Haematology Flashcards
Discuss haemostatic/sealant agents.
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Physical agents / Passive Topical
- Dry matrix
- oxidised regenerated cellulose - Surgicell (mesh) or Fibrillar (fleece)
- gelatin matrix - Gelfoam, Surgifoam, Spongostan
- microporous polysaccharide spheres - Arista, PerClot (powders)
- microfibrillar collagen - Avitene (powder or foam sheet)
- Bone wax and putty
- External agents
- chitosan - HemCon bandage or Chitoflex
- kaolin-based - Quickclot
- Nustat
- Dry matrix
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Biologically active topicals
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topical thrombin
- combined with gelatin - Gelfoam plus, Floseal
- fibrin sealant
- Tisseel (liquid - fibrinogen, factor XII, thormbin, calcium), Tachosil (gelfoam sponge + thrombin + fibrinogen)
- tranexamic acid
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topical thrombin
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Tissue adhesives and sealants
- fibrin sealant (above)
- cyanoacrylate - Dermabond, Histoacryl
- albumin-based - Bioglue
- Polyethylene glycol hydrogel - Coseal
- Urethane-based - TissueGlue
POTENTIAL ALGORITHM FOR BLEEDING
- Localised bleeding = matrix application
- Cellulose (Surgicel)
- Porcine gelatin (Gelfoam)
- Polysaccharide spheres (Arista, Perclot)
- Localised bleeding but more significant = above agents impregnated with thrombin
- Floseal
- Gelfoam Plus
- Diffuse bleeding = spray sealant
- Vascular: PEG polymer (Coseal) or albumin+glutaraldehyde (Bioglue) or Cyanoacrylate (Omnex)
- Colon: fibrin sealant (Tisseel)
- Diffuse bleeding from discrete area: TachoSil
What is the massive transfusion protocol?
A system designed to rapidly replace blood producs at an approximate 1:1:1 ratio in a patient who is exsanguinating.
(Massive transfusion is defined as either replacement of >1 blood volume in 24 hours or replacement of >50% of blood volume in 4 hours)
Aim in a massive transfusion scenario is to:
- Recognise and assess blood loss
- Restoration of intravascular volume and Hb levels
- Control of bleeding by surgical or radiological means
- Correction of other parameters eg coagulopathy
At our institution the MTP is activated for massive bleeding with either shock or ABC ≥2 or abnormal coagulopathy
- 2g TXA IV bolus (if not yet given - if 1g given pre-hospital consider further 1g)
- Ensure crossmatch sample delivered to blood bank
- Give 2 units O-neg or type specific RBC
- Trauma: add 2 units FFP or thawed plasma
- Ring blood bank to activate MTP
- MTP Box ONE:
- 2 whole blood OR 2 RBC + 2 FFP
- Trauma: add 3 cryoprecipitate (or 4g FC) + 1 pack platelets
- MTP Box TWO
- 4 RBC + 4 FFP
- 1 platelets
- MTP BOX THREE
- 4 RBC + 4 FFP
- 3 units cryoprecipitate
- MTP BOX FOUR
- 4RBC + 4FFP
- 1 platelets
- and alternate 3&4
- check at time of box 1 and repeat every 30mins: coags, FBC, ABG, calcium
- Additional treatment thresholds:
- PR >1.5 or aPTT >40, consider additional 4 units FFP
- fibrinogen <1.5g/L, consider additional 3 units cryo or 4 units FC
- if platelets <75 x 109 consider additional 1 pack platelets
- if ionised Ca <1.2mmol/L give 10mL calcium ** this is important
Recombinant factor VIIa is out
Thromboelastography (TEG) or rotational thromboelastometrey (ROTEM) can be used as adjuncts if available
ABC score is a massive bleeding score - 1 point each for penetrating injury, SBP ≤90, HR ≥120, positive E-FAST - positive if ≥2/4
What are the commonly used anti-platelet drugs?
How do they work?
-
Aspirin
- Irreversibly acetylates a serine residue which inhibits COX-1 > COX-2 (irreversible non-selective COX inhibitor)
- Prevents production of TXA2 which is pro-coagulant and pro-platelet.
- Effects last for duration of platelet’s life - 7 days
- Reversal - platelet transfusion
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Dipyridamole
- Phosphodiesterase inhibitor; prevents cAMP breakdown, reduced Calcium, reduced platelet shape change/activation.
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Clopidogrel/Ticagrelor
- P2Y12 blocker; prevents ADP to ATP-dependent platelet aggregation.
