Haematology Flashcards
Acute Leukaemia clinical features (ALL & AML)
Clinical features are either related to bone marrow failure, infiltration of organs by leukemic cells, or a combination of both.
General features of acute leukaemia:
Sudden onset of symptoms and rapid progression (days to weeks)
Anemia: fatigue, pallor, weakness
Thrombocytopenia: epistaxis, bleeding gums, petechiae, purpura
Immature leukocytes: frequent infections, fever
Hepatosplenomegaly (caused by leukemic infiltration) [2]
Signs of oncologic emergencies: can be the first sign of leukemia, e.g., an elderly patient presenting with priapism or DIC may be a sign of leukostasis (more common in AML than ALL)
See “Complications” below for details.
Clinical features of ALL
Fever, night sweats, unexplained weight loss
Painless lymphadenopathy
Bone pain (presenting as limping or refusal to bear weight in children)
Airway obstruction (stridor, difficulty breathing) due to mediastinal or thymic infiltration (primarily in T-cell ALL) [15][16]
Features of SVC syndrome
Meningeal leukemia (or leukemic meningitis) → headache, neck stiffness, visual field changes, or other CNS symptoms (caused by CNS involvement) [1][16]
Testicular enlargement (rare finding)
AML
Leukemia cutis (or myeloid sarcoma): nodular skin lesions with a purple or gray-blue color
Gingival hyperplasia (AML subtype M4 and M5)
Signs of CNS involvement, e.g., headache, visual field changes (uncommon)
Fever and lymphadenopathy are rare in AML, but can be common first signs in ALL!
Acute leukemia
Acute leukemia is a malignant neoplastic disease that arises from either the lymphoid cell line (acute lymphoblastic/lymphocytic/lymphoid leukemia, ALL) or the myeloid cell line (acute myeloid/myelogenous/myelocytic leukemia, AML). ALL is the most common childhood malignancy, whereas AML primarily affects adults. An underlying cause is rarely identifiable, but risk factors include prior chemotherapy and radiation therapy, as well as hereditary syndromes such as Down syndrome. AML is also associated with pre-existing hematologic disorders (e.g., myelodysplastic disorder, myeloproliferative disorders). Acute leukemias are characterized by the proliferation in the bone marrow of immature, nonfunctional white blood cells (“blasts”) that impair normal hematopoiesis and lead to pancytopenia manifesting with symptoms and signs of anemia (↓ RBCs), clotting disorders (↓ thrombocytes), and increased susceptibility to infection (↓ fully functional, mature WBCs). Leukemic cells also infiltrate extramedullary organs, resulting in hepatosplenomegaly and, less commonly, involvement of the skin, CNS, and/or scrotum. Patients with AML, in particular, may develop extremely high WBC counts, increasing the risk of leukostasis and DIC. The first diagnostic steps include a complete blood count and peripheral blood smear to determine the WBC count and the presence of blasts. Bone marrow biopsy or aspiration with subsequent cytogenetic analysis and immunophenotyping confirm the diagnosis. A chemotherapy regimen consisting of high-dose (induction) and low-dose (consolidation and maintenance) cycles is the mainstay of treatment. Additional measures, such as allogeneic stem cell transplantation, may be indicated in patients with poor prognostic factors (e.g., unfavorable cytogenetics) or if initial chemotherapy fails.
Acute lymphoblastic leukaemia epidemiology
Acute lymphoblastic leukemia [1]
Peak incidence: 2–5 years
Most common malignant disease in children
∼ 80% of acute leukemias during childhood are lymphoblastic.
♂ > ♀
Acute myeloid leukemia [2]
Peak incidence: 65 years
80% of acute leukemias during adulthood are myelogenous.
Epidemiological data refers to the US, unless otherwise specified.
Aetiology for acute leukaemia
Acute lymphoblastic leukemia (ALL)
No identifiable cause or risk factors in most cases
Prior bone marrow damage due to alkylating chemotherapy or ionizing radiation
Adult T-cell leukemia/lymphoma is linked to infection with HTLV. [3][4][5]
Genetic or chromosomal factors
Down syndrome: Risk of ALL is, like that of AML, 10–20 times higher in patients with Down syndrome compared to the general population. [6][7]
Neurofibromatosis type 1
Ataxia telangiectasia.
Acute myeloid leukemia (AML)
No identifiable cause or risk factors in most cases
Pre-existing hematopoietic disorder (most common identifiable cause) [8]
Myelodysplastic syndromes
Aplastic anemia
Myeloproliferative disorders (e.g., osteomyelofibrosis, CML)
Environmental factors [2]
Alkylating chemotherapy
Ionizing radiation
Benzene exposure
Tobacco
Genetic or chromosomal factors
Down syndrome: The risk of AML is, like that of ALL, 10–20 times higher in patients with Down syndrome compared to the general population. [7]
Fanconi anemia
Pathophysiology of acute leukaemia
Acquired somatic mutations (chromosomal translocations and other genetic abnormalities) in early hematopoietic precursors → clonal proliferation of a lymphoid or myeloid stem cell line and arrest in cell differentiation and maturation in early stages of hematopoiesis → rapid proliferation of abnormal and dysfunctional blasts (with impaired apoptosis pathways) → accumulation of leukemic white blood cells in the bone marrow → disrupted normal hematopoiesis → leukopenia (↑ risk of infections), thrombocytopenia (↑ bleeding), and anemia
Immature blasts enter the bloodstream → infiltration of other organs (particularly the CNS, testes, liver, and skin)
Diagnostics Acute leukaemia
Initial tests: CBC and peripheral blood smear (determine WBC count and the presence of blasts)
Confirmatory test: bone marrow aspiration and biopsy (examine morphology, histochemistry, cytogenetics, and immunophenotyping)
Further tests: if organ involvement is suspected (e.g., imaging, CSF analysis)
Laboratory studies
Complete blood count
Leukocytes: The white blood cell count (WBC) may be elevated, normal, or low and is not a reliable diagnostic marker.
Leukemic hiatus in AML: A gap in the differentiation of white blood cells in which there is a high number of blast cells and mature leukocytes but no intermediate forms
Thrombocytopenia
Anemia
Peripheral blood smear: presence of blasts
AML
↑ Myeloblasts
Some subtypes (especially M3, or APL) exhibit Auer rods
Pink-red, rod-shaped granular cytoplasmic inclusion bodies in malignant immature myeloblasts or promyelocytes
Auer rods are myeloperoxidase positive.
ALL: ↑ lymphoblasts
Additional laboratory studies
Coagulation studies: rule out DIC
Electrolytes and metabolic markers: ↑ PO43-, ↓ Ca2+, ↑ K+, ↑ LDH, and ↑ uric acid indicate increased cell lysis.
Bone marrow aspiration and biopsy
Confirmatory diagnostic tests
AML: > 20% myeloblasts in the bone marrow [18]
ALL: > 20% lymphoblasts in the bone marrow [19]
ALL-Morphology:
Large blasts (1.5–3 times the size of RBC)
Blasts with large, irregular nuclei (high nuclear-to-cytoplasm ratio)
Inconspicuous nucleoli
Coarse granules
No Auer rods
AML morphology Large blasts (2–4 times the size of RBC) Blasts with round or kidney-shaped nuclei, comparatively more cytoplasm than in ALL Prominent nucleoli Fine granules Auer rods (present in 50% of cases).
Further tests:
Cerebrospinal fluid analysis: relevant for diagnosis and treatment of leukemic meningitis
Chest x-ray: mediastinal mass in the case of thymic infiltration (occurs primarily in T-cell ALL) or mediastinal lymphadenopathy
Abdominal ultrasound: organ enlargement (especially the liver and/or spleen)
Treatment of ALL
Aggressive chemotherapy is the mainstay of treatment; prognosis is good with treatment.
Radiation and/or targeted therapy are considered depending on the type and stage of disease.
Allogeneic stem cell transplantation is indicated in patients with poor prognostic factors or who do not achieve remission with chemotherapy.
Supportive measures are vital to manage severely immunocompromised patients and prevent treatment-related complications.
