Table of content
- Hematology
- Anemias and Hemorrhagic Disorders
- Myeloproliferative Neoplasms (CML,PV, ET, PM)
- Lymphoma
- CLL
- MM
- Acute Leukemias
- Aplastic Anemia
- Myelodysplastic Syndrome
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Year 4
Year 5
Year 6
Hematology
Anemias and Hemorrhagic Disorders
- Hypochromic + microcytic anememia (might be normocytic initially)
- low serum iron
- low ferritin
- incr. TIBC + Transferrin
- Normal/Low Reticulocytes
- Thrombocytosis
- high RDW
- 🦴-marrow → Absent iron reserves (Perl's stain)
- Has to present decreased MCV and MCH Values in the complete blood count
- Can be a Thalassemia, Anemia of a chronic Disease, Iron deficiency anemia or sideroblastic anemia
- Low serum iron
- Low TIBC
- Normal/high ferritin (elev. due to inflammation) -associated with elevation in acute phase reactants (ESR, CRP, fibrinogen, platelets)
Heterozygotes (minor beta talassemia)
- normal clinical status
- mild pallor
- hepatosplenomegaly (HSM)
Homozygotes (major beta talassemia)
- growth retardation
- bone deformeties - short limbs, mongoloid facies
- intense pallor, jaundice + melanodermia (pseudo-tanned)
- HSM
- Iron overload! → organe dmg (HF, LF, hypogondism, DM,RF)
→📷
- severe microcytic anemia
- target cells, basophilic inclusion
- teardrop cells
- Erythroblasts in periph blood
- indirect hyperbili
- normal-high iron, ferritin, transferrin
- Perls stain → incr. hemosiderin in target organs
- low RDW
- Electrophoresis! → low HbA1, incr. HbA2 + HbF
Hereditary: Bernard-Soulier (Gp1b), Glanzmanns (G2b-3a), storage pool disease, (vWD if associated with FVIII); or vWD Type 2
Acquired: drugs (NSAIDS, ASS), Uremia, myeloproliferative disorders
- Splenomegaly due to:
- TTP, Hemolytic Uremic Snd, Heparin induced Thrombocytopenia, DIC
- ITP → Idiopathic + secondary
→idiopathic children; second. adults
- idiopathic: auto-AB platelet destruction
- secondary→Antibiotics, Lupus, Aids, Hep C
- classic clinical picture:
- petechia, echymosis, purpura
- epistaxis
- gum bleeding
- no splenomegaly
MUCO-CUTANEOUS BLEEDING
- Steroids (1-2mg/kg)
- Splenectomy (if no response to steroids)
- IVIG (IV immunoglobulins)
- Thrombopoietin receptor agonist (Eltrombopag + Romiplostim)
- abrupt onset
- mucocutaneous bleeding
- pallor
- jaundice
- thrombotic events (cerebral, cardiac)
- neuro-psychiatric symptoms
- renal failure
LAB
- thrombocytopenia
- hemolytic anemia
- reticolocytosis
- Schisocytes (red helmet cells)
- BUN+Crea elev.