- Platelet transfusion less effetive than it is for aspirin reversal
What are the pros and cons of UFH versus LMWH?
In the setting of anticoagulation:
UFH
- Half life of 60-90 minutes
- Less reliably metabolised so IVI best with measurement of ApTT
- Higher risk of HIT
- Heparin infusion beneficial in renal failure as close monitoring and control available.
- Higher bleeding risk (5%) cf LMWH
LMWH (depolymerised Heparin)
- Has largely superceded UFH
- Higher anti-Xa activity due to depolymerization
- Lower risk HIT
- Worse in underweight patients and renal failure
Outline the key points in anticoagulation in pregnancy.
- LMWHs are the anticoagulant of choice in pregnancy
- Do not cross placental interface
- Warfarin is teratogenic
- The half life of LMWH is shorter in pregnancy so twice daily dosing is preferred
Provide an overview of haemostasis
Arteriolar vasoconstriction
- Reflex neurogenic mechanism augmented by endothelin (a potent endothelial-derived vasoconstrictor)
Primary haemostasis - formation of the platelet plug
- subendothelial ECM exposed
- platelet adhesion and activation (ie shape change and secretory granule release) by binding to exposed ECM
- platelet-ECM adhesion = mediated through vWF which acts as a bridge between platelet receptors (mostly glycoprotein Ib) and exposed collagen
- platelet aggregation - secreted products (ADP and thromboxane A2)recruit other platelets to form a temporary haemostatic plug
Secondary haemostasis - activation of coagulation cascade
- release of tissue factor (aka thromboplastin/factor II), a membrane-bound lipoprotein procoagulant factor synthesised by endothelium activates the cascade by activating factor VIIa
- coagulation culminates in thrombin generation & conversion of circulating fibrinogen to insoluble fibrin
- thrombin also induces additional platelet recruitment & granule release
- polymerised fibrin and platelet aggregates together form a solid, permanent plug
Clot stabilisation and absorption - activation of counter-regulatory mechanisms
- Counter-regulatory mechanisms are set into motion to limit VTE/restrict the haemostatic plug to the site of injury
- t-PA etc eventually resorb plug
Provide and overview of the coagulation cascade
An orchestrated pathway where sequential activation of key enzymes eventually leads to fibrin maturation.
Likened to a dance, that takes place on a phospholipid surface in the presence of calcium…
- tF activates VII to VIIa…
- Which activates X to Xa…
- Activated Xa then accelerates the activation of II (Prothrombin) to IIa (Thrombin)
- Thrombin converts fibrinogen to fibrin.
What is in Prothrombinex?
What is the dose?
Prothrombinex®-VF is a sterile freeze-dried powder containing purified human coagulation factors II, IX and X and low levels of factors V and VII.
25-50IU/kg for haemorrhage.
What is DIC?
- Disseminated intravascular coagulation is a potentially life-threatening condition associated with a state of paradoxical haemorrhage and microthrombosis.
- Identifying DIC and the underlying condition responsible for it are critical to proper management.
- In DIC, the processes of coagulation and fibrinolysis become abnormally (and often massively) activated within the vasculature, leading to ongoing coagulation and fibrinolysis.
- Inciting factors include:
- LPS endotoxins
- Amniotic fluid
- Widespread tissue factor release
- Widespread release of DAMPS, PAMPS
- Acute haemolytic transfusion reaction
- Once widespread exposure to procoagulant factor is initiated, microvascular thrombosis, widespread fibrinolysis, and end-organ damage occurs.
What is thromboelastography?
Describe a thromboelastogram.
- TEG is a method of testing dynamic coagulation using a sample of blood either spun around a needle (ROTEM), or with a needle spun within it (TEG) to measure the speed and strength of clot formation.
- R = reaction time (citrated kaolin test) = time taken for coagulation factors to initiate clot formation
- if prolonged (>9min): give FFP 2-4u or prothrombinex 25-35u/kg
- MA = max amplitude - strength of clot formed by fibrinogen crosslinking with platelets
- 2 types - CFF MA (uses citrated functional fibrinogen, measures fibrinogen only) and CRT MA (citrated rapid TEG, measures fibrinogen and platelets)
- CFF MA <20mm = give cryoprecipitate of fibrinogen
- CFF normal and CRTMA <52mm = give platelets
- K = achievement of certain clot fimness
- alpha angle = kinetics of clot development (should be >55 degrees
- LY30 = percent lysis 30mins after MA (should be <2.2%)
- ?TEG-ACT activated clotting time?
