Abnormalities of haemostasis Flashcards
Appreciate how minor bleeding abnormalities are common
Easy bruising 12% Gum bleeding 7% Frequent nosebleeds 5% Bleeding after tooth extraction 2.5% Post operative bleeding 1.4% In women Menorrhagia 23% Post partum bleeding 6%
Family history 44%
When is bleeding also common
After removing tonsils (tonsillectomy)
e.g % of easy bruising, frequent bruising and epistaxes are increased in patients with no known bleeding disorders and comparable to statistics in those with known bleeding disorders
however the severity is not comparable (i.e the % of epistaxes lasting greater than 10 mins is very low in those with no known bleeding disorders).
This highlights how the bleeding history is the most important investigation.
What are the key elements of a significant bleeding history
Epistaxis not stopped by 10 mins compression or requiring medical attention/transfusion.
Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).
Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound. Spontaneous GI bleeding leading to anaemia.
Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions (e.g fibroids) of the uterus.
Heavy, prolonged or recurrent bleeding after surgery or dental extractions.
When is primary haemostasis sufficient
In small blood vessels- bleeding is stopped without the need for a fibrin meshwork.
Summarise the causes of abnormal haemostasis
Lack of a specific factor
Failure of production: congenital and acquired
Increased consumption/clearance
Defective function of a specific factor
Genetic defect
Acquired defect – drugs (anti-platelet drugs or anti-coagulants), synthetic defect, inhibition
Summarise platelet adhesion in primary haemostasis
Can attach to collagen indirectly via VWF- platelet binds to VWF via Glp1b
Can attach to collagen directly via Glp1a
This leads to platelet activation, leading to release of ADP and thromboxane
The platelets then aggregate, via fibrinogen and Ca2+
Platelets bind to fibrinogen via Glp2b/3a
Describe a low number of platelets as a disorder of primary haemostasis
Low numbers: “thrombocytopenia”
Bone marrow failure eg: leukaemia, B12 deficiency (megaloblastic anaemia- cells grow and grow without means of synthesising new DNA- thus they cannot divide)- both of these ‘clog’ up the bone marrow and interfere with normal haemostasis.
Accelerated clearance eg: immune (ITP)- making lots of platelets- but they are destroyed in the circulation, DIC.
Pooling and destruction in an enlarged spleen
Describe the pathogenesis of auto-ITP
Auto-Immune Thrombocytopenic Purpura (auto-ITP)
Purpura means bruising
Antiplatelet antibodies
Sensitised platelet
Sensitised platelets cleared by the macrophages in the reticulo-endothelial system (especially in the spleen)
Summarise the mechanisms and causes of thrombocytopenia
Failure of platelet production by megakaryocytes
- Shortened half life of platelets
- Increased pooling of platelets in an enlarged spleen
(hypersplenism) + shortened half life
Describe an impaired function of platelets as a cause of a disorder in primary haemostasis
Impaired function
Hereditary absence of glycoproteins or storage granules
Acquired due to drugs: aspirin, NSAIDs, clopidogrel
These drugs can be given to prevent strokes, but increased risk bleeding will be a major side effect.
State three hereditary platelet defects
Glanzmann’s Thrombasthenia – absence of GlpIIb/IIIa (prevents platelet aggregation)
Bernard Soulier Syndrome – absence of GlpIb (prevents binding to von Willebrand factor)
Storage Pool Disease – storage granules are not able to release adequately (no release of ADP,ATP, serotonin or Ca2+ from dense granules)
What is a distinctive feature of thrombocytopenia
Petechiae
Describe VWD as a disorder or primary haemostasis
Von Willebrand disease
Hereditary decrease of quantity +/ function (common)
Acquired due to antibody (rare)
What are the two functions of VWF in primary haemostasis
VWF has two functions in haemostasis
Binding to collagen and capturing platelets
Stabilising Factor VIII
Factor VIII may be low if VWF is very low
Describe the genetic defects in VWF
VWD is usually hereditary
Deficiency of VWF (Type 1 or 3)
VWF with abnormal function (Type 2)
Type 3 - complete absence – autosomal recessive
the other 2 are AD
Describe problems with the vessel wall as cause of primary haemostasis
The vessel wall
Inherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders
Blue sclera, especially seen in females.Atypical ears: prominent “winged”, small, round, lobeless, lobe attached to face, ears with different shapes: kidney shape, “Dumbo ears”, “Mr. Spock ears”, soft ears, with bent helix.Abnormal nose: with a lump in the union of the bone and the cartilage, nasal septum deviation,
Acquired: Scurvy, Steroid therapy, Ageing (senile purpura), Vasculitis - can all thin the blood vessel and make it weak.
