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AP0509 Component 2 Exam > Disorders of Haemostasis > Flashcards

Disorders of Haemostasis Flashcards

1
Q

Primary haemostasis

A
  • results in platelet formation

- doesn’t involve coag pathways

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2
Q

Quantitative and qualitative primary haemostasis

A
  • qualitative; functional defect can be inherited or acquired
  • quantitative; thrombocytopenia or thrombocytosis
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3
Q

Acquired primary haemostasis

A
  • drugs
  • alcohol
  • uremia
  • myeloproliferative disorders
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4
Q

What does the immediate arrest of haemorrhage depend on?

A
  • formation of fibrin clot
  • vasoconstriction
  • adhesion
  • aggregation
  • activation of coag system
  • leading to platelet plug
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5
Q

Healthy endothelium

A
  • expresses ecto-ADPase (CD39)
  • produces prostacyclin (PGI2) and nitric oxide (NO)
  • block platelet adhesion to and activation by healthy endothelium
  • Also has active anticoagulant mechanisms
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6
Q

Normal platelet count

A
  • 150 - 350 x 10^9/L
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7
Q

Thrombocytopenia platelet count

A
  • <150 x 10^9/L
  • mild: 50-150
  • moderate: 20-50
  • severe: <20
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8
Q

Bleeding and platelet count

A
  • Bleeding seldom occurs >50x10^9/L.
  • Minor >10x10^9/L.
  • Spontaneous <10x10^9/L.
  • Clinical bleeding doesn’t always correlate with plt count due to other factors e.g. endothelium integrity and platelet functionality.
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9
Q

Diagnosis of thrombocytopenia

A
  • Full blood count.
  • Blood fill: Number, size, plt colour
  • Plt clumping - citrate sample
  • Large plts - congenital thrombocytopenias or increased plt turnover
  • Small plts – Wiskott-Aldrich
  • RC fragments - thrombotic microangiopathy.
  • Hypogranular neutrophils - myelodysplasia
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10
Q

Aetiology of thrombocytopenia

A
  • Exclude congenital thrombocytopenia’s - previous normal count
  • Exposure to drugs e.g. Alcohol or quinine
  • Viral infections e.g. HIV or CMV
  • Post op; dilutional - will resolve, cardiac surgery - may persist
  • autoimmune; ITP, Anti-phospholipid syndrome and post transfusion purpura
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11
Q

Immune thrombocytopenia (ITP)

A
  • Incidence 2.5/100k, >60yrs 4.5/100k
  • Petechial rash or oral bleeding
  • Platelets >50 - no treatment necessary
  • usually acute, self limiting in children
  • may be prolonged in adults
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12
Q

Adult ITP

A
  • <30 or bleeding - prednisone given

- <20 – hospitalised. Anti-D, IgG, Rituximab, cyclophosphamide splenectomy

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13
Q

Thrombotic microangiopathies

A
  • Include TTP, HUS, HELLP (Haemolytic anaemia with Elevated Liver enzymes and Low Platelet count) and HIT.
  • Ischaemic injury to one or more organ or tissue.
  • RC fragments, reticulocytosis, thrombocytopenia and raised LDH
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14
Q

Treatment of thrombotic microangiopathies

A
  • TTP - plasma exchange (ADAMTS13)
  • HUS - withdrawal of drugs
  • HELLP - delivery of foetus and placenta
  • HIT - cessation of heparin and administration of antithrombotic agents
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15
Q

Bernard Soulier GP Ib-IX-V

A
  • platelet function defect
  • Thrombocytopenia
  • large platelets
  • impaired binding of VWF (Von Willebrand factor)
  • Poor platelet adhesion and aggregation
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16
Q

Glanzmann thrombasthenia. GP IIb/IIIa

A
  • platelet function defect
  • Fails to bind fibrinogen.
  • Platelet count is normal but no aggregation w/ agonists e.g. ADP, epinephrine and collagen
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17
Q

Platelet transfusions

A
  • Contraindicated in TTP and HIT
  • Limited indications
  • Transmit infections
  • Sensitise recipient to platelet antigens – HLA matched platelets necessary.
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18
Q

How would you diagnose a platelet functional defect?

A
  • perform platelet aggregation tests
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19
Q

Secondary haemostasis

A
  • end of coagulation cascade is fibrin clot

- involve coag pathways; extrinsic, intrinsic, common

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20
Q

Extrinsic pathway

A
  • Main pathway for initiation of coagulation
  • Exposure of tissue factor (TF) binds to FVII activating FX.
  • Prothrombinase complex (FX, FV, calcium and plt phospholipid activates prothrombin to thrombin (a small amt)) which then activates FXI leading to intrinsic pathway
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21
Q

Intrinsic pathway

A
  • amplifies the coag cascade

- FIXa, FVIII, calcium and phospholipid (tenase complex) amplify FX activation generating large amts of thrombin.

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22
Q

Thrombin

A
  • part of intrinsic pathway
  • cleaves fibrinogen to form soluble fibrin monomers which polymerise to form soluble fibrin polymer.
  • then activates FXIII which with calcium cross links and stabilises the fibrin polymer forming cross linked (insoluble) fibrin.
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23
Q

Positive feedback

A
  • Thrombin activates FXI on the platelet surface which can activate FIX to enhance FXa generation
  • High levels of thrombin can cleave PAR4 - plt shape change - Stabilisation of platelet plug
  • High levels of thrombin generated at propagation phase bind to fibrin and are protected from inhibition by antithrombin.
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24
Q

Localisation

A
  • Thrombin released from the plt plug is swept downstream- antithrombin - half life of thrombin <1 minute.
  • FXa is rapidly inhibited by TFPI.
25
Q