Chemotherapy
Chemotherapy regimens are comprised of induction, followed by consolidation, and finally maintenance therapy. The choice of chemotherapeutic agents is based on the cytogenetics of the leukemic cells. [21]
Induction therapy (goal: massive reduction of tumor cell count)
Duration: 4–6 weeks
High-dose chemotherapy regimens are effective but usually cause severe side effects.
Re-induction therapy (goal: massive reduction of tumor cell count)
Only indicated in case of relapse or failure of primary induction therapy
Duration: 4–6 weeks
Consolidation therapy (goal: destruction of remaining tumor cells)
Begin after complete remission is achieved
Duration: several months
Medium doses
ALL regimen: variable drug regimens
Maintenance therapy (goal: maintaining remission)
Duration: up to 24 months
Low doses
ALL regimen: may include methotrexate, vincristine, glucocorticoids.
85% of children with ALL achieve complete remission with chemotherapy!
Allogeneic stem cell transplantation
Indication: poor prognostic factors (e.g., unfavorable cytogenetics) or patients who do not achieve remission through chemotherapy.
Preventing infection is very important as patients are severely immunocompromised.
Surveillance: regular inspection of oropharynx, skin, and catheter sites; regular chest x-rays or CT to detect pulmonary infection
Advise patients to pay special attention to personal hygiene (e.g., daily bathing and tooth brushing, cleaning of minor wounds, maintaining a germ-free environment; i.e., avoiding crowds and contact with sick individuals, wearing a face mask outside if WBC counts are low)
Antibiotic prophylaxis in afebrile neutropenic patients is controversial
If infection is suspected or neutropenia and fever are present: IV broad-spectrum antibiotics (see neutropenic fever)
PCP prophylaxis with TMP-SMX in all neutropenic patients
Mucositis prophylaxis with local antimycotics
Herpes simplex prophylaxis with acyclovir
Updating immunizations
Colony-stimulating factor administration can be considered for febrile neutropenia
Managing treatment side effects
Antiemetics (e.g., ondansetron)
Enteral and parenteral nutritional support
Transfusion for severe cytopenia
Uric acid stone prophylaxis: begin prior to chemotherapy to prevent hyperuricemia and urate induced nephropathy
Hydration and fluid administration
Allopurinol and rasburicase
Complications of ALL
Oncologic emergencies
Mediastinal or thymic infiltration (primarily in T-cell ALL) → SVC syndrome, airway compromise
Febrile neutropenia
Severe thrombocytopenia or anemia
Leukostasis
Description: ↑ blood viscosity caused by an excessive number of leukocytes (usually > 150,000/mm3 in patients with AML and > 400,000/mm3 in patients with ALL)
Pathophysiology: very high number of immature leukocytes → increased viscosity of blood → increased risk of vascular obstruction → cerebral and pulmonary complications, DIC
Occurrence: more common in AML than ALL
Clinical features
Chest pain (ischemic injury)
Headache, altered mental status, cranial nerve disorders
Priapism
DIC: frequent complication of APL
Treatment
Cytoreduction: hydroxyurea with or without leukapheresis to rapidly reduce WBC count
Preventive measures for tumor lysis syndrome (see “Prophylaxis” below)
Tumor lysis syndrome (TLS) [38]
Description: The rapid destruction of tumor cells leads to a massive release of intracellular components, which subsequently damage the kidneys and may cause potentially life-threatening renal failure.
Etiology: mostly occurs after initiating cytotoxic treatment of ALL, AML, or NHL
Pathophysiology: tumor cell lysis → release of intracellular components (e.g., K+, PO43-, nucleic acid) into the bloodstream
Hyperkalemia
Hyperphosphatemia: PO43- binds Ca2+ and forms calcium phosphate crystals that obstruct renal tubules → acute kidney injury
↓ Ca2+ secondary to PO43- binding → hypocalcemia
↑ Nucleic acid → conversion to uric acid → hyperuricemia → urate nephropathy and risk of acute renal injury
Clinical features
Nausea, vomiting, and diarrhea
Lethargy
Hematuria
Seizures
Cardiac arrhythmias
Tetany, muscle cramps
Paresthesia
Prophylaxis
All patients
Hydration (most effective preventive measure)
Avoid potentially nephrotoxic drugs such as NSAIDs
Possibly in addition to hydration
In patients with a low to intermediate risk of TLS: allopurinol
In patients with a high risk of hyperuricemia due to TLS (e.g., extremely high WBC): rasburicase, a recombinant uricase, which catalyzes the breakdown of uric acid to allantoin
Consider alkalinization of the urine
Treatment
Treat electrolyte abnormalities
Hyperkalemia
Glucose and insulin (rapid action)
Sodium polystyrene sulfonate (delayed action)
Last resort: hemodialysis or hemofiltration
Hypocalcemia: calcium administration
Hyperphosphatemia: hydration and possibly phosphate binding agents
Rasburicase, if not already given as prophylaxis
Fluid administration with or without loop diuretics to aid renal excretion of uric acid crystals
Renal replacement therapy may be necessary
Prognosis acute leukaemia
ALL: The 5-year survival rate is generally higher compared to AML (varies from ∼ 20% in elderly patients to ∼ 80% in children and adolescents)
AML: ∼ 30%, but it varies according to the patient’s age. The survival time has increased more recently due to improvements in treatment
Chronic myeloid leukemia
Chronic myeloid leukemia (CML) belongs to the group of myeloproliferative neoplasms. It is a malignancy of the hematopoietic stem cells with excessive proliferation of the myeloid lineage (especially granulocytes). It is caused by a cytogenetic aberration (Philadelphia chromosome 22) that results in the formation of a BCR-ABL fusion gene. The increased activity of this gene’s product – a tyrosine kinase – promotes unregulated proliferation of myeloid progenitor cells, which eventually differentiate into mature cells. CML has three distinct clinical phases. The chronic phase is characterized by nonspecific symptoms (fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years. The accelerated phase is characterized by complications secondary to the suppression of the other cell lines (thrombocytopenia, anemia, recurrent infections). The clinical picture of the terminal phase, blast crisis, resembles that of acute leukemia. Important diagnostic features are severe leukocytosis (> 500,000/μl), basophilia, and extreme splenomegaly. The most important therapeutic principle is targeted therapy with imatinib, which selectively inhibits BCR-ABL tyrosine kinase. This drug has revolutionized CML treatment and greatly improved the prognosis of CML.
Epidemiology:
Sex: ♂ > ♀
Incidence: peak incidence is 50–60 years.
Aetiology: Idiopathic (in most cases) Ionizing radiation (e.g., secondary to therapeutic radiation) Aromatic hydrocarbons (especially benzene).
Pathophysiology: Philadelphia chromosome
Reciprocal translocation between chromosome 9 and chromosome 22 → formation of the Philadelphia chromosome t(9;22) → fusion of the ABL1 gene (chromosome 9) with the BCR gene (chromosome 22) → formation of the BCR-ABL gene → encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity
Result: inhibits physiologic apoptosis and increases mitotic rate → uncontrolled proliferation of functional granulocytes.
Genetic changes and clinical course
Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia.
Clinical features:
Chronic phase
Can persist for up to 10 years and is often subclinical
When symptomatic, features include:
Weight loss, fever, night sweats, fatigue
Splenomegaly: abdominal discomfort in the left upper quadrant
Lymphadenopathy is not typical in CML.
Unlike AML, CML is not characterized by recurrent infections during early stages, since the granulocytes are still fully functional.
Accelerated phase
Erythrocytopenia: anemia
Neutropenia: infection and fever
Extreme pleocytosis
Infarctions: splenic and myocardial infarctions, retinal vessel occlusion
Leukemic priapism
Terminal phase: myelofibrosis
Extreme splenomegaly : palpable in lower left quadrant or pelvic cavity.
Blast crisis
The blast crisis is the terminal stage of CML.
Symptoms resemble those of acute leukemia.
Rapid progression of bone marrow failure → pancytopenia, bone pain
Severe malaise
Subtypes :
Myeloid blast crisis → AML (⅔ of cases)
Lymphoid blast crisis → ALL (⅓ of cases).
CML peripheral blood analysis
Peripheral blood analysis
CBC and blood smear
Leukocytosis with midstage progenitor cells (e.g., myelocytes, metamyelocytes) and mature cells (e.g., neutrophils, myelocytes)
Basophilia and eosinophilia
Blasts can indicate transition to the accelerated phase.