- Low ADAMTS13 + AB
- muco-cutaneoal bleeding (esp. Ear-nose-throat)
- prologend BT
- normal PT + APTT (→ APTT high if low FVIII)
- low vWF
- Ristocetin cofactor activity → neg. in vWD
Hemophilia A → FVIII
Hemophilia B → F IX
deep bleeding:
- hemarthrosis (knee, shoulder, elbow, hip)
- hematomas
- hematuria
severe →spontaneous hemorrh (<1% residual factor)
medium → after minor trauma (1-5%)
mild → after trauma or surgery (5-25%)
⇒ DG
- incr. APTT
- normal PT, ThrombinT, BT
Causes:
"STOP Making Trouble"
- infections (sepsis)
- trauma
- Obstetric complications
- Pancreatitis
- malignancies (acute leukemia)
- Acute hemolytic transfusion reaction
Lab:
- increased aPTT, PT + bleeding time
- high D-DImers,
- low Fibrinogen
- Thrombocytopenia
- Schistocytes
Myeloproliferative Neoplasms (CML,PV, ET, PM)
- can persist up to 20 years + often subclinical
- B-symptomatic: weight loss, fever, night sweats, fatigue
- splenomegaly
- pallor
- hepatomegaly
- priapism (painful permanent erection ≥2h)
- dyspnea
→ might develop into accelerated phase (anemia, infection, extr. splenomegaly) or blast crisis (terminal stage: symptoms like acute leukemia, pancytopenia, prog. splenomegly)
- severe Leukocytosis (often >100k) with Metamyelocytes, Promyelocyte + Myelocytes, myeloblasts (left shift)
- Basophilia + Eosinophilia
- Blast can indicate transition to accelerated phase
- mild anemia
- Thrombocytosis
→ bone marrow: incr. granulopoiesis, left shift, basophilia
→ cytogenetics: Philadelphia chromosome (BCR-ABL gene) → high TK-activity
→ hyperuricemia + high LDH
⇒ if incr. basophils + blasts (>20%) → blastic phase
Chronic phase:
- TK-inhibitors (1:Imatinib; 2: Dasatinib, Nilotinib)
- only curative treatment: bone marrow transplant (not preffered → high transplant related mortality)
- hydroxyurea + alpha-interferon
Blastic phase:
- TKI + chemo (depending on type: AML or ALL)
- allogenic stem cell transplant
- Hyperviscosity synd (mucosal bleeding, neurological symptoms, visual changes)
- Thromboembolism (MI, stroke, DVT )
- Pruritus (aquagenic)
- Red skin, face, palms
- splenomegaly
- Budd-chiari syndrome
- might progress to AML or Myelofibrosis
Major Criteria: Hb>18,5 / 16,5; Jak2 mutation
Minor Criteria: trilineage prolif (bonemarrow), low EPO, endogenous erythroid colony growth (EEC)
→ 2 major + 1 minor OR 1 major + 2minor
(!in lab: trilinage = major → pos.= all major or 2 maj+1minor; without EEC)
Additional symptoms:
- erythrocytosis + high Hct
- Leuko + Thrombocytosis
- Low/normal EPO
- High LDH
- Low iron
DD→ secondary polycythemia
- high altitude
- chronic hypoxia
- renal artery stenosis
- chronic bronchitis + chain smoker
- cor pulmonae
- congenital cardiopathies
- EPO-secr. tumors
Treatment
- phlebotomy (until normal Hct) - repeat when needed (1m)
- aspirin (75-150mg/d)
- hydroxyurea (1-2g/day)
- Jak2 inhibitors (Ruxolitinib) - future shizzl
- antihistaminika
- alpha IFN
Criteria: → all must be present!
- Plt >450k (often >1mil)
- Megakaryocyte hyperproliferation (large + lobulated)
- JAK2 or CALR mutation
- Exclusion other myeloid proliferations (CML, PV, PMF)
in lab: +minor criteria: clonal markers or absent of evidence for reactive thrombocytosis (pos = 4 major or 3maj + 1min)
other lab markers:
- rule out reactive causes: iron def, infection, malignancy, splenectomy, surgery trauma
- normal iron + ferritin
- no philadelphia chrom
- no polycthemia
- WBC could be high + left shift basophilia
DD: infection, inflammation, malignancy, hemorrhage, iron deficiency anemia, hemolytic anemia, post-splenectomy, post-chemo, other myeloprolif. synd.
Treatment:
- Low risk (<1,5mil, <40, no thrombosis+hemorrh): aspirin low dose (75-150mg/day)
- intermediate (<1,5mil, 40-60y): aspirin low dose; if other thrombosis risk factors → add hydroxyurea or anagrelide
- high risk (>1,5mil) → asprin low dose + hydroxyurea or anagrelide
→ no aspirin in hemorrhage!
