8.3 - Myeloproliferative + Other Blood Disorders Flashcards
in broad terms, what are myeloproliferative disorders?
overproduction of blood cells
aka myeloproliferative neoplasms
☞ proliferation of bone marrow cells from myeloid lineage
☞ myeloid lineage cells include: RBCs; platelets; granulocytes (neutrophils, basophils, mast cells and eosinophils)
☞ each disorder can potentially cause proliferation of all myeloid cells, but classified based on dominant cell line involved
☞ diagnoses of exclusion, need to consider all other causes first
examples
- essential throbocythaemia (overproduction of platelets)
- polycythaemia vera (overproduction of RBCs)
- chronic myeloid leukaemia (overproduction of WBCs)
- myelofibrosis (bone marrow fibrosis - odd one out)
all of these disorders involve dysregulation at the multipotent haematopoietic stem cell
what are some clinical features of myeloproliferative disorders
- overproduction of one or several blood cell types from myeloid lineage, with one dominant type
- hypercellular bone marrow or marrow fibrosis
- cytogenetic abnormalities
- thrombotic and/or haemorrhagic diatheses
- extramedullary haemopoiesis (liver/spleen)
- potential to transform to acute leukaemia
cytogenic = producing cells
diathesis = predisposition to a disease or other disorder
polycythaemia vera
overproduction of RBCs
* mutation in single haematopoietic stem cell
* JAK2 gene mutation in 95% of PV patients
* normally, EPO activates JAK2 gene and stimulates haemopoiesis
* in PV, this mutation keeps JAK2 activated all the time, so haemopoiesis occurs all the time, even in absence of EPO, producing too many RBCs
* over time, these cells start to die out, leading to fibrosis of bone marrow
* bone marrow can no longer produce blood cells
* this leads to anaemia (low RBC), thrombocytopenia (low platelets), leukaemia (low WBC)
symptoms
* thick blood + sticky → causes clots and bleeding (due to pressure)
* these clots can occur in brain (blurred vision, headache, strokes), heart (angina, MI), stomach (peptic ulceration), hepativ veins (budd-chiari syndrome)
* face can appear plethoric (constant blush) as more red cells
* pruritis (itching) after warm showers, perhaps due to excess mast cells
* erythromelalgia (episodes of redness, pain, intense warmth in hands and feet, due to small blood clots in distal extremities)
* splenomegaly (early satiety ⇢ weight loss)
* gout (due to hyperuricemia due to increased purine metabolism, due to increased DNA/RNA synthesis due to increased production of cells)
☞ median age 60 yrs
☞ male = female
how is polycythaemia diagnosed
- high hematocrit (or raised red cell mass) + increased haemoglobin
- low levels of erythropoietin
- bone marrow biopsy is done, showing JAK2 mutation and proliferation of all myeloid cells
- some patients have high platelets and neutrophils (and uric acid)
- arterial and venous thombrosis
- haemorrhage into skin or GI tract
- pruritis (itchy skin)
- splenic discomfort + splenomegaly
- gout (crystals of urate forming in joints, leading to multi-site arthritis)
- can transform to myelofibrosis or acute leukaemia
polycythaemia management
- venesection to maintain hematocrit
- aspirin 75mg unless contraindicated (decreases chances of thombrosis)
- manage CVS risk factors
- sometimes drugs, such as JAK inhibitors, to reduce the overproduction of cells, should be considered
polycythaemia: what else could it be due to?
