Malignant disorder of the blood-forming organs (cancer of white blood cells)

Neoplasms with widespread involvement of the bone marrow and often, though not always, peripheral blood

Etiology:

– Unknown, chemo, radiotherapy, exposure to chemicals (benzene), genetic (E.g. Down’s Syndrome associated with increased risk for AML)

Pathophysiology:

– Replacement of bone marrow (BM) and/or lymphoid organs with leukemic (immature) cells

– There is a depression of normal bone marrow function; red cells, white cells, platelets

– Organomegaly (organs enlarge) of organs related to the immune system

o E.g. Lymph nodes and spleen

Clinical manifestations

– Anemia (reduced RBCs)

– Increased susceptibility to infection (abnormal WBCs)

– Bleeding manifestations (low platelets)

o Petechiae

o Purpura

o Ecchymosis

o Hemorrhage eg epistaxis, GIT bleeding

– Weight loss

– Lymphadenopathy, hepatosplenomegaly

o Results from leukemic cells multiplying in organs

– Bony aches

o The BM hyper activity puts pressure on bones.

– Elevated uric acid

o As the abnormal cells and their DNA are destroyed, uric acid builds up.

o Manifests as renal stones, uric acid crystals in urine

*LEUKEMIC TRIAD = ANEMIA + INFECTION + BLEEDING

Classification/Types of Leukemia

Acute Leukemia

Immature cells (blast cells)

– Blasts leak from the bone marrow to cause acute disease

Acute Lymphoid leukemia (ALL)

– More common in children

Acute Myeloid leukemia (AML)

– More common in adults

– Also, more serious in adults too

Chronic Leukemia

Mature cells, but abnormal function

– Cells are more differentiated and cause disease over a longer period of time

Chronic lymphoid leukemia (CLL)

– More common in adults

Chronic myeloid leukemia (CML)

– More common in adults

Stem Cell Classification

ALL and CLL come from the lymphoid stem cell

AML and CML come from the myeloid stem cell

ALL

Most common childhood leukemia

Pathological features:

Marked leukocytosis

Lymphoblasts in peripheral blood and bone marrow

Cytogenetics:

T(4;11) (q21;q23)

T(8;14)(q24;q32)

T(11;14)(p13;q11)

Note: When reading translocation mutations:

– E.g. T(4;11)(q21;q23)

– chromosome 4, band 21 is translocated with chromosome 11’s band 23”

AML

Most common adulthood acute leukemia

Down syndrome and Fanconi anemia are known to increase the risk for AML

Pathological features:

Marked leukocytosis

Myeloblasts in peripheral blood and bone marrow

Cytogenetics

T(8;21)(q22;q22)

Inv (16)(p13.1;q22)

T(16;16)(p13.1;q22)

CML

Most common adulthood chronic leukemia

Pathological features:

Marked leukocytosis

– Present in terminal phase of CML

Myeloblasts in the peripheral blood and bone marrow

– Peripheral blood look like bone marrow!!

Basophilia

– Basophilia present in terminal, final stage of CML

Splenomegaly

Blastic crisis

– Occurs in stage 2, the acute/ accelerative phase

– Very painful

Lymphadenopathy

– Usually only found in the acute phase of the disease

Cytogenic

Philadelphia chromosome:

– T(9;22)(q34;q11) that creates the BCR-ABL fusion gene (oncogene)

Lymphomas

Malignant transformation and proliferation of lymphocytes and their precursors/derivatives in lymphoid tissues

– A cancer of both the blood (lymphocytes) and lymphatic system (lymphoma)

– Lymphomas primarily affect the lymph nodes

– The patient usually presents with a mass

2 major categories of lymphoma:

Hodgkin lymphoma

– Neoplasm of Reed-Sternberg cells

Non-Hodgkin lymphoma

– Includes 4 cell-types as classified by WHO

o Precursor (immature) B-cell neoplasms

o Peripheral (mature) B-cell neoplasms

o Precursor (immature) T-cell neoplasms

o Peripheral (mature) T-cell neoplasms

Pathophysiology & manifestations (for both Hodgkin and Non-Hodgkin Lymphoma):

Main pathophysiological feature is lymphadenopathy

Weight loss and night sweats

Fever, mediastinal mass, splenomegaly, abdominal mass, pruritus

Diagnostic Testing and Staging

Anemia, leukocytosis, eosinophilia

Elevated ESR and ALP

LN biopsy and staging

Histopathology: Reed-Sternberg cells; essential for diagnosis

Ann-Arbor staging (see Table below)

– Staging classification used for Hodgkin lymphoma

Hodgkin Lymphoma

HL affects people aged 20-40 and 60-80

Typical cases associated with infectious mononucleosis (EBV is oncogenic virus)

Presence of abnormal B cells called Reed-Sternberg cells (RS)

– RS cells are usually infected with EBV which is likely linked to the cause

– The cells are large and binucleate, they are necessary for diagnosis but are not specific to HL

Curable disease

Non-Hodgkin Lymphoma

Lymphoma from either B cell, T cell and/or NK cell neoplasms

– Proliferation occurs through lymphoid tissue with differing patterns and responses to treatment

