Haematological - the basics Flashcards
Haematological general history, exam, Ix
Symptoms
- fatigue/lethargy, weight loss
- fevers, sweats, rigors
- rashes/spots, lumps/bumps, mouth pain
- body or joint pain or swelling
- easy bruising/bleeding (malena, menorrhagia, epistaxis, post op)
- headaches/visual dist/neuropathy
- cp/sob or reduced ex tol/palp/dizziness/leg swelling
- n/v/d/abdo pain, dysuria/freq
PMHx/FHx:
- malignancy (aml, all, cml, cll, myeloma, lymphoma)
- siblings (their ages and medical issues)
- myeloproliferative neoplasm (PCV, essential thrombocytosis)
- anaemia (aplastic, IDF, chronic dis, haemolysis, thal, sickle cell)
- bleeding (haemophilia, VW def)
- thrombosis (DVT/PE, APL syndrome)
- platelets (ITP/DIC/TTP/HUS/HELLP/HITS)
- haemochromotosis/amyloidosis
- immunodeficiency
Further Hx:
- recurrent infxns
- transfusion rxns
- HSCT (indication, complications)
- race/ethnicity (African ass/w sickle cell anaemia)
Meds:
- Bleeding: NSAIDs, antiplts, anticoags, SSRI, herbal meds
- clotting: OCP, HRT, cox-2 inh, EPO, warfarin (initially)
- new drugs? (drug induced ITP, drug-induced neutropenia/neurophilia/eosinophilia)
- supplements/OTC
- steroids
Allergies?
SHx:
- DVT risks (immobility, phx clots, surgery)
- travel / contacts
- smoking
- EtOH
- rec drug use
- ECOG (baseline mobility, ?aids, ?assistance w ADLs, ascertain function)
- existing advanced care directives
Exam:
- obs
- general appearance (frail? anaemic? well/unwell)
- peripheries (warmth, pulse, palmer erythema/pallor)
- arms/skin (?rashes - macular/petechiael/purpuric, bruising)
- eyes (?jaundice ?anaemic)
- mouth (hydration, ulcers, hypertrophied gums, infxn, dendition), lymphadenopathy (submandib/cervical chain/axillary)
- CVS exam: JVP, HS, breath sounds, expans, percuss)
- abdo (pain, hepato/splenomegaly, groin LN)
- legs (oedema, haemosiderin, rashes/ulcers, calves)
- neuro: CNS, upper limb (tone, sens w eyes closed, power, coordination, RAM, reflexes), lower limb (same), gait (walk straight, heel-toe, heels, toes)
Ix:
- FBE and blood film (?fragments ?blasts)
- Coags (INR, apTT, fibrinogen, D-dimer)
- UEC/CMP
- haemolysis screen (hapto, LDH, bili urine haemosiderin) - consider
- TFTs
- BMAT
- flow cytometry (immunophenotyping)
- molecular genetics (karyotyping, FISH, RNA polymerase)
- imaging (CXR, skeletal survey, CT B/C/A/P)
IMP:
- Haematological diagnosis
- complications of that diagnosis
- other diagnoses and complications
- complicating / other issues
Plan:
- further hx (?collateral ?other issues to explore)
- further exam required?
- further Ix (bloods, imaging, BMAT, etc)
- emergency mx (airway, breathing, circ/bleeding, disability —?o2, IVFT, transfusions/products, TXA, anticoagulants, dexamethasone)
- disposition ?ward ?ICU ?transfer
- other teams to be involved
- NOK to contact
https: //medschool.co/history/haem
https: //www.derangedphysiology.com/files/HEMATOLOGICAL%20HISTORY%20AND%20EXAM.pdf
Haematological malignancies - overview, causes
Haematological (blood) malignancies come from haemopoietic tissue including:
- Bone marrow (medullary)
- these inc leukemia, lymphoma, myeloproliferative disease
- leads to orthopedic (bony), neurologic, metabolic complications - Liver/spleen (extra-medullary)
- manifests with hepatosplenomegaly - Lymphoid organs
- LN’s (nodal), manifests with lymphadenopathy or compressive symptoms
- Lymphoid tissue (extranodal) inc thymus and spleen
Cancer is a genetic disease involving chromosomal abnormalities and specific genetic mutations. These allow for specific diagnosis, prognosis (predicting response to therapy), and targeted therapies.
Majority of the mutations are acquired, or occur spontaneously without an obvious precipitating cause.
Viral associations:
- EBV is associated with Hodgkin’s lymphoma, Burkitt lymphoma, Post transplant lymphoproliferative disorder
- HTLV-1 is associated with acute T lymphoblastic leukemia/lymphoma
- HIV is associated with cerebral DLBCL, Hodgkin’s lymphoma, DLBCL
- HHV6 is associated with primary effusion lymphoma
Environmental exposures can increase the risk of blood malignancies.
