Session 10: Blood and Bleeding Disorders Flashcards
What are the majority of abnormalities in the FBC due to?
Laboratory screening tests of coagulation attempt to replicate haemostatic processes in vitro. However, this does not necessarily reflect coagulation status in vivo and normal results do not exclude a bleeding disorder. Results should be interpreted in conjunction with the bleeding history, particularly the response to haemostatic challenges and drug history.
The majority of abnormalities in the FBC will be reactive rather due to primary haematological disease. Reactive changes in other blood cell components. Reactive blood changes associated with renal failure and inflammatory conditions.
Reactive Changes in WBC & Platelets
Neutrophils
Basophils
Monocytes
Eosinophils
Lymphocytes
Describe Neutrophils and possible causes of Neutrophilia
Ability to phagocytose – engulf invader and destroy pathogens using hypochlorous acid
- Specific granules: lactoferrin, hCAP18, lysozyme
- Azurophil granules: alpha-defensin lysozyme
Multi-lobular nuclei
Neutropenic sepsis is life-threatening!
Neutrophilia
- Infection is the most common cause
- Can be caused tissue damage, acute inflammation, malignant disease, cytokines: G-CSF (given to patients who have had chemo to prevent neutropenia), smoking, myeloproliferative (also raised WCC), acute haemorrhage, drugs/reaction
Describe Monocytes and causes of Monocytosis
Monocytes
- Bi-lobed nuclei with very fine granules
- Response to inflammation and antigenic stimuli
- Migrate to tissues – become macrophages
- Lysosomes contain lysozyme, complement, interleukins, arachdonic acid, CSF
- Phagocytosis, pinocytosis
Monocytosis is seen in
- Chronic inflammatory conditions: rheumatoid arthritis, SLE, Crohn’s, UC
- Chronic infections e.g. TB
- Sometimes in carcinoma
- Very rare myeloproliferative disorders/leukaemias: chronic myelomonocytic leukaemia, acute chronic myeloid leukaemia, juvenile myelomonocytic leukaemia, acute myeloid leukaemia. So monocytosis in this case is due to a primary haematological disorder rather than a reactive event.
Describe Eosinophils and causes of Eosinophilia
Mediate hypersensitivity reactions, asthma, skin inflammation
Phagocytosis of antigen-antibody complexes
Large distinct granules, which contain arginine, phospholipid, enzymes
Eosinophilia
- Most common cause: allergic diseases: asthma, eczema, urticarial, hay fever, aspergillosis
- Drug hypersensitivity: penicillin
- Churg-Strauss: eosinophilic granulomatosis – autoimmune condition that causes inflammation of small- and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy)
- Parasitic infection: round worm, tapeworm, flukes (so taking a travel history is very important)
- Skin diseases: bullous pemphigoid
- Hodgkin Lymphoma
- Acute lymphoblastic leukaemia
- Acute myeloid leukaemia
- Myeloproliferative disorders
- Eosinophilic leukaemia (very rare, eosinophilia is due to a primary haematological disorder rather than a reactive reason – normally in primary haematological conditions, eosinophilia is due to reactive event)
- Idiopathic hypereosinophilic syndrome.
Describe Basophils and causes of Basophilia
Active in allergic reactions and inflammatory conditions
Purple-blue large, coarse, dense granules contain histine, heparin, hyaluronic acid, serotonin
Become mast cells in tissue
Basophilia
- Reactive causes: immediate hypersensitivity reactions, Ulcerative Colitis, Rheumatoid Arthritis
- Myeloproliferative disorders (more commonly seen in): CML; MPN (myeloproliferative neoplasm) – essential thrombocythemia, polycythemia vera, primary myelofibrosis), systemic mastocytosis
Describe Lymphocytes and causes of Lymphocytosis
Lymphocytes originate in bone marrow.
Includes B cells (humoral immunity) – antibody forming cells, T cells (cellular immunity) - CD4+ helper cells, CD8+ suppressor cells and Natural killer cells (cell mediated cytotoxicity)
Approximately the size of RBCs, have a very high nuclear:cytoplasm ratio and generally are agranular.
Reactive causes of lymphocytosis:
- Viral infections (particularly in children)
- Bacterial infections especially whooping cough
- Stress related: MI/cardiac arrest, found in smokers
- Splenectomy (lymphocytes normally rest in the spleen)
Lymphoproliferative causes of lymphocytosis
- Chronic Lymphocytic Leukaemia (increase in white cells in peripheral blood circulation)
- Lymphoma
Describe causes of Thromocytosis
Reactive causes (most common) – can take weeks for thrombocytes to settle
- Infection (raised but not normally outside normal range)
- Inflammation
- Post surgery
- Malignancy
- Bleeding
- Iron deficiency (mechanism for association unclear)
- Splenectomy
Primary haematological disorder causes (rare)
- Essential thrombocythaemia
- CML
- Myelofibrosis
- Polycythaemia vera
What would you see on a Leucoerythroblastic film? And when?
Leucoerythroblastic Film: Granulocyte precursors and nucleated RBC on film
- Bone malignancy infiltration: carcinoma or haem malignancy e.g. myelofibrosis (normally nucleated RBCs stay in bone marrow)
- Sepsis/shock
- Severe megaloblastic anaemia (due to B12/Folate deficiency)
- Storage diseases
- Primary Myelofibrosis
- AML (Acute myeloid leukaemia)/MDS (myeloid dysplasia)
Renal Disease: abnormalities in FBC (remember primary haematological disease unlikely; reactive cause far most likely)
Describe possible RBC, WCC and Platelet Changes
RBC
- Anaemia: anaemia of renal disease; anaemia of chronic disease (most likely – due to suppressed erythropoietin response); blood loss; haematinic causes (individual and collective deficiencies of iron, B12 and folate); cardiac causes; marrow infiltration
- Polycythaemia (increased RBCs): post-renal transplant (increased erythropoietin drive); renal tumour
WCC
- High: associated inflammation; infection – acute chronic
- Low: sepsis marrow infiltration e.g. myeloma, cyclophosphamide
Platelets
- High: reactive; bleeding; iron deficiency
- Low: direct effect of uraemia on production of platelets (uraemia damages megakaryocytes); drugs; haemolytic uraemic syndrome (platelets get used up).
