Session 10: Blood and Bleeding Disorders Flashcards Preview

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Flashcards in Session 10: Blood and Bleeding Disorders Deck (25):
1

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

2

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

3

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.

4

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.

5

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

6

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

7

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

8

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)

9

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).

10

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. 

11

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.

12

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

13

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). 

14

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

15

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)

16

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)

17

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)

18

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

19

Which congenital and acquired problems with the vessels affect haemostasis?

Congenital

  • Hereditary Haemorrhagic Telangiectasia (HHT)
    • Autosomal dominant
    • Diluted microvascular swellings increase with time
    • GI haemorrhage can lead to iron deficiency anaemia
  • Connective Tissue disorders – Ehlers Danlos

Acquired

  • Senile Purpora: common benign condition characterised by recurrent formation of purple ecchymoses (bruises) on the extensor surfaces of forearms following minor trauma.
  • Steroids
  • Infection e.g. measles, meningococcal infection
  • Henoch Schonlein purpura – Immune Complex deposition in vessels causing extensive bruising classically buttocks and extensor surfaces (joint swelling, haematuria abdominal pain; can develop renal failure
  • Scurvy – Vit C definitely causing defective collagen production

Clinically: Vessels

  • Easy bruising
  • Spontaneous bleeding from small vessels
  • Skin mainly
  • Can be mucous membrane 

20

Which disorders of platelet function affect haemostasis?

Hereditary (very rare)

  • Bernard Soulier
  • Associated with impaired platelet granule content release

Acquired (common)

  • Aspirin/NSAIDS/Clopidogrel
  • Uraemia
  • Hyper gammaglobulinaemia e.g. myeloma
  • Myeloproliferative disorders
  • Von Willebrand’s
    • Abnormal platelet adhesion to vessel wall
    • Reduced FVIII amount/activity – due to lack of vWF
    • Severe genetic defects cause this condition
    • Main type due to a reduction in vWF production is not enough (others where activity reduced)

21

How may platelet associated bleeding present clinically?

Skin and mucous membrane bleeding

  • Epistaxis
  • Gum bleeding
  • Bruising

Prolonged bleeding after trauma

Heavy periods

Post surgery

Post dental extraction

Spontaneous joint or muscle bleeds are rare

22

How may problems with clotting factors affect haemostasis? Clinical signs?

    Clotting proteins – factor’s

  • Congenital
    • Haemophilia A (Factor 8)
    • Haemophilia B (Factor 9) etc
  • Acquired
    • Liver disease – produces clotting factors
    • Vit K deficiency – made in liver
    • Warfarin (inhibits Vit K)

    Clinically: Clotting factors – clinical severity correlates with extent of deficiency

  • Recurrent haemarthroses
  • Muscle haematomas
  • Joint pain and deformity
  • Prolonged bleeding post dental extraction
  • Life threatening post op and post traumatic bleeding

Intracerebral haemorrhage

23

Summarise

Reactive changes in blood

  •     Reactive changes in the cellular components of the blood is a common occurrence
  •     Largely reflect inflammatory changes associated with underlying disease and primary haematological diseases are relatively rare
  •     Mechanisms to prevent bleeding are multifactorial, complex and heavily controlled
  •     Distinct patterns of bleeding are associated with abnormalities in different parts of this complex system.

Extra notes

  •     The most common cause of microcytic anaemia – is iron-deficiency
  •     Splenectomy – increased platelets as normally platelets rest in spleen
  •     Low  platelet count – more likely to suffer from nose and gum bleeds than a major joint bleed
  •     Aspirin does not prolong the INR – does not affect clotting cascade
  •     A prolonged APTT is found in patients with Haemophilia A (factor VIII)

24

Describe anaemia of chronic disease

    The anaemia associated with any chronic inflammatory condition, such as TB, RA, or malignancy

    The anaemia that presents is a normochronic, normocytic anaemia that is the frequent anaemia present in hospitalised patients.

    It is the result of cytokine release, such as TNF-alpha, IL-1 and IL-6, as a result of inflammatory which causes three main outcomes:

  • Interfere with iron haemostasis
  • RBC progenitors are reduced as they become less responsive to EPO
  • Low production of EPO

    The iron haemostasis interference involves the cytokines produced stimulating excessive hepicidin levels. Iron in the blood is transported via transferrin and stored as ferritin yet there is no main mechanism for its excretion, so as a consequence levels can be controlled by hepcidin; hepcidin acts to reduce iron absorption at the gut and reduce macrophage iron release, so as a consequence any excess will cause anaemia. Cytokine levels are normally inversely proportional to degree of anaemia in ACD

    Consequently, this may appear very similar in a blood test to an iron-deficient anaemia, as both will have reduced serum iron levels. However, important differences include ACD shows increased ferritin levels, raised inflammatory markers, and potentially low % transferrin saturation.

    Treatment is with EPO, transfusion, and, most importantly, treating the underlying disease.

25

Describe anaemia in CCF

Anaemia with CCF is high and is an important predictor for morbidity and mortality in CCF patients. The onset of anaemia is a multi-factorial process:

  • Cytokine release
  • Haemodilation

Associated Chronic Kidney Disease

Damage to EPO-producing cells via action of ACEi and ARBs causing glycocylation of these cells

Little can be done about the treatment apart from attempt to treat the underlying cause