Hematology

• MMA: elevated in B12
• Homocysteine: elevated in both

• Give IM dose B12 to saturate all the binding sites
• Follow this with PO dose labeled B12
• Then measure radioactivity in 23-hr urine sample
• -Abnormal is low level, likely not absorbed
• Then follow with B12 plus intrinsic factor
• -Will correct the absorption if due to lack of intrinsic factor
• -If no correction, then must be ileal disease such as bacterial overgrowth (can give antibiotics) or malabsorption

• Pancytopenia
• Occurs secondary to a stem cell d/o
• Majority of cases are idiopathic
• Treatment options include:
• -Immunosuppression with ATG/cyclosporine in older pts and younger pts with no marrow donor
• -Bone marrow transplant in younger pts with a donor

• Acquired stem cell defect
• Hemolytic picture
• RBCs more susceptible to complement degradation secondary to the absence of: Decay accelerating factor (DAF) and Homologous Restriction Factor (HRF)
• Dx test: Flow cytometry for DAF (CD55) and HRF (CD59)
• Treatment options:
• -RBC transfusions during episodes of hemolysis
• -Steroids
• -Androgens, i.e., Danazol

• Aplastic crisis from parvovirus B19
• Functional asplenia
• Develoe microinfarcts of organs such as brain - CVA
• Develop priapism and also retinal detachment

• Elevated levels of Hgb A2.
• Alpha thalassemia electrophoresis is normal

• Beta thalassemia minor - mild anemia with marked microcytosis
• Beta thalassemia intermedia - some B globin production and usually does not require transfustional support
• Bete thalassemia major (Cooley's) - no productin of hgb and transfusion-dependent

• Expect macrocytosis secondary to an elevated reticulocyte count
• Should see spherocytes on peripheral smear
• Shoud have elevated levels of LDH and bilirubin (toral and indirect)
• Diagnose with Coombs test - will be +

• Demonstrate antibody of the RBC surface
• Mix pts blood with anti-IgG or C3 antibodies
• Agglutination indicates a positive test

• Demonstrates antibody in the serum
• Mix patient's serum with known panel of RBCs
• Agglutination indicates a positive test

• React at room temperatures
• IgG antibodies
• Associated with lymphoproliferative and collagen vascular diseases
• Usually respond to therapy with immunosuppression or splenectomy

• React at loser temperatures
• IgM antibodies
• Hemolysis is via the complement pathway
• Associated with lymphoproliferative diseases or infection
• Not responsive to therapy - stay warm

• Clonal stem cells of the elderly
• Often present with pancytopenia although may have only one or two cytopenias
• Peripheral smear and lab findings suggestive of a MDS state include:
• -Dimorphic RBC population
• -Macrocytic RBCs
• -Pseudo Pelger-Huet anomaly
• -Large agranular platelets
• -Decreased reticulocyte count
• Diagnosis is made by bone marrow evaluation

Pseudo Pelger-Huet anomaly, seen in myelodysplastic syndrome, after chemo, and in leukemia states and infection. May also be congenital (Pelger-Huet anomaly). This is the "pince nez" cells.

Different size RBCs

• Ringed sideroblast, seen in myelodysplasia
• Refractory anemia with ring sideroblasts, a clonal hematopoietic neoplasm, is a form of MDS characterized by anemia, bone marrow erythrodysplasia, and ring sideroblasts; ring sideroblasts represent 15% or more of nucleated erythroid precursors

• A specific syndrome in myelodysplasia
• Usually found in females
• Thrombocytosis instead of thrombocytopenia
• Has a more favorable prognosis

• Treatment options include:
• Supportive care
• B6, B12, and folate
• Growth factors
• Chemotherapy
• Bone marrow transplant

• Polycythemia vera
• Essential thrombocytosis
• Myelofibrosis
• CML

• Generally diseases of the elderly
• All clonal disorders classified by the cell line most affected
• Marrow will be hypercellular in all
• Splenomegaly is a common physical finding in all

• Chronic course
• Presents with subjective symptoms such as fatigue and early satiety, although often found on routine CBC
• Linked to radiation exposure, but not clearly to any other environmental or infectious etiologies
• Typical lab presentation:
• -Markedly elevated WBC count
• -Left shift to early precursors
• -"Myelocyte spike"
• -Eosinophilia and basophilia