Summarise the disorders of primary haemostasis
Platelets
Thrombocytopenia
Drugs
Von Willebrand Factor
Von Willebrand disease
The vessel wall
Hereditary vascular disorders
Scurvy, steroids, age
What is the key function of primary haemostasis
Formation of the platelet plug
Describe the pattern of bleeding in disorders of primary haemostasis
Typical primary haemostasis bleeding: Immediate Prolonged bleeding from cuts Epistaxes Gum bleeding Menorrhagia Easy bruising Prolonged bleeding after trauma or surgery
The primary platelet plug isn’t strong enough to stop the bleeding
Summarise the other key features of disorders in primary haemostasis
Thrombocytopenia – Petechiae
Severe VWD – haemophilia-like bleeding- due to loss of stabilisation of FVIII
Purpura and petechiae
Summarise the different tests available for the disorders of primary haemostasis
Platelet count, platelet morphology
Bleeding time (PFA100 in lab)
Assays of von Willebrand Factor
Clinical observation
Summarise the clotting cascade
- Biological amplification system in which proteins are activated sequentially
- Incredibly efficient: 1 mole XIa generates ~107 moles thrombin
- Clotting factors numbered I - XIII
I Fibrinogen
II Prothrombin
III Tissue Factor
IV Calcium ions
VI Activated factor V (Va) - Factors II, VII, IX & X require a post-translational vitamin K dependent modification
- Most clotting factors (except V, VIII and XIII) are serine proteases
- Factors V & VIII are co-factors/Factor XIII is a transglutamidase
- Phospholipid derived from activated platelet membrane
Fibrin mesh binds and stabilises platelet plug and other cells
What is needed for the actions of FVa and FIXa
Ca2+ and PI
How can we measure thrombin generation by the coagulation cascade
We can visualise the process of coagulation by measuring thrombin generation over time. This is often called the thrombogram and looks like this…
Normal large spike
Haemophilia- generate less thrombin ,, Haemophilia
Factor VIII <1%
Much smaller peak
What is the role of the coagulation cascade
The role of the coagulation cascade is to generate a burst of thrombin which will convert fibrinogen to fibrin
Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation
When is primary haemostasis sufficient
The primary platelet plug is sufficient for small vessel injury
In larger vessels it will fall apart
Fibrin formation stabilises the platelet plug
Essentially, what happens in haemophilia
Haemophilia: failure to generate fibrin to stabilise platelet plug
Describe deficiencies in coagulation factor production as a disorder of coagulation
Deficiency of coagulation factor production
Hereditary
Factor VIII/IX: haemophilia A/B
Describe the differing consequences of the different coagulation factor deficiencies
Factor VIII and IX (Haemophilia)
Severe but compatible with life
Spontaneous joint and muscle bleeding
Prothrombin (Factor II)
Lethal
Factor XI
Bleed after trauma but not spontaneously
Factor XII
No excess bleeding at all
State the acquired causes of deficiencies in coagulation factor production
Acquired
Liver disease
Dilution
Anticoagulant drugs – warfarin
Describe some acquired causes of deficiencies in coagulation factor production
Liver failure – decreased production
Most coagulation factors are synthesised in the liver
Dilution
Red cell transfusions no longer contain plasma
Major transfusions require plasma as well as rbc and platelets- i.e after a haemorrhage
State disorders of coagulation as a result of (acquired) increased consumption of clotting factors
Increased consumption
Acquired
Disseminated intravascular coagulation (DIC)
Immune - autoantibodies
Describe DIC
Consumption
Disseminated intravascular coagulation
increased consumption
Generalised activation of coagulation – Tissue factor
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors
Platelets consumed
Activation of fibrinolysis depletes fibrinogen
Deposition of fibrin in vessels causes organ failure
Need to treat the cause:
deliver the baby
teat the sepsis
Describe the pattern of bleeding in coagulation disorders
superficial cuts do not bleed (platelets)
bruising is common, nosebleeds are rare
spontaneous bleeding is deep, into muscles
and joints
bleeding after trauma may be delayed and is prolonged
frequently restarts after stopping
Superficial cuts DO NOT bleed (because primary haemostasis is fine)
What is a hallmark of haemophilia
