blood coagulation and anticoagulation Flashcards
what is haemostasis
the mechanism that leads to cessation of bleeding from a blood vessel - blood coagulates to allow for healing of vessel
haemostasis process pathway
injury -> vasoconstriction to reduce blood loss from damaged vessel -> platelet plug forms -> fibrin mesh forms due to activation of clotting system on platelet surface ->clot dissolusion (via plasmin)
what keeps the blood in its non-coagulated form
the endothelium
what molecule is important in the make up of the subendothelium
collagen
what activates the coagulation system
damage to the endothelium which results in exposure of the subendothelium (incl, collagen and other CT proteins) which activated the coagulation cascase (hageman factor XII)
what changes happen to the platelets post vasoconstriction (during clot formation)
inactive -> active;
non-sticky -> sticky, resulting in aggregation to form a platelet mass which will plug the hole
what do active clotting factors act as (2)
as anchors between platelets and collagen, and between the platelets themselves
function of the Von Willebrand factor (pathway)
binds to collagen -> platelets can then bind to VWF though surface receptors -> platelet activation occurs -> platelet undergo shape change to maximise their SA:V ratio -> promotes aggregation -> amplified to a level which will fill the hole
what granules are found in the platelet (2)
dense granules - ADP (nucleotides), Ca2+, 5-HT (seratonin);
alpha granules - fibrinogen, FV, vWF
what does release of the the platelet granules cause
- promotes platelet activation + aggregation;
- recruits other clotting factors (e.g. Thromboxane A2, 5-HT, ADP) to the area of injury;
- activation of the clotting cascade + generation of fibrin to stabilise the plug;
what do aspirin and clopidogrel inhibit
aspirin - thromboxane A2;
clopi - ADP (via P2Y12)
what is the most common congenital inherited bleeding disorder
von Willebrand disease
presentation of vW disease
mucosal haemorrhage; bleeding at times of trauma/surgery; menorrhagia (heavy periods); nose bleeds
what is secondary haemostasis
stabilisation of the platelet plug
what causes inactive blood clotting factors to activate
phospholipid on the surface of the platelets
what is fibrin
an insoluble protein that is produced in response to bleeding and is the major component of the blood clot - long strands are generate and act like glue, giving the platelet mass strength
what is the purpose of fibrin generation
LOCALISED production to produce a stable haemostatic plug
what is the clotting cascade (draw out)
see osmosis/lecture
intrinsic system clotting pathway factors and why is it known as intrinsic
XII -> XI -> IX –(VIII)–> X (common)
all the factors circulate inside the blood vessels in their inactive form
extrinsic system pathway factors
VII + tissue factor (III) -> VIIa:TF -> X
TF comes from outside the blood vessels (=> extrinsic)
what kind of process is the coagulation cascade
amplification
where does the coagulation cascade take place
phospholipid surface generate by the platelets
congential disorders of secondary haemostasis
Haemophilia A (boys with low levels of factor VIII); Hameophilia B (boys with low levels of factor IX)
presentation of haemophliia A/B (4)
bleeding into joints + soft tissues; ‘target’ joint bleeds (due to weaking on that joint/muscle surrounding) ; bleed into retroperitoneum; bleeding at times of trauma/surgery
varying bleeding presentation which depends on levels of factor 8/9 present
acquired disorders of secondary haemophilia
warfarin side effects (2,7,9,10); liver disease (liver produces clotting factors)
what are the 3 endogenous anticoagulants circulating the blood
antithrombin; protein C; protein S
what does antithrombin inhibit (4)
factors Xa, IXa, XIa, thrombin
what do protein C/S inhibit
factor V
what does a deficiency in one of the endogenous anti-coagulating factors cause
shift in equilibrium towards clotting
what breaks down the clot flormed
plasmin (product of plasminogen)
fibrin degredagtion pathway
fibrin –(plasmin)–> fibrin degredation products, FDPs (D-dimers)
what does a test for D-dimer indicate
the likelihood someone has had a clot in the venous system
how is a blood sample kept in its anticoagulated state
put into a tube with an anticoagulant in it -> citrate
serum vs plasma and what tests is serum used for
serum does not have coagulation proteins present as they been used to for the blood clot -> used for biochemitsry investigations (Na+, K+, creatine etc.)
