What is the main genetic abnormality in sickle cell disease? Describe why patients with sickle cell disease are at risk of vascular crises.
Sickle cell disease includes all conditions associated with hemolytic anemia and vaso-occlusive pain. Over 20% of people in equatorial Africa are heterozygous for the sickle gene, as it is believed to offer protection against malaria. The pathophysiology arises from an amino acid switch in the 6th position (11th chromosome) from glutamic acid to valine.
When hemoglobin S encounters a deoxygenated state, the hemoglobin is less soluble and the Hb S tetramers aggregate or polymerize. The sickled RBCs adhere to the vascular surface, causing occlusion and an increased hypercoagulable state.
Not surprisingly, sickle cell disease patients have the potential for many co-morbidities:
- Vaso-occlusive crises including chest crises
- Pulmonary hypertension
- Splenic sequestration crises
- Growth retardation
- Avascular necrosis
- Increased risk of infection from encapsulated organisms
You are referred a patient with normocytic anemia (Hgb 88g/L), calcium of 2.93mmol/L, and creatinine of 140mmol/L. She is speculated to have multiple myeloma.
What investigations are prudent for diagnosis? What complications are associated with myeloma?
Definition of Multiple Myeloma: Any M protein or bone marrow plasmacytosis with evidence of end organ dysfunction from clonal plasma cell growth (also known as “CRAB”).
- Renal failure
- Bony disease
Complications include from myeloma include:
- Bony pain from osteolytic lesions and compression fractures.
- Systemic features such as fatigue due to the anemia and accumulating tumour burden.
- Hematological complications:
- Bone marrow failure.
- Renal failure.
- Increased incidence of infections.
- Neurological complications:
- Spinal cord and nerve root compression.
- Peripheral neuropathy.
- Intracranial plasmacytomas.
Investigations for myeloma: Skeletal survey, bone marrow biopsy (with specimens sent for cytogenetics), 24 hour urine collection for UPEP, and proteinuria.
Blood work must include a full CBC, calcium profile, Serum protein electrophoresis with immunofixation, beta2 microglobulin level and free light chain analysis.
A 25 year old male is referred for the evaluation of head and neck lymphadenopathy in the context of weight loss and malaise.
Consider the following points for discussion:
- What are B symptoms?
- What type of specimen would be required to confirm a diagnosis of lymphoma?
- Discuss the differential diagnosis of lymphadenopathy.
The B symptoms are:
- Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
- Unexplained fever >38 degrees C.
- Drenching night sweats.
The single most useful diagnostic test is a representative, technically adequate, and properly evaluated biopsy, with either an excisional or Core biopsy. An FNA is not acceptable for a diagnosis of lymphoma.
A differential diagnosis for lymphadenopathy is shown below:
|Bacterial (any infection, TB, Lyme, brucellosis, cat-scratch disease)||Collagen vascular disease (RA, dermatomyositis, SLE, vasculitis, Sjögren)||Lymphoproliferative disorder/Lymphoma|
|Viral (EBV, CMV, HIV)||Drug hypersensitivity||Metastatic cancer|
|Parasitic (toxoplasmosis)||Sarcoidosis, amyloidosis, Kikuchi’s disease||Langerhans Histiocytosis|
|Fungal (histoplasmosis)||Serum sickness|
A 56 year old female is referred to clinic for a RBC count of 6.98 x 1012/L and hemoglobin of 190g/L with a platelet count of 750 x 109/L.
Differentiate between primary (bone marrow) and secondary causes of polycythemia.
|Low Erythropoeitin Level||High Erythropoeitin Level|
|Myeloproliferative Neoplasm: Polycythemia Vera||Hypoxia: COPD, OSA, high altitude, smoker, right to left shunts|
|Cancer: hepatocellular carcinoma, renal cell carcinoma, cerebellar hemangioblastoma, pheochromocytoma, uterine myoma|
|Endocrine: Cushing’s, hyperaldosteronism|
|Medications: Epo, testosterone|
|Familial: Von Hippel Lindau mutation|
|Spurious: volume contraction|
Her erythropoietin level is low at 2 IU/L and she has splenomegaly on exam. A JAK2 level is requested on the patient’s peripheral blood as there is suspicion of a myeloproliferative neoplasm.
What does the JAK2 level stand for?
Janus kinase 2 is a non-receptor tyrosine kinase, a genetic mutation identified on the short arm of chromosome 9p associated with constitutive tyrosine phosphorylation activity of the JAK-STAT pathway.
It is found in >96% of Polycythemia Vera patients, 50% of essential thrombocythemia, and 50% of myelofibrosis patients.
Rituximab is a therapy no used in both indolent and aggressive B cell lymphomas. What is the mechanism of action of Rituximab? List the major disorders for which Rituximab is approved for use.
Recall that CD20 is expressed on over 90% of B cells and is a protein that is not shed or internalized.
Rituximab is an anti-CD20 chimeric monoclonal antibody that on contact to CD20 on the surface of a B cell causes cytotoxicity mediated by compliment and antibody-dependent cellular cytotoxicity.
Indications for Rituximab use:
- Treatment of CD20 positive lymphoproliferative disorders
- Treatment of Connective tissue disease such as Rheumatoid arthritis
- Can be requested on special access for second line therapies in autoimmune disorders such as immune thrombocytopenia, autoimmune hemolytic anemia, or Thrombotic Thrombocytopenia Purpura
Garvey B. British Journal of Haematology Volume 141, Issue 2, pages 149–169, April 2008