Haemostasis, investigation and disorders Flashcards
What are the principles of haemotasis?
Platelets- normal number, normal function
Functional coagulation cascade
Normal vascular endothelium
Describe the ultrastructure of a platelet
Membrane glycoproteins- Metabolites Receptors for primary agonists Dense granules- ADP/ATP, calcium ion, serotonin Lysosomal granules Mitochondria a-granules- VWF fibrinogen
What are the three distinct stages involved in the formation of a platelet rich thrombus?
Platelet adhesion
Platelet activation/ secretin
Platelet aggregation
Describe the process
?
The conversion of fibrinogen to fibrin by thrombin, and polymerisation of fibrin stabilises the platelet thrombus, resulting in a platelet- fibrin (white) clot
Describe platelet adhesion and activation
Normal platelets in flowing blood
Platelets adhere to damaged endothelium and undergo activation
Aggregation of platelets into a thrombus
Describe haemostatic plug formation
Primary= aggregation of platelets- clotting
Secondary= coagulation- thrombin- fibrin
Haemostatic clot
What is early haemostatic response to injury triggered by?
Exposure to subendothelial collagen and the release of tissue factor
What are types of platelet defects?
-Reduced number of platelets= thrombocytopenia
-Abnormal platelet function= mostly commonly drugs such as aspirin, clopidogrel, renal failure= uraemia- platelet dysfunction
Give rise to prolonged bleeding time
What is thrombocytopenia?
Reduced number of platelets
Caused by- bone marrow failure, peripheral consumption (like immune TP disseminated intravascular coagulation- DIC, drug-induced)
What are types of abnormal vessel walls?
Scurvy
Ehlers Danlos syndrome
Henoch Schonlein purpura
Hereditary Haemorrhagic Telangiectasia
What is abnormal interaction between platelets and vessel wall?
Von Willebrand disease
What is scurvy?
Classical findings of peri-follicular haemorrhage
What is Hereditary Haemorrhagic Telangiectasia?
Also known as Osler Weber Rendu syndrome
Telangiectasia in skin, hut, lungs
Can bleed causing anaemia, blood loss
Name drugs that inhibit platelet function
Aspirin and COX inhibitors
Reversible COX inhibitors (NSAIDs)
Dipyridamole (inhibits phosphodiesterase)
Thienopyridines (inhibit ADP-mediated activation- clopidogrel)
Integrin GP2b/ 3a receptor antagonsist (abciximab, tirofiban, prevent Fgn binding)
How does the waterfall theory fail to accurately reflect haemostasis?
- Patients with fX2 deficiency do not bleed
- Patients with fV2 deficiency bleed abnormally
- Patients with fV3 and f1X deficiency have severe haemorrhagic diathesis despite a normal extrinsic coagulation pathway
- Patients with fX1 deficiency have a variable and mild bleeding diathesis
What are the enzyme complexes of the coagulation cascade?
Extrinsic Tenase= V2a+TF
Intrinsic Tenase= V3a+ 1Xa
Prothrombinase= 2+2a
What steps lead to coagulation?
Initiation
Amplification
Propagation
Termination
What are the natural inhibitors of the coagulation cascade in regulation?
- Tissue factor pathway inhibitor= TF-V2a complex/ fXa inhibited by TFP1
- Antithrombin= Thrombin and fXa activity inhibited
- Protein C pathway= inhibits fVa and fV3a
How is Prothrombin time (PT) measured?
Measured in seconds
Reflects the ‘extrinsic pathway’ and the ‘common pathway’
How is Activated Partial Thromboplastin Time (APTT) measured?
Measure in seconds
Reflects the ‘intrinsic pathway’ and the ‘common pathway’
How is fibrinogen measured?
Measured in grams/L
Reflects the functional activity of the fibrinogen protein
How are defects inherited and what is the incidence?
- X11- no bleeding- Autosomal- relatively common
- X1- autosomal- rare
- 1X: Haemophilia B- X-Linked recessive- 1:30,000 live male births
- V111: Haemophilia A- X-Linked recessive- 1:5000-8000 live male births
- Von Willebrand Disease- autosomal dominant- common
- V11- autosomal recessive- very rare
- X, V, 11, 1, X111- autosomal recessive, very rare
Describe Haemophilia A
X-linked recessive disorder= expressed in males, carried in females
- 1:5-8000 males (30% cases are sporadic mutation)
- Deficiency of fV111/ dysfunction
- Severity same within different generations
What are the clinical severities of haemophilia A?
-Clinical severity correlates to fV111 level=
Severe- frequent hemarthroses- less than 1%
Moderate- bleeding after minor trauma- 2-10%
Mild- bleeding after surgical challenge- 11-30%
Normal= 50-150%
What is the traditional management of haemophilia?