Haemarthrosis – hallmark of haemophilia
Bleeding in the joints- spontaneous
Intramuscular injections should be avoided
Compare bleeding defects in primary haemostasis and secondary haemostasis
Platelet/Vascular
Superficial bleeding
into skin, mucosal
membranes
Bleeding immediate
after injury
Coagulation
Bleeding into deep
tissues, muscles,
joints
Delayed, but severe
bleeding after
injury. Bleeding
often prolonged
This is a simplistic distinction. Note that
either defect can be life threatening
Describe the tests for the different coagulation disorders
Screening tests (‘clotting screen’)
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Full blood count (platelets)
Factor assays (for Factor VIII etc) Tests for inhibitors
Describe the APTT
Measures coagulation disorders in the intrinsic pathway:
Factor 12 – Factor 11 – Factor 8 and 9 — factor 5, 10 and 2
Describe the PT
Factor 7 — factor 5, 10 and 2
Describe the bleeding disorders not detected by routine clotting tests
Mild factor deficiencies von Willebrand disease Factor XIII deficiency (cross linking) Platelet disorders Excessive fibrinolysis Vessel wall disorders Metabolic disorders (e.g. uraemia) (Thrombotic disorders)
Urea can interfere with platelet function.
- Describe the APTT and PT results for a patient with haemophilia.
Prolongs APTT but normal PT
This is because the defect lies in the intrinsic pathway (factor 8 or 9)
Summarise the disorders of fibrinolysis
Disorders of fibrinolysis can cause abnormal bleeding but are rare
Hereditary
antiplasmin deficiency
Acquired
drugs such as tPA
Disseminated intravascular coagulation
Why is there a wide range in FVIII and FIX levels in femal carries of haemophilia
Wide range in carriers- depends on which X Is inactivated
Summarise the genetics of common bleeding disorders
Haemophilia Sex linked recessive (SLR) Von Willebrand disease Autosomal Type 2, (Type 1) AD Type 3 AR All the rest (V, X etc.) Autosomal recessive (AR) And therefore much less common
Summarise the treatment for abnormal haemostasis
Failure of production/function Replace missing factor/platelets Prophylactic Therapeutic Stop drugs Immune destruction Immunosuppression (eg prednisolone) Splenectomy for ITP Increased consumption Treat cause Replace as necessary
Describe factor replacement therapy
Plasma
Contains all coagulation factors
Cryoprecipitate
Rich in Fibrinogen, FVIII, VWF, Factor XIII
Factor concentrates
Concentrates available for all factors except factor V.
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X- used to reverse actions of warfarin
Recombinant forms of FVIII and FIX are available - but body can develop antibodies against these
Describe some novel approaches for the treatment of haemostasis
Novel approaches In development Bispecific antibody Anti TFPI antibody Antithrombin RNAi
Bispeficic antibody- mimc=is FVIII- does its binding but no inhibitors form- unlike FVIII given to haemophilics- will develop antibodies against it
Sc in skin once a fortnight- unlike previous daily injections
Anti TFPI- risk of too much antibody
RNAi- reduce antithrombin- resulting in more clotting
Describe gene therapy
Haemophilia B, (Haemophiia A)
Describe platelet replacement therapy
Pooled platelet concentrates available
State some additional haemostat treatments
DDAVP
Tranexamic acid
Fibrin glue/spray
Describe desmopressin
Vasopressin derivative
2-5 fold rise in VWF-VIII (VIII>vWF)
Releases endogenous stores -
Hence only useful in mild disorders
Describe traneximic acid
Inhibits fibrinolysis
Widely distributed – crosses placenta
Low concentration in breast milk
Competes with fibrin for binding of tPA
tPA needs to bind to fibrin and plasmin for activation
Staboilise the clot
Useful adjuvants:
Intravenous: 0.5g tds
Oral: 1.5g tds
Mouthwash: 1g (10ml 5%) qds
Summarise how we can assess platelet function
There are three laboratory tests to monitor platelets, the platelet count, the bleeding time and platelet aggregation. The most important of these is the platelet count, as progressive reduction of platelets dramatically increases the risk of bleeding. Platelet aggregation is performed to monitor platelet dysfunction and can be used to measure von Willebrand factor activity.
The bleeding time is now rarely used in clinical practice although it is sometimes required if it is necessary to assess vessel wall function.