Able to spread throughout body

– In contrast HL is usually localized, affecting a certain chain of lymph nodes

Median age for diagnosis is 67 years

Multiple Myeloma (MM)

Malignant proliferation of plasma cells

Pathophysiology:

Proliferation of plasma cells

– These cells infiltrate bone marrow and aggregate creating tumor masses in bone

Myeloma cells produce monoclonal immunoglobulins (antibodies) which are proteins

– High levels of these proteins in the blood leads to increased blood viscosity

Clinical and lab manifestations:

Anemia

– Depressed bone marrow so can’t make RBCs

Bone lesions

– Lead to bone aches

– Prone to bone fractures

Bence-Jones protein

– The plasma cells can make a “free immunoglobulin light chain” (the Bence-Jones protein)

– Circulate in blood and kindey, can cause renal failure

Hypercalcemia

– From bone break down

– Leads to reduced bone density

Renal failure

– BJ protein buildup can block kidney tubules

Disorders Related to Alterations of the Clotting System (Bleeding Defects)

Disorders that lead to an inability to form fibrin at an injured site

Pathophysiology:

3 potential causes leading to development of clotting system disorder:

– Clotting factor defects

– Platelet defects

– Vascular (blood vessel) issues

o Impaired myogenic effect

o Impaired endothelium (vasculitis)

Diagnostics Used for Diagnosis and Treatment

*Should know the normal CBC*

PT (Prothrombin time)/ INR

– The length of time it takes make prothrombin (a clot)

– Normal range is 10-14 seconds

– Longer times indicate bleeding issues

o Potential cause from vitamin K deficiency

o Oral anticoagulants (warfarin); titrated according to INR

– Shorter times indicate clotting issues

aPTT (Activated partial thromboplastin time)

– A substance is added to the blood sample to make it clot faster

– Normal range is 30-40 seconds

– If you take heparin, your result would be higher.

o Heparin is titrated according to aPTT

Selected Disorders Related to Clotting factors

Hereditary:

Haemophilia A (deficiency of coagulation protein VIII)

Von Willebrand disease (vWD) (vWF protein defects)

– The most common mild bleeding disorder

– Impaired VWF dependent platelet functions

Both Haemophilia and Von Willebrand disease are very common

Acquired:

Vitamin K deficiency

Liver disease

– Due to defective synthesis of coagulation factors

– Impaired synthesis of vitamin k dependent factors (II,VII,IX,X) and proteins C and S (natural anticoagulants)

Platelet Disorders

Thrombocytopenia

Platelet count <150,000/mm3

Selected Causes for Thrombocytopenia:

Hypersplenism

– Overactive spleen that destroys RBCs and platelets

DIC (disseminated intravascular coagulation)

– Excessive generation of thrombin and fibrin, usually from exposure to tissue factor in the circulation, leading to activation of the coagulation cascade

– Platelet aggregation combined with consumption of coagulation factors leads to a combination of clot formation and bleeding

– Thrombocytopenia resulting from platelet consumption in formation of clots

HIT (heparin induced thrombocytopenia)

– Within 7-10 days of heparin use

– Abnormal antibodies against heparin; bound to a protein called platelet factor 4

– Bleeding due to low platelets

– Thrombosis may result from activated platelet

ITP (idiopathic/immune thrombocytopenia purpura)

– Mainly children

– IgG against platelets

– Antibody-coated platelets are sequestered and removed from the circulation

– Leads to splenomegaly

Manifestations

Petechiae, purpura

Major bleeds

Thrombocytosis

Elevated platelet production

Platelet count >500,000/mm3

Selected causes:

Essential thrombocythemia

Myeloproliferative disorder affecting all lineage or just platelet precursor cells

Manifestations

Microvascular thrombosis (blockages in small blood vessels)

– Symptoms depend on vessels affected

– Primarily occurs in hands and feet, lead to:

o Redness

o Warm to touch

o Feel burning sensations in affected digits and/or limbs

o Standing and warmth make it worse and relief from elevation and cooling

o May develop erythromyalgia secondary to microvascular thrombosis

• This is the paroxysmal vasodilation of small arteries (most often in hands and feet but can include face, ears and knees)

• Causes burning pain, redness, and localized warmth

– Microvascular thrombosis in other areas with associated symptoms include:

o Eye (ocular migraines)

o CNS (transient ischemic attacks)

o Chest (pulmonary embolism)

Bleeding events associated with thrombocytosis include easy bruising, GI bleeds, and epistaxis

Thrombophilia conditions

Hypercoaguability of the blood

Causes:

– AT-III (antithrombin III) deficiency

– Protein C deficiency and factor V Leiden (protein C resistance)

– Protein S deficiency

– Prothrombin gene mutations

– Antiphospholipid syndrome

Thrombosis

Blood clot forms inside vessel

3 conditions (Virchow’s triad) together increase risk/ can lead to thrombosis

– Hypercoagulability of blood

– Vessel wall injury

– Stasis of blood End of Module

End of Module