Thrombocytosis.
Cytochemistry: ↓ leukocyte alkaline phosphatase (LAP) versus a leukemoid reaction
Cytogenetics: confirmation of BCR-ABL (Philadelphia chromosome) fusion gene
Low LAP is a distinct feature of CML that distinguishes it from all other forms of leukaemia.
Bone marrow
Hyperplastic myelopoiesis: predominantly granulocytosis
Elevated granulocytic precursor cells (especially myelocytes and promyelocytes). Chronic CML if blast count in peripheral blood and bone marrow <10%.
Accelerated CML if blast count 10-19%.
Blast crisis is greater than or equal to 20%.
Differential diagnosis of CML
Polycythemia vera: CBC and peripheral blood smear: erythrocytosis, thrombocytosis, leukocytosis, Cause: JAK2 mutation in 95% of cases.
Primary myelofibrosis: progressive pancytopenia, dacryocytes. Cause: JAK2 mutation in up to 60% of cases.
Essential thromocythemia: isolated thrombocytosis, JAK2 mutation in 50% of cases.
Chronic myeloid leukemia: Extreme leukocytosis, basophilia, cause: philadelphia chromosome.
Leukemoid reaction: leukocytosis: cause: no mutation, typically secondary to infections or drugs (steroids). Associated with certain solid tumours (e.g lung and kidney cancer).
Treatment of CML
Targeted therapy: first-line for chronic and accelerated phase
Tyrosine kinase inhibitors: e.g., imatinib, dasatinib, nilotinib
Mechanism of action: selectively inhibit the enzyme tyrosine kinase by binding to its active ATP site → no transfer of phosphate (from ATP) to tyrosine residues on the enzyme’s substrates (i.e., cell signaling proteins of the BCR-ABL1 pathway) → inhibits proliferation and induces apoptosis of malignant cells that carry the mutant tyrosine kinase
Adverse effects include: fluid retention, pulmonary edema, QT prolongation, nausea, vomiting, diarrhea, and pancytopenia
Lifelong treatment
Allogeneic stem cell transplantation: if targeted therapy is not successful or in young patients without any major comorbidities (the only curative option)
Cell count normalization: supportive therapy if targeted therapy fails
Hydroxyurea
Blast phase: acute leukemia treatment
prognosis of cml
Survival rate without treatment:
Chronic phase: 3.5–5 years
Blast phase: 3–6 months
In most patients, life expectancy can be markedly improved through targeted therapy with imatinib. In some cases, it even results in molecular remission.
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) belongs to the group of low-grade non-Hodgkin lymphomas (NHL) and is a B-cell lymphoma that presents with lymphocytic leukocytosis. CLL is the most common form of leukemia in adults and is typically considered a disease of the elderly. Clinical features include painless lymphadenopathy, fatigue, chronic pruritus, and an increased susceptibility to infections. Important diagnostic markers are smudge cells (Gumprecht shadows) in a blood smear, a high percentage of small, mature lymphocytes in the bone marrow, and detection of B-CLL antigens in flow cytometry. The Rai staging system is primarily based on lymphocyte count, sites of lymphatic tissue involvement, anemia, and platelet count. The medical treatment of CLL consists of chemotherapy and monoclonal antibodies, but does not necessarily increase survival time. Allogeneic stem cell transplantation, which is the only curative treatment option, is often not viable because of the advanced age of most patients.
Chronic lymphocytic leukemia: low-grade B-cell lymphoma with lymphocytic leukocytosis.
Epidemiology: Sex: ♂ > ♀ (∼ 2:1)
Age: The median age at the time of diagnosis is 70–72 years (incidence of CLL increases with age).
Most common type of leukemia in adults
Risk factors:
Advanced age
Environmental factors: organic solvents
Family history
Pathophysiology:
Acquired mutations in hematopoietic stem cells → increased proliferation of leukemic B cells with impaired maturation and differentiation in the bone marrow, resulting in:
Suppression of the proliferation of normal blood cells
Immunosuppression
Hypogammaglobulinemia
Granulocytopenia
Thrombocytopenia
Anemia
Infiltration of the lymph nodes, liver, and spleen.
Clinical Presentation:
About half of cases of CLL remain asymptomatic for a long period, resulting in late or incidental diagnosis.
Weight loss, fever, night sweats, fatigue (B symptoms)
Painless lymphadenopathy
Hepatomegaly and/or splenomegaly may occur.
Repeated infections
Severe bacterial infections (e.g., necrotic erysipelas)
Mycosis (candidiasis)
Viral infections (herpes zoster)
Symptoms of anemia and thrombocytopenia
Dermatologic symptoms
Leukemia cutis
Chronic pruritus
Chronic urticaria
Lymphadenopathy is a typical finding in lymphoid malignancies such as CLL and helps to differentiate CLL from CML, a myeloid malignancy!
Diagnosis/investigations:
Laboratory analysis
CBC
Persistent lymphocytosis with a high percentage of small mature lymphocytes
Findings that indicate suppression of normal myelopoiesis:
Granulocytopenia
Low RBC count (due to autoimmune hemolysis)
Low platelet count
Blood smear: smudge cells (Gumprecht shadows) – mature lymphocytes that rupture easily and appear as artifacts on a blood smear
False positive results possible: Smudge cells may also appear if the quality or handling of the blood sample was inadequate → Positive results are not sufficient to confirm the diagnosis of CLL.
Flow cytometry: detection of B-CLL immunophenotype (CD5, CD19, CD20, CD23), light chain restriction (kappa or lambda)
Serum antibody electrophoresis: antibody deficiency (decreased γ globulin fraction)
Gumprecht shadows in chronic lymphocytic leukemia (CLL)Smudge cells in chronic lymphocytic leukemia (CLL)Smudge cells in chronic lymphocytic leukemia.
-Bone marrow aspiration
Ddx: Acute lymphoblastic leukemia (ALL) Autoimmune hemolytic anemia (AIHA) Mantle cell lymphoma Hairy cell lymphoma The differential diagnoses listed here are not exhaustive.
Treatment:
The treatment regimen is primarily based on the risk of disease progression according to the Rai staging system, whether the patient is symptomatic or has comorbidities, and the patient’s age and level of fitness.
Asymptomatic CLL (Rai stage 0, slow disease progression): observe and monitor disease progression
Symptomatic CLL or advanced stage (Rai stage > 0, accelerated disease progression)
Chemotherapy
If CD 20 positive: rituximab
Targeted therapy with ibrutinib
Refractory CLL or early recurrence in fit, young patients : allogeneic stem cell transplantation.
Treatment regimens
< 65–70 years
FCR: fludarabine, cyclophosphamide, rituximab
Stem cell transplantation
> 65–70 years
Chlorambucil + monoclonal antibody (e.g., rituximab)
Possibly a single agent: chlorambucil or rituximab
Ibrutinib
Del(17p13) positive
Enrollment in clinical trials is recommended.
No standard approach; options include:
Monoclonal antibody (e.g., alemtuzumab)
Chronic lymphocytic leukemia complications
Immunosuppression with subsequent infections (most common cause of death)
Secondary malignancies
Hyperviscosity syndrome
Autoimmune hemolytic anemia (of both the warm and cold agglutinin type)
Richter transformation or Richter syndrome: transformation into a high-grade NHL (usually diffuse large B cell lymphoma)
Occurrence: ∼ 5% of cases
Diagnostic indicators:
Rapidly progressive lymphadenopathy → lymph node biopsy required
New onset of B symptoms
↑ LDH
Treatment: similar to symptomatic CLL and advanced stages
CLL prognosis
Prognostic factors
Advanced age is associated with a poor overall survival rate
Genetic abnormalities: e.g., del(17p13) is associated with a poor overall survival rate because of the high risk of disease progression and poor response to chemotherapy.
