Hematology

Decrease in ≥1 of:

• hеmoglobiո concentration,

• hеmаtоcrit

• RBС count

• RBC: O2 carrying cell

• Hemoglobin: the protein in RBC that binds to O2 (is composed of heme and globin)

• Ferritin: iron stores in body

• Hematocrit: the % of RBC in the total blood volume

• Transferrin Saturation: the % of transferrin that is bound to iron (usually 33%)

• Acute blood loss

• Sequestration

• Hypoproliferative causes (production or maturation defects)

• Survival defects (intrinsic or extrinsic defect)

• Malasportion or dietary deficiency

Fatigue, weakness, pallor, descreased exercise tolerance

Specific to iron deficiency anemia: Pica, restless leg syndrome, brittle nails, hair loss

• CBC (decreased ferritin, hemoglobin, hematocrit, and tranferrin saturation)

• Blood smear: microcytosis and hypochromia

• Find Ex

• Oral iron: uncomplicated iron deficiency (GIT SE)

• Intravenous iron: severe anemia (hg <7 g/dL), low oral iron tolerance or absorption.

• Blood Transfusion: life-threatening anemia, hemodynamic compromise, cardiac ischemia

B12 is necessary for:

• DNA synthesis, key in RBC production (leads to macrocytic megaloblastic)

• Neurological function: mantains myelin sheath integrity

• Malasportion or dietary deficiency

• Prolonged NO exposure (inactivates B12)

• Impaired exposure due metformin, PPI, histamine 2 blockers

• Fish tapewarm

• Pernicious anemia

• Hematologic: fatigue, weakness, pallor

• Neurological: symmetric peripheral neuropathy, subacute degeneration, cognitive symptoms

• GIT: glossitis, diarrhea

• Mild jaundice or hyperpigmentation in some cases

• CBC and blood smear: macrocytosis, hypersegmented neutrophils, pancytopenia in severe cases

• Decreased serum B12

• Metabolite testing: elevated methymalonic acid (MMA) and homocystine

• Intrinsic factor antibodies (in pernicious anemia)

• MRI: “inverted V” pattern in spinal cord

• Oral B12: dietary deficiency, non-severe cases

• Parenteral B12: impaired absorption, severe cases

Notes:

• Rapid correction in pregnancy and neonates to prevent neurological damage

• Neurological recovery may take up to a year

Premature destruction of RBC (reduced lifespan)

• Intravascular: within blood vessels

• Extravascular: within spleen, liver, bone marrow)

• Intrinsic RBC defects: membrane abnormalities, hemoglobinopathies, enxyme deficiencies

• Extrinsic factors: immune-medicated destruction, mechanical damage, infectious agents, drugs, toxins, antibodies…

• Inherited (intracospuscular): hemoglobinopathies, membrane defects, enzyme deficiencies

• Acquired (extracospuscular): immune-mediated, mechanical trauma

• Site of hemolysis: intravascular or extravascular

Fatigue, weakness, pallor

Specific: jaundice, dark urine, splenomegaly, gallstones

• Labs: Increased reticulocyte count, increased indirect bilirubin and LDH, low haptoglobin

• Direct antiglobulin test (coombs): positive in immunne-mediated hemolysis

• Peripheral blood smear: Schistocytes (MAHA); spherocytes (AIHA or hereditary spherocytosis); bite cells and heiz bodies (G6PD deficiency)

• Special tests: osmotic fragility (hereditary spherocytosis), flow cytometry and donath-lansteiner test (PNH)

General: Folate and iron supplements, avoid triggers in G6PD deficiency

Specific therapies depending on Ex:

• Immune hemolysis: steroids (AIHA) rituximab or splenectomy (refractory cases), cold avoidance (agglutinin disease)

• Thrombotic microangiopathies (TMA): plasma exchange (TTP), complement inhibitors

• Inherited diseases: blood transfusions, iron chelation (thalassemia), bone marrow transplant

A life-treathening condition caused by a hypocellular bone marrow due to damage to hematopoetic stem cells.

Leads to decrease in all blood cell types (pancytopenia)

• Autoimmune destruction: T cells attact hematopoetic stem cells (primary cause)

• Direct damage: drugs, toxins, radiation, viral Ex…

• Genetic factors: hematopoeitic regulatory genes

• Clonal disorders: co-evolution w/or transition to other conditions

• Idiopathic (most cases)

• Drugs: chemotherapy, antibiotics, antiepileptics, immunosupressants.

