Haematology — USMLE Step 2 CK Notes

Iron Deficiency: increased RDW

Anemia of Chronic (Inflammatory) Disease (Hepcidin inhibits iron coming into body)

Ferritin high just inaccessible; Low TIBC (measure of transferrin); Low Fe

Decreased Reticulocytes with increased RWD

Thallasaemia: Really Low MCV with DECREASED RDW ==> Think of Thalassemia as high Fe disease

Sideroblastic: BM biopsy showing ringed sideroblasts (increased iron) eg d/t INH

——->> INH use often manifests as microcytic hypochromic anemia (mimics Fe Def)

—> dimorphic RBC population (hypochromic and normochromic)

Macrocytic:

Hypersegmented neutrophils (5 or more lobes): Impaired DNA synthesis

B12 deficiency (TAKES YEARS!!!!!!): increased MMA

Folate Deficiency —> increased both!

Non megaloblastic: EtOH and Cirrhosis: Acanthocytes on a Smear; diamond Blackfan

Others: Hypothyroidism; myelodysplasttic syndromes; AML

Diamond Black fan anemia

D/t cong impairments affecting ribosome synthesis

Thumb abnormalities: Triphalangeal

Craniofacial abnormalities eg hypertelorism

Predisposed to AML and myelodysplastic syndromes

Increased HbF

Red cell aplasia; decreased Reticulocytes

Tx: corticosteroids and transfusions; transplantation

Hb <7 needs transfusion generally

Changes over chronic periods do not necessarily need transfusion -> Acute changes do

Normocytic Anaemia

Hemolysis: Increased LDH, Increased indirect Bilirubin, decreased Haptoglobin

SCD: Sickle cell crisis (aplastic crisis)

Sickle Cell trait

Autoimmune hemolytic anaemia:

Cold Agglutinin: Destruction in liver (IgM)

Warm Agglutinin: Destruction in spleen (IgG)

Tx: steroids then splenectomy if refractory

Spherocytes on Direct Coombs

Hereditary Spherocytosis: AD (Fam Hx); NE descent

Splenomegaly, bilirubin gallstones, increased MCHC (can be within high norm range)

Labs: Negative Coombs; abnorm eosin-5-maleimide binding test;

increased osmotic fragility on acidified glycerol lysis test

Tx: Folic acid supplementation; blood transfusion; splenectomy

Paroxysmal Nocturnal Hemoglobinuria:

Tends to manifest in 40s

Defect in PIG-A

Cytopoenias d/t impaired hematopoeisis eg low Plt; hypercoagualibility

Increased risk of aplastic anemia

Dark urine in morning, Budd Chiari syndrome (clots in weird places)

Dx: RBC CD55 and CD59 protein testing

Tx: Iron and Folate; Eculizumab (inhibits complement activation)

G6PDH Deficiency

Heinz Bodies (denatured Hb d/t oxidant damage)

——>>> damages membrane and precipitates ——>> macrophages try to remove

damage/precipitate ——>> bite cells

Prosthetic Valve dysfunction

Thrombocytopoenia as Plts also destroyed

RBC Fragments and schistocytes

Paravalvular regurg (holosystolic murmur) also often presents

PLATELETS

Primary Hemostasis = Plt Plug

Secondary Hemostasis = Factor Clotting

Begins with Fibrinogen ( Factor 1 surrounds Plt Plug)

Fibrinogen converted to Fibrin (Factor IA)

Fibrin converted to D Dimer by Plasmin

Plasminogen converted to Plasmin via tPA

Pseudothrombocytopoenia

Mild

Periph blood smear shows Plt clumping

—> lab error d/t Plt aggregation in vitro

—> Abs to EDTA (anticoagulant) common cause

DIC

Patient forms fibrin clots where they should not and use up resources

Can no longer clot where appropriate

Chronic DIC (Cirrhosis)

Acute DIC: Patient looks v v sick

DIC Panel: Plts, Hb, Peripheral Smear for Schistocytes

Deceased Plts, Decreased Hb, Fibrinogen consumed degrading clots

Increased D-Dimer; PT; PTT and INR (Consumption of Factors)