Thrombin on healthy endothelial cells

A
  • negative feedback loop
  • binds to thrombomodulin causing conformational change - no longer cleave fibrinogen
  • rapidly inhibited by protein C inhibitor; rapidly dissociates
  • activated protein C and S inactivate FVa and FVIIIa, confines thrombin generation to site of injury
26
Q

Fibrinolysis

A
  • When injury is healed, the dissolution of the fibrin clot begins - Plasminogen is central enzyme.
  • Activators are tissue plasminogen activator (t-PA) and urokinase (u-PA).
  • Plasmin cleaves the fibrin network and releases FDP (D and E) and fibrinogen - fragment X and Y, can impair plt aggregation and fibrin polymerisation.
  • Plasmin also inactivates FVa and FVIIIa
  • u-PA precursor is mediated by FXIIa, kallikrein and by plasmin.
27
Q

Fibrinolysis defects

A
  • Hyperfibrinolysis – disposes to bleeding and thrombosis. Plasmin inhibitor and Plasminogen inhibitor 1 prevent this.
  • Hypofibrinolysis – deficiencies of t-PA or u-PA, plasminogen, contact factors. Associated with thromboembolic disease
28
Q

Factor I

A
  • defects: afibrinogenaemia
    hypofibrinogenaemia
    dysfibrinogenaemia
  • bleeding: spontaneous; spontaneous abortions/severe post-op, Asymptomatic/bleeding/ thrombosis
  • treatment: Fibrinogen concentrate/FFP/Cryoprecipitate, Keep levels >1.0, Half-life 5 days, Treat every 3 days
29
Q

Factor II

A
  • defects: hypoprothrominaemia, dysprothrombinaemia
  • bleeding: mild to severe bleeding , mucosal membrane bleeds
  • treatment: Prothrombin complex concentrate (PCC)/ FFP
30
Q

Factor V

A
  • defects: autosomal recessive trait
  • bleeding: mild bleeding in childhood, mucosal membranes/CNS
  • FFP/Platelet Transfusions
31
Q

Factor VII

A
  • defects: rare autosomal disorder, heterozygotes – asymptomatic, acquired
  • Moderate bleeding - mucous membrane, epistaxis and menorrhagia.
  • Severe bleeding (homozygous) – bleeding into CNS (early onset) leads to high morbidity and mortality
  • treatment: FVII concentrates, Novoseven, Half-life 5hrs
32
Q

Factor VIII (Haemophilia A)

A
  • 1 in 10,000 affected.
  • X-linked.
  • Most common mutation (up to 50%) in severe Haem A is a major inversion in Intron 22.
  • Severe <1% - recurrent spontaneous bleeding.
  • Moderate 1-5% -may be spontaneous bleeding, bleeding after trauma and surgery.
  • Mild 5-50% - bleeding after trauma or surgery but no spontaneous bleeding.
33
Q

Presentation of Haemophilia A

A
  • Severe - 6-9months (earlier if intramuscular injection received).
  • Mild /moderate usually present later dependant on levels.
  • Common sites - joints, muscles, brain.
  • Repeated hemarthroses leads to joint destruction. Compartment syndrome leading to necrosis and muscle shortening.
34
Q

Treatment of Haemophilia A

A
  • Treat until bleeding stops
  • FVIII Concentrates - Beriate.
  • Recombinant Prophylaxis – Recombinate, Refacto. Thrice weekly.
  • Complication is the development of inhibitors (10-15%).
  • New extended half-life factor concentrates - Elocta, Novo8
  • Hemlibra; a novel antibody that mimics FVIII - subcutaneous injection licensed for Severe Haem A Monitored by a modified Factor VIII assay
35
Q

Combined FV and FVIII

A
  • Rare autosomal recessive bleeding disorder found around the Mediterranean sea.
  • Moderate bleeding tendency.
  • FV and FVIII levels - 5-30%.
  • Normally due to a mutation in transport protein .
  • Treatment: FVIII concentrate, FFP/ Octaplas
36
Q

Factor IX (Haemophilia B)

A
  • 1 in 50-100,000.
  • Similar clinical picture to Haem A. Recurrent spontaneous joint bleeds occur.
  • Bleeding in carriers more common.
  • Treatment: Berifix, once daily. Refixia - pegulated FIX, different assay needed.
  • Inhibitors are less common.
  • Gene Therapy
37
Q

Factor X

A
  • One of the rarest autosomal recessive.
  • Similar clinical picture to FVII.
  • Due to the longer half-life 36hrs treatment can be given as Prothrombin complex concentrate or FFP daily.
  • For major surgery FX is kept >30%. 10-40 % haemostatic
38
Q

Factor XI (Haemophilia C)

A
  • Ashkenazi Jews up to 13% population affected.
  • Heterozygous have a partial deficiency, homozygous or compound heterozygous have severe deficiency.
  • 3 mutations majority type II or III
  • Type II – stop codon in exon 5. homozygous state results in levels ~1%.
  • Type III Phe283 is replaced with Leu (missense mutation) results in levels ~10%.
  • Type II/III heterozygotes result in levels ~3%
39
Q

Factor XI deficiency

A
  • can lead to excessive haemorrhage after surgery or trauma but doesn’t cause bleeds into joints or muscles.
  • Bleeding can be immediate or delayed
  • lower limit normal range 60-70%. There is poor correlation between factor level and bleeding tendency.
  • Heterozygotes level is 25-70 %
40
Q

FXI treatments and complications

A
  • Treatment: FFP or FXI concentrate (half life 52hrs).

- Complications: thrombosis and inhibitors (type 2).

41
Q

Factor XIII

A
  • Rare autosomal recessive.
  • Homozygotes present with life long bleeding from the umbilical cord.
  • Spontaneous intracranial bleeds common. Spontaneous abortions in early pregnancy. Delayed wound healing.
  • Rate assays