- chemotherapy (inc etoposide, anthracyclines, autologous stem cell transplants) can cause treatment related AML/MDS
- radiation is linked with secondary AML, CML, myelodysplasia
- petrochemicals/benzene increases risk of multiple myeloma
- Hair dye increases the risk of follicular lymphoma
Familial risk
- cancer syndromes inc Li Fraumeni syndrome (p53), Blood syndrome (BLM gene, DNA helicase) run in families
- Specific heritable gene mutations inc RUNX1 (acute leukemia), and GATA2 (myelodysplasia)
Relapsed is the term for disease that responded to therapy but, after 6 or more months, stopped responding. Refractory disease is the term that does not result in a remission (but may be stable) or disease that gets worse within 6 months of the last treatment.
Neutropenia
Definition
Neutropenia is usually defined as an ANC <1500
- Mild – ANC ≥1000 and <1500 cells/microL
- Moderate – ANC ≥500 and <1000 cells/microL
- Severe – ANC <500 cells/microL
Mechanism
Neutropenia can result from three basic mechanisms:
●Decreased neutrophil production/differentiation in bone marrow (eg, drug-associated, infection, nutritional deficiency)
●Redistribution of circulating neutrophils to the vascular endothelium or to the spleen (termed “margination”)
●Immune destruction (eg, drug reaction, autoimmunity)
cause
Infection esp hepatitis, HIV, EBV, bacterial, parasitic
Medications -cytotoxic or immunosuppressive agents, other anti-cancer agents (eg, rituximab, tyrosine kinase inhibitors
Hematologic malignancies - Large granular lymphocyte (LGL) leukemia, hairy cell leukemia, other lymphoproliferative disorders, myelodysplastic syndromes, or other hematologic malignancies
Rheum - RA, SLE
Auto-immune
Aplastic anaemia
Nutritional – Deficiencies (vitamin B12, folate, copper)
Familial neutropenia (usu mild neutropenia)
Congenital neutropenia
History
Active or prior infection or inflammatory processes (eg, trauma, rheumatologic disorders)
aphthous (mouth) ulcers
hematologic malignancy
Gastrointestinal disorders (eg, inflammatory bowel disease), liver disease
Infections (viral)
Meds
occupational/travel exposure
ethnicity
Exam
Evidence of infection (fever, localising syx)
Findings that may help to determine the cause of the neutropenia (rash, LN, nutritional def^y, liver disease, joint/bone pain/swelling)
Ix:
FBE + film (toxic granulations/Dohle bodies due to sepsis; bilobed/dysplastic due to MDS; Hypersegmented due to megaloblastic; blasts suggests leukemia; schistocytes)
Also look at lymphocytes, and RBC on film.
Vitamin B12, folate, and copper levels
LFTs, hepatitis, HIV
coags
ESR/CRP (infxn/inflammation)
pancytopenia
definition
decreases in all peripheral blood lineages - RBC, WBC, (esp neuts), platelets
Mechanisms
Bone marrow infiltration/replacement e.g. myeloma/leuk/lymphoma, TB, fungal
Bone marrow aplasia – Nutritional disorders, infections, auto-imm
Blood cell destruction or sequestration - DIC, TTP, hypersplenism
History
Prior laboratory results
Symptoms associated with cytopenias
- Recurrent, severe, or unusual infections that may be due to leukopenia/neutropenia
- Fatigue, dyspnea, chest pain, hemodynamic instability, or claudication due to anemia
- Bleeding or easy bruising due to thrombocytopenia or disseminated intravascular coagulation
- Constitutional symptoms, including fevers, night sweats, and/or weight loss
- Nausea, vomiting, and jaundice that may be associated with liver disease
Previous treatments (transfusion etc)
Other medical conditions
Problematic medications
Personal and occupational exposures (toxins, etoh, travel hx)
Exam
Rashes
infection
Oral lesions
Lymphadenopathy and/or splenomegaly
Jaundice and stigmata of liver disease
Ix:
FBE, diff, red cell indices
blood film
reticulocytes
INR, apTT, fibrinogen, D dimer
UEC, LFT, LDH, CMP, uric acid
Blood type and screen
B12/fol
HIV/hep
BMAT (if suspecting haem cancer)
Flow cytometry
cytogenetics (FISH or karytope of Bone marrow or peirpheral blood)
Lymphocytosis
Blood film:
- Atypical lymphocytes (picture 7) suggest a viral cause (eg, EBV, cytomegalovirus [CMV])
- “Smudge” lymphocytes (picture 8) are characteristic of CLL
- “Hair-like” projections on lymphocytes (picture 9) are seen in hairy cell leukemia
- Lymphocytes with azurophilic granules (picture 10) may be seen in LGL leukemia
anaemia
specific causes
Iron deficiency
●B12 and folate deficiency
●Chronic disease/inflammation
●Hemolytic anemia
●Drug-induced
●Myelodysplastic syndrome
●Hemoglobinopathies
●Aplastic anemia
●Microangiopathic hemolytic anemia
thrombocytosis
Definition
increased platelet count >450,000/microL
causes
Reactive thrombocytosis — Reactive processes, also described as secondary thrombocytosis. caused by:
●Anemia/Blood loss – Iron deficiency, blood loss, hemolysis
●Infection – Viral, bacterial, mycobacterial, and fungal causes
●Non-infectious inflammation – Malignancy, rheumatologic conditions, trauma, reactions to medications
●Post-splenectomy – Post-splenectomy or functional asplenia (eg, sickle cell disease)
Hematologic malignancies — Hematologic malignancies that are associated with thrombocytosis include:
●Essential thrombocythemia – Essential thrombocythemia (ET) is an MPN that is manifest as thrombocytosis
●Polycythemia vera – Polycythemia vera (PV) is an MPN that is manifest as polycythemia (elevated hemoglobin and/or hematocrit) and is often accompanied by thrombocytosis; thrombo-hemorrhagic complications; splenomegaly; pruritus, flushing, erythromelalgia; and/or constitutional symptoms (eg, fever sweats, weight loss). PV is nearly invariably associated with an acquired mutation of JAK2.