Often associated with MAHA: Elevated LDH, Reticulocyte count and Bilirubin

Malignancy Associations: Gastric, breast and lung cancer most common

——>>> GRAM - Sepsis, rhabdo, adenocarcinoma, heatstroke, pancreatitis, snake bites,

pregnancy, Tx of M3 AML

Transfuse Plts

Transfuse packed RBCs to increase Hb

Fresh Frozen Plasma to decrease INR

Heparin

Cryoprecipitate to increase Fibrinogen

If Cirrhotic then give albumin to boost volume

TTP

Deficiency/inhibition of metalloproteinase ADAMTS13 Large vWF multimers—> increase PLT ADHESION—> THROMBOSIS

Hyaline Clot not Fibrin

Shred RBCs but does not consume factors

Fibrinogen, D Dimer, PT/PTT/INR all normal but increased bleeding time

Triggers: Drugs eg clopidogrel (ticlodipine more so), cyclosporine, quinine

SLE, infections eg HIV/AIDS, malignancies

Pt: Fever

MAHA

Thrombocytopenia

Renal

Neuro

Dx can be made with FAT alone

Tx: Plasma Exchange

Do not give Plts (makes them worse!), Plts being consumed as part of pathology!

Traumatic macrovascular hemolysis

Most d/t dysfunctional mechanical or severely calcified AV

—-> High P Gradients across irregular valve cause RBC shearing

Dx: Echo to visualise valve function and determine valvular gradients

Heparin Induced Thrombocytopenia. TYPE 2

IgG Abs to Plts (PF4)

—-> Ab Plt complexes removed by macrophages etc ——> thrombocytopenia

Arterial/venous thrombosis

Necrotic skin lesions at heparin injection sites (abdomen if sc enoxaparin)

Acute systemic (anaphylactoid) reaction

Dx: Serotonin release assay gold standard. ——->> start tx prior to confirmatory test

Tx: Stop Heparin/enoxaparin and start argatraban/ lepirudin (depending on renal function)

——>>>>>> Both direct Thrombin Inhibitors but argatroban hepatically cleared

Wait to start warfarin until Plts recover

Type 1 HIT presents in first 2 days and resolves; mild

Venous thrombosis complication —->>> adrenal hemorrhage!

—->> shock

ITP

ASYMP but v low Platelets (<10)

—-> anemia not seen

Dx of exclusion: BM (malignancy), blood tests (infection), autoimmune check etc

Large Plts may be seen d/t increased turnover

Associated with HIV and HCV

Dx: Antinuclear Ab testing

Tx: >30k Plt then observe —-> steroids —-> IVIg if refractory to steroids/steroids CI

Splenectomy if refractory

Rituximab

HUS

Vascular damage and microthrombi formation

EHEC (shigella less commonly)

Normal Coagulation times!!! Thrombocytopoenia; hemolysis (schistocytes etc); AKI Do not give Plts (makes them worse!), Plts being consumed as part of pathology! Tx: Most improves in 2-3 wks; Supportive (correct electrolytes and Tx HTN)

Dont give antibiotics or antimotility agents for EHEC bloody diarrhoea as increases risk of HUS

Coagulopathies

VWD

Recurrent Epistaxis, heavy menses, petechiae, prolonged mucosal bleeding

Impaired Plt adhesion

NORMAL Plts

Normal/Increased PTT (may have adequate VII to maintain PTT) and increased bleeding time

States that increase vWF syn (preg, OCP, acute stress, thyroid hormone supplementation)

—->> more likely to have normal PTT (vWF and Factor VIII are acute phase reactants also)

Dx: vWF testing: vWF Ag, ristocetin cofactor activity, Factor VIII levels

Tx: often only needed if surgery/trauma

DDAVP for bleeding or pre-op

Haemophilia

Recurrent Bruising, hematuria and hemarthoses (joint pain and swelling)