• Chemicals: benzenes, solvents, pesticides

• Ionizing radiation

• Viral infections: Hepatitis, HIV, EBV

• Inherited syndromes: fanconi anemia…

Fatigue, pallor, bleeding tendencies (thrombocytopenia), recurrent infections (neutropenia).

Petichiae, mucosal bleeding, fever (infections) hemolytic anemia or thrombosis (suggestng coexisitng condition)

Laboratory findings: pancytopenia, low reticulocytes, normal or mycrocytic RBC on smear

Bone marrow: hypocellular bonemarrow w/ fatty infiltration, absence of malignancy or fibrosis

• Supportive: blood transfusions, infection management and prevention, iron chelation if transfusion depentent patient

• Triple immunosupressive therapy

• Hematopoetic cell transplantation

Proliferation of immature blast cells w/ disruption of normal hematopoesis

(malignant clonal neoplasia of stem cells from the lymphoid or myeloid cell lines)

Primary mechanism:

• acquired somatic mutation in hematopoetic precursors

• Arrest in differentiation and maturation of blasts

Key features:

• clonal proliferation of blasts

• infiltration of blasts in tissue

• Supression or normal hematopoesis

• Environmental: radiation, chemicals

• Medications: cytostatic, immunosuppresive

• Viral infections: HTLV-1 and HTLV-2

• Genetric predesposition: down syndrome

• Others: family history, chemotherapy…

Acute lymphoblastic leukemia:

• Kids

• lymphoid cell line

Acute myeloid leukemia

• Kids and adults

• Myeloid cell lines

• General: fatigue pallor (anemia) bruising bleeding (thrombocytopenia), infections fever night sweats (leukopenia/neutropenia) hepatosplenomegaly and bone pain

• ALL Specific: painless lymphadenopathy, headache, neck stiffness, weight loss

• AML specific: leukemia cutis (nodular lesions) gengival hyperplasia

• CBC: anemia, thrombocytopenia, leukocyte variability (leukocytosis w/ blasts or leukopenia w/o blasts)

• Blood smear: >20% lymphoblasts

• Flow cytometry: CD10,19,20 (B cell) CD 2-8 (T cell)

• Immunohistochemistry: TdT+; PAS+

• Genetic studies: philadelphia translocation; BRC-ABL1

• CNS infiltration screening: CSF

• CBC: anemia, thrombocytopenia,

• Blood smear: >25% myeloblasts, hiatus leukemicus (blasts and mature cells but no intermediate forms), auer rods

• Flow cytometry: CD13,33,13,117; HLA-DR

• Immunohistochemistry: MOP + (myeloperoxidase)

• Induction of remission: intensive chemotherapy

• CNS prophylaxis: intrathecal chemotherapy

• Consolidation: high-dose chemotherapy (sustain remission)

• Maintenance therapy (especially in ALL) to prevent relapse)

• Stem cell transplantation (high-risk or relapsed)

• Supportive therapy: infection prophylaxis, RBC and platelet transfusions, antiemetics

L-asparaginase; vincristine; MTX, cyclophosphamide

cytarabine; idarubicin,

uncrontroled proliferation of mature and maturing granulocytes, mostly neutrofils.

Associated with the philadelfia chromosome

Chronic phase:

• asymptomatic, most commonly diagnosed here

• Fatigue, weightloss, night sweats, abdominal fullness (splenomegaly)

Accelerated phase:

• Worsening symptoms

• Worsening anemia and thrombocytopenia

• Increased blasts (blood and bone marrow)

Blast crisis:

• resembles acute leukemia: rapid progression with fever, bone pain, bleeding, infections

• Blasts ≥20% of blood or bone marrow

• CBC: normochromic normocytic anemia, thrombocytopenia or thrombocytosis, leukocytosis, left shift: immature granulocytes, basophilia and eosinophilia,

• Blood smear: all stages of granulocyte maturation, elevated basophils and eosinophils

• Bone marrow aspiration: hypercellularity and myeloid displasia

• Cytogenic and molecular testing (FISH and PCR): philadelphia chomosome t(9:22) translocation, detects BCR-ABL1 fusion genes

• increased LDH and uric acid (increased cell turnover)

• Tyrosine kinase inhibitor: imatinib

• Allogenic hematopoetic stem cell in advanced stage or TKI resistance

• Supportive: hydroxyurea (control WBC count before TKI) and leukopheresis (if extreme leukocytosis causing symptoms)

progressive accumulation of functionally incompetent clonal B lymphocytes in blood, bone marrow and lymphoid tissue

tissue dominant manifestation of CLL - lymphadenopathy

• Can be asymptomatic

• B symptoms: fever, night sweats, weight loss, fatigue

• Cytopenia related symptoms: fatigue (anemia), bleeding/bruising (thrombocytopenia), recurrent infections (neutropenia)