CML

• Diagnosis is made by finding:
• -low LAP (leukocyte alkaline phosphatase)
• -marrow that is hypercellular
• -characteristic chromosomal abnormality
• --t(9,22) - Philadelphia chromosome
• --Additional chromosomal findings dependent upon the phase of the disease

• Usually relatively asymptomatic
• Easily controlled counts
• Disease duration
• -2 years untreated
• -3-4 years with hydroxyurea
• -4-5 years with interferon
• -Unknown with imatinib

• Increasingly difficult to control counts
• Increasing eosinophilia and basophilia
• Accumulation of additional cytogenetic abnormalities
• Treatment is difficult

• Transforms to acure leukemia: myeloid or lymphoid!
• - 80% AML
• - 20% ALL
• Poor prongosis with survival measured in months despite therapy

• A new class of drug designed to take advantage of the t(9, 22) abnormality
• A tyrosine kinase inhibitor
• Majority have a cytogenetic remission but duration unknown
• Few side effects

• Bone marrow transplantation
• --therapy of choice for young patients with a matched available donor
• Only curative therapy known to date
• Best when performed ealy in the disease

• Primarily expansion of the erhtroid line but usually see mild degrees of leukocytosis and thrombocytosis as well
• Growth is independent of erythropoietin
• Typically affects an older patient population
• Sx may include aquagenic pruritus
• Presentation:
• -plethora
• -Splenomegaly
• -Thrombosis
• -Hyperviscosity
• -Gout
• -Erythromelalgia -- erythema and pain of digits
• -PUD
• -Increased histamine release
• -Small vessel thrombosis
• Diagnostic criteria
• 1. Increased RBC mass
• 2. Normal PaO2
• 3. Splenomegaly
• 4. Low serum erythropietin levels
• Other diagnostic criteria:
• -elevated platelet cound
• -elevated WBC count
• -elevated LAP
• -elevated B12
• Diagnosis requires exclusion of secondary causes of erythrocytosis
• -Gaisbock syndrome (stress polycythemia)
• -Hypoxic states
• -Renal disease
• -Malignancy

• Progression ot a fibrotic or spent phase (PPMM)
• Conversion to AML
• Progression occurs over many years to decades

• Phlebotomy
• Drugs
• Low dose ASA - if no contraindication

• By definition -- thrombocytosis sustained over 6 months that is unexplained
• May be associated with splenomegaly but not usually massive
• No clear diagnostic tests exixt
• Must rule out other causes for "reactive" thrombocytosis
• -Iron def anemia
• -Malignancy
• -Collagen vascular disease
• -Infection
• -Postsplenectomy state
• -Other MPDs

• Complications may include either bleeding or thrombosis
• Plateley function tests are not indicative of tendency to bleed or clot
• May see erythroelalgia
• May see spurious hyperkalemia

• Observation
• If with complications, i.e. stroke, start meds
• Hydroxyurea and busulfan
• Interferon-a
• Anagrelide
• *very little evolution to acute leukemia

• JAK-2 genetic abnomality found to be associated with the majority of patients with p vera and about 50% of those with ET
• A tyrosine kinase activated in response to certain growth factors (GM-CSF and erythropoietin)

• No, it does not put you at risk or bleeding or clotting
• There is no absolute number that denotes primary from secondary thrombocytosis

• Also known as Agnogenic myeloid metaplasia or myelofibrosis with myeloid metaplasia
• Older patients
• Clonal disorder with cytopenias
• Marrow fibrosis - so has to make blood somewhere else.
• Extramedullary hematopoiesis - primarily in spleen resulting in...
• Massive splenomegaly
• Characterized by a myelopthisic picture on peripheral smear
• -teardrop-shaped RBCs
• -nucRBCs (nucleated RBCs)
• -Left-shifted WBC series
• Anemiz
• LAP nondiagnostic

Myelofibrosis

• Natural history is shorter than most MPDs
• Median survival is only 5 years
• Progressive marrow failure with increasing transfusion dependence and organomegaly
• Infectious complications
• May convert to acute leukemia

• Supprotive care
• Androgens
• Growth factors
• Hydroxyurea or busulfan
• Splenectomy - but be careful because they will just shift their hematopoiesis activity to their liver and end up with massive hepatomegaly
• Bone marrow transplant if young enough