→ very high platelets + hemorrhage or thrombosis → platelet apheresis
- symtoms of anemia
- severe splenomegaly (+hepatomegaly)
- b-symtomatic: weight loss, sweating, fever
- abdominal pain + bloating
- hemorrhage
Major:
- Proliferation with atypical megakaryoctes + fibrosis (reticulin/collagen)
- Exclusion other myeloid proliferative (CML, PV, ET)
- JAK2 or CALR or exclusion reactive myelofibrosis
Minor:
- Leucoerythroblastic picture
- high LDH
- Anemia
- Splenomegaly
→3 major + 2 minor (lab: only 1 minor)
- dacriocytes (extramedullary hematopoesis)
- bonemarrow biopsy → myelofibrosis
- evtl. autoimmune hemolytic anemia (reticulocytosis, jaundice, pos. coombs)
- thrombocytopenia
→transfusion + JAK inhibitors, hydroxyurea, stem cell transplant (=only curative T)
Lymphoma
Hodgkin Lymphoma
- lymphadenopathy (cervical, firm, mobile, painless)
- b-symptomatic (weight loss, fever, night sweats)
- alcohol induced pain
- dry cough
- pruritus
- compressive edema
→ biopsy (lymphnode, bonemarrow, liver): Reed-Sternberg + Hodgkin cells + reactive normal cells
→ chest imaging xray, CT, PET
→Lab:
- high ESR + anemia
- Leucocytosis (Neutrophilia, Eosinophilia + Lymphopenia)
- Altered liver test (ALT, AST, bili)
- High LDH
→ assessment of HL diseases extension
- 1 group of lymph nodes
- ≥2 groups, on one side of diaphragm
- ≥2 groups, both sides of diaphragm
- DIffuse visceral - liver, bone marrow, etc.
A=absence general symtoms
B=presence ≥1 general symptoms (weightloss, sweating, fever)
treatment → 40-90% cured
adverse prognostic factors:
- MC (mixed cellularity) or LD (lymphocyte depletion)
- >40y + male
- B-symptoms
- ESR>40
- stage III/IV
- bulky disease
⇒ Treatment:
Chemo +- Radiotherapy(in bulky disease L-node >10cm)
→ ABVD x 2-8 (Adriblastin, Bleomycin, Vinblastin, Dacarbazin) every 30 days
→alternative: BEACOPP x6-8
⇒ if relapse >12month → repeat ABVD
⇒ <12month → Salvage regimen (DHAP, IGEV) + High dose chemo (BEAM) + stem cell transplant
Non-Hodgkins Lymphoma
Predisposing factors:
- genetic (family!)
- EBV, HCV, HIV, HTLV-1, HHV-8
- heliobac pylori, campilobacter jejuni
- radiation + chemicals (solvents)
Clinic:
- slow or rapid onset
- lymphadenopathy
- b-symptomatic (fever, night-sweats, weightloss)
- splenomegaly, hepatomegaly
- skin tumors , rash
- anemia signs
- extranodal: diarrhea, neurological symtpoms, dypnea
→ mediastinal lymphadenopathy: thoracic edema
→ inguinal, abdominal: lower limb edema
→ abdominal, splenomegaly, hepatomegaly → abdominal pain
B-cell vs. T-cell
Indolent NHL vs. Agressive NHL
B-cell
indolent: CLL/lymphcytic NHL, MALT lymphomas, Follicular (small or mixed cell)
aggressive: Diffuse large cells, B-cells lymphblastic NHL(B-ALL), Burkitt
T-cell
indolent: Mycosis fungoides(cutaneous T-cell lymphoma), Large granular cell leukemia
aggressive: Periph. T-cell NHL, T-lymphoblastic NHL(T-ALL), Angioimmunoblastic NHL
- indolent → incurable (advanced stages at dg)
- aggressive → potentially curable (40-50%)
- adverse prognostic factors:
- >60y
- Ann Arbor III,IV (both sides of diaphragm)
- >1 extranodal site (diarrhea, neurological sym, dypnea)
- high LDH
- Performance status ≥2 (unable to carry out any work activities or worse)
- line:
- Indolent: COP (cyclophosphamide, vincristine, prednisone) or FluCyD (Fludarabine, cyclophosphamide, prednisone) → in B-cell: add Rituximab → R-COP / R-FluCyd; in T-cell: add alemtuzumab
- Aggressive: Bcell: R-CHOP (Rituximab, Cylclophosphamide, DOxorubicin, Vincristine, Prednisone;[ repeat every 21days x4-8]); T-cell: CHOP