• hepatosplenomegaly

• Generalized lymphadenopathy

• PBS: absolute lymphocytosis (small mature) w/ smudge cells

• Bone marrow: ≥ 30% lymphocytic infiltration (not necessary for diagnosis)

• Cytopenias: anemia, thrombocytopenia, neutropenia

• Flow cytometry:

  • Immynoglobulin abnormalities: hupogammaglobulinemia (typically IgM and IgD)

  • CD5, CD19,20,23

  • Cyclin D1 negative (excludes MCL)

BINET Staging

For all: infection prophylaxis

Stage A: watch and wait

Symptomatic, higher risk, bone marrow failure:

• Chemotherapy: FCR (fludarabine + cyclophosphamide + rituximab)

• Targeted therapy: Bruton TK-i, BCL2

Hodgkins:

• Only B cell (reed sternberg cell)

• Rare (10%)

• Bimodal age: 15-35 + ≥55

• Localized to single axial group of lymphnodes w/ contiguous spread

• Rare extranodal involvement

• Good prognosis

Non-hdgkins:

• Can involve T cell, B cell and NK cells

• More common (90%)

• Age: ≥60

• Multiple peripheral lymphnodes - w/ non contiguous spread

• Common extranodal involvement

• Variable prognosis

malignant prolipheration of B-cell origin in lymphoreticular system (lymph nodes, liver, spleen, bone marrow)

• Painless lymphadenopathy: single or contiguous lymphnode chain, mostly cervical

• Mediastenal mass

• hepatoslenomegaly

• B symtoms

• Pel-ebstein fever

• Pruritus

Early stage (I/II)

• Chemo + radio ABVD

  • Adriamycin, bleomycin, vinblastine, dacarbazine

Advanced State (III/IV)

• Chemo +/- radio ABVD or BEACOPP

  • adriomycin, bleomycin, etoposide, cyclophosmamide, oncocilin, procarbazine, prednisolone

malignant prolipheration of B, NK or T cell origin in lymphoreticular system (lymph nodes, liver, spleen, bone marrow)

Low grade (indolent form)

• Insidious onset

• Hepatosplenomegaly

• Pancytopenia

• Undulating painless lymphadenopathy

High grade (aggressive form)

• Rapidly growing mass

• B symptoms

• Painless lymphadenopathy

• hepatosplenomegaly

• Extranodal disease

• Paraneoplastic syndromes

• Bone marrow involvement

CBC: anemia, leukpenia, thrombocytopenia

EXCISIONAL lymphnode biospy + immunohistochemistry: no reed-sternberg cells

Imaging: PET-CT and Cranial MRI (if neuro symptoms)

CSF: lymphoma cells or EBV DNA

Low grade

• limited stage: curative radiation therapy

• advanced: palliative treatment

High grade

• agressive treatment in all stages

Chemotherapy regiments:

CHOP: cyclophosphamide, duxorubicin, vincristine, prednisolone

increased tendency to bleed due to disorders or abnormalities in:

• hemostasis

• vascular system, platelets, coagulation factors…

• Primary hemostatis defects (platelets and vascular wall)

• Secondary hemostasis defects (coagulation cascade)

• fibrinilytic defects (excessive breakdown of fibrin clots)

• vascular wall abnormalities (structural or functional defects in BV walls)

Primary hemostatis defects: mucosal bleeding, petechiae, purpura

Secondary hemostatsis defects: deep tissue bleeding, hematomas, hemarthrosis

Fibrinolytic defects: delayed bleeding after trauma or surgery

Vascular wall abnormalities: non-palpable purpura or bruising

• CBC: platelet count

• Coagulation tests: prothombin time, activated partial, thromboplastin time, fibrinogen level, Thrombin time

• Platelet function analyzer: defects qualitative platelet dysfunction

• PBS: morphology of platelets and RBC

Malignancy of plasma cells (b cell neoplasm)

uncontrolled replication of plasma cells and secretion of immunoglobulin proteins (IgG and IgA with urinary free light chains - bence jones protein)

Bone pain

Renal dysfunction (light chain neprhopathy)

Hypercalcemia (fatigue, confusion, kidney issues…)

Anemia

Infections (due to immunoparesis and suppressed immunoglobulin levels)

Rare neuro symptoms

Both criteria:

1. confirmatory diagnosis: bone marrow biopsy

   • >10% clonal plasma cells or plasmocytoma

2. on the the following:

   • CRAB CRITERIA Calcium

     Renal insuffiency (creatinine and uric acide high)

     Anemia (normo normo)

     Bone lesions

   • Any of the cancer biomarkers:

     plasma cells above 60%

     serum light chains above 100mg/dl

   • more than one focal lesions on MRI

Transplant eligible:

• induction + stem cell collection + autologous stem cell trnasplant

Transplant ineligible

• induction and maintenance

Chemotherapy regimen:

Induction:

• Immunomodulator: thalidomide

• Protease inhibitors: bortezomib

• Steroids: dexamethasone

Maintenance:

• thalidomide + ixazomib + corticosteroid

decreased neutrophils:

Grade 0 (normal)

Grade 1(mild)

grade 2(moderate)

grade 3(severe)

grade 4(agranulocytosis)

• decreased production: bone marrow suppresion, nutritional deficiencies, bone marrow infiltration

• increased destruction: immunemediated, infections

• Redistribution: neutrophils marginate to vascular endothelium or spleen sequestration

• combined mechanisms

• Infectious symptoms: fever, frequent bacterial infections maybe in atypical sights

• Localized symptoms: oral ulcers, gengivitis, skin infections or abcesses, perirectal inflammation

• Systemic symptoms: fatigue, malaise, symptoms or underlying conditions

Repeated CBC

PBS: assess for possible malignancy

anamnesis and physical examination (meds, infections, autoimmune conditions…)

Urgent hospitalization:

• severe neutropenia w/ fever and sepsis signs

• emperic broad spectrum a/b for debrile neutropenia

Outpatient monitoring

• mild or moderate symptoms

• repeat CBC

Specific Tx:

• treat Ex (discontinue meds, treat pathology…)

Preventative measures:

• infection prophylaxis w/ ab/antifungals

chronic myoprolipherative neoplasm with proliferation of erythroid, granulocytic and megakaryoblastic hematopoetic cells

elevated RBC, WBC and platelets

JAK2 mutation association

• Vasomotor symptoms: headache, dizziness, blurred vision, paresthesis

• Aquagenic pruritus: itching by contact with water

• erythromelalgia: bruning pain w/ erythema

• constitutional symptoms: fatigue, night sweats, weight loss…

Complications: thrombosis, splenomegaly, minor mucocutaneous bleeding

Major criteria (M)

1. Elevated hemoglobin/hematocrit or red cell mass

2. hypercellularity with trilineage proliferation on bone marrow biopsy

3. JAK2 mutation

Minor Criteria (m)

• Low serum EPO

Diagnosis:

All M or (1.M+2.M+m)

Low-dose aspirin (helps with thrombosis risk, erythromelagia and vasomotor symptoms)

cytoreductive therapy: hydroxyurea

smoking cessation, BP, lipid control…

X-linked bleeding affecting cloting factors:

VIII Hemophilia A

IX hemophilia B

A comes before B

8 comes before 9

delayed bleeding, “deep” bleeds, spontaneous hemarthrosis

Severe cases show in infancy less severe cases show up later

Bleeding sites:

Infants: CNS, circulation sites

Children: hemarthrosis, muscle, oral injuries

Adults: joints, muscle, GIT, CNS

Bleeding related

• joint destruction

• pseudotumors

• neurological damage

Treatment related

• infections from plasma derived products

• inhibitor development: alloantibodies to infused factor

Long term risks

• Cardiovascular disease and osteoporosis

Screening tests: prolonged aPTT w/ normal platelets and prothombin time

mixing studies distinguish deficiency from inhibitors

• in deficiency, aPTT will be corrected

Specific testing: factor VIII and IX acitivity

genetic testing

replacement therapy w/ factor concentrates (VIII or IX)

for inhibitors: bypassing agents or immune tolerance therapy

acquired autoimmune condition

plateled destruction and impaired production due to autoantibodies

DIAGNOSIS BY EXCLUSION

autoantibodies attack glycoprotein 2b and 3a in platelets - accelerated platelet clearance

Bleeding symptoms

• skin: petichiae, purpura

• mucosa: hemorrhagic blisters, epistaxis

Thrombocytopenia

• platelet morphology is normal

Others: fatigue

DIAGNOSIS OF EXCLUSION

Initial evaluation: anamnesis, physical examination, CBC, PBS (rule out othercauses)

Additional tests: H. pylori, bone marrow biopsy, immunologic studies…

Goals: prevent bleeding and raise platelets to save levels (not necessarily normal)

Initial management (bleeding): platelet transfusion + IVIG or glucocorticoids

long term management: glucocorticoids + rituximab