• Primary platelet vs coagulopathy can be diffetentiated by the type of bleeding
• Primary platelet bleeding is mucosal with petechia, epistaxis, gum bleeding and GI tract bleeding
• Coagulation cascade bleeds are generally joint and soft tissue bleeds

Bleeding time or PFA 100

• In childhood, this is usually post-vral and a self-limited illness
• In adults, it is usually a chronic disease
• Antibody-mediated -- IgG
• Significant bleeding rare
• No diagnostic test
• -diagnosis of exclusion
• -Rule out HIV and Hep C
• -rule out SLE
• -Evaluate drug history

• Platelets > 30,000 -- observe
• Platelets < 30,000 -- treat
• --Steroids - high dose
• --IVIg
• --Splenectomy
• Optional therapies for patients failing steroids and splenectomy:
• -Danazol
• -Colchicine
• -Pulse decadron
• -Vincristine
• -Vinblastine
• -Rituximab - may try before splenectomy
• -Anti-RhD
• -TPO Receptor antagonist

• 1. Fever
• 2. Neurological signs
• 3. Microangiopathic hemolytic anemia
• 4. Thrombocytopenia
• 5. Renal dysfunction

• Mitomycin C
• Ticlopidine
• Cyclosporine

• Schistocytes
• Thrombocytopenia
• Normal WBC series
• Shift cells
• nRBCs

Schistocyes

• a gene defect found in many pts
• Encodes for a vW antigen protease responsible for cleaving unusually lage vW multimers
• Takes too long to get the result so not good for acute symptoms

• This is considered a medical emergency
• Plasma therapy -- preferably by plasma exhnge
• Steroids
• Platelet transfusions are contraindicated unless there is a life threatening emergency -- other symptoms will become rich

• PT: prolonged
• PTT: prolonged
• Plt Ct: decreased
• Fibrinogen: decreased
• Fibrin Degradation Products (FDP): increased
• Protamine: positive

If platelet cound falls by 50% or falls below 100,000

Bleeding time/PFA 100

• von Willebrand disease
• Bernand-Soulier Syndrome
• Glanzmann's thrombasthenia
• ASA and NSAID use

• Most common inherited bleeding disorder
• Autosomal dominant inheritance
• Affected individuals are heterozygous
• Bleeding ranges from mild to severe and spontaneus

• Autosomal dominant inheritance
• Most common variety
• Mild decrease in vW ag, FVIII levels and ristocetin cofactor
• All multimers present but decreased

• Autosomal dominant inheritance
• Less common
• Normal levels of dysfunctional multimers
• Type IIa and IIb variants
• Type IIb associated with thrombocytopenia

• Extremely rare
• Autosemal recessive inheritance
• Severe mucosal bleeding
• No vWF:AG or vWF:RCoF
• May have low enough Factor VIII for mild hemophilia symptoms

• Desmopressin (DDAVP) -- raises plasma vWF and F VIII levels by release from the endothelium. Best used in mild Type I disease
• Should always test response prior to surgery
• Only used for short-term hemostasis
• Develop tachyphylaxis after 48 hours
• Cryoprecipitate is rich in vWF and F VIII and may be used to treat emergent bleeding or for surgery
• Factor VIII concentrates with high vWF fractions may be used for all types of vWD. These should be given twice daily for active bleeds or surgery and continued at least 48 hours

• Also called the giant platelet syndrome
• Glycoprotein Ib platelet defect
• Unable to bind vWF, which is important for adhesion ro the endothelium
• Have abnormal ristocetin aggregation
• Have mild thrombocytopenia

• Autosomal recessive inheritance
• Mucosal bleeding
• Glycoprotein IIb-IIIa defect
• Unable to crosslink fibrinogen, which is important for aggregation
• Have abnormal ADP and EOI aggregation

This syndrome presents with hypochromic, microcytic anemia, secondary to an iron deficiency. Atrophic glossitis, dysphagia, and esophageal webs can also be seen with Plummer-Vinson syndrome.