Describe treatment in renal failure
Anaemia common
Treatment of patients with CKD 3 or more with significant anaemia is erythropoietin
Need adequate iron stores to ensure adequate response
So iron also infused (IV iron) to keep ferritin >200 (normal range 15-400) – keep iron stores high
Any renal failure will cause a reduced EPO production due to damage that occurs to the EPO-producing cells in the kidney. If the underlying condition that causes the renal failure is an inflammatory condition, there may be inflammatory cytokines produced that can worsen the anaemia already seen.
The white cell count may increase due to any associated inflammation or infection whilst platelet levels may be high from iron deficiency yet may be low from direct effect of uraemia on the production of platelets.
It can be treated by EPO infusion as well as ensuring sufficient iron stores to ensure an adequate response.
Describe the RBC, WCC and platelet changes possible in RA
RBC
- Anaemia: anaemia of chronic disease; blood loss; haematinic causes; immune mediated; viral infection
WCC
- High: associated inflammation; infection-acute chronic; drug reactions….
- Low: sepsis; drugs e.g. methotrexate (immunosuppression)
Platelets
- High: reactive; bleeding; iron deficiency related to NSAID use (NSAIDs may cause GI bleeding)
- Low: drugs; immune; splenomegaly (Felty’s – combination of RA, splenomegaly and neutropenia).
RA will show anaemia from ACD or immune mediated causes; WBC count can be high due to associated infection or low from drug mediated response, and platelets can be high from reactive causes or low from drug use or immune response.
What are the key mechanisms in clotting? (overview)
Keep blood moving (continuous flow) – heart, venous valves, calf pumping. Most-MI blood is more prone to clotting as blood pools.
Blood vessels are important
Platelets: qualitative and quantitative
Coagulation factors: qualitative and quantitative
Anticoagulant factors: qualitative and quantitative
What does the blood vessel wall do in response to injury? What is Von Willebrand’s Factor?
Vasoconstriction
Production of Von Willebrands factor (vWF) which has 2 functions
- Assists in platelet plug formation by attracting circulating platelets to sites of damage -essential for platelet adhesion
- Carrier and ‘protector’ of Factor 8 (clotting protein) – stabilises Factor 8 protecting it from premature destruction.
- Von Willebrand disease is due to a deficiency or abnormality in Von Willebrand factor. The common pattern of bleeding is mucosal bleeding reflecting the inadequate platelet function and adhesion. Patients with Von Willebrand disease can vary from being asymptomatic to having a severe bleeding disorder.
Exposure of collagen and tissue factor which initiates activation of clotting factors (clotting cascade – proteins).
Describe the Primary Haemostasis function of platelets
Primary haemostasis (forming the first platelet plug before clotting factors arrive)
·Adhesion: to vessel wall at site of injury
·Secretion: granules => secrete ADP, thrombaxane, fibrinogen to encourage further aggregation (pulls in more platelets)
- Alpha granules release: glycoproteins, vWF, fibrinogen, coagulation factors
- -Dense granules release: ADP, serotonin, calcium etc
·Aggregation:
- -At site of vascular injury to form platelet plug
- -Fuse together to improve stability
·Activation
- -Act as a site for coagulation factor activation (to start clotting cascade to make the big substantial clot)
- Provide some coagulation factors by secretion from internal stores
Give an overview of clotting (recap)
Blood vessel injury
Exposed collagen fibres/connective tissue
vWF released from endothelial cells, which binds collagen on exposed tissue and platelets via receptors on platelets
Platelets can also bind collagen directly using other receptors
Adhesions causes release/activation of an umber of proteins which lead to:
Platelet activation and shape change and aggregation (improves binding of platelets together to form a more stable plug)
What is meant by clotting is a controlled system?
Clotting: what does it mean?
Controlled system
Few initiating substances
Stimulation leads to activation of a cascade of precursor proteins
Leads to generation of insoluble fibrin
Enmeshes platelet plug (insoluble fibrin make lots of fibres => to produce a mesh that prevents any further blood loss)
Natural anticoagulants to inhibit activation – anticoagulants stop clot from propagating
Clot destroying proteins which are activated by the clotting cascade (carefully balanced)
What is the Clotting Cascade and how do we measure it?
Amplification system activation of precursor proteins to generate thrombin (IIa)
Tissue factor exposure is most important in activating clotting cascade – activates FVII
Thrombin converts soluble fibrinogen into insoluble fibrin
Fibrin enmeshes initial platelet plug to make stable clot
How do we measure the clotting cascade/
- Prothrombin Time – measure of extrinsic pathway
- APTT (partial thromboplastin time) – measure of intrinsic pathway (and common pathway)
Describe the initation and amplification of the clotting cascade
Initiation:
- Tissue factor exposure is the most important in activating clotting cascade
- Activates FVII
Amplification
- Initiation produces small amounts of thrombin – thrombin feeds back (thrombin burst – dramatic event)
- Activated Thrombin (IIa) cleaves fibrinogen to fibrin – clot forms
Natural anticoagulants
- Stop further coagulation
- Protein C
- Protein S
- Anti-thrombin
