2s: Coagulation Flashcards
List some pro-coagulation and anti-coagulation factors
Pro-coagulation:
- platelets
- endothelium
- vWF
- COAGULATION CASCADE
Anti-coagulation:
- anti-thrombin
- Protein C/S
- TFPI
- FIBRINOLYSIS
3 responses to vessel injury
- vasoconstriction = minimise blood loss
- platelet activation = form primary haemostat plug
- activation of the coagulation cascade
Components of blood clot formation
Vascular endothelium
Platelets
Coagulation proteins
White blood cells
Role of vascular endothelium
prevents exposure of pro-coagulant sub endothelial structures
Endothelial damage exposes these pro-coagulant substances which then triggers a haemostat response
The exposure of sub endothelial pro-coagulant factors leads to platelet aggregation at the site of damage
What do endothelial cells produce? (4)
Prostaglandins (PGI2)
vWD
Plasminogen activators (activators fibrinolysis)
Thrombomodulin
Where do platelets come from
how long do they last, clinical relevance of this
what are some thrombopoeitic factors
Produced in bone marrow and originate from megakaryocytes
Each megakaryocytic can produce up to 4000 platelets
Platelets have a life span of 10 days (anti-platelet drugs halt platelet activity for 10 days)
- clinical relevance: someone on aspirin needs surgery -→ stop aspirin 7-10 days before surgery
Platelet production is regulated by a range of thrombopoietic factors (e.g. thrombopoeitin, IL-6, IL-12)
These can be given therapeutically to stimulate platelet production
What is the structure of platelets (3)
Glycoproteins = cell surface proteins via which platelets interact with the endothelium, vWF, and there platelets
Dense granules = contain energy stores (ATP/ADP)
‘Open canalicular system’ and ‘microtubules and actomyosin’ = expand surface area
Platelet adhesion (2 ways) and migration
Adhesion:
- DIRECT = Glp1a
- INDIRECT = vWF via Glp1B
Adhesion of platelets to exposed structures → release of ADP and thromboxane A2 → platelet aggregation
Platelets attach to each other via Glp11b/11a i.e. the fibrinogen receptor
ADP receptors are also important for platelet aggregation
- examples of inhibitors: clopidogrel, ticagrelor
Platelet adhesion (2 ways) and migration
Adhesion:
- DIRECT = Glp1a
- INDIRECT = vWF via Glp1B
Adhesion of platelets to exposed structures → release of ADP and thromboxane A2 → platelet aggregation
Platelets attach to each other via Glp11b/11a i.e. the fibrinogen receptor
ADP receptors are also important for platelet aggregation
- examples of inhibitors: clopidogrel, ticagrelor
Coagulation Proteins
Fibrin mesh, Intrinsic pathway, extrinsic pathway, Factor Xa, thrombin
- A fibrin mesh needs to be generated to reinforce the clot
- Intrinsic pathway = in-vitro during clotting studies
- Extrinsic pathway = the body
- Factor Xa is the rate-limiting step for fibrin formation
- Pathway triggered by trace amounts of thrombin (which is formed following the activation of the platelet plug)
Effects of thrombin aka FIIa (4)
- Activates fibrinogen
- activates platelets
- Activates pro-cofactors FV and FVIII
- Activates zymogens (FVII, XI, XIII)
These all link together to form a prothrombinase complex → activation of prothrombin to thrombin
the most iMPORTANT step of the coagulation cascade is the generation of THROMBIN
- thrombin will catalyse the breakdown of fibrinogen to FIBRIN which is the final step in the coagulation cascade
3 phases of clotting
Initiation
Amplification
Propagation
Factor 10a binds Factor 5a = 1st step of the coagulation cascade
- Factor 5 Leiden will not be able to bind Factor 5a to Factor 10a
Activated platelet → thrombin burst (convert fibrinogen → fibrin)
Rate of prothrombin activation changes