• Intrinsic: XII, XI, IX, VIII
• Extrinsic: VII
• Common: X, V, II, fibrinogen

• 1:1 mix of patient and normal plasma
• -will detect a factor deficiency -- should see correction with mix
• -will detect inhibitor -- doesn't correct with mixing

• Factor VIII deficiency
• Tx: Desmopressin will increase the plasma level of F VIII 2-3 fold and is useful in mild hemophilicas.
• For more severe patients or bleeds, replacement with cryoprecipitate is feasible, but factor products are preferable

• Develop in 10-20% of pts receiving factor infusions
• Thesea are IgG antibodies
• Detected when the 1:1 mix does not correct
• Tx: Activated F IX product, porcine VIII, Factor VIIA (NovoSeven) or immunosuppression

• Factor IX deficiency
• Synthesized in the liver
• Also known as "Christmas Disease"
• Required vitamin K as a cofactor for modification
• Tx options:
• -FFP
• -Factor IX concentrates -- monoclonal and recombinant are available
• -Twice the volume of distribution to consider when calculating replacement doses

• Third most common
• Autosomal recessive inheritance
• Correlation between factor level bleeding tendency is poor
• Less spontaneous bleeding
• Treat with FFP

• Deficiency is very rare
• Acquired deficiency occurs with amyloidosis
• Treat with FFP

• XII is also known as the Hageman factor
• Have very prolonged PTT
• No evidence of clinical bleeding and have normal hemostasis

• Stabilizes fibrin clot after clot formation
• Autosomal recessive inheritance
• Normal screening coagulation tests
• Have late bleeding and poor wound healing
• Dx: Abnormal euglobulin clot lysis assay
• Tx: FFP

• Autosomal dominant inheritance
• Rare
• Inactivates activated IX, X, XI, XII
• Action is enhanced with heparin
• Protein may be decreased or dysfunctional
• Should always measure prior to the institution of heparin therapy
• Should measure with both a functioal assay as well as an antigenic assay
• Tx options:
• -Heparin -- remember: these pts may be relatively "heparin resistant"
• -Warfarin for long-term anticoagulation
• -Recombinant ATIII is available for surgery

• Autosomal dominant inheritance
• Rare
• Cleaves activated Factor V and Factor VIII
• Vitamin K dependent
• Should measure prior to the initiation of warfarin therapy

• Autosomal dominant inheritance
• Rare
• Functions as a cofactor with Protein C
• Vitamin K dependent
• Should measure prior to the initiation of warfarin therapy

• For an acute clot, pts should be anticoagulated with heparin
• Long-term therapy should be with warfarin

• Protein C and S function as anticoagulants, and both are vitamin K dependent
• When warfarin is initiated, the levels of the anticoagulants may decrease more quickly the tne procoagulant levels, resulting in a hypercoagulable state
• This is especially prominent in the patients who are protein C deficient

• Mutation in Factor V resultin in resistance to activated protein C
• Most common inherited hypercoagulable defect
• Found in up to 25% of patients with recurrent thrombosis
• Additive to other risk factors (OCPs, pregnancy, other defects)
• Tx: Heparin/LMWH followed by heparin
• Usually continued lifelong after pt has had an event

• Prolonged PTT
• Paradoxical clotting - may be venous or arterial
• Recurrent spontaneous fetal loss
• Tx options:
• -Anticoagulants -- Warfarin, Heparin/LMWH
• -ASA

• 1. Acute leukemia
• 2. Myeloid blasts
• 3. Chronic leukemia
• 4. CLL
• 5. CML

• Auer rod
• Indicates myeloid leukemia

• Myeloid
• Sudan Black
• Myeloperoxidase
• Esterases
• Auer rods
• More nucleoli

• Lymphoid
• PAS
• Fewer nucleoli

Positive sudan black, point toward a myeloid malignancy such as AML

• Associated with t(15,17)
• Translocation involving the retinoic acid receptor gene
• Good prognosis category
• Prominent Auer rods
• Commonly associated with DIC

• Monocytic
• Commonly associated with skin and soft tissue disease
• Gingival hyperplasia
• CNS disease may occur

• AML M5
• Will see gingival hyperplasia, skin involvement (leukemia cutis), soft tissue disease

• Cytogenetics
• Age -- the older pt has an adverse prognosis
• Secondary AML -- particularly resistant to therapy
• Performance status -- a poor performance starus is an adverse prognostic indicator