anticoagulant vs serum bottle colours in hospitals
blue - anticoag; yellow - serum
what do the lab coagulation tests measure
the time it takes to generate a fibrin clot - activator must be added to cancel the anticoagulating effects of citrate, different activators target particular pathwyas (good for info about where the defect exists)
3 commonly used lab coagulation tests
- prothrombin time;
- activated partial thrombooplstin time (APTT);
- thrombin time
what does the prothrombin time assess
the extrinsic pathway (play tennis (PT) outside -> extrinsic)
how is prothrombin time measured
thrmoboplastin + Ca2+ put into test tube as an activator -> clock started -> time taken to form clot measured (light detector used as in unclotted form the liquid is more transparent)
lack of what factors can increase prothrombin time
2, 7, 9, 10 (i.e. what warfarin targets); usually factor 7
what does the APTT measure
the intrinsic system (8, 9, 11, 12) - play table tennis (TT) inside -> intrinsic
what activators are used in APTT
contact factor, Ca2+, phospholipid
what conditions will result in prolonged APTT
Hameophilia A (>35s); vWF; DIC;
what deficiency picked up by APTT is not associated with a bleeding phenotype
factor 12
what can cause and artificially long APTT
proteins interfering with the reaction e.g antiphospholipid
does a prolonged APTT always indicate an increased risk of bleeding
no - factor 12 deficiceny and interfering proteins can also cause prolonged APTT
what does thrombin time measure
fibrinogen -> fibrin (thrombin is the activator)
what is thrombin time abnormal in (5)
low fibrinogen states; heparin; trauma; factor 1 deficiency; dabigatran
3 causes of hypercoagulability
- too many cells - increased platelets/rbcs;
- deficency of natural anticoagulants - e.g. due to drugs or congenital;
- coagulation of factor abnormalities - facto V leiden variant, prothrombin gene variant
what occurs in factor V leiden variant
factor V becomes resisitant to inactivation by protein C
4 causes for bleeding disorders
- vascular - inherited (haemorrhagic telangictasia, CTDs) or acquired (steroids, scurvy, amyloid, senile purpura);
- von willebran disease;
- platetles - low: inherited (rare), acquired (ITP, bone marrow failure, drugs); platelet abnormalities: inherited, acquired (drugs e.g. clopi, uraemia);
- coagulation cascade problems - inherited (haemophilia A/B), acquired (drugs, liver disease, DIC, massive blood loss)
what is thrombotic thrumbocyotpenic purpura
a rare condition in which absent ADAMTS13 leads to ulta larger multimers of vWF which cause thrombosis in the the microcirculation -> leads to ischaemia in critical organs
classic pentade of thrombotic thrumbocyotpenic purpura
- fever;
- microangiopathic haemolytic anaemia;
- renal impariment;
- fluctuation neurological signs (clots in brain microcirculation);
- thrombocytopenia (all the platelets are being consumed and so production can’t keep up)
blood film of thrombotic thrumbocyotpenic purpura
“cheese-wired” RBCs (by fibrin strands inside the rbcs cutting them in half) - no longer round
thrombotic thrumbocyotpenic purpura maagement
haematological EMERGENCY - ask for senior help, treatment to remove plasma which has the large multimers and replace it with plasma from the lab (plasma exchange)
6 common indications for anticoag prescription
- prevention of stroke in AF;
- treatment of DVT/PE;
- prevention of recurrent venous thrombiembolis;
- preventio of valvular themobosis/embolism in metallic heart vavles;
- treatment of acute coronary syndrome;
- thromboprophylaxis
what are the 3 types of anticoagulant drugs
- reduce clotting factors - prevent liver synthesis e.g warfarin;
- inhibit clotting factors indirectly e.g. heparins, fondaparinux;
- directly inhibit clotting factors - usually factor Xa e.g. apixaban, revaroxaban etc. or thrombin inhibitors e.g. dabigatran
warfarin MOA
competitively antagonises vit K (necessary for production of factors 2,7,9,10) stops the conversion of vit K epoxide back into vit K and so further synthesis cannot take place
vit K coagulation metabolism pathway
precursors for factors 2,7,9,10 –(vit K)–> completed factors 2,7,9,10 + Vit K epoxide (must be reduced back to vit K to allow for cycle to repeat)
what is INR
PT patient/ PT control
what is used for warfarin monitoring
yellow book which documents:
1. the pt’s target INR;
2. their last INR reading;
3. their current does of warfarin;
4. when their next INR test is due
usual INR target
2.5
when is a high INR target indicated
pts with a clotting tendacny?
5 reasons why INR can fluctuate
- individual variation/genetic;
- drugs interacting w warfarin (incl alcohol);
- diet (vit K content);
- intercurrent illness;
- mistakes (elderly, visually impaired etc.)
what are the 2 main types of heparin
unfractionated heparin (rarely used); LMWH
why can heparins not be given orally
destroyed by gastric acid
unfractionated heparin MOA
increased the anticoagulant effect of the endogenous anticoag - antithrombin
when is unfractionated heparin used
when anticoag is required with a rapid onset and offset action (short half life)
side effects of heparin
bleeding; heparin induced thrombocytopenia (HIIT) - immune reaction
UH vs LMWH
LMWH - more targeted effect on coagulation system, mostly focuses on anti-Xa
can APTT be used to assess heparin effects
yes for UH, no for LMWH
2 main targets of DOACs
factor Xa inhibiton, thrombin inhibition
what usually decide what anti-coagulation is given
time of onset - rapid (thrombosis treatment), slow onset (long term prevention)
what is used to treat VTEs
LMWH and warfarin - both rapid and slow onset; DOACs may be used now
durations of giving anticoag post VTE (4)
1st calf vein thrombosis - 6wks;
1st provoked VTE - 3 months;
1st unprovoked VTE - 3-6 months (may be indefinate);
2nd VTE - consider lifelong
6 risk factors for bleeding on anticoagulants
minor skin brusing; epistaxis; GI haemorrahe; muscle haematoma; haemturia; intracranial haemorrage
what can be given to reverse warfarin
vit K (slow) + prothrombin complec concentrate (PCC)
what can be done to stop bleeding due to DOAC
stopping the drug - short half life so should be fine within 12hrs; tranexamic acid; idaracuzimab; PCC
What are the clotting test results in DIC (PT,APTT etc)
Increased PT, APTT
What does the presence of howl-jolly bodies indicate
Spleen not functioning - meant to remove them