- line: if refractory or relapsed
⇒ Treatment:
→ DHAP +- Rituximab
→ high dose chemo (BEAM)+ stem cell transplant
Radiotherpy (in bulky) or Superficial skin irradion in cutaneos T-cell lymphome
Radioimmunetherapy
CLL
- non-symptomatic (30% → incidental finding)
- b-symptomatic (fever, sweating, weightloss)
- lymphadenopathy (generalized, soft, painles)
- signs of anemia + thrombocytopenia (pallor, jaundice, hemorrhage)
- infections
- splenomegaly, hepatomegaly
- extra-lymphatic involvement: skin, GI, lungs
LAB
- Leucocytosis
- Lymphocytosis (>5k)
- nuclear shadows
- Bone marrow → lymphocytic infiltration
- Anemia
- due to infiltration
- AUtoimmune hemolysis: anemia, reticulocytosis, indirect bili, positive Coombs
- thrombocytopenia
- hypogammagloblinemia
→immunophenotyping: B-cell (CD 5,19,20,23)
- infections
- Autoimmune:
- Hemolytic anemia
- thrombocytopenia
- rheumatoid arthritis
- aggressive transformation → Richter syndrome
- secondary malignancies: epiteliomas, GI cancer, lung cancer
→ depens on RAIU stage
0: Lymphos >5k + Bone marrow lymphocytosis >40%
1: 0 + lymphadenopathy
2: 0 (+-1) + heptosplenomegaly
3: 0 (+- 1+2) + anemia
4: 0 (+- 1,2,3) + thrombocytopenia
⇒ 0,1,2 ,asymptomatic → watch + wait
⇒ 3+4 or symptoms
→ Fit patients <65y → FCR x6 every 28days (fludarabin, cylophosphamide, rituximab)
→ Unfit >65y → R-COP (every 21days);
→ consider CAMPTH (antibodies), young: stemcell transplant
→ steroids in autoimmune hemolytic anemia
→ transfusion + antibodies
→ secondary cancer treatment
MM
- Anemia signs
- Bone pain (back pain) + fractures
- RF-signs (renal amyloidosis)
- recurrent infections
- CNS+PNS abnormalities
- b-symptomatic
- hypercalcemia symptoms
- foamy urine (bence jones)
- hepatic + cardiac amyloidosis
- hyperviscosity snd
Dg criteria:
- Monoclonal(M)-protein in serum or urine
- Bonemarrow → Clonal plasma cells or Plasmacytoma
- Related organ impairment - CRAB (HyperCa, RF, Anemia, Osteolytic bone lesions)
- high ESR
- Hyperproteinemia (peak gamma fraction)
- incr. of 1 Ig → low others (i.e. high IgG→ low IgA,M)
- signs of RF (urea + crea)
- electrophoresis with immunofixation → presence of monoclonal fractions (i.e. IgG + lambda or others (IgA, IgE,Bence jones)
- proteinuria (bence jones prot)
- Hypercalcemia
- Anemia
- Bonemarrow → plasma cells >30%
- Chemo:
- Melphalan + Prednisone
- VAD (Vincristine, doxorubicin and dexamethasone)
- High dose chemo + autologous Hematopoetic stem cells
- BCD → Bortezomib (proteasome inhibitor), Cyclophosph, Dexamethasone; repeat at 28 days; → 6 cycles + followed by STEM cell transplant; 8 cycles if no Stem cell transplant (lab)
- Bortezombin with Velcade, Dexamethasone + Melphalan (lect)
- Trauma avoidance
- Painkills
- Treat RF
- Biphosphonates
- Transfusion or EPO
Clinical picture:
- Anemia signs
- Lymphadenopathy
- Hepatosplenomegaly
- Hyperviscosity synd (blurred vision, neurological disturbances)
- Renal failure sign
- Hemorrhage
- Infections
Lab:
- Anemia
- high ESR
- Thrombocytopenia
- Periph smear: Lymphocytosis
- Hyperproteinemia (gamma peak on )
- high igM (electrophoresis with immunofix)
- Bonemarrow: Lymphoplasmacytoid cells
- evtl. osteolysis + hyperCa
Acute Leukemias
COMMON:
- sudden onset (days-weeks)
- Anemia
- Thrombocytopenia (bleeding, petechia, purpura, etc)
- Infections
- Hepatosplenomegaly
- leukostasis → DIC, priapism
ALL:
- fever
- lymphadenopathy (painless) !
