Defects of Primary Haemostasis Flashcards
What are the two types of platelet disorders?
Quantitative defect- abnormal number of placelets:
- thrombophilia
-thrombocytopenia
Qualitative defect- functional abnormality
What does thrombophilia result in?
Hypercoagulability
Genetic conditions associated with thrombophilia
-protein C deficiency
-prothrombin gene mutation
-factor 5 Leiden mutation
-myeloproliferative conditions (essential thrombasthenia, polycythaemia vera)
Acquired conditions associated with thrombophilia
-anti-phospholipid syndrome
-inflammatory bowel disease
-severe reactions to infections such as sepsis
What is thrombocytopenia ?
Impaired production- insufficient production in the bone marrow:
- viral infections e.g., HIV, parvovirus
-radiation
-some medications
-alcohol toxicity due to long term alcohol abuse
-leukaemia and lymphomas
- metastatic cancers invading the BM
-vitamin B12 deficiency
Thrombocytopenia and increased destruction or consumption
Non-immunological mechanisms- sepsis, trauma, burns, vasculitis, disseminated intravascular coagulation, haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenia purpura (TTP)
Immunological mechanisms- idiopathic thrombocytopenia purpura (ITP), transfusion reaction, some medications, rheumatological conditions e.g., SLE
Thrombocytopenia and splenic sequestration
Splenic sequestration occurs when the spleen enlarges (for examples, due to cirrhosis of the liver or certain types of leukaemia) and captures, or sequesters, more platelets from the circulation than normal
Where is haemolytic uraemic syndrome (HUS) frequently seen?
Children as a result of e-coli train of bacteria O157:H7
In qualitative platelet disorders…
- platelet count is normal
-bleeding time is prolonged
-platelets do not function normally: drug induced, genetic condition
Drugs prescribed to inhibit platelet function
Aspirin- cyclo-oxygenase inhibitor prevents TXA2 formation
Clopidogrel, prasugrel, ticlopodine, ticagrelor- agonist of ADP receptor
Tirofiban, Eptifibatide, Abiciximab- competitively bind to GPIIbIIIa receptor
Qualitative platelet disorders:
Dense granule defect deficiency- Wiskott-Aldrich syndrome
Alpha granule defect- gray platelet syndrome
Membrane abnormality- glycoprotein defiency, Ib/IX Bernar Soulier,IIb/IIIa Glanzmann’s Thrombasthenia
Defect of thromboxane synthesis (release defect)
What is Glanzmann’s thrombasthenia?
Autosomal recessive trait, mutations impacting biosynthesis and assembly of GpIIbIIIa complex
What are characteristics of Glanzmann’s thrombasthenia?
- platelet count and size is normal
-adherence to subendothelium and granular release is normal
-platelets fail to form aggregates and hence bleeding is prolonged
-platelet transfusions required for severe bleeding episodes - asymptomatic carrier state
What is Bernard-Soulier Syndrome?
Rare autosomal recessive disorder (1:1,000,000)
Mutations in GpIB/IX/V complex (receptor for VWF)
What ae the characteristics of Bernard-Soulier syndrome ?
- giant platelet and mild to moderate thrombocytopenia
- some patient respond to DDVAP which increases VWF release from endothelium
- platelet transfusions in severe bleeding episodes
What is the large platelet size in Bernard-Soulier syndrome?
Arise from the lack of an interaction between actin-binding protein in the platelet cytoplasm-skeleton and the cytoplasmic domain of the GpIba polypeptide.
Lack of sialic acid in BSS may shorten platelet survival and lead to thrombocytopenia
Diagnosis of platelet abnormality
-routine investigation to exclude coagulation defect
- platelet count and microscopy to assess morphology
-exclude drug treatment, VWD and primary condition
-light transmission aggregometry (LTA) to determine platelet response to various agonists
-platelet protein analysis by flow cytometry or immunoflurescent staining-glycoproteins presence
- high throughput sequencing and other molecular diagnostic testing to determine specific mutation analysis
Symptoms of disorder of primary Haemostasis ?
- petechiae
- epitaxis
-mucosal bleeding - prolonged bleeding at a site of injury
- heavy menstrual bleeding
-haematomas, easy bruising
What are initial investigations of defects of primary Haemostasis ?
-routine coagulation screening is normal (PT and APTT)
-bleeding time is prolonged
-platelet count (ref range 150-400x10^9 platelets/l)
Then
- normal count- platelet functions test e.g., platelet aggregometry
OR
-abnormal count- diagnose primary aetiology (cause)
What are key facts about Von Willebrand Disease (vWD)?
- first described 1926 by Dr. Eric Adolf Von Willebrand
- autosomal bleeding disorder
- arises from missense mutations
- variable clinical severity
- present in 1% of population
- variety of subtypes of VWF deficiency which reflect pathophysiology
- 3 types a and 4 subtypes in type 2 VWD
Defects of primary Haemostasis- VWD
- VWD most commonly inherited bleeding disorders
- caused by a qualitative or a quantitative defect in vWF
- 3 groups: type 1 (quantitative partial deficiency of vWF), type 2 (qualitative deficiency hence functional abnormality of vWF + 4subtypes), type 3 (complete deficiency of vWF)
Von Willebrand Factor
- large protein produced by endothelial cells needed for stable platelet adherence to vessel wall at site of injury
- VWF adheres to damaged vessel wall, forms framework that allows platelets and coagulation factors to adhere, interact and form a clot
- forms complex factor with VIII and maintains its normal levels
Lab tests and findings for Von Willebrand
APTT -> Factor VIII clotting assay, if low FVII/VWF binding assay is performed -> Platelet count and function tests (PFA-100 test or collagen-binding function)