β-2 microglobulin levels: correlate with the severity of the disease
Blood lymphocyte doubling time: Rapid doubling is associated with a high risk of disease progression
Hodgkin Lymphoma Dr Deac Pimp
D: Hodgkin lymphoma (HL) is a malignant lymphoma that is typically of B-cell origin. The incidence of HL has a bimodal age distribution, with peaks in the 3rd and 6th–8th decades of life. The WHO classifies HL into two types: classical HL (CHL) and nodular lymphocyte predominant HL (NLPHL). CHL is further divided into four subtypes, which are nodular sclerosis (most common), mixed cellularity, lymphocyte-depleted, and lymphocyte-rich CHL. Risk factors for developing HL include a history of infectious mononucleosis caused by the Epstein-Barr virus (EBV) and immunodeficiency (e.g., HIV infection). HL typically presents with painless cervical lymphadenopathy, fever, night sweats, and involuntary weight loss. Pel-Ebstein fevers (cyclical fever with periods of both high and normal temperature) and alcohol-induced pain at affected lymph nodes are less common but specific for HL. Suspicious lymph nodes are excised and definitive diagnosis is made via histological analysis, which characteristically reveals pathognomonic Reed‑Sternberg cells (malignant B-cells). The modified Ann Arbor classification (Cotswold staging system) is used to stage HL based on both the localization of the lymphoma with respect to the diaphragm and on the presence of systemic symptoms. Treatment is typically initiated with curative intent. In early stages, treatment is generally limited to involved-field radiation and chemotherapy. In later stages, when local radiation is often unsuccessful or not feasible due to tumor spread, polychemotherapy is the mainstay of treatment.
R:
D: Ddx of lymphadenopathy:
Examining lymph nodes can yield important diagnostic clues. Generalized lymphadenopathy is usually a sign of systemic illness, such as HIV, mycobacterial infection (e.g., tuberculosis), infectious mononucleosis, systemic lupus erythematodes, or serum sickness. Signs of malignancy include rapid growth, painlessness, hardness/coarseness, and being fixed to underlying or surrounding tissue. Most often, though, there is no discernible cause or pathology. It is malignancy if lump is greater than 1cm, hard, rubbery, nontendor, and fixed to the underlying tissue.
Differential diagnosis of B symptoms Non-Hodgkin lymphomas, Hodgkin lymphomas Other hematopoietic malignancies (e.g. CML, ALL) Solid tumors Tuberculosis HIV Differential diagnosis of granulomatous disease: -Sarcoidosis Tuberculosis Hodgkin lymphoma Non-hodgkin lymphoma Pneumoconiosis Granulomatosis with polyangiitis Histoplasmosis
E: Incidence
2–3/100 000 per year
Subtype variance with age (see “Pathology” below)
Young adults: nodular sclerosing HL
Elderly adults: mixed-cellularity HL
Age: bimodal distribution
1st peak: 25–30 years
2nd peak: 50–70 years
Sex: ♂ > ♀
Male predominance, especially in pediatric cases
Exception: ♀ = ♂ in nodular sclerosing HL (most common type)
A: The exact causes are unknown, but several risk factors have been associated with HL:
Strong association with Epstein-Barr virus (EBV)
Immunodeficiency: e.g., organ or cell transplantation, immunosuppressants, HIV infection , chemotherapy
Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis)
C: Painless lymphadenopathy
Cervical lymph nodes (in ∼ 60–70% of patients) > axillary lymph nodes (in ∼ 25–35% of patients) > inguinal lymph nodes (in ∼ 8–15% of patients)
Mediastinal mass → chest pain, dry cough, and shortness of breath
Splenomegaly or hepatomegaly may occur if the spleen or liver are involved.
B symptoms
Night sweats, weight loss > 10% in the past 6 months, fever > 38°C (100.4°F)
Can occur in a variety of diseases, such as non-Hodgkin lymphoma, other malignancies, tuberculosis, and various inflammatory diseases
The presence of only one of the symptoms – in the case of confirmed HL – is considered positive for B symptoms.
Pel-Ebstein fever
Alcohol-induced pain
Pruritus (focal or generalized)
P: Reed Sternberg cells.
I:
M: Early stage (I and II): combination of chemotherapy and radiation therapy
The most widely used chemotherapy approach is ABVD: adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
Advanced stage (III and IV and often II with bulky disease): combination chemotherapy with radiation therapy in select cases
Three possible treatment approaches are commonly considered:
ABVD
Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone
BEACOPP: bleomycin, etoposide, adriamycin (doxorubicin), cyclophosphamide, oncovin (vincristine), procarbazine, prednisone
Primary refractory or relapsed disease: trial of alternative chemotherapy or consideration of high-dose chemotherapy and autologous stem cell transplantation.
P: Good prognosis
5-year survival rate ∼ 80–90% (in children > 90%)
Best prognosis: lymphocyte-rich classical HL and (LRHL) and nodular lymphocyte predominant HL (NLPHL)
Prognosis is largely determined by disease stage (i.e., lower stage has a better prognosis)
∼ 10–20% of patients will develop secondary malignancies (complications related to radiation therapy and chemotherapy)
Unfavorable factors for Hodgkin lymphoma (relevant when selecting a treatment regimen)
High ESR
Involvement of three or more lymph node areas
Large mediastinal tumor
Bulky disease (tumors measuring ≥ 10 cm across)
Iron deficiency anaemia
D: Iron deficiency anemia (IDA) is the most common form of anemia worldwide and can be due to inadequate intake, decreased absorption (e.g., atrophic gastritis, inflammatory bowel disease), increased demand (e.g., during pregnancy), or increased loss (e.g., gastrointestinal bleeding, menorrhagia) of iron. Prolonged deficiency depletes the iron stores in the body, resulting in decreased erythropoiesis and anemia. Symptoms are nonspecific and include fatigue, pallor, lethargy, hair loss, brittle nails, and pica. Diagnostic lab values include low hemoglobin, microcytic, hypochromic red blood cells on peripheral smear, and low ferritin and iron levels. Once diagnosed, the underlying cause should be determined. Patients at risk for underlying gastrointestinal malignancy should also undergo a colonoscopy. Iron deficiency anemia is treated with oral (most common) or parenteral iron supplementation. Severe anemia or those with concomitant cardiac conditions may also require blood transfusions. The underlying cause of IDA should also be corrected.
R:
D: Normocytic anemia Acute blood loss anemia Occult bleeding Anemia of chronic disease Hemolytic anemia Chronic kidney disease Aplastic anemia Microcytic anemia Thalassemia Sideroblastic anemia Lead poisoning (esp. in children) Anemia of chronic disease (may co-exist with IDA)
E: Most common form of anemia worldwide [1]
∼ 3% of the general population in the United States is affected [2]
Ethnic variations: African-American and Mexican-American populations in the US are at increased risk.
Prevalence highest in:
Children ages 0–5 years
Young women of child-bearing age (due to menstrual blood loss)
Pregnant women
A: The most common causes of IDA can be divided by age groups and pathophysiologic mechanisms.
Based on age [6][1]
Infants
Exclusive intake of nonfortified cow’s milk
Exclusive breastfeeding after 6 months of age [7]
Children
Malnutrition (mainly developing countries)
Meckel diverticulum
Excessive intake of cow’s milk (> 24 ounces/700 mL per day): In addition to low iron content, the calcium and proteins in cow’s milk disrupt iron absorption.
Adolescence: menarche/menstruation
Adults (20–50 years)
Menorrhagia or pregnancy (females)
Peptic ulcer disease (males)
Adults > 50 years:
Colon polyps/carcinoma in developed countries
Hookworm (Ancylostoma duodenale, Necator americanus) in developing countries.
In developed countries, adults > 50 years that present with IDA should have colon polyps/carcinoma ruled out as a potential underlying etiology!