Hemarthroses ——>>> typically starts in toddlerhood when child becomes ambulatory

Hematoma after minor trauma: hemorrhage into skeletal muscle

Most common sites of bleeding (80%) are joints, esp knee

Increased PTT that corrects with mixing studies

Tx: Factor replacement; desmopressin (+ cryoprecipitate and FVIII) for mild Hemophilia A (VIII def)

Vitamin K Deficiency

Decreased Factors II, VII, IX and X

Pt only eats meat and finished course of antibiotics

Increased PT (Increased PTT if severe)

Tx: FFP acutely + IM Vit K shot (same as warfarin toxicity)

Liver Disease

Thrombocytopenia

First Factor depleted is VII so PT rises first (before PTT)

Factor VIII and vWF made in endothelium so unaffected

Lupus Anticoagulant (antiphospholipid)

Increased PTT, DVTs

Protein C/S Deficiency

Skin necrosis after warfarin started

Factor V Leiden: Resistant to Protein C

Most common inherited Procoagulable State; norm coag times

ATIII Deficiency: Heparin wont work!

Nephrotic Syndrome: Pee out ATIII, Protein C and S preferentially

Increased risk of Renal Vein Thrombosis

Anticoagulation in end stage renal disease

Warfarin preferred LT but must be started on unfractionated heparin for 4-5 days until INR 2-3 (therapeutic range)

ANTICOAGULATION in malignancy:

Heparin; enoxaparin

Reversal of Warfarin: Prothrombin Complex Concentrate (Vit K dependent factors)

FFP takes longer to prep/administer but also effective

Reversal of heparin: Protamine Sulfate

Reversal of antiplatelet therapy (aspirin/clopidigrel)/thrombocytopenia: Plt transfusion

Tranexamic acid: antifibrinolytic agent used to tx blood loss in some surgeries

Reactive (secondary) thrombocytosis

D/t cytokines —> driven by inflamm state (infection/surgery/malignancy)

Transient (resolves after infection gone etc)

Splenectomy causes dramatic thrombocytosis

—> spleen removes senescent Plts

——> thrombocytosis usually resolves in wks/months (minority persist for years)

WARFARIN METABOLISM

Metabolised by P450

Acetaminophen interrupts Vit K recycling in liver —-> prolongs INR

Diet of high Vit K: leafy green veg

—-> decreased effect of warfarin

Abs reduce bacterial Vit K production in gut —> raises INR

Sickle Cell Anemia

Splenic sequestration crisis:

Common in younger patients whose spleens have yet to become fibrotic d/t recurrent vasospasm occlusion

Rapidly enlarging spleen —> Splenomegaly and signs of Shock

Thrombocytopenia (platelets also trapped in spleen) w reticulocytosis

Bacteraemia, sepsis, pneumonia and meningitis most likely d/t Strep Pneu

MCC of osteomyelitis still staph aureus (salmonella effects SCD pts more but not MCC overall) Avascular necrosis can have normal XRAYS for months w norm inflamm markers

—> crescent sign in adv stage

Sickle Cell Stroke

Tx: Exchange Transfusion

Aplastic Crisis: Acute Severe Anemia In SCD

Transient arrest in Erythropoiesis

Secondary to infection eg Parvo —> non specific flu like sx

Decreased Reticulocytes w norm Plt number (cf splenic crisis)

Acute Lymphoblastic Leukaemia

Peak age 2-5yrs

M>F

Bone Pain

Nontender LAD and Fever

Hepatosplenomegaly d/t leukaemia infiltrates (swollen gums also)

Pancytopenia

Aplastic Anemia

Pancytopenia

BM Failure d/t HSC Deficiency

D/t Autoimmune; Infection (B19/EBV); Drugs (carbamazepine, chloramphenicol, sulfonamides);

Radiation/Toxin (benzene, solvents)

Hypocellular BM with fat infiltration and Stroma cells

No Bone Pain or Splenomegaly Tx: Remove offending agent —> often resolves

Persistent requires immunosuppressives/ HSCT

Thalasseamia:

Norm Hb: 2 alpha and 2 beta (HbA) or 2 alpha with 2 gamma (kids) (HbF)

Beta Thalassemia Major: genes mutated

Absent beta globin

Increased HbF and Hb A2 (2Alpha, 2 theta)

No HbA

Masks DM?

