signs

• Plethoric congestion of tissues from increased blood volume and viscosity

  • Vascular stasis and infarction common in heart, spleen, and kidneys

  • Intense pruritis (maybe form increased release of histamine by basophils; this may also cause the increased incidence of gastric ulcers)

  • Platelet dysfunction may lead to hemorrhage of GI tract or brain

  • H/A, dizziness, GI symptoms, hematemesis, and melena are common

  • High cell turnover leads to hyperuricemia (goes on to gout in 5-15%)

• Hyperplastic bone marrow, but serum EPO low

  • Neoplastic stem cells have increased sensitivity to EPO and other growth factors

  • Disease progression may be seen as increasing marrow fibrosis or leukemic transformation

Most patients are treated with therapeutic phlebotomy (leads to mean survival of 10 years); avoid chemo as long as possible (increases progression to AML to 15% [2% with phlebotomy])

“spent phase”

• Marrow been working hard and shuts down

• Begin to see increased fibrosis and decreased cellularity in the marrow

• May see an increase in splenomegaly from myeloid metaplasia trying to make up for failing marrow

• Start to develop peripheral cytopenias

A rare, persistent thrombocytosis without secondary causes (such as chronic inflammation)

There may or may not be platelet dysfunction and chromosomal abnormalities

• Platelet dysfunction would show that this was not a secondary thrombocythemia

• Demonstration of chromosomal abnormalities would tell you that it is a secondary thrombocythemia, since there are no known chromosomal abnormalities associated with this d/o

The Ph¹ (t(9;22) forming bcr-c-abl) is in 90+% of CML (even those without Ph¹ will have bcr-c-abl gene)

The 210-kd protein has tyrosine kinase activity (blocked by Gleevec)

Proliferation of neoplastic myeloid stem cells mostly in the spleen (myeloid metaplasia)

Without a pre-existing syndrome (such as p. vera or CML) this is called agnogenic (idiopathic) myeloid metaplasia

Mostly in people > 50 YOA who c/s of splenomegaly and progressive anemia

Peripheral smear shows tear-shaped erythrocytes (dacrocytes), leukoerythroblastosis (from extramedullary hematopoiesis and fibrosis pushing out precursors), and abnormal (“giant”) platelets

Marrow typically hypocellular with atypical appearing megakaryocytes and a variable degree of fibrosis (fibroplastic proliferation from elaboration of growth factors by neoplastic megakaryocytes)

Myelofibrotic pattern may be seen in the “burnt out” phases of CML and p. vera

Course is highly variable and people often die from infection, thrombosis, bleeding, or transformation into leukemia (5-20% of cases)

Median survival from 1-5 years

Low-grade

• 50 – 70% 5YS

• Tend to be widespread at diagnosis, indolent, and poorly responsive to chemo (due to slow growth)

• Mostly in older folks

• May transform to a higher grade lymphoma called Richter’s syndrome

• If the spleen is involved, only the white pulp is affected; if the liver is involved, only the periportal zone is affected (both of these areas are where lymphocytes are seen in these organs)

• All are associated with t(14; 18), which involves bcl-2 overexpression

• If > 75% of the growth pattern is follicular, there is a longer survival regardless of cell type; all follicular patterns can become diffuse over time (shortens survival time)

• Malignant lymphoma, small lymphocytic

  • This lymph node counterpart to CLL is the only diffuse low-grade lymphoma

  • Preferentially involves nodes, marrow, and peripheral blood

  • The more big cells the see, the worse the prognosis

• Malignant lymphoma, follicular, mostly small cleaved cells

  • <>

  • Follicular growth pattern

• Malignant lymphoma, follicular, mixed small cleaved and large cell – mixture of small cleaved and large cleaved and/or large non-cleaved cells

Intermediate-grade

• 35-45% 5YS

• May transform to higher grade

• Malignant lymphoma, follicular, predominately large cell

  • > 50% large cleaved or noncleaved cells

  • Only follicular intermediate grade lymphoma

• Malignant lymphoma, diffuse, small cleaved cell

• Malignant lymphoma, diffuse, mixed small and large cell

  • Cells of both sizes may be cleaved and/or non-cleaved

  • Mostly B cells

• Malignant lymphoma, diffuse, large cell cleaved and/or non-cleaved – most common intermediate grade

High-grade

• 23-32% 5YS

• Tend to be localized at diagnosis, aggressive, but up to 60% respond to chemo

• Liver or spleen involvement characterized by large destructive masses

• Malignant lymphoma, large cell immunoblastic

  • Look like plasma cells (“plasmacytoid”), with discrete cytoplasmic margins, eccentric nucleus, and prominent nucleolus

  • Localized or extranodal disease more common; marrow, liver, and spleen not to often involved

  • Mostly B cells

  • About 50% are associated with a history of autoimmune disease or immunosuppression

• Malignant lymphoma, lymphoblastic

  • Most common lymphoma in kids

  • Frequently associated with mediastinal mass, early marrow involvement, and progression to ALL

  • Very aggressive

  • Mostly T cells

• Malignant lymphoma, small non-cleaved (Burkitt’s)

  • Intermediate in size between small mature lymphocytes and large non-cleaved cells

  • Starry-sky pattern with frequent mitoses

  • Burkitt’s type is associated with EBV exposure

Miscellaneous

• Mantle zone (intermediate differentiated) lymphoma

  • This is a high-grade malignant lymphoma

  • Morphology, however, looks like low-grade, so need to pick this one up

  • Arise from memory or virgin B cells in the mantle zone around the follicular center (which is crushed when the cells begin expanding)

• Hairy cell leukemia

  • Partial monocytic derivation

  • Seen in the red pulp of the spleen because that’s where the monocytes live (also in marrow and peripheral blood)

• Monocytoid B cell lymphoma

  • MALT lymphoma

  • Associated with H. pylori infection of the stomach

  • Treatment with surgery first and chemo if there’s a recurrence

• Mycosis fungoides/Sezary syndrome

  • Skin lymphoma involving T cells

  • Called Sezary syndrome when the cells spill into the blood

  • Medium to large cells with convoluted (cerebriform) nuclei

• Adult T cell leukemia/lymphoma

  • Seen in Japan and the Caribbean

  • Associated with HTLV-1 infection

  • See skin lesions, hepatosplenomegaly, generalized lymphadenopathy, and hypercalcemia