Based on underlying mechanism [6]
Iron losses
Bleeding
Gastrointestinal bleeding
Occult gastrointestinal malignancy (e.g., colon cancer) [6]
Hookworm infestation (e.g., Ancylostoma spp, Necator americanus)
Peptic ulcer disease
Increased risk with NSAID use [8]
Menorrhagia
Hemorrhagic diathesis (e.g., hemophilia, von Willebrand disease)
Meckel diverticulum
Dialysis-dependent renal failure
Frequent blood donation
Decreased iron intake
Chronic undernutrition
Cereal-based diet
Strict vegan diet [1]
Decreased iron absorption
Achlorhydria/hypochlorhydria (e.g., due to autoimmune or H. pylori infection-induced atrophic gastritis)
Inflammatory bowel disease, celiac disease
Bariatric surgery
Increased demand
Pregnancy
Lactation
Growth spurt
EPO therapy
C: Signs and symptoms of anemia
Fatigue, lethargy
Pallor
Cardiac: tachycardia, angina, dyspnea on exertion, pedal edema
Brittle nails, koilonychia , hair loss
Pica, dysphagia
Angular cheilitis: inflammation and fissuring of the corners of the mouth
Atrophic glossitis: erythematous, edematous, painful tongue with loss of tongue papillae (smooth, bald appearance)
IDA may also manifest as Plummer-Vinson syndrome (PVS): triad of postcricoid dysphagia, upper esophageal webs, and iron deficiency anemia
P:
I: Diagnosis of IDA requires the presence of anemia (low hemoglobin or hematocrit) and evidence of low iron stores (usually determined by serum ferritin and iron levels).
Typically manifests as microcytic, hypochromic anemia with anisocytosis, low serum ferritin, and low serum iron levels
Laboratory tests
Complete blood count with differential
↓ Hemoglobin: anemia is typically defined as a hemoglobin level less than 2 standard deviations below normal (for age and sex) [1]
♂: < 14 g/dL
♀: < 12 g/dL
↓ Hematocrit
RBC: initially normal; decreased (with prolonged deficiency)
↓ Mean corpuscular volume: microcytic
↓ Mean corpuscular hemoglobin: hypochromic
Normal or ↓ reticulocyte count
↑ Red cell distribution width : differentiates IDA from anemia of chronic disease and thalassemia trait (where the RDW is usually normal)
Iron studies
↓ Serum ferritin
↓ Serum iron
↑ Serum transferrin and total iron binding capacity (TIBC)
↓ Transferrin saturation (< 20%)
↑ Serum free erythrocyte protoporphyrin
Peripheral blood smear:
Anisocytosis
Increased zone of central pallor
Bone marrow biopsy (rarely indicated): in patients with suspected IDA and nondiagnostic iron studies, low bone marrow iron is diagnostic of IDA
Low ferritin and iron levels in combination with an elevated TIBC are diagnostic of iron deficiency anemia!
Increased ferritin does not rule out iron deficiency anemia. It can be increased in response to simultaneous inflammation!
Evaluation for underlying cause [1]
Occult gastrointestinal bleeding
Recommended for:
Patients at risk for GI malignancy
All men (especially if > 50 years old)
Nonmenstruating women
Patients with history or signs of bleeding (e.g., melena, epigastric pain, hematochezia)
Initial workup
Stool guaiac test (screening only)
Colonoscopy ± EGD: to evaluate for GI malignancy, polyps, inflammatory bowel disease, celiac disease, etc.
Other causes
If no risk factors (e.g., advanced age) for occult GI bleeding → consider treat empirically with oral iron and monitor for response
Evaluation for menorrhagia, celiac disease, Crohn disease, ulcerative colitis, etc.
See heavy menstrual bleeding.
Examination of stool for ova and parasites if concern for Ancylostoma duodenale, Necator americanus (e.g., patient from a developing country, eosinophilia on CBC )
Repeat stool tests may be necessary since egg laying may be delayed.
Note that hookworms can also cause a positive stool occult blood test.
M: Dietary modifications
Infants and young children: restrict cow’s milk intake, use iron-fortified formula, introduce iron-rich foods (pureed form)
Adults: increase consumption of iron-rich diet (meats, iron-fortified food, fresh green leafy vegetables)
Oral iron therapy:
Indicated in all patients with IDA (if tolerated)
Should initially be administered for 3–6 months [6]
Adverse effects: gastrointestinal discomfort, nausea, constipation, black discoloration of stool
Absorption may be enhanced by simultaneous consumption of vitamin C (e.g., with lime juice).
Foods (e.g., tea, cereals) and drugs (e.g., calcium, antacids, PPIs) that decrease intestinal absorption of iron should be avoided.
Parenteral iron therapy
Indicated in
Nonadherence/intolerance to oral iron therapy
Intestinal malabsorption
Patients with Hb < 6 g/dL who decline blood transfusions
Available forms (ferric preparations): iron dextran, sodium ferric gluconate, and iron sucrose
Adverse effects:
Thrombophlebitis
Iron dextran can cause myalgia, arthralgia, headaches, and, rarely, anaphylactic shock within 1–2 days of infusion.
Blood transfusion
See transfusion
Recommended for severe anemia (Hb < 7 g/dL)
Treat the underlying disease (e.g., antihelminthics for hookworm, OCPs for menorrhagia)
P:
Iron deficiency anemia in pregnancy
Epidemiology
> 40% of pregnant women are iron deficient
Second most common cause of anemia in pregnant women (after physiologic anemia)
Etiology: increased iron requirements
Complications
Increased risk of adverse pregnancy outcomes
Impaired fetal neurodevelopment
Treatment: oral iron supplementation (see “Treatment” above)
Hemolytic anaemia
D: Hemolytic anemias are a group of conditions characterized by the breakdown of red blood cells. Hemolysis is caused by either abnormalities in the RBCs themselves (in hemoglobin, the RBC membrane, or intracellular enzymes), known as corpuscular anemia, or by external causes (immune-mediated or mechanical damage), known as as extracorpuscular anemia. All hemolytic anemias result in varying degrees of fatigue, pallor, and weakness (from asymptomatic disease to life-threatening hemolytic crisis), although some forms of hemolytic anemia have more specific findings (e.g., venous thrombosis in paroxysmal nocturnal hemoglobinuria). They also have common laboratory findings, including elevated indirect bilirubin and lactate dehydrogenase, reticulocytosis, and decreased haptoglobin levels. The Coombs test helps to distinguish between autoimmune (positive Coombs test) and nonautoimmune anemias (negative Coombs test). Treatment involves RBC transfusions as required but otherwise depends on the specific type of hemolytic anemia and its causes.
R:
D:
E:
A:
C: Signs of anemia
Pallor
Fatigue
Exertional dyspnea
In severe cases: tachycardia, angina pectoris, leg ulcers
Signs of hemolysis
Jaundice
Pigmented gallstones
Splenomegaly
Back pain and dark urine in severe hemolysis with hemoglobinuria
Signs of increased hematopoiesis (mostly in severe chronic anemias, e.g., thalassemia)
Bone marrow expansion: widening of the diploic space of the skull, biconcave deformity of the vertebral bodies
Cortical thinning and softening of bone → ↑ risk of pathologic fractures
Extramedullary hematopoiesis: hepatosplenomegaly
P:
I:
-Serum studies
-coombs test
-perippheral blood smear
Hemoglobin electrophoresis: abnormal hemoglobin patterns, e.g., in thalassemia
Flow cytometry
Absence of CD55 and CD59 on RBC surface in PNH
Detection of CD19, CD20, and CD23, light chain restriction (kappa or lambda) in CLL
Genetic analysis: mutations in congenital hemolytic anemia
Bone marrow biopsy
Rarely used in the workup of anemia due to its invasiveness
Indication: pancytopenia, presence of abnormal cells (e.g., blasts) in CBC/peripheral blood smear
Pathologic findings are most common in malignancies that replace bone marrow (e.g., CLL).
M:
P:
Myelodysplastic syndromes DR DEAC PIMP
D: Myelodysplastic syndromes (MDS) are a group of hematological cancers in which malfunctioning pluripotent stem cells lead to hypercellularity and dysplasia of the bone marrow. This, in turn, leads to cytopenia of one or more cell lines (thrombocytopenia, erythrocytopenia, leukocytopenia). Most cases of MDS have a primary, idiopathic etiology, while a minority of cases are secondary to an underlying cause. MDS usually affects elderly patients and has a slowly progressive course. Clinical features vary depending on the type of MDS and the affected cell lines, and may include signs of anemia (e.g., fatigue, weakness, pallor), recurrent infections, and/or petechial bleeding. Diagnosis of MDS requires blood tests, bone marrow biopsy, and possibly genetic analysis. While mild cases may be closely monitored, severe disease typically requires blood transfusions supplemented with erythropoietin, vitamins, and, in some cases, granulocyte colony-stimulating factor. Medical therapy (e.g., chemotherapy or immunosuppressants) may also help to manage the disease, but allogenous stem cell transplantation is the only curative treatment. In 30% of cases, the disease progresses to acute myeloid leukemia.