- Supportive measures
- Replacement of missing clotting protein
- Antifibrinolytic agents
What are supportive measures for haemophilia treatment?
Ice
Immobilisation
Rest
What are missing clotting proteins replaced by in haemophilia treatment?
Coagulation factor concentrates (plasma-derived, recombinant, extended half-life products)
Desmopressin (DDAVP)- used to increase factor V111 levels in mild/ moderate haemophilia A
Novel therapies- monoclonal antibodies, knock-out AT
What are antifibrinolytic agents in haemophilia treatment?
Tranexamic acid
Clinical presentations of congenital haemophilia
Hemarthroses
Muscle bleeds
Soft tissue bleeds
Clinical presentations of acquired haemophilia
Large haematomas Gross haematuria Retropharyngeal and retroperitoneal haematomas Cerebral haemorrhages Compartment syndromes
What types of treatment/ services are involved in haemophilia management?
Specialised centres- Comprehensive Care Haemophilia Centre Multidisciplinary Approach Home treatment Patient Education and Social Support Physiotherapy, Psychology Orthopaedic advice and treatment Treat and diagnosis of Liver Disease Specialised management for HIV positive patients Genetic counselling
What are the roles of the Von Willebrand Factor?
Promote platelet adhesion to subendothelium at high shear rates
Carrier molecule for FV111
Describe Von Willebrand disease
Most common heritable bleeding disorder= mainly autosomal dominant, both sexes
Associated with defective primary haemostasis
Variable reduction in Factor V111 levels= mucocutaneous bleeding including menorrhagia, post-operative and post partum bleeding
Describe the autosomal dominant inheritance of Von Willebrand Disease
Variable penetrance for mild types
Diagnosis of mild vWD difficult due to confounding factors- blood group O: lowers VWF levels
Describe the management of Von Willebrand Disease
Antifibrinolytics: tranexamic acid
DDAVP (for type 1 vWD)
Factor concentrates containing vWD= plasma derived; no recombinant concentrates yet available, vaccination against hepatitis A and B
Contraceptive pill for menorrhagia
What are the types of causes of acquired coagulation disorders?
Underproduction of coagulation factors
Anticoagulants
Immune
Consumption of coagulation factors
Describe underproduction of coagulation factors
Liver failure
Vitamin K deficiency- haemorrhagic disease of the new-born due to liver immaturity, lack of gut bacterial synthesis of vit k2 and fall in coagulation factors if breast fed- haemorrhage at days 2-4 or at 2 months
1mg vit K intramuscular at birth
Name anticoagulants
Warfarin, direct oral anticoagulants
Name immune acquired coagulation disorders
Acquired haemophilia
Acquired VW syndrome
What leads to consumption of coagulation factors?
DIC- Disseminated intravascular coagulation
How does liver disease lead to acquired coagulation disorder?
Reduced hepatic synthesis of clotting factors
Thrombocytopenia secondary to hypersplenism (enlarged spleen)
Reduced vitamin K absorption due to cholestatic jaundice causing deficiencies of factors 11, V11, 1X AND X
Treat with plasma products and platelets to cover procedures and vitamin K
Describe the syndrome DIC
- An acquired syndrome of systematic intravascular activation of coagulation- thrombin explosion
- Widespread deposition of fibrin in circulation
- Tissue ischaemia and multi-organ failure
- Consumption of platelets and coagulation factors to generate thrombin, may induce severe bleeding
- To maintain vascular patency, plasmin generated in excess, leads to fibrinogenolysis
Describe the aetiology of DIC
- Sepsis- G+ or -ve sepsis, fungal infection, parasitic infection
- Tumour- solid, haematological (Acute Promyelocytic Leukaemia)
- Trauma- fat embolism, head injury, burns, lightning strikes
- Pancreatitis
- Obstetric- amniotic fluid embolism, abruptio placentae, pre-eclampsia/ eclampsia syndrome
- Vascular- Kasabach Merritt syndrome (haemangioma) (incidence of DIC is 25%), aortic aneurysm (incidence of DIC 0.5-0%)
- Toxic- recreational drugs, snake bites, bugs, bats, caterpillars, creepy crawlies
- Transfusion of ABO incompatible cells
What might histology o DIC show?
Patient with metastatic breast cancer- peripheral blood smear, bone marrow aspirate
Red cell fragments- examination of the peripheral blood film may show red cell fragments
Describe DIC coagulation parameters
Prolonged prothrombin time (PT)
Prolonged activated partial thromboplastin time (APTT)
Low fibrinogen
=markers of consumption of coagulation factors
Raised D-dimers= marker of increased fibrinolysis
