Haemostasis and Thrombosis

• The coagulation system - 3 main parts:

  1. Coagulation = making the clot
  2. Anticoagulants = limiting the size of the clot
  3. Fibrinolysis = remodelling (strengthening) and resolving the clot
• • Endothelial surface = inner side of blood vessels - usually helps to promote blood flow, but when activated, it can help to promote clotting
  • Endothelial surface, platelets, von Willebrand factor and coagulation factors all work together to form a blood clot
  • Natural anticoagulants are present in our body to help counter the other factors
  • Fibrinolysis works to either remodel or remove the blood clot

  
• • If you lost a part of the system that helps you to clot, you end up with a patient that has a bleeding tendency
  • If you lose/have a reduced amount of natural anticoagulants, the patient may have a tendency to form a blood clot when they don't need to

  
• Blood vessel constriction: first response to injury

  • Vasoconstriction; body tries to stop blood loss
  • Platelets release Serotonin (5HT) and Thromboxane A2 - they then become activated and start to form a blood clot
  • Pain (leads to activation of sympathetic nervous system, which helps to cause vasoconstriction)

  
• Forming the platelet plug:

  • When platelets become activated, they take on different shapes and become v adhesive - they can stick together or to the endothelium, which is what forms the first kind of plug in the damaged endothelium
  • Collagen is exposed when the vessel wall is damaged
  • Platelets can bind directly to the endothelium (using GP1a receptor) and through von Willebrand factor (using GP1b receptor)
  • The platelets actually bind to the collagen, which is underneath the vessel wall, and has been exposed when the endothelium has been disrupted

  
• How platelets combing:

  • vWF binds directly to collagen and to activated endothelium, and then to the platelet receptor GPIb (glycoprotein 1 b) - therefore helping to form the platelet plug
  • vWF and fibrinogen then work to add more platelets and create the plug
  • vWF also has the important role of being the main carrier of Factor VIII in the plasma
  • Factor VIII is a v important clotting factor that we need to form fibrin strands

  
• Common pathway in the coagulation cascade:

  • Involves the formation of fibrin strands into a mesh over activated platelets
  • Activated factor 10 activates factor 5, which activates thrombin, which breaks down fibrinogen into fibrin strands

  There are 2 pathways that lead to the common pathway: the intrinsic pathway and the extrinsic pathway.

  
• There are 2 pathways that lead to the common pathway: the intrinsic pathway and the extrinsic pathway.

  • Intrinsic pathway
  • Represented by the APTT blood test in the hospital lab
  • Factor 12 activates factor 11, which activates factor 9, which activates factor 8, which then activates factor 10 (and thus leads on to the common pathway)

  
• There are 2 pathways that lead to the common pathway: the intrinsic pathway and the extrinsic pathway.

  • Extrinsic pathway
  • Most similar to what happens in vivo, but is still not completely accurate
  • Activated by tissue factor, which is what activates coagulation in our bodies - it's released by activated endothelium and by some other white blood cells when infection/sepsis is present
  • Tissue factor binds strongly to factor 7 and activates it, factor 7 then activates factor 10 (this leading on to the common pathway)

  
• What we need for healthy coagulation:

  • Platelets
  • Pts with a platelet function disorder have the right number of platelets, but they might not be doing the right job
  • Pts may also be taking drugs that stop the platelets from working (they inactivate them), so again, they'd have the normal number, but no function - e.g., aspirin
  • von Willebrand's Factor
  • Helps platelets bind to endothelium & carries factor VIII
  • Coagulation factors
  • Need these to work together to form fibrin strands
  • Clot stability
  • More to do with the fibrinolyis pathway
• Pts with a known bleeding disorder:

  • They should tell you
  • Registered at local haemophilia centre
  • Carry haemorrhagic states card (some may have a bracelet/necklace instead)
  • Bleeding history should be consistent with clinical severity of disorder
• Haemophilia:

  • X-linked condition - genetically inherited - carried on the X chromosome
  • Congenital deficiency in factor 8 (Haemophilia A) and factor 9 (Haemophilia B)
  • Unable to stabilise the 'platelet plug'
• Haemophilia:

  • X-linked condition - genetically inherited - carried on the X chromosome
  • Therefore a vast majority majority of women that have the mutation for haemophilia are infected but have v little problems; they'll usually have it on 1 X chromosome, but the other one will be fine - so they won't have any problems
  • If a boy inherits the X-chromosome from his mum that has the haemophilia mutation, he won't be able to counter the mutation; his other chromosome will be a Y chromosome - therefore boys are more commonly affected than girls
• Haemophilia:

  • Congenital deficiency in factor 8 (Haemophilia A) and factor 9 (Haemophilia B)
  • Some women may have a slightly low factor 8 level - for these patients have to be careful when doing surgery
  • Unable to stabilise the 'platelet plug'
  • When the patient forms a platelet plug in response to bleeding, the fibrin strands can't be formed properly because they're missing an important clotting factor - therefore the clots become unstable and often cause bleeding further down the line
• Clinical severity of haemophilia is considered by looking at the % of clotting factor:

  • A normal level is >50%
  • A level <50% and a mutation on the X chromosome would be consistent with the diagnosis of haemophilia

  Spontaneous bleeding = bleeding without an injury
• Managing a pt with haemophilia during surgery:

  1. Close liaison with haemophilia centre
  2. DDAVP (desmopressin acetate) infusion for mild haemophiliacs - this is a hormone that, when given, forces the vWF to release a lot of extra Factor 8 - this may be sufficient to cover surgery for some patients without needing them to have a factor replacement
  3. Factor VIII/IX replacement for moderate/severe haemophiliacs (check levels)
  4. Atraumatic technique used during surgery
  5. Secure local haemostasis
  6. Oral tranexamic acid or tranexamic acid mouthwash
• Oral tranexamic acid/tranexamic mouthwash is an anti-fibrinolytic - therefore it prevents the remodelling and removal of the blood clot, and helps to stabilise it, which would be a problem for haemophiliacs.
• von Willebrand's disease:

  • Variable phenotype - quite a few mutations can cause this disease - some can cause lots of problems, some v few
  • Bruising - may present as suspected NAI (non accidental injury)
  • Mucosal bleeding - compared to people with haemophilia, who have bleeding into joints
  • Nosebleeds
  • Menorrhagia (heavy periods)
  • GI (gastrointestinal bleeding)
  • Post-surgical problems
  • Post-trauma problems
• vWF helps to bind platelets and initiate the platelet plug when there's been damage the endothelium - it's also a main carrier for Factor 8, so if you have low vWF levels then you can almost act like a mild haemophilia patient

  
• Different types of von Willebrand's disease:

  • Type I - mild deficiency in VWD - most common - most patients with this can get through life without any problems - may not be picked up until they have surgeries
  • Type II - qualitative not quantitative problem - so they have a normal level of vWF but it's not doing its job - maybe it can't bind platelets very well or maybe it can't bind to the endothelium v well
  • Type III - severe deficiency in VWD - quite rare - can almost behave like a haemophilia patient; may have bleeding into joints as well as mucosal bleeding
• Managing a pt with von Willebrand's disease during surgery:

  1. Close liaison with haemophilia centre (because they cover all bleeding disorders, not just haemophilia)
  2. DDAVP (desmopressin acetate) infusion for Type I vWD
  3. vWF replacement
  4. Atraumatic technique
  5. Secure local haemostasis
  6. Oral tranexamic acid or tranexamic acid mouthwash
• Problems with platelets:

  • Important to find out the cause of low platelet numbers
  • Best to delay the surgery, if possible, until the cause can be found and potentially reversed
  • In general though, dental surgery is safe if the platelet count is above 50
  • Can also have a functional defect in patients taking aspirin or clopidogrel; they stop the platelets working
  • Other defects are rare, but may require platelet transfusions or DDAVP or recombinant Factor 7
• Managing a pt with a platelet problem during surgery:

  1. Close liaison with haemophilia centre
  2. May need platelet transfusion or DDAVP (desmopressin acetate)
  3. Atraumatic technique
  4. Secure local haemostasis
  5. Oral tranexamic acid or tranexamic acid mouthwash
• Warfarin - monitored by measuring INR:

  • Normal is <1.5 (for someone who is not taking Warfarin and has normal liver function)
  • Usual range is 2-3 (for pts who receive warfarin)
  • One of the main actions of warfarin is to inhibit thrombin

  
• • Once you get to an INR > 4.5, your risk of bleeding goes up exponentially, and your risk of major bleeding (a bleed in the head/brain) goes up v fast as well
  • Therefore pts' INRs are monitored closely; want to keep tight control
  • In the 2-3 range the risk of bleeding is fairly low, although this does increase as patients get older

  
• Warfarin and dental surgery - controversial topic - options:

  • Don't alter warfarin and go ahead with the surgery
  • Check not over-anticoagulated
  • Check that on the day the patient hasn't accidentally got an INR > 4.5 before doing surgery
  • Omit warfarin until INR below 2 (or 1.5) and then do the surgery
• Summary of key recommendations for dental treatment for pts taking warfarin:

  • The risk of significant bleeding...with a stable INR...range 2-4 is very small and the risk of thrombosis may be increased in patients in whom oral anticoagulants are temporarily discontinued
  • Oral anticoagulants should not be discontinued in the majority of patients requiring out-patient dental surgery including dental extraction
• Summary of key recommendations for dental treatment for pts taking warfarin:

  • For pts stably anticoagulated on warfarin (INR 2-4) and who are prescribed a single dose of antibiotics as prophylaxis against endocarditis, there is no necessity to alter their anticoagulant regimen
  • The risk of bleeding may be minimised by:
  • The use of oxidised cellulose (Surgicel) or collagen sponges and sutures
  • 5% tranexamic acid mouthwashes used 4 times a day for 2 days. Tranexamic acid is not readily available in most primary care dental practices
• Summary of key recommendations for dental treatment for pts taking warfarin:

  • ...a check INR is recommended 72 hours prior to dental surgery
  • Pts taking warfarin should not be prescribed non-selective NSAIDs and COX-2 inhibitors as analgesia following dental surgery; they can affect how the platelets work
• Dabigatran:

  • Pro-drug (it's metabolised in the body to an active form)
  • Reversible thrombin inhibitor - therefore it's a reversible anticoagulant
  • This and warfarin are the only reversible anticoagulants you're likely to come across
  • Peak plasma levels reached in 6 hours
  • Half life of 12-14 hours (if normal renal function) - fairly short
  • Renally excreted (excreted through kidneys) - so if a patient develops kidney impairment then it can take a v long time for Dabigatran to leave their system
  • Has a v specific effect - works directly on thrombin

  
• As your renal function deteriorates, clearance decreases and the half-life of dabigatran increases. If you were going to do major surgery, you'd have to wait; you'd have to stop the drug quite a few days before the surgery for it to have left their system.
• The Xa inhibitors (type of DOAC):

  • Examples = apixaban, rivaroxaban, edoxaban
  • Bind directly to Xa (activated factor 10)
  • Reach peak levels at 2-4 hours
  • Rivaroxaban renally excreted
  • Apixaban mainly hepatically cleared but some renal (30%)
  • Half-life: rivaroxaban 8 hours, apixaban 12 hours - again, fairly short
  • Affect activated Factor 10, at the start of the common pathway

  
• Dental surgery and DOACs:

  • No pre-operative testing required; behave the same way in all patients
  • For all extractions, scaling etc. Proceed without altering the drug regime
  • Multiple extractions and surgical procedures are considered safe for patients continuing to take these anticoagulant drugs. When practical limit extractions to 3-4 teeth, assess bleeding after first tooth
• Dental surgery and DOACs:

  • For pts on short courses of anticoagulant, post orthopaedic surgery, delay any elective treatment until the patient is recovered
  • Where a pt taking these drugs presents with a post operative haemorrhage, contact the Haematology Department for advice
• Other than the lack of a requirement for pre-operative INR testing, the dental management for patients taking Rivaroxaban, Apixaban and Dabigatran is the same as would be the case for a patient taking Warfarin, who has a stable INR with readings consistently less than 4.0.