• Supportive care with transfusions
• Leukophoresis if blast count > 100,000 or for symptoms of hyperviscosity
• Combination chemo
• Treatment scheme:
• -Induction chemo -- designed to take a pt wo aplasia with recovery of "normal" hematopoieses and a remission state
• -Consolidation chemo -- designed to reinforce the remission obtained; usually multiple cycles given

• Treatment for this subtype is different
• -Based on the translocation of the retinoic acid receptor
• -Uses All Trans Retinoic Acid (ATRA) as a maturational agent
• -Avoids development or worsening of DIC
• -Must also include chemo with at least an anthracycline

• Primarily occurs in children
• Lymphadenopathy and splenomegaly occur in 50%
• Classic description: "A young male with an anterior mediastinal mass with peripheral T cell lymphocytosis"
• CNS disease is common

• Age -- the young fare better
• Blast count -- >30,000 do poorly
• Cytogenetics -- hyperdiploidy is a good finding, while a Philadelphia chromosome t (,22) is a poor prognostic finding

• Similar to AML, consists induction, consolidation, and multiple cycles of maintenance
• CNS prophylaxis - needed because they will relapse in the CNS without prophylaxis
• Adults have only a 30-40% long-term survival with standard therapy
• For relapsed and poor prognosis pts, bone marrow transplant offers long-term disease control

• Typicaly a disease of older individuals
• Commonly is asymptomatic at presentation with lymphocytosis found incidentally
• Lymphadenopathy and splenomegaly are common physical findings
• Workup includes:
• Flow cytometry, which is usually diagnostic
• -typically a B-cell disorder with an abnormal pattern
• -CD19, CD20, CD23 positive
• -CD5 Positive
• -Light chain restricted

• O Lymphocytosis > 10 years
• I Lymphadenopathy 6-7 years
• II Splenomegaly 6-7 years
• III Anemia 2-3 years
• IV Thrombocytopenia 2-3 years

• Symptomatic disease
• Rapid doubling of the WBC count
• Anemia
• Thrombocytopenia

• Transformation of CLL heralded by rapidly growing nodes or extranodal disease
• Upgrade to a more aggressive lymphoma such as diffuse large cell

• Rare
• B cell in phenotype
• Increased risk for infections
• Affects males over females 4:1
• Older patients affected
• Usual presentation is :
• -Pancytopenia
• -Large splenomegaly
• -Dry bone marrow tap

Hairy cell leukemia

• Diagnosis hinges upon flow cytometry findings:
• -CD 19, CD20 positive
• -CD5 negative
• -CD11C, CD 103 positive
• Bone marrow with hypercellularity and increased reticulin fibrosis "dry tap"
• TRAP stain positivity
• -- Tartrate-resistant acid phosphatase stain

• Symptomatic disease
• Infectious complications
• Anemia
• Thrombocytopenia

• Splenectomy
• 2-CdA
• Other purine analogs

Results in prolonged disease free survivals and possibly cures

• Stage I 1 node or group
• Stage II 2 or more lymph node groups, same side of the diaphragm
• Stage III Spans the diaphragm
• Stage IV Disseminated disease

• Bimodal age distribution
• Often see the "B" symptoms
• -Fever
• -Night sweats
• -Weight loss
• Pruritus is common
• Unusual complaint of pain with alcohol ingestion

• Treatment involves either:
• Combination chemotherapy
• -ABVD or MOPP
• Radiation therapy
• Combined modality therapy with both

• Hypothyroidism
• Infertility
• Secondary malignancy including
• -MDS/AML
• -Solid tumors such as breast and lung

• Very rapid growth pattern
• Looks like "starry sky" under low power
• Associated with a t(8,14)
• -involves c-myc proto-oncogene
• -moves to immunoglobulin gene loci
• Involves CNS and marrow frequently

• Low-grade lesions:
• -"Watch and wait" with treatment reserved for symptomatic disease
• -Treat until symptoms resolved, then observation again
• -Treament should be more aggressive if younger patient
• Intermediate and high-grade lesions:
• -Treat at time of diagnosis
• -Use combination chemo +/- radiation therapy
• -Standard of care is CHOP plus monoclonal antibody therapy with rituximab

• Usually an older population of patients
• Consider in older patients with unexplained anemia
• Consider in older patients with unexplained back pain
• May present with recurrent infections or hypercalcemia

• A low anion gap
• Rouleaux on peripheral smear
• An elevated globulin fraction (TP-Alb)