Tx: Blood transfusion w iron chelation

Alpha Thalassemia: genes deleted

Minima: 1 gene loss —> asym

Minor: 2 genes lost —-> mild microcytic anaemia

HbH: 3 alpha genes lost: tetramers of beta chains: children/adults

Chronic hemolytic anaemia

Hb Barts: tetramers of gamma chains: foetuses/infants (death in utero often occurs)

High output HF; anasarca

Chronic hemolysis d/t short RBC lifespan and increased splenic sequestration

Target cells on peripheral smear d/t reduced RBC volume

Neonatal Polycythemia

Hematocrit >65% in term infants

D/t intrauterine hypoxia; diabetes, HTN or smoking; RBC transfusion; delayed cord clamping; twin-twin transfusion

Most commonly asymptomatic

Ruddy complexion

Hypoglycaemia, hyperbilirubinaemia

Resp distress, cyanosis, apnea, Irritability

Abdo distension

Tx: IV Fluids; Glucose; Partial exchange transfusion

Anemia of prematurity

Impaired EPO Production; short RBC life span and iatrogenic blood sampling

Usually asymptomatic

Tachycardia; apnea; poor weight gain

Low Hb and hematochezia w low Reticulocyte count

Normocytic, normochromic RBCs

Tx: minimise blood draws; Fe supplementation; Transfusions

Neuroblastoma

Neural crest origin

Precursors to adrenal medulla and Sympathetic chain ganglion (Can cause Horners Syndrome)

Harlequin Sign: Absent facial flushing on one side

Median age <2

Abdo mass

Periorbital Ecchymoses (Orbital metastases): Racoon eyes

Spinal Cord Compression d/t epidural invasion (dumbbell tumour)

Opsoclonus-myoclonus Syndrome (Opsoclonus—rapid eye movement)

Elevated catecholamine metabolites: vanillylmandellic and homovanillic acid)

Small round blue cells on histology

N-myc amplifications

Fanconi Anemia

Inherited DNA repair defect

BM Failure

Short

Hypo/hyperpigmentation macules

Abnormal thumbs

Genitourinary malformations

Pancytopenia (Aplastic Anemia)

Polydactyly or flat thenar eminence

Tx: Hematopoietic SC Transplant

Langerhans histiocytosis

Rash similar to candida diaper rash:

Beefy erythematous plaques w satellite papules

Lytic bone lesions

Most common brain tumour in children is low grade astrocytoma

New onset seizures may be presenting sign

Craniopharyngioma

Endocrinopathies d/t pituitary stalk compression eg growth delay

20% BLASTS defines acute leukaemia

ALL

Most common cancer in kids

CALLA or TdT

Tx: Intrathecal methotrexate for CNS penetration

BM Transplant after first remission

AML

More common in adults

Risk Factor: Radiation Exposure; Downs; myeloproliferative disease

Auer rods, myeloperoxidase, esterase

Hairy Cell Leukaemia (mature B Cells)

Enlarged spleen but no adenopathy

TRAP; decreased monocytes

CD11 & CD22 +

Tx: Cladribine

Lymphoma

B Symptoms, >40, increased ESR & LDH, large mediastinal LN all equal bad Px

Hodgkin: orderly centripetal spread; painless LAD

Mediastinal LAD -> enlarged cardiac silhouette/mediastinal mass

Epitrochlear nodes!!!

