Case 06 - Clotting Disorders Flashcards
In a normal blood vessel, how is thrombus formation prevented?
- Endothelial cells release nitric oxide, endothelin + prostacyclin
- Endothelin (vasoconstrictor) and nitric oxide (vasodilator) work together to control blood flow
- Prostacyclin inhibits platelet activation + is also a potent vasodilator
Most immediate protection against blood loss
Vasoconstriction (caused by injury to endothelial SMCs)
How is vasoconstriction prolonged?
- Activated platelets release thromboxane A2 (TXA2), adenosine diphosphate (ADP) and serotonin, all of which cause vasoconstriction
- TXA2 also activates more platelets
- ADP also promotes platelet aggregation by causing platelets to swell
Platelets
(1) Produced in
(2) Fragment of
(3) Die if damaged bc
(4) When levels are low, production stimulated by
(5) Take X amount of time to be produced
(6) Lifespan
(7) Number of time can donate in a year
(1) Bone marrow
(2) Megakaryocytes
(3) Have no nucleus
(4) Thrombopoietin (TPO) - Produced mainly in liver, some in kidneys
(5) 7 days
(6) 8-9 days
(7) 24
Constituents of blood and their proportions
- Plasma, 55% of whole blood
- Erythrocytes, 45% of whole blood
- Buffy coat (leukocytes + platelets), <1% of whole blood
What activates platelets?
- Adhesion to exposed collagen
- TXA2 + ADP released by already activated platelets
- Thrombin
How do activated platelets differ from resting platelets?
Activated platelets
- Change shape (swell)
- Express adhesion molecules, such as GPIIb/IIIa (for adhesion to collagen and/or other platelets)
- Develop pseudopodia (to come into contact with other platelets)
- Degranulate (release TXA2, ADP, serotonin, calcium)
vWF
(1) What it stands for
(2) What it is/does
(3) Produced by
(1) von Willebrand factor
(2) Interlinking molecule needed by some glycoproteins (e.g. GPIIb/IIIa + GPIb, not GPIa) for platelet-collagen adhesion. Stabilises FVIII, preventing it from being broken down prematurely.
(3) Synthesised by endothelial cells + megakaryocytes
Difference between GPIIb/IIIa + GPIb
With the help of vWF, GPIb binds platelets to exposed collagen, activating them. Only then do platelets express GP IIb/IIIa, which can be used in platelet-collagen or platelet-platelet adhesion (aggregation).
3 main stages of haemostasis
- Vasoconstriction
- Platelet plug formation
- Coagulation pathway (how coagulation factors work to form a stable fibrin clot)
(1) 3 main stages of the coagulation pathway
(2) Subsections of the coagulation pathways
(1) Initiation, amplification + propagation
(2) Intrinsic, extrinsic + contact pathways
Coagulation phase
(1) Coagulation initiated by contact pathway + extrinsic pathway
(1a) Contact pathway: Exposure to collagen (also pre-kallikrein -PK, or high molecular weight kininogen - HK) activates FXII (FXIIa). FXIIa activates FXI (FXIa). FXIa activates FIX (FIXa).
(1b) Extrinsic pathway (initiation): Sub-endothelial TF comes into contact with circulating FVII, activating it (FVIIa). TF-FVIIa complex binds to FX, forming the extrinsic tenase complex. This activates some FX (FXa) and some FIX (FIXa). FXa is not yet associated with its co-factor FVa, so can only convert a small amount of prothrombin to thrombin.
(2a) Intrinsic pathway (amplification): In addition to platelets, trace thrombin activates factors V, VII, VIII, XI and XIII. FVa is a co-factor for FXa, and FVIIIa is a co-factor for FIXa.
(2b) Intrinsic pathway (propagation): Together, FIXa and its co-factor FVIIIa form the intrinsic tenase complex, which can activate much more FX (FXa) than the extrinsic tenase complex in the extrinsic pathway. In turn, FXa and its cofactor FVa form the prothrombinase complex, which can convert much more prothrombin to thrombin than FXa alone could. This occurs at the surface of the platelet plug and results in large-scale thrombin production. Thrombin converts fibrinogen to fibrin, which enmeshes + strengthens the platelet plug.