PT vs APTT
- PT = INR = extrinsic pathway
- APTT = intrinsic pathway
Role of vitamin K
PRO-COAGULATION
Biological activation = vitamin K is required as a co-enzyme for the gamma-carboxylation of the clotting factors
Vit-K dependent factors = 2, 7, 9, 10 (produced in the liver)
Important notes:
- Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption
- Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)
- Most common cause of vitamin K deficiency = WARFARIN
Fibrinolysis inhibitors and stimulators
Name 3 physiological anticoagulants
Anti-thrombins
Protein C an d S
TFPI
Antithrombins (ATs)
Antithrombins will bind to thrombin on a 1:1 ratio and it will then be excreted in the urine
There are 5 types of antihrombin but the most active is AT-III
- Heparin = AT-III portentiator (monitor levels with F Xa assay)
The lack or deficiency of antithrombin is the MOST THROMBOGENIC condition
Protein C and S
F5A and F8A inactivated → thrombin stopped
Thrombin (from start) activates thrombomodulin
This opens up the receptor for thrombomodulin to bind Protein C through endothelial protein C receptor (EPCR)
- leads to a activated protein C (APC)
- APC in the present of protein S will fully activate protein C
Full activation inactivates F5a and F8a
2 causes of APC resistance
Factor V Leiden → prothrombotic
High levels of Factors 8
TFPI
- Inhibit F7a
Bleeding disorders
Excessive Bleeding and excess thrombosis
Genetic and Acquired
4 disorders of haemostasis
Vascular disorders - scurvy, easy bruising
Platelet disorders - low number or abnormal function
Coagulation disorders - factor deficiency
Mixed/consumption - DIC
Clinical features of bleeding disorders
Local vs general (spontaneous)
Haematoma or joint bleed (associated with haemophilia)
Skin/mucous petechia and purpura (suggestive of platelet deficiency or VWD)
Wound/surgical bleeding
Timing
- immediate = issue with primary haemostatic plug (platelets, endothelium, vWF)
- delayed = issue with coagulation cascade
Differentiating platelet disorders and coagulation disorders
Platelet = petechiae, purpura
Coagulation = haemarthrosis
Microscopy = always inspect under a microscope because…
- pseudothrombocytopaenia = platelets clump together creating an erroneously low platelet count
- Grey Platelet Syndrome = you see large platelets
2 types of platelet disorders
decreased number (thrombocytopenia)
- decreased production
- increased consumption (DIC)
- decreased survival (ITP)
- dilution
Defective platelet function
- acquired (e.g. aspirin, ESRF)
- congenital (e.g. thrombasthenia)
- cardiopulmonary bypass
Clopidogrel = ADP-R blocker → reduce Glp2b/3a crosslinking
COX inhibitors (aspirin, NSAIDs) → reduce TXAx production
3 genres of thrombocytopenia
Immune-mediated
- idiopathic
- drugs (e.g. rifampicin, vancomycin)
- lymphoproliferative disease (e.g. AML)
- sarcoidosis
- connective tissue damage (e.g. rheumatoid arthritis, SLE)
Non-immune mediated
- DIC
- MAHA
ITP
- autoantibodies against plts
- plus tagged by antibodies and destroyed in reticuloendothelial system (liver, spleen and bone mwarrow/anywhere with macrophages)
- non-blanching petechiae
features of acute and chronic ITP
- Childhood ITP is usually ACUTE (usually following a previous illness)
- Childhood ITP is usually SEVERE (but it is self-limiting and resolves without any treatment)
- In adults, ITP is usually chronic and indolent
ITP treatment
Treatment of ITP:
- It depends on platelet count and symptoms
- IVIG works by competing with the anti-platelet antibodies
- Haematomas and subconjunctival haemorrhages are features of thrombocytopaenia
- It is important to look at the blood film in patients with thrombocytopaenia because there are various causes of thrombocytopaenia that can be diagnosed from the blood film