——>>> best px: lymphocyte predominant

Bimodal 15-35 and >60

Pruritus (paraneoplastic syndrome)

Eosinophilia

Worsens after alcohol

Potential SVC syndrome and erythema nodosum

A driamycin (aka hydroxydaunorubicin)

B leomycin

V inblastine

D acarbazine

Those treated for Hodgekins at LT increased risk of solid organ malignancy (radiation)

And haematological malignancy (chemo) as well as CV disease

Non Hodgekins most likely to affect extranodal sites: BM and spleen etc

Diffuse nontender LAD

Latent oncogenic viruses pose RF in immunocompromised: EBV

Tx: Stage 1/2 get radiation; 3/4 get ABVD (Hodgekins) Chemo or CHOP (non hodgekins)

C yclophosphamide

H ydroxydaunorubicin

O ncovin (Vincristine)

P rednisone/prednisolone

Subtypes:

Burkitt lymphoma: t(8;14)

—>> translocation of c-myc and heavy-chain Ig

diffuse large B-cell lymphoma

—> Bcl-2 and Bcl-6

follicular lymphoma: t(14;18)

—> translocation of heavy-chain Ig and BCL-2

Indolent with painless peripheral LAD (waxing and waning)

B sx and elevated LDH, cytopoenia etc generally absent

mantle cell lymphoma: t(11;14)

—>. translocation of cyclin D1 and heavy-chain Ig

marginal zone lymphoma: t(11;18)

—> promotes the continuous activation of the transcription factor NF-κB

Primary CNS Lymphoma

EBV and HIV Association

NHLs of T-cell origin

—> adult T-cell lymphoma

mycosis fungoides (cutaneous T-cell lymphoma)

Polycythemia Vera

Hydroxyurea can prevent thromboses

Multiple Myeloma

IgG, IgA, Light Chains

10% clonal B cells

Rouleaux

Osteolytic fractures

Increased Total PROTEIN

Tx: Young get BM Transplant

Old: Melphalan (nitrogen mustard alkylation) + prednisone

Hydration and furosemide then biphosphonates for hyperCa

Waldenstrom Macroglobulinaemia

Hyperviscosity

Bleeding, LAD, Hepatosplenomegaly

Cryoglobulinaemia——-> worsens hyperviscoity; vasculitis, skin necrosis

Rouleaux

> 10% Clonal B Cells

Prostate metastasis

Osteoblastic lesion ——->>> focal sclerosis

Chronic Lymphocytic Leukaemia

Multi chain LAD, hepatosplenomegaly

Thrombocytopenia (mild), lymphocytosis and normocytic anemia

Often asymptomatic

Median age of dx is 70 —> median survival 10 years

Dx: Flow cytometry

Severe lymphocytosis with smudge cells

Increased risk of severe infections

—-> Hypogammaglobulinaemia and irregularities in immune cell signal/function

Autoimmune hemolytic anemia

Secondary Malignancy: eg Richter transformation

Tx: Rituximab —>> mAb against CD20 Ag

Single brain metastasis NSCLC

Surgical resection

Brain Metastases

Well circumscribed enhancing lesions usually located at grey-white junction

Leading cause are cancer of: Lung, Breast, Melanoma and Renal Cell carcinoma

Parinaud Syndrome (dorsal midbrain syndrome)

D/t pinealoma, medulloblastoma

Limited upward gaze (downward also poss)

Upper eyelid retraction (Collier Sign)

Pupillary abnormalities (ie reactive to accommodation but not to light)

—-> light-near dissociation

Pinealoma

Headache and Parinaud syndrome

Obstructive hydrocephalus (block aqueduct of Sylvius)

Myelofibrosis

Increased/decreased Periph Blood count

Superior Sulcus Tumour

Referred Shoulder/neck/arm pain

Horner Syndrome (invasion of paravartebral sym chain/stellar ganglion)

Invasion of C8-T2 nerves (ulnar n): Weakness/atrophy of intrinsic hand muscles

Pain/parathesia of 4th/5th digits and medial arm/forearm

Supraclavicular LAD

Weight loss

Hemidiaphragm paralysis d/t phrenic nerve involvement

SVC Syndrome

Progesterone analogue used to tx cancer related cachexia

Myelodysplastic syndrome

HSC Neoplasm

RF: Age; prev chemo/radiation

May transform into acute leukaemia

Cytopoenias

Hepatosplenomegaly/LAD are rare!