What is in Cyroprecipate?
What is in Fresh Frozen Plasma?
What is in Prothrombinex?
Cryoprecipitate
- Fibrinogen
- vWF
- Factor VIII
- Factor XIII
FFP
- All coagulation factors except platelets
Prothrombinex
- Factor II
- Factor IX
- Factor X
- Low levels of factors V and VII
Classify the causes of coagulation disorders.
- Inherited
- Haemophilia A - XLR VIII deficiency
- Haemophilia B - XLR IX deficiency
- von Willebrand’s disease - low on vWF and VII
- Acquired
- Immune-mediated - SLE antiboides
- Vitamin-K deficiency
- Liver disease
- DIC, Massive transfusion
Categorise VTE risk in general sugery.
High risk (should all get VTEP unless contraindications):
- Major abdominal surgery
- Resectional cancer surgery
- Arthroplasty surgery
- Previous VTE and any surgery
Low risk (VTEP if additonal risk factors)
- Any other surgery
- Note any additional risk factors
- Immobility
- Hyperoestrogenic
- Inflammation
- Obesity
- Family history
What are the contraindications to VTE prophylaxis?
Absolute:
- Previous reaction to anti-coagulants e.g. HIT
- Active bleeding
Relative:
- Previous GI or intracranial bleed
- Liver disease
- Caution in renal disease
- High falls risk
- Palliative outlook
What scoring systems are validated for pre-operative classification of VTE risk?
- Very low risk: Caprini score 0
- corresponding to an EBL <0.5 percent
- Low risk: Caprini score 1 to 2
- corresponding to an EBL of about 1.5 percent
- Moderate risk: Caprini score 3 to 4
- corresponding to an EBL of about 3 percent
- High risk: Caprini score ≥5
- corresponding to an EBL of at least 6 percent
What is Heparin Induced Thrombocytopaenia?
Heparin-induced thrombocytopenia is the development of thrombocytopenia due to the administration heparin; this occurs because abnormal antibodies form that activate platelets. HIT predisposes to thrombosis (HITT) because platelets release microparticles that activate thrombin, thereby leading to thrombosis.
Type I
- Mild, non-antibody mediated reaction. Develops after 1-3 days. No VTE sequelae. Expectant management.
Type II
- Moderate-severe. Antibody mediated. Develops after 5-10 days. Requires cessation of Heparin and alternative anti-coagulation commencement.
Warfarin
- vitamin K antagonist therefore blocks the effects of vit K which is needed by the liver for the production of functional factor II, VII, IX and X
- also inhibits formation of protein C and S and its action on these two is earlier than its action on clotting factors so in first 24hrs warfarin is a procoagulant - need to cover with clexane
- reversal
- vit K (takes 9-10hrs)
- prothrombinex 50u/kg (recombinant factors II, VII, IX and X; reverses effect in 15mins)
- FFP 15mL/kg (contains all clotting factors + fibrinogen + plasma proteins, but risk of fluid overload & other complications)
- electively stop 5 days before, check INR on day of surgery
Dabigatran
- Direct thrombin inhibitor
- normal renal function stop 48hrs pre-op; impaired 72-96hrs pre-op
- if CrCl <30 shouldn’t be on dabigatran
- blood test to check if active: APTT and thrombin
- Reversal: Praxbind (idarucizumab) - targeted monoclonal antibody 5g IV in 2 doses. Half life 47 mins but biphasic decay so some efficacy for 10 hours
- or dialysis (renally cleared)
Rivaroxaban and Apixaban
- Direct factor Xa inhibitors
- Test for activity: rivaroxaban will prolong PT; apixaban measure anti-Xa levels
- less dependent on renal function for clearance but clearance may still be impaired
- normal renal function: withold for 24-48hrs (48 it high risk surgery); if impaired w/h 72hrs
- no reversal agent ??can give prothrombbinex or FFP or FEIBA??. dialysis woun’t work
Unfractionated heparin
Activates antithrombin III which then inactivates thrombin and factor Xa
Half life 1-2hrs
Monitor with APTT
Reversal: protamine - 1mg per 100units received in the last 4hrs
Low molecular weight heparin (enoxaparin)
Antithrombin III activator (potentiates antithrombin III, a serine protease inhibitor) - has both anti Xa and anti IIa effects (but less anti-IIa activity than UFH)
Higher ratio of inactivation of factor Xa (over thrombin) cf unfractionated heparin
Partially (60%) reversible with protamine (the Xa effect is not reversed). Can also give cryoprecipitate, FEIBA or FFP
Half life (enoxaparin) - 4.5hrs (wears off 6-12h)
Dose adjust for renal failure
Can measure anti-Xa levels
Thromboprophylaxis very high risk surgery vs high risk surgery
What is the recommended duration for anticoagulation thromboprophylaxis for each group
???