WHO Classification of Primary Myelodysplastic Syndromes
The WHO classification distinguishes between eight different primary myelodysplastic syndromes, based on the number of dysplastic cell lines and the percentage of blasts in the bone marrow, among other criteria
The most common types are refractory cytopenia with multilineage dysplasia, refractory anemia with ringed sideroblasts, and refractory cytopenia with unilineage dysplasia
R:
D:
E:
A: Primary MDS (90% of cases) [1]
Tends to occur in elderly patients
Unknown etiology: likely due to spontaneous mutations
Secondary MDS (10% of cases): caused by exogenous bone marrow damage
Treatment-related MDS: following cytostatic therapy (alkylating agents, topoisomerase II inhibitors, azathioprine, etc.)
Benzene and other organic solvents
Radiation damage: therapeutic radiation, radioiodine therapy, ionizing radiation
Paroxysmal nocturnal hemoglobinuria
C: Asymptomatic in 20% of cases
Dependent on the affected cell line
Erythrocytopenia (70% of cases) → symptoms of anemia
Leukocytopenia with increased susceptibility to bacterial infections, especially of the skin
Thrombocytopenia with impaired primary hemostasis → petechial bleeding
Hepatosplenomegaly (uncommon)
P:
I: CBC with peripheral smear
Normocytic or macrocytic anemia (rarely microcytic) of refractory type (refractory anemia)
Other possible findings
Leukocytopenia and/or thrombocytopenia
Nucleated RBCs, ringed sideroblasts, Howell-Jolly bodies, basophilic stippling
Pseudo-Pelger-Huet anomaly
Neutrophils with hyposegmented nuclei (usually bilobed)
Seen in peripheral blood smears of patients undergoing chemotherapy
Large, agranular platelets, and megakaryocytes (in MDS-F)
Bone marrow biopsy: hypercellular, dysplastic bone marrow with numerous cells of all three cell lines with blasts, megakaryocytes, etc.
The amount of dysplastic cells depends on the type (see “Classification” above)
Ringed sideroblasts
Chromosome analysis: In > 50% of patients, chromosomal aberrations can be detected at the time of diagnosis
M; The therapeutic approach depends on a patient’s presentation, age, and comorbidities. More aggressive therapy (e.g., chemotherapy, stem cell transplantation) is generally reserved for younger, healthier patients.
Mild cytopenia: “watch and wait”
Severe cytopenia
Supportive treatment
Mainstay of treatment: RBC and platelet transfusions depending on cell counts
To compensate for the high cell turnover: vitamin supplementation (Vitamin B6, B12, folate)
In cases of symptomatic anemia and low erythropoietin (EPO) levels: synthetic EPO
In cases of neutropenia: granulocyte colony-stimulating factor
If infection occurs: antibiotics
Medical therapy:
Chemotherapy: If myeloblasts are elevated and since the disease may progress to acute myeloid leukemia (AML)
Immunosuppressive agents
Lenalidomide: the drug of choice for patients with 5q deletion
Allogenous stem cell transplant is the only curative option.
P: Depending on the chromosomal aberrations detected in pluripotent stem cells, up to 30% of MDS cases may progress to acute myelogenous leukemia
Myeloproliferative neoplasms
Dr DEAC PIMP
D: Myeloproliferative neoplasms (MPN) are a group of disorders characterized by a proliferation of malignant hematopoietic stem cells that belong to the myeloid cell lineage. The most clinically relevant MPN include chronic myeloid leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET). An important etiological factor is the mutation of the Janus kinase-2 (JAK2) gene, which is present in almost all cases of PV and in approximately 50% of patients with ET and PMF. In contrast to the other subtypes, CML is characterized by a distinct translocation between chromosome 9 and 22 (BCR-ABL1 fusion gene). Each of these neoplasms has a typical pattern of cell proliferation: granulocytes are increased in CML, thrombocytes in ET, and all cell lines show increased proliferation in PV. PMF, on the other hand, shows an initial hyperproliferative phase, but eventually progresses to pancytopenia. All myeloproliferative neoplasms may lead to elevated uric acid levels and gout as a result of increased cellular breakdown. They are also associated with an increased risk of acute myeloid leukemia. Treatment involves hydroxyurea to reduce the cell count, polychemotherapy to halt the proliferation of malignant cells, and, in young patients, allogeneic stem cell transplantation.
Primary myelofibrosis
Description: any myeloproliferative neoplasm leading to bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly.
Epidemiology: peak incidence between age 60–70 years
Etiology: unknown
Genetics: JAK2 mutation in 50% of cases
Clinical features
Weakness, fatigue, weight loss
Splenomegaly: left upper quadrant abdominal pain
Hyperproliferative phase (early phase): thrombocytosis (→ thromboembolic events) and leukocytosis
Pancytopenic phase (late phase):
Erythrocytopenia → anemia
Thrombocytopenia → petechial bleeding
Leukopenia → increased susceptibility to infections
Diagnosis
Laboratory studies: ↑ leukocyte alkaline phosphatase, LDH, and uric acid
Peripheral blood smear: dacrocytes (teardrop cells)
Bone marrow aspiration: punctio sicca
Treatment
Curative: allogeneic stem cell transplantation (option for younger patients)
Supportive
Hyperproliferative phase
Prevent thromboembolisms: antiplatelet drug (aspirin 100 mg)
Control cell count: hydroxyurea, interferon alpha, cladribine
Pancytopenic phase
JAK2 inhibitor: ruxolitinib
Periodic transfusions
Low-dose thalidomide plus glucocorticoids
In myelofibrosis, RBCs shed tears (teardrop cells), because they have been forced out of the fibrosed bone marrow (extramedullary hematopoiesis).
Essential thrombocythemia
Epidemiology
Median age at diagnosis: 60 years
♀ > ♂ (2:1)
Genetics: JAK2 mutation in 50% of cases
Clinical features
50% asymptomatic
Thromboembolic events
Increased risk of fetal loss
Vasomotor symptoms (headache, visual disturbances, acral paresthesias)
Acute gouty arthritis
Petechial bleeding
Diagnostics
ET is a diagnosis of exclusion; all other causes of thrombocytosis must be ruled out before the diagnosis can be made.
Thrombocytosis (> 600,000/μL)
↑ LDH and uric acid
Bone marrow aspiration: hyperplasia of megakaryocytes
Differential diagnosis
Reactive thrombocytosis: platelet proliferate as a reaction to a certain condition, and not because of an intrinsic defect
Can be particularly severe in children, with platelet counts reaching 1,000,000/μL.
Etiology
Inflammation, infection
Iron deficiency
Malignancy
Increased cellular turnover following acute blood loss
Pregnancy
Following cytostatic therapy
Treatment
Prevent thromboembolisms: low dose aspirin
Reduce thrombocyte count: hydroxyurea or interferon alpha
Chronic eosinophilic leukaemia
Description: leukemia with monoclonal proliferation of eosinophilic granulocytes, that causes peripheral eosinophilia and tissue damage
Clinical features
Hepatosplenomegaly
Anemia and/or coagulation disorders
Diagnosis
CBC: ↑↑↑ eosinophilic granulocytes
Peripheral blood smear and bone marrow aspiration: monoclonal blast cells or cytogenetically abnormal eosinophils
Macrocytic anaemia
Insufficient nucleus maturation relative to cytoplasm expansion due to
Defective DNA synthesis
Defective DNA repair.
Ddx: Megaloblastic anemia: impaired DNA synthesis and/or repair with hypersegmented neutrophils Vitamin B12 deficiency Folate deficiency Medications Phenytoin Sulfa drugs Trimethoprim Hydroxyurea MTX 6-mercaptopurine Fanconi anemia Orotic aciduria Nonmegaloblastic anemia: normal DNA synthesis without hypersegmented neutrophils Liver disease Alcohol use Diamond-Blackfan anemia Myelodysplastic syndrome Multiple myeloma Hypothyroidism.
Both iron deficiency anemia and anemia of chronic disease can manifest with normocytic anemia in the initial phase and microcytic anemia later on.