(3) FXIIIa stabilises the fibrin clot by cross-linking fibrin strands. A stabilised fibrin clot can only be broken down by the process of fibrinolysis.
How does a platelet plug differ from a stable fibrin clot functionally
If squeeze a finger that has been pricked, in which only a platelet plug has formed, will resume bleeding. Once a fibrin clot has formed, will not resume bleeding as easily.
Coagulation inhibitors (natural anticoagulants) are necessary to ensure coagulation process doesn’t spiral uncontrollably, name some
- Tissue Factor Pathway Inhibitor (TFPA)
- Antithrombin III (ATIII)
- Proteins C + S
TFPI
(1) What stands for
(2) What it is
(3) What it does
(4) Where it comes from
(1) Tissue Factor Pathway Inhibitor
(2) First coagulation inhibitor to act
(3) Inhibits FVIIa + FXa
(4) Released by activated platelets during initiation
Antithrombin III (ATIII)
(1) What it is
(2) What it does
(3) Where it comes from
(1) Main coagulation inhibitor
(2) Forms complexes with coagulation factors to inactivate them; IIa (thrombin), VIIa, IXa, Xa and XIa
(3) Produced in the liver + endothelial cells
Protein C and protein S
(1) What it is
(2) What it does
(3) Where it comes from
(1) Coagulation inhibitors
(2) Protein C inactivates co-factors Va + VIIIa, protein S enhances the actions of protein C
(3) Produced in the liver
Fibrinogen
FI
Fibrin
FIa
Prothrombin
FII
Thrombin
FIIa
Tissue factor (TF)
FIII
Tenase complexes
(1) Extrinsic tenase complex
(2) Intrinsic tease complex
(1) FVIIa + TF (FIII), activates FX (FXa)
(2) FIXa + FVIIIa, activates FX (FXa)
Tenase refers to the fact that both complexes activate FX (FXa), one in the extrinsic pathway, the other in the intrinsic pathway
Trace thrombin activates
- Platelets (potent platelet activator)
- Factors V, VII, VIII, XI, XIII
Main initiator of the coagulation process
TF (FIII)
Needed in almost every stage of the coagulation process
Calcium
Coagulation factors are produced in the liver, but can also be found
In the granules of platelets
Fibrinolysis is necessary for stable fibrin clots to be broken down once the damaged endothelium is repaired. What does it involve?
Tissue plasminogen activator (tPA) activates plasminogen to plasmin, which in turn degrades fibrin (insoluble) into soluble fibrin degradation products (FDPs)
What is D-dimer?
- Type of fibrin degradation product (FDP)
- High serum levels of D-dimer (positive D-dimer test) indicates thrombosis, but could also be due to other causes
- In contrast, a negative D-diner test excludes thromboembolic disease (where the probability is low)
FXIa does what
Activates FIX (FIXa)
FIXa does what
Alongside co-factor VIIIa, activates a lot of FX (FXa)
FX does what
On its own, converts some prothrombin (FII) to thrombin (FIIa), more if associated to its co-factor Va
FVIIIa does what
Co-factor for FIXa
FVIIa does what
Forms a complex with TF (FIII) to activate FX (FXa) + some FIX (FIXa)
Factor Va does what
Co-factor for FXa
FIII does what
TF, activates FVII (FVIIa)
FIIa does what
Thrombin, converts fibrinogen (FI) to fibrin (FIa)
Also activates:
- Platelets (potent platelet activator)
- Factors V, VII, VIII, XI, XIII
FXIIa does what
Activates FXI (FXIa)
FXIII does what
Stabilises the fibrin clot
Collagen does what
- Activates platelets
- Activates FXII (FXIIa)
(1) Primary haemostasis vs (2) Secondary haemostasis
(1) Vasoconstriction + formation of the primary platelet plug
(2) Involvement of coagulation factors to form a stable fibrin clot
Most common cause of abnormal bleeding
Thrombocytopenia
Thrombophilia
Inherited deficiency or abnormality of coagulation inhibitors —> increased risk of venous thromboembolism (VTE)
Deficiency of GPIb
Bernard-Soulier syndrome
Deficiency of FXII
Asymptomatic (no bleeding)
Vascular/platelet bleeding is characterised by
- Bruising
- Bleeding from mucosal membranes
- Bleeding into the skin: petechiae (small capillary haemorrhages), ecchymoses (larger)
Coagulation disorders are characterised by
- Bleeding after trauma or surgery
- Spontaneous haemarthroses (bleeding into joints)
- Muscle haematomas
Haemophilia A - Aetiology and epidemiology
(1) Caused by
(2) How is it inherited?