Very high - 28-35 days (hip or knee arthroplasty; major trauma)
High - 5-10 days (major surgery >40yrs defined as any surgery >45mins or any intraabdominal surgery.
?up to 28 for major abdo/pelvis cancer surgery
Tranexamic acid
Anti-fibrinolytic agent (synthetic lysine analogue) - prevents conversion of plasminogen to plasmin resulting in a reduction in fibrinolysis
Recommended for cardiac surgery and for noncardiac surgery if substantial blood loss is anticipated
In critically ill pts with UGI bleeding, consider use of TXA
In acutely bleeding critically ill trauma pts, TXA should be given within 3hrs of injury
- CRASH2 showed use of TXA had an overall survival benefit (70% improvement in survival) & for every 15min delay there was a 10% decrease in that survival up to 3hrs; after that there was no benefit and even possible harm
- subgroup analysis also showed there might have been harm in those with TBI
- MATTERs study (military application of txa in trauma emergency resus)
- showed txa benefits were confirmed
- but lots of datas/papers that have entire opposite opinoin of txa
- one of criticisms of CRASH2 was that there was a reasonable gropu of pts that didn’t have significant bleeding - so may not be targeting the subgroup with most benefit & potential for some harm by treating all
- CRASH3 - specifically looking at TXA in head injury pts; showed its safe
- STAMP trial: comparison of pre-hospital TXA (1g + infusion) vs 2g bolus - showed no difference so chch hospital moved to 2g bolus
- in NZ if you have a severely bleeding trauma pt a bolus of TXA ideally in a prehospital setting has benefit w v little risk
What causes thrombosis?
Thrombosis = inappropriate activation of blood clotting in uninjured vasculature or thrombotic occlusion of a vessel after relatively minor injury
3 primary influences on thrombus formation = Virchow’s triad
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Endothelial injury
- can be secondary to haemodynamic stresses (eg HTN or turbulent flow), endotoxin, radiation or noxious agents (eg hypercholesterolaemia or cigarette smoke)
- thrombosis results form exposed subendothelial ECM –> increased platelet adhesion; or procoagulant production (ie tissue factor, PAI); or reduced anticoagulant activity (ie PGI2, thrombomodulin, t-PA)
- eg endocarditis, ulcerated atherosclerotic plaque
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Alterations in normal blood flow
- normal blood flow laminar (cellular elements flow centrally in vessel lumen, separated from endothelium by a plasma clear zone)
- stasis and turbulence
- disrupt laminar flow & bring platelets into contact w endothelium
- prevent dilution of activated clotting factors by flowing blood
- retard inflow of clotting inhibitors
- promote endothelial cell activation
- stasis causes thrombosis in venous circulation, cardiac chambers & arterial aneurysms
- turbulence causes thrombosis in arterial circulation as well as endothelial injury
- hyperviscosity syndromes (eg polycythaemia) or deformed erythrocytes (eg sickle cell anaemia) result in small vessel stasis & also predispose to thrombosis
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Hypercoagulability
- loosely defined as any alteration of coag pathways that predisposes to thrombosis; contributes less frequently to thrombosis but critical in certain conditions
- heritable hypercoagulable states
- factor V gene mutations (factor V Leiden) - renders factor V resistant to protein C inactivation
- deficiencies of antithrombin III, protein C or protein S
- acquired hypercoagulable states
- OCP or hyperoestrogenic state of pregnancy - increases hepatic synthesis of coag factors & reduced synthesis of antithrombin III
- certain malignancies - can release procoagulant tumour products
- heparin-induced thrombocytopenia syndrome (HIT) - heparin products induce circulating antibodies that activate platelets & injure ECs
- antiphospholipid antibody syndrome - pts w antibodies against anionic phospholipids that activate platelets or interfere w protein C activity
Venous thrombi characteristically occur in sites of stasis & are occlusive
Arterial or cardiac thrombi usu begin at sites of endothelial injury (eg atherosclerotic plaque, endocarditis) or turbulence (vessel bifurcation), typically non-occlusive unless smaller arteries