- bone pain
- airway obstruction (stridor) due to thymic infiltration
- superior vena cava syndrome
- Metastasis
→ meningeal leukemia (neurologic symtoms)
→ testicular enlargement
AML:
- Leukemia cutis (purple nodules)
- gingival hyperplasia
CBC:
- Anemia + THrombocytopenia
- WBC high/normal/low
Periph smear:
- Blasts!
- low neurophils
Bone marrow:
- blast >20%
- reduced normal precursors
- peroxidase pos → AML
Immunophenotyping:
- Lymphoid markers for B (CD10, 19,20) and T + early lympoid markers
- Myeloids markers for Granulocytic (CD13, CD33)
Karyotyping
- normal → good prognosis
- translocations (esp. philadelphia + t(4,11) → bad prognosis)
Molecular testing (PCR, sequencing)
→ FLT3 mutation(bad prog); NPM1 mutations (good prog) → in AML
Supportive measures:
- Isolation
- hygene
- hyperuricemia prophylaxix (allopurinol)
- Antibiotics, antifungals, antivirals
- transfusion (Hb<7 or Plt<10-20k)
- growth factor in severe neutropenia
Treatment
- Remission induction → 3/7 regimen x1-2
- Remission consolidation high dose Ara-C x3-4
→in M3 (acute promylocytic leukemia): induction with all-trans retinoic acid, consolidation,
maintenance (up 2 years)
→ consider stem cell transplant in intermediate/bad risk patients + relapse/refractory diseases
Supportive measures:
- Isolation
- hygene
- hyperuricemia prophylaxix (allopurinol)
- Antibiotics, antifungals, antivirals
- transfusion (Hb<7 or Plt<10-20k)
- growth factor in severe neutropenia
Treatment phases
- Remission induction: antracyclines, vincristine, L-asparaginasa, corticosteroids
- CNS prophylaxis: MTX, Ara-C
- Consolidation: high dose MTX, AraC
- Maintenance (up to 3 years): Low dose 6MP, MTX
→evtl. add TKI in philadelphia translocation
→ consider stem cell transplant in bad prognostic factor <60y + with philadelphia chromosome
- general bad prognosis → median survival <1y
- good prognostic factors (30-50%cure)
- <60y
- FAB M3 with t(15;17) → 70-80% cure
- NPM1 mutation
- bad prognostic factors (5-10% cure)
- >60
- AML therapy related
- "Bad" karyotype (i.e. philadelphia, t(4,11)
- FLT3 mutations
- AML with myelodysplastic changes
Aplastic Anemia
Patho:
- Autoimmune T-cell mediated → expansion of CD8+ T-cells → Cytokines (gamma-Interferon + TNF) → supress progenitor-cell growth by affecting mitotic cycle + inducing apoptosis
- myeloablative agents → direct toxicity
Clinical picture:
- slow onset
- Anemia signs
- Low Neutrophils - infections
- thrombocytopenia - bleeding
- ATG (anti-thymocyte globulin) + Cyclosporin
- Transfusion (Platelets + RBC)
- Antibiotics
- Hematopoetic growth factors (EPO or Granulocyte colony stimulating factor)
- (allogeneic hematopoetic) stem cell transplant → <40y + failure of immunosupressive treatment (ATG+Cyclosp)
Myelodysplastic Syndrome
- CBC:
- Cytopenias → always anemia - bicytopenia - pancytopenia
- Periph. Smear:
- Macro/microcytosis
- Dysplastic granules
- Hypolobulated + Hypogranulated Neutrophils
- blastic cells (late stage)
- Giant platelets
- Bone marrow:
- Hypercellularity (rarely hypocell)
- Diserythropoesis
- Megaloblastosis
- Multinucleated erys
- ring sideroblasts
- Disgranulopoiesis
- Giant precursors
- incr blasts
- Dismegakaryopoiesis
- Micromegakaryocytes
- Karyotyping → different prognosis