Dx: Peripheral Smear shows dysplastic RBC & WBC

BM biopsy required for Dx ——>> hypercellular marrow

Tx: Transfusions for symptomatic cytopoenias

Chemo; HSCT

DDX —> Myelofibrosis

Always associated w massive splenomegaly d/t extramedullary hematopoesis

Chemo related diarrhoea

Voluminous, watery and persistent (nocturnal)

—-> secretory

Tx: Loperamide

TTP associated with ticlopidine

Tx: Plasmaphoresis, do not give Plts AS CONSUMED!

Remember that coagulation times norm in HUS and TTP

Testicular Cancer

Germ Cell Tumours: GCT ## Ages 15-35

RF: Family hx; cryptorchidism

Metastatic sx: lung and liver common; retroperitoneal LNs —> lymphatic spread

SOB (lung); anterior neck mass (LAD); low back pain (bulky retroperitoneal LAD)

95% cure rate (radical orchiectomy; chemo)

Seminoma GCT: Norm AFP

Most common germ cell tumour

Peaks incidence 30s

Fried egg appearance (~Dysgerminoma in F)

Increased placental alkaline phosphate (PLAP) and Beta hCG

Tx: Radical inguinal orchiectomy (also to confirm dx)

Non seminoma GCT:

Scrotal US: Lesions w cystic areas and calcifications

Tx: Radical inguinal orchiectomy (also to confirm dx)

Yolk Sac Tumour (endodermal sinus tumour)

Infants/Children

Schiller-Duval Bodies (glomerulus)

AFP and alpha 1 antitrypsin

Choriocarcinoma

Highly malignant —> brain and lung mets

Increased hCG —->> gynecomastia, hyperthyroidism

—-> structurally similar to FSH/LH and TSH

Teratoma

Malignant

Any age

Embryonal carcinoma

M 20s/30s

Painful, aggressive

Normal AFP unless mixed

Elevated hCG

Sex Cord-Stromal Tumours

Leydig Cell

Often produce excessive estrogen (gynecomastia) or testosterone (acne)

—-> can cause precocious puberty —-> decreased LH

Golden brown

Contains crystalloids of Reinke in cytoplasm

Sertoli cell

Most benign and hormonal silent

Rare

NHL

Testicular Lymphoma

Most common testicular neoplasm in M >60

Usually diffuse large B Cell

Often involve CNS

CA 125

Fibroids and endometriosis can cause elevations

===>>> unlikely in postmenopausal F

Used in conjunction with pelvic US to categorise ovarian mass as likely malignant/benign

Used to monitor for recurrence also

Osteoid Osteoma

Benign

Proximal femur most common site

Pain: Worse at night

Relieved by NSAIDs

Unrelated to physical activity

No systemic sx

X-RAY: Small, round lucency w sclerotic margins (looks lytic)

Tx: NSAIDs

Monitor for spontaneous resolution

Osteoblastoma

Spine

Not relieved by NSAIDs

All neurogenic mediastinal tumours are in posterior mediastinum

—> neuroblastoma; lymphoma;

Dx: MRI to evaluate

Lynch Syndrome

Colon, ovarian and endometrial cancer

Head and Neck SCC (HNSCC)

HPV common cause

RF: Smoking; Occupational (Welding fumes)

Cervical LAD

Referred otalgia d/t CNIX and CNX involvement

Dx: Flexible Bronchoscopy? to identify primary tumour site

Ant Mediastinal Mass: 4Ts

Thymoma, Thyroid, Teratoma (GCT), Terrible LAD (lymphoma)

Oligodendroma

Fried egg cells

Calcifications

Frontotemporal

Tx: resection

Pilocytic astrocytoma

MCC glial tumour in kids

MC in cerebellum

Rosenthal fibres

NF1 association

MCC Dx brain tumour: MRI w gandolinium

Glioblastoma

MRI

Pseudopalisade around central necrosis

Ring enhancing lesion w serpentine margins

Butterfly glioma

Meningioma

Psammoma

NF2

Hydrocephalus

Compress motor stripe