Bone marrow failure (e.g., due to myeloproliferative malignancy, myelodysplastic syndrome) can manifest with microcytic, normocytic, or macrocytic anemia.
The causes of microcytic anemia can be remembered with IRON LAST: IRON deficiency, Lead poisoning, Anemia of chronic disease, Sideroblastic anemia, Thalassemia.
Normocytic anemia
MCV (fL) = 80-100
Mechanism: Decreased blood volume and/or decreased erythropoiesis
Microcytic anaemia
MCV (fL) <80.
Insufficient hemoglobin production.
Anaemia
D: Definition: a decrease in the absolute number of circulating RBCs; exact cutoffs vary from source to source. WHO criteria for anemia [1] Men: Hb < 13 g/dL Women: Hb < 12 g/dL Revised WHO/National Cancer Institute [2] Men: Hb < 14 g/dL Women: Hb < 12 g/dL American Society of Hematology [3] Men: Hb < 13.5 g/dL Women: Hb < 12 g/dL
R:
D:
E:
A:
C: Asymptomatic Pallor (e.g., on mucous membranes, conjunctivae) Exertional dyspnea and fatigue Pica (craving for ice or dirt) Jaundice (in hemolytic anemia) Muscle cramps Worsening of angina pectoris Features of hyperdynamic state Bounding pulses Tachycardia/palpitations Flow murmur Pulsatile sound in the ear Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g., thalassemia, myelofibrosis). Hepatosplenomegaly Paravertebral mass Widening of diploic spaces of the skull. Pulse acceleration is often the first sign of hemodynamically relevant blood loss.
P:
I: Reticulocyte count, peripheral blood smear, bone marrow biopsy, imaging (if bleeding is suspected). Haemoglobin electrophoresis,
M: Identify and treat the underlying cause
Blood transfusion with RBCs for severe anemia:
Hb ≤ 7 g/dL
Hb ≤ 8 g/dL if the patient either has a preexisting cardiovascular disease or is undergoing cardiac or orthopedic surgery
See transfusion for further details
Bone marrow transplantation may be indicated in certain cases (e.g., aplastic anemia).
P:
Thalassemia
D: Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia. Based on the defective globin chain, they are classified as either alpha or beta subtypes. Thalassemias are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in patients of Asian or African origin, whereas beta thalassemias are predominant in patients of Mediterranean descent. Beta thalassemia can be further divided into a heterozygous minor and a homozygous major variant. The minor variant features only a low risk of hemolysis; however, the major variant presents with severe anemia as early as infancy and often causes growth retardation. The severity of alpha thalassemias varies as well, with significant anemia generally first arising with a deletion of three of the four alleles (HbH disease). Deletion of all four α-globin alleles (Hb Bart disease) is usually fatal in utero or shortly after birth. In all forms of thalassemia, insufficient erythropoiesis can lead to extramedullary hematopoiesis as well as bone marrow hyperplasia. The latter frequently results in periosteal reactions that are observed as the classic “hair-on-end” sign on skull radiographs. Diagnosis is confirmed via electrophoresis or DNA analysis. If a patient with thalassemia requires transfusion therapy, it is important to consider the possible development of secondary iron overload, which should be treated with chelating agents (e.g., deferoxamine).
R:
D:
E: Beta thalassemia: most commonly seen in people of Mediterranean descent
Alpha thalassemia: most commonly seen in people of Asian and African descent
Thalassemia provides partial resistance against malaria.
Alpha thalassemia is common in Asia and Africa.
A: General
Cause: gene mutations
Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites
β-globin locus - short arm of chromosome 11
Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles
The α-globin gene cluster is located on chromosome 16
Inheritance pattern: autosomal recessive
Beta thalassemia
In a normal cell, the β-globin chains are coded by a total of two alleles Thus, there are two forms of the disease.
Beta thalassemia minor (trait): one defective allele
Beta thalassemia major (Cooley anemia): two defective alleles
Sickle cell beta-thalassemia: a combination of one defective β-globin allele and one defective HbS allele
Alpha thalassemia
In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.
Silent carrier (minima form): one defective allele (-α/αα)
Alpha thalassemia trait (minor form)
Two defective alleles (-α/-α or –/αα)
Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart.
Hemoglobin H disease (intermedia form): three defective alleles (–/-α) → results in excessive production of pathologically altered HbH
Hemoglobin Bart disease (major form): four defective alleles (–/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers)).
C: Beta thalassemia
Minor variant (heterozygous): unremarkable symptoms (low risk of hemolysis, rarely splenomegaly)
Major variant (homozygous)
Severe hemolytic anemia that often requires transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis
Hepatosplenomegaly
Growth retardation
Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla)
Transient aplastic crisis (secondary to infection with parvovirus B19)
Sickle cell beta thalassemia
Features of sickle cell disease
Severity depends on the amount of β-globin synthesis.
Alpha thalassemia
Silent carrier: asymptomatic
Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW
Hemoglobin H disease
Jaundice and anemia at birth
Chronic hemolytic anemia that may require transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis
Hepatosplenomegaly
Skeletal deformities (less common)
Compared to thalassemia beta, symptoms in adults are generally less severe.
Hb-Bart’s hydrops fetalis syndrome (most severe variant of alpha thalassemia)
Intrauterine ascites and hydrops fetalis, severe hepatosplenomegaly, and often cardiac and skeletal anomalies
Incompatible with life (death in utero or shortly after birth).
P: Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient’s exact genotype.
Inefficient erythropoiesis → anemia
Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.
HbF protects infants up to the age of 6 months, after which HbF production declines and symptoms of anemia appear.
Alpha thalassemia intermedia (HbH disease) and Bart disease: faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb-Bart’s
In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia.
Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities.
I: Blood sample: microcytic hypochromic anaemia: Iron deficiency anaemia usually presenting with a low RBC count and a high RDW. Blood smear: target cells, teardrop cells, anisopoikilocytosis. Bone marrow biopsy: reactive hyperplaia. Confirmatory tests: Hb-electrophoresis: alpha thalassemia can usually be detected if >3 alleles are defective. Abnormal pattern depends on the exact subtype. Diagnosis of beta-thalassemia minor is confirmed by HbA2> 3.5%. DNA analysis: to test for alpha thalassemia minor and minima (<3 alleles defective). Can do imaging: skseletal deformaties (e.g high forehead, prominent zygomatic bones and maxilla, referred to as ‘chipmunk facies’ can be seen on all imaging modalities.
X-ray: hair on end (‘crew cut’) sign.
Family history plays an important role in diagnosing patients with clinically silent thalassemia. The possibility of thalassemia in these patients may only be investigated once a family member is diagnosed with a more severe form!
Suspect thalassemia in a patient with microcytic anemia that is nonresponsive to iron supplementation!
M: Minor and minima variants
Usually no therapy required
Supplementation of iron or folic acid may be indicated in some patients.
Major variants and hemoglobin H disease
Curative: allogeneic stem cell transplantation
Symptomatic treatment
Transfusion of erythrocyte concentrate
Indication: Hb < 7–8 g/dL or marked clinical symptoms
Target: Hb > 10 g/dL
Chelating agents (e.g., deferoxamine) in patients with
Serum ferritin concentration > 1000 μg/L
Secondary iron overload
Folic acid supplementation
Splenectomy
P:
Sickle cell disease Dr Deac Pimp
D: Sickle cell syndromes are hereditary hemoglobinopathies. Homozygous sickle cell anemia (HbSS, autosomal recessive) is the most common variant of the sickle cell syndromes and occurs predominantly in individuals of African and East Mediterranean descent. Sickle cell trait occurs in heterozygous carriers (HbSA). Other rare variants of sickle cell syndrome occur in individuals with one HbS allele and one other allele (HbC or Hb-β thalassemia). A point mutation in the beta chain of hemoglobin leads to substitution of glutamic acid by valine, thus changing the structure (and properties) of hemoglobin. Abnormal hemoglobin polymerizes when deoxygenated, resulting in sickle-shaped erythrocytes, which cause vascular occlusion and ischemia. Sickle cell anemia manifests in early childhood with symptoms associated with vascular occlusion and hemolytic anemia. Infarctions in the spleen, kidneys, bone, CNS, and other organs are common and cause progressive loss of organ function and acute and chronic pain in affected parts of the body. Acute, painful vaso-occlusive crises are provoked by conditions associated with reduced oxygen tension. Neonatal screening for sickle cell anemia has been implemented across the U.S., allowing the diagnosis to be made before the first manifestation of the disease. In older children and adults, hemoglobin quantification tests are used to diagnose the condition. The cornerstones of treatment involve the management of painful vaso-occlusive crises, hemolytic anemia, and disease complications as well as prevention of infection. Allogeneic bone marrow transplantation is the only curative treatment option.
R:
D:
E: Predominantly affects individuals of African and East Mediterranean descent
Africa has the highest prevalence of the disease (30% heterozygote prevalence).
HbS gene is carried by 8% of the African American population. [1]
Sickle cell anemia is the most common form of intrinsic hemolytic anemia worldwide.
A:
C: Sickle cell trait
Often asymptomatic
Painless gross hematuria due to renal papillary necrosis: often the only symptom
Hyposthenuria: nocturia, enuresis
Recurrent urinary tract infections
Renal medullary carcinoma
Very rarely, symptoms of sickle cell disease may occur as a result of severe oxygen deficiency.
Sickle cell disease
Onset
∼ 30% develop symptoms in the first year of life; > 90% by age 6 years
Manifests after 6 months of age as the production of HbF decreases and HbS levels increase
Acute symptoms
Acute hemolytic crisis (severe anemia)
Splenic sequestration crisis
Splenic vaso-occlusion → entrapment and pooling of large amounts of blood in the spleen → acute left upper quadrant pain, anemia, reticulocytosis, and signs of intravascular volume depletion (e.g., hypotension)
Aplastic crisis
Aplastic anemia with an acute, severe drop in hemoglobin and associated reticulocytopenia due to an infection with parvovirus B19
Dysmorphic erythrocytes in sickle cell disease and hereditary spherocytosis are susceptible to parvovirus B19 infection, which can temporarily suppress bone marrow erythropoiesis.
Hyperhemolysis: intravascular and extravascular hemolysis triggered by mild oxygen deficiency (rare)
Infection
Pneumonia
Meningitis
Osteomyelitis (most common cause: Salmonella spp., Staphylococcus aureus)
Sepsis (most common cause: Streptococcus pneumoniae)
Vaso-occlusive events
Vaso-occlusive crises (painful episodes, painful crisis): recurrent episodes of severe deep bone pain and dactylitis → most common symptom in children and adolescents
Acute chest syndrome
Priapism
Stroke (common in children)
Infarctions of virtually any organ (particularly spleen) and avascular necrosis with corresponding symptoms (see “Complications” below)
Chronic symptoms
Chronic hemolytic anemia: fatigue, weakness, pallor; usually well-tolerated
Chronic pain
Cholelithiasis (pigmented stones)
Symptoms of other forms of sickle cell syndrome (HbSC disease and HbS/beta-thalassemia) are similar to sickle cell anemia but less severe.
P: Genetics
Heterozygotes (HbSA): carry one sickle allele and one other (usually normal) → sickle cell trait
Homozygotes (HbSS): carry two sickle alleles → sickle cell anemia
Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine (single amino acid substitution) → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS).
Glutamic acid can also be replaced with a lysine, creating hemoglobin C.
Hemoglobin SC disease
Heterozygosity for hemoglobin S and hemoglobin C
Results in a phenotype more severe than sickle cell trait but not as severe as sickle cell disease (e.g., fewer acute sickling events).
Pathomechanism
HbS polymerizes when deoxygenated, causing deformation of erythrocytes (“sickling”). This can be triggered by any event associated with reduced oxygen tension.
Hypoxia (e.g., at high altitudes)
In homozygotes, up to 100% of the hemoglobin molecules are affected, leading to sickle cell formation under minimally decreased oxygen tension.
In heterozygotes, sickling only occurs due to severe reduction in oxygen tension.
Infections
Dehydration
Acidosis
Sudden changes in temperature
Stress
Pregnancy
Sickle cells lack elasticity and adhere to vascular endothelium, which disrupts microcirculation and causes vascular occlusion and subsequent tissue infarction.
Extravascular hemolysis and intravascular hemolysis are common and result in anemia.
Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency.
The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease.
I: Prenatal testing: may be conducted in select cases: chorionic villus sampling and DNA analysis at 8–12 weeks of gestation
Neonatal screening (mandatory in all states)
If positive: Repeat hemoglobin electrophoresis (gold standard) confirms the diagnosis and distinguishes between heterozygotes and homozygotes and other forms of sickle cell syndrome (e.g., HbSC disease)
Migration towards the anode: HbA > HbF > HbS > HbC
Older children and adults
Liquid chromatography and isoelectric focusing to quantify hemoglobin subtypes (best tests)
Sickle cell test: detects sickle cells in a blood smear under anaerobic conditions.
Peripheral blood smear
Sickle cells (drepanocytes): crescent-shaped RBCs
Target cells
Possibly Howell-Jolly bodies
Reticulocytosis
Imaging: X-ray of the skull shows hair-on-end (“crew cut”) sign due to periosteal reaction to erythropoietic bone marrow hyperplasia (also present in thalassemia).
Disease monitoring
Laboratory analysis
See “Laboratory signs of hemolysis” in hemolytic anemia.
Liver and kidney function tests
Pulmonary function tests
Transcranial Doppler ultrasound is used to identify and monitor children with a high risk of stroke.
M: Longterm management
Prevent infections
Pneumococcal vaccines
Meningococcal vaccines
Daily penicillin prophylaxis (at least until the age of 5 years)
If sepsis is suspected, treat with IV third-generation cephalosporin (e.g., ceftriaxone)
If meningitis is also suspected: add vancomycin
Second-line therapy (e.g., due to allergy): levofloxacin, clindamycin
Prevent vaso-occlusive crises and manage anemia
Avoid triggers
Hydroxyurea: first-line treatment
Indications
Frequent, acute painful episodes or other vaso-occlusive events
Severe symptomatic anemia
Effect: stimulates erythropoiesis and increases fetal hemoglobin → sickled hemoglobin is proportionally reduced → red blood cell polymerization decreases → fewer vaso-occlusive episodes
Possible adverse effects: myelosuppression (beneficial in patients with myeloproliferative disease, e.g., polycythemia vera)
Can cause an atypical form of macrocytosis (nonmegaloblastic anemia)
If the response to hydroxyurea alone is not adequate
Combine with erythropoietin
Blood transfusions
Folic acid supplementation
Cholecystectomy to treat cholelithiasis
Management of acute sickle cell crisis
Prompt and adequate supportive treatment
Hydration
Pain management with nonsteroidal anti-inflammatory agents and opioids
Thromboembolic prophylaxis
Nasal oxygen
Bed rest
Blood transfusions
Indications
Acute, severely symptomatic anemia (e.g., aplastic crisis)
Secondary prophylaxis of acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure)
Surgery (preoperative transfusions)
Pregnancy
Exchange transfusions (erythrocytapheresis): automated removal of erythrocytes containing HbS and simultaneous replacement with HbS free erythrocytes
Indication: acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure)
Advantages
Rapid effect!
Allows precise control of HbS levels and iron accumulation
Disadvantages
Expensive and equipment not readily available
Requires experienced practitioner
Curative therapy
Allogeneic bone marrow transplantation
Indications: homozygotes, children < 16 years with severe disease.
P: Organ damage
Recurrent vascular occlusion and disseminated infarctions lead to progressive organ damage and loss of function. In homozygotes, this progress is associated with high morbidity and mortality. In heterozygotes, organ damage is very rare.
Male cancers (0-14 years)
Brain 26% Leukaemias 31% Lymphomas 13% SNS STS Other
Male cancers (15-24 years)
Brain 13% Carcinomas 9% Germ cell tumours 27% Leukaemias 10% Lymphomas 22% Other 19%
Females (0-14)
Brain 28%
Leukaemias 29%
Lymphomas 7%
Females (15-24)
Brain 14%
Carcinomas 31%
Leukaemias 7%
Lymphomas 20%