- Vitamin B12 deficiency
- Acute leukaemia (i.e. Auer rods in AML)
Coagulation factor disorders: inherited vs acquired
Haemophilia
- Congenital deficiency of Factor 8 or 9; X-linked
- Characterised by deep bleeding into joints and muscles
- Caused by isolated abnormality in the INTRINSIC pathway:
- Prolonged APTT
- Normal PT
- Treatment = clotting factor replacement is required for life
- Clinical Features (A & B are clinically indistinguishable):
- Haemarthroses (fixed joints) most COMMON
- Soft tissue haematomas (e.g. muscle atrophy, shortened tendons) & ecchymoses
- Other sites of bleeding (e.g. urinary tract, CNS, neck)
- Prolonged bleeding after surgery or dental extractions
VWD (THE MOST COMMON COAGULATION DISORDER)
mucocutaneous bleeding
- type 1 = PARTIAL quantitative deficiency
- type 2 = QUALITATIVE deficiency
- type 3 = TOTAL QUANTITATIVE deficiency
- T3 similar to haemophilia A (strong relationship between vWF and F8)
- binding of factor 8 to vWF protects factor 8 being destroyed in the circulation
Vit K deficiency
sources
what does it synthesise
causes of deficiency
treatment
Sources of Vitamin K Reverse warfarin with PCC
- Green vegetables (Prothrombinase Complex Concentrate)
- Synthesised by intestinal flora
Required for synthesis of:
- Factors 2, 7, 9 and 10
- Protein C, S and Z
Causes of deficiency:
- Malnutrition Biliary obstruction (reduces absorption of Vit-K)
- Malabsorption Antibiotic therapy (kills gut flora)
- Warfarin
Treatment
- Vitamin K
- FFP
- PCC when warfarin is the cause
DIC = what is it, causes, mechanism and pathogenesis
coagulation and fibrinolysis BOTH ACTIVATED
Causes:
- sepsis (MOST COMMON)
- trauma (e.g. head injury, fat embolism)
- obstetric complications (abruption placentae, amniotic fluid embolism)
- malignancy
- vascular disorders
- reaction to toxin (e.g. snake venom)
- immunological disorders (e.g. severe allergic reaction, transplant rejection)
Mechanism
- Systemic activation of coagulation → deposition of fibrin in small blood vessels (which can cause kidney damage, brain damage and damage to the extremities requiring amputation)
- The simultaneous depletion of platelets and coagulation factors leads to increased risk of bleeding
Pathogenesis
- release of thromboplastic material into the coagulation → activation of thrombin → activates coagulation cascade
DIC clotting studies and treatment
- Prolonged APTT Prolonged PT
- Prolonged TT Decreased fibrinogen
- Increased FDP Decreased platelets
- Schistocytes (fragmentation of RBCs as they pass through the fibrin mesh in the small blood vessels)
Treatment:
- Treatment of underlying disorder Anticoagulation with heparin
- Platelet transfusion FFP
- Coagulation inhibitor concentrate (Activated Protein C concentrate)
Liver disease: how does it lead to bleeding disorders
- Leads to bleeding disorders because:
- Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen
- Dietary vitamin K deficiency (inadequate intake or absorption)
- Dysfibrinogenaemia
- Enhanced haemolysis (decreased alpha-2 antiplasmin)
- DIC
- Thrombocytopaenia due to hypersplenism
Management of Haemostatic Defects in Liver Disease
- Treatment for prolonged PT/PTT
- Vitamin K (usually ineffective)
- FFP (immediate but temporary effect)
- Treatment for low fibrinogen
- Cryoprecipitate (1 unit/10kg body weight)
- Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia
- Replacement therapy
Managing high INR values and managing high INR values in bleeding patients
Novel anticoagulants
Warfarin is on its way out and NOACs/DOACs are coming to the forefront
The benefit of warfarin is that we can rapidly reverse the bleeding