●Primary myelofibrosis – Primary myelofibrosis (PMF) is an MPN in which bone marrow fibrosis and a leukoerythroblastic blood smear may be accompanied by thrombocytosis, splenomegaly, thrombo-hemorrhagic complications, and/or constitutional symptoms.
●Chronic myeloid leukemia
MAHA
Microangiopathic hemolytic anemia (MAHA) — MAHA is a descriptive term for non-immune hemolysis (ie, Coombs-negative hemolysis) resulting from intravascular red blood cell fragmentation that produces schistocytes on the peripheral blood smear (picture 1) [1]. Abnormalities in the microvasculature, including small arterioles and capillaries, are frequently involved. However, intravascular devices such as a prosthetic heart valve or assist devices may also cause MAHA. Characteristic laboratory data are a negative direct antiglobulin (Coombs) test (DAT), an increased lactate dehydrogenase (LDH), increased indirect bilirubin, and low haptoglobin.
Haematopoesis
Sites of haematopoesis:
- vertebrae, sternum and manubrium, pelvic bones, and metaphyses of long bones
- When sites are infiltrated by disease (e.g. myelodysplasia), the body return to its former sites of haematopoesis inc the liver, spleen, and lymph nodes and may also be found in the adrenal glands, cartilage, adipose tissue, thoracic paravertebral gutters, and even in the kidneys
Cell surface antigen markers:
- In humans, the most primitive human hematopoietic cells are CD34+ and CD38-. The most frequently used markers are the CD34 antigen, expressed on HSC and progenitors, and CD38, expressed on a subset of more mature progenitors and on maturing cells, but not on HSC.
Cell surface markers
In humans, the most primitive human hematopoietic cells are CD34+ and CD38-.
CD = cluster of differentiation
CD34 antigen: expressed on HSC and early progenitor cells. CD34 is considered the most critical marker for HSCs. Under normal conditions, CD34+ cells in peripheral blood range from 0.01 to 0.05%; in the bone marrow, the concentration is usually <1% (~0.55%) of normal mononuclear cells. Not expressed on mature bone marrow cells.
CD38 antigen: surface glycoprotein found on many immune cells (white blood cells), inc CD4+, CD8+, B lymphocytes and NK cells. Multifunctional (acts as a receptor or an enzyme). Expressed on a subset of more mature progenitors and on maturing cells, but not on HSC.
CD19: B lymphocyte antigen. A biomarker for normal and neoplastic B cells, as well as follicular dendritic cells. CD19 is a less specific marker of B cell lineage; it is expressed on earlier progenitors starting at the pre-B cell stage.
CD20: B lymphocyte antigen. CD20 is expressed on all B cells beginning in the pro-B phase. It is more robust for naive and mature B cells and is more specific for B cell lineage.
CD123: interacts with IL-3, IL-5 and GM-CSF receptors to form a high affinity IL-3 receptor. Binding stimulates stem cell differentiation, proliferation and survival. Expressed at high levels on plasmacytoid DCs and basophils, expressed at lower levels on monocytes, eosinophils, and myeloid dendritic cells in peripheral blood. Also expressed on subsets of hematopoietic progenitor cells (multipotent and myeloid precursors, but not lymphoid precursors) and is described as unique stem cell marker in AML.
CD44: P-glycoprotein 1. A transmembrane glycoprotein expressed on leukocytes, erythrocytes, epithelial cells and weakly on platelets. Is involved in adhesion of cells to their extra cellular matrix through hyaluron. It mediates cell survival
CD90 (Thy1): GPI-linked membrane glycoprotein expressed on the surface of various HSCs, thymus, and non lymphoid tissues (neurons, peripheral T cells, fibroblasts, stromal cells). Is an important regulator of cell-cell and cell-matrix interaction and is involved in inflammation, wound healing and other non immunological functions such as tumor suppression, cell adhesion, migration and apoptosis signaling. Highly expressed on cord blood primitive cells.
CD96: also called TACTILE (T cell activated increased late response) is a type I membrane protein which belongs to immunoglobulin superfamily. A T cell receptor which is also expressed on NK cells.
CD117 (C-Kit): protein tyrosine kinase expressed on pluripotent hematopoietic progenitor cells (~1.4% of BM cells), mast cells and AML cells.
CD135 (also known as Flk-2, FLT3): tyrosine kinase receptor expressed in normal CD34+ HSCs and malignant HSCs in AML, ALL, CML.