Rouleaux formation, associated with multiple myeloma

• 95% will have an abnormal protein on SPEP or UPEP
• The M spike is most commonly IgG followed by IgA, light chain disease, and IgD
• < 5% will be non-secretory and have no evidence of protein secretion

Multiple myeloma with "M spike"

< 10% marrow plasma cells and < 3 gm M spike

> 10% marrow plasma cells or > 3 gm M spike

• > 10% marrow plasmacytosis with and M spike and end-organ involvement
• -calcium, anemia, renal dysfunction, bone disease

• lesions are purely lytic and will not show up on bone scan
• Assess with metastatic bone survey

• Observation until clear progression of disease or the patient becomes symtomatic
• Melphalan and prednisone
• Combined chemo regimens
• Thalidomide/lenalidomide
• Bortezomib
• Bone marrow transplant

No therapy is indicated, but these pts should be followed at least yearly for progression of their diease

• Increased IgM levels
• More common in older men
• More consistent with a lymphoma with associated lymphadenopathy and organomegaly
• Presentation:
• -Lymphadenopathy/organomegaly
• -Purpura
• -Neuropathy
• -Hyperviscosity syndrome

• Burkitt's lymphoma
• -remember the "starry sky"

G6PD deficiency

Fe deficiency

AutoImmune Hemolytic anemia

Renal disease

• Liver disease
• Also called "acanthocytes"

• Hgb C
• Liver disease
• Thalassemia

• 1. CLL
• 2. Myeloproliferative d/o (CML, P.vera, ET, myelofibrosis)
• 3. Hairy cell leukemia
• 4. B12 and folate deficiency
• 5. Infection
• 6. Myelodysplasia
• 7. AML

Sβ+ thalassemia is characterized by a hemoglobins S level greater than 60%, with an elevated hemoglobin A2 level and mild microcytosis

Patients with sickle cell trait (AS), who are often confused with patients with Sβ+ thalassemia, have a hemoglobin S level that is less than 50% and a hemoglobin A level that is correspondingly greater than 50%. Patients with the sickle cell trait also have normal-sized erythrocytes.

Patients heterozygous for hemoglobin S with hereditary persistence of fetal hemoglobin have less than 70% hemoglobin S and greater than 30% hemoglobin F on electrophoresis.

Hemoglobin SC disease have painful crises in addition to an approximately 50:50 ratio of hemoglobin S to hemoglobin C on electrophoresis. Patients with hemoglobin SC disease also typically have hepatosplenomegaly. Sickled erythrocytes, reticulocytosis, and Howell-Jolly bodies are found on the peripheral blood smear in affected patients.

Positive results for anticardiolipin antibody or lupus inhibitor assay should be confirmed over time to ensure that they are not transient, which can occur after viral infections. Ideally, at least two positive laboratory tests (anticardiolipin antibody or lupus inhibitor assay) at least 12 weeks apart should be documented to confirm the presence of an antiphospholipid antibody syndrome before a patient is committed to lifelong anticoagulation.

One option in determining the risk for recurrent venous thrombosis in high-risk individuals is to measure the D-dimer concentration after 6 months of anticoagulation therapy. Patients at high risk may include those with idiopathic DVT occurring at a young age, in unusual locations, or with a strong family history. An elevated D-dimer level, obtained while the patient has ceased taking therapy for 1 month, is associated with an increased recurrence risk compared with a normal D-dimer level.

• Paroxysmal nocturnal hemoglobinuria is characterized by direct antiglobulin (Coombs)–negative hemolysis, pancytopenia, and thrombosis.
• Two such proteins, CD55 and CD59, help reduce erythrocyte sensitivity to complement. Deficiency of CD55 and CD59 can be detected by flow cytometry.
• Recently, eculizumab, a monoclonal antibody to C5, has been reported to offer a sustained response to patients with PNH.

Initial treatment of aplastic anemia involves withdrawal of any potentially causative agents and a CT scan of the chest to rule out an associated thymoma. If a thymoma is found, surgical excision can be curative.

• Start IV antibiotics. If no response after 5 days, start empiric antifungals.
• If there is still no response and the pt remains neutropenic and critically ill, GCSF is added to the regimen.

Erythrocyte osmotic fragility

Lenalidomide