(3) How common is it?
(1) FVIII deficiency (due to a mutation in the F8 gene)
(2) X-linked recessive
(3) 1 in 5000 males
Haemophilia A - Classification and clinical features
- Severity of clinical features depends on mutation + resulting levels of FVIII
- Classified according to plasma levels of FVIII
- Mild: Bleeding after trauma or surgery // < 1 times/month
- Moderate: Severe bleeding after (slight) trauma or surgery, occasional spontaneous bleeding into muscles/joints // 1 times/month
- Severe: Frequent spontaneous bleeding into muscles/joints (muscle haematomas, spontaneous haemarthroses) // 1-2 times/week
Haemophilia A - Investigations
- Decreased plasma levels of FVIII
- Prolonged APTT
- Normal PT, bleeding time + vWF
Haemophilia A - Management
ACUTE
- Minor bleed: Desmopressin (IN, SC, IV)
- Major bleed (e.g. spontaneous haemarthrosis): IVI of recombinant FVIII concentrate (rise x weight)/2), increase FVIII levels to 50% of normal, 1-3 times/day
- Life-threatening bleed (e.g. cerebral haemorrhage): IVI of recombinant FVIII concentrate (rise x weight)/2), increase FVIII levels to 100% of normal, 1-3 times/day
- Tranexamic acid (PO)
LONG-TERM (Prophylaxis)
- Home therapy: IV recombinant FVIII concentrate on alternate days (or 3 times/week)
- Avoid contact sports
contact sports + medications that promote bleeding (e.g. aspirin)
Desmopressin
(1) What it is
(2) Two main indications
(3) MOA for each indication
(1) Synthetic vasopressin/ADH
(2) Diabetes insipidus; mild-moderate haemophilia A + von Willebrand’s disease
(3a) Diabetes insipidus: replaces lacking vasopressin/ADH –> reabsorption of H2O in the CD –> decreased urine output
(3b) Haemophilia A / von Willebrand’s disease: Increases levels of vWF + FVIII by stimulating release of vWF from endothelial cells, which in turn prevents premature breakdown of FVIII
Tranexamic acid
(1) Type of drug
(2) MOA
(3) Indication in the context of bleeding disorders
(4) Formulation
(1) Anti-fibrinolytic
(2) Slows down fibrinolysis by inhibiting activation of plasminogen to plasmin
(3) Acute bleeding in haemophilia A + B
(4) Oral
Haemophilia A - Complications
- Cerebral haemorrhage (much more common than in gen. population)
- Arthritis due to recurrent bleeding into joints
- 10% develop antibodies to FVIII* + need massive doses of recombinant FVIII concentrate
*Seen as foreign bc their bodies don’t produce it
Haemophilia B
(1) Caused by
(2) How is it inherited?
(3) How common is it?
(4) Classification and clinical features
(5) Mangement
(1) FIX deficiency (due to a mutation in the F9 gene)
(2) X-linked recessive
(3) 1 in 30,000 males
(4) Same as haemophilia A
(5) Same as haemophilia except:
- Acute: IVI of recombinant FIX concentrate (rise x weight*) OD, desmopressin is not an option
- Long-term (prophylaxis): IV recombinant FIX concentrate 2 times/week
*Not divided by 2
Primary treatment of haemophilia
Start treatment bw the ages of 18 months + 3 years
Secondary treatment of haemophilia
Start treatment after 3 joint bleeds
In spontaneous haemarthroses + muscle haematomas, aside from treating with a recombinant concentrate of the deficient factor, don’t forget
R - Rest
I - Immobilise
C - Cool
E - Elevate
What to do if a person with haemophilia presents with bleeding in A&E
- Fast-track triage
- Do not wait for clinical signs to develop / investigation results
- Treat immediately (even if in doubt)
Is haemophilia more common in males or females?