other than PV
polycythaemia = increase in circulating red cell concentration typified by a persistently raised hematocrit
- increase can be relative (normal red cell mass with decreased plasma volume) or absolute (increased number of erythrocytes)
- absolute can be primary (abnormality originates in bone marrow - polycythaemia vera) or secondary (increased levels of EPO)
- secondary polycythaemia can be physiologically appropriate (eg in response to tissue hypoxia) or an abnormal pathologic production of EPO (eg renal carcinoma, renal artery stenosis) or may be giving themselves EPO (eg to improve athletic ability)
☞ EPO stimulates JAK2 gene to increase erythropoiesis
essential thrombocythaemia
too many platelets
* 50% caused by JAK2 mutation, sometimes caused by MPL mutation (thrombopoietin receptor), or CalR mutation (chaperone protein)
* normally, thrombopoeitin is proudced by kidneys + liver which stimulates JAK2 gene, stimulating haematopoietic cell to divide and mature into megakaryocytes, which produce platelets
* mutation causes signalling pathway to be active all the time, where platelets produced in absence of thrombopoietin
* in rare cases, can develop into myelofibrosis and acute leukaemia
CBC shows
* increased platelet count
* bone marrow biopsy showing increased megakaryocytes and genetic mutation
* possibly increased WBC count and haemoglobin
* iron studies can help rule out reactive thrombocytosis (ie due to iron deficiency anaemia)
* no alternative diagnosis, and absence of any indicator of reactive thrombocytosis
essential thrombocythaemia symptoms
- fatigue
- headache
- dizziness
- nausea
- tinnitus
- numbness in hands and feet
- complications similar to polycythaemia vera (eg thrombotic complications, erythromelalgia, splenomegaly)
- however, pruritis is uncommon in ET
note: if platelet count really gets too high, platelets can’t function in such a crowded environment, and therefore patient can bleed
essential thrombocythaemia management
- exclude reactive causes (on another card) that could also cause a high platelet count
- any CVS risk factors should be aggressively managed
- aspirin given to reduce clotting
- in high risk patients, where thombrosis or haemorrhage more likely, return platelet count to normal with drug such as hydroxycarbomide
essential thrombocythaemia - reactive causes also causing high platelet count could be due to…
- infection
- inflammation (eg IBD or rheumatoid arthritis)
- other tissue injury (eg surgery, trauma or burns)
- haemorrhage
- cancer
- redistribution of platelets (eg hyposplenism or splenectomy)
- ensure high platelet counts are persistent before investigating for ET
(primary) myelofibrosis
☞ secondary myelofibrosis is caused by another disorder
☞ aka chronic idopathic myelofibrosis
- even though myelofibrosis is a myeloproliferative neoplasm, it doesn’t always cause an increased cell count
- causes abnormal proliferation of megakaryocytes
- these megakaryocytes make cytokines, instead of normal platelets
- these cytokines stimulate excessive collagen deposition in bone marrow
- these replace the haematopoietic stem cells, causing anaemia
- the WBC + platelet counts are variable ⇢ can be increased, normal or decreased, depending on bone marrow fibrosis
- 50% of patients have JAK2 mutation, and 25% have CalR mutation (the same as essential thrombocythaemia)
symptoms of myelofibrosis
- cytokines released in blood can cause fever, weight loss and decreased appetite
- bone marrow stops working, so stops producing new blood cells… this causes symptoms of anaemia (pallor, fatigue)
- extramedullary hematopoiesis (splenomegaly and hepatomegaly)
what are some causes of secondary myelofibrosis
technically not on LOs
- leukaemia
- autoimmune diseases
- toxins, eg benzene
- glycogen storage diseases
characteristic clinical signs of myelofibrosis
- teardrop cells on blood smear (from blood cells squeezing out of tight environment
- ‘dry tap’ from attempting to aspirate bone marrow (cells can’t get out due to fibrosis)
chronic myeloid leukaemia
genetic cause on sep card
- develops insiduously
- usually presents with very high white cell count (WCC) but this may be incidental
- CML affects granulocytes (neutrophil, basophil and eosinophil) where the cells mature only partially (with acute leukaemia, the cells don’t mature at all)
- the partially matured granulocytes don’t work effectively, and divide too quickly
- dividing too quickly → increased risk of mutations → might progress into acute leukaemia
- too many of these cells, which accumulate in bone marrow and then spill out into blood → hepatomegaly and splenomegaly
- this causes healthy blood cells to get ‘crowded out’, leading to disorders such as anaemia, thrombocytopenia and leukopenia etc