Males
Which is more common, haemophilia A or B?
A
von Willebrand’s disease - Aetiology and classification
(1) Caused by
(2) Classification
(1) Deficiency of vWF (and, consequently, FVIII)
(2a) Types 1 + 2: Autosomal dominant, mild, characterised by mucosal bleeding (esp. nose + GI bleeds) + prolonged bleeding after dental treatment or surgery
(2b) Types 3: Autosommal recessive, severe bleeding (unlike haemophilia A, rarely bleed into joints/muscles)
von Willebrand’s disease - Investigations
- Decreased plasma levels of FVIII + vWF
- Prolonged APTT
- Prolonged bleeding time
- Normal PT
von Willebrand’s disease - Management
- Recombinant FVIII concentrate
- Desmopressin
Another name for haemophilia B
Christmas disease
Warfarin
(1) Type of drug
(2) Main indication
(3) MOA
(1) Anticoagulant
(2) Prophylaxis + treatment of venous thrombosis + PE
(3) Vitamin K antagonist; inhibits the formation of vitamin K-dependent factors (II/prothrombin, VII, IX + X), resulting in a prolonged PT + INR
Vitamin K deficiency
(1) Causes
(2) Investigations
(3) Treatment
(1) Liver disease*, malnutrition, malabsorption, warfarin treatment
(2) Prolonged PT and APTT
(3) Phytomenadione
*Vitamin K is fat-soluble, so liver disease that results in decreased bile salt synthesis can lead to impaired vitamin K absorption
Heparin
(1) Type of drug
(2) Main indication
(3) MOA
(1) Anticoagulant
(2) VTE where LMWHs are contraindicated (e.g. renal failure)
(3) Inhibits coagulation by increasing the action of ATIII on FXa + thrombin (binds to ATIII, inducing a conformational change that increases its affinity to these factors)
Low-molecular-weight heparins (LMWHs)
(1) Type of drug
(2) Examples
(3) Main indication
(4) MOA
(1) Anticoagulants
(2) Fondaparinux, enoxaparin, dalteparin
(3) VTE - preferred over unfractionated heparin
(4) Inhibit coagulation by increasing the action of ATIII on FXa, but not on thrombin*
*To inhibit thrombin, heparin has to bind to both thrombin (FII) + ATIII. To inhibit FXa, it only has to bind to ATIII. LMWHs are fragments of heparin + too small to bind to both thrombin (FII) + ATIII. Hence, they only increase the action of ATIII on FXa.
Direct/novel oral anticoagulants (DOACs/NOACs)
(1) Examples
(2) Main indication
(3) MOA
(1) Rivaroxaban, apixaban edoxaban, dabigatran
(2) VTE
(3a) Rivaroxaban, apixaban, edoxaban: Directly inhibit FXa (by binding to its active site), thereby preventing thrombin (FIIa) generation
(3b) Dabigitran: Directly inhibits thrombin (FIIa) (by binding to its active site), thereby preventing fibrin (FIa) generation
Synthetic form of vitamin K
Phytomenadione / phylloquinone
Indications for phytomenadione / phylloquinone
- To counteract the effects of anticoagulant overdose
- To prevent haemorrhagic disease of the newborn (the liver of newborns is often not mature enough to produce the necessary coagulation factors)
Vitamin K dependant factors
- Prothrombin (FII), FVII, FIX + FX
- Protein C, protein S
Rare complication of chickenpox
Post varicella purpura fulminans, in which the natural anticoagulant protein S is inhibited
What technique is used in the diagnosis of bleeding disorders?
The Diagnostic Triad
- Personal history of bleeding
- FH of bleeding
- Supportive diagnostic tests
Personal history of bleeding - things to ask about
- Bruising (unexpected places, no associated injury)
- Epistaxis* (>30 min, frequency)
- GI bleeding
- Menses (duration, flooding/clots)
- Haematuria
- Prolonged bleeding after surgery, dental treatment or injuries
*Nosebleeds
Family history of bleeding - things to ask about
- Known bleeding disorder (tested where, by whom + when?)
- Prolonged bleeding after surgery, dental treatment or injuries
Diagnostic tests for bleeding disorder can be split into 3 main categories
- Platelet tests
- Coagulation tests/screen
- Tests of clot stability
Platelet tests
- FBC with platelet count
- Microscopy (to assess size/shape of platelets)
- Platelet function analysis (PFA, to assess platelet function - not every sensitive; doesn’t pick up all platelet disorders)
Coagulation tests/screen
- PT
- APTT
- TT (uncommon)
- Fibrinogen level
- 50/50 mixture test (if PT/APTT prolonged)
PT
(1) What it stands for
(2) What it is
(3) What is used for
(1) Prothrombin time
(2) Coagulation test that measures the integrity of the EXTRINSIC + common pathways
(3) To diagnose coagulation disorders + monitor dosage of anticoagulants, e.g. warfarin
INR
(1) What it stands for
(2) What it is
(3) What is is used for
(4) Advantage over PT
(5) Normal value
(1) International normalised ratio
(2) Ratio of a patient’s PT to a standardised ‘normal’ PT
(3) To monitor dosage of anticoagulants, e.g. warfarin
(4) PT time tests can vary, INR standardises them (meaning anticoagulant control can be compared across the world)
(5) <1.2
APTT
(1) What it stands for
(2) What it is
(3) What is used for
(1) Activated partial thromboplastin time
(2) Coagulation test that measures the integrity of the INTRINSIC + common pathways (3) To diagnose coagulation disorders + monitor dosage of anticoagulants, e.g. heparin
TT
(1) What it stands for
(2) What it is
(3) Why it is not routinely used / what is used instead
(1) Thrombin time
(2) Coagulation test that measures the integrity of the common pathway
(3) Abnormalities of the common pathway often also result in prolonged PT + APTT - Can measure plasma levels of fibrinogen instead
Bleeding time
(1) What it measures
(2) What is is used for
(1) Time taken for bleeding to cease from a small wound (e.g. finger-prick) / for vasoconstriction and platelet plug formation to occur
(2) Used as a test of platelet function
Lab version of bleeding time
Platelet function analysis (PFA)
Causes of prolonged PT
- Most common: warfarin (II, VII, IX, X), FVII deficiency
- Less common: abnormality of factors X, V, II or I
Causes of prolonged APTT
- Abnormalities of any of the following factors: XII, XI, IX, VIII, X, V, I
- Heparin
- von Willebrand’s disease (not always, often normal in types 1 + 2)
Causes of prolonged PT and APTT
- Vitamin K deficiency (low fibrinogen)
- DIC (low fibrinogen)
- Heparin overdose (normal fibrinogen)
- Deficiencies of factors X or V (normal fibrinogen)
What is a 50/50 mixture test?
- Test used to determine whether a prolonged PT or APTT is due to deficiency of a coagulation factor or the presence of an inhibitor
- PT or APTT is repeated using a mixture of the patient’s plasma (50%) + normal plasma (50%)
- If there is an inhibitor present, the PT or APTT will remain prolonged
- If there is a coagulation factor deficiency, the PT or APPT will be normal (factor replaced by normal plasma)
1st line tests to do if suspect a bleeding disorder
- FBC with platelet count
- PT
- APTT
- Fibrinogen level
- 50/50 mixture if PT and/or APTT prolonged
Suspect what if initial tests reveal nothing, but there is a good bleeding history
von Willebrand disease
DIC
(1) What is stands for
(2) What it is
(1) Disseminated intravascular coagulation
(2) Overstimulation of the blood-clotting mechanisms in response to disease/injury (e.g. severe infection, trauma, burns or haemorrhage; malignancy) –> generalised blood coagulation that consumes all of the coagulation factors –> deficiency of coagulation factors –> potential spontaneous bleeding
Medical term for nosebleeds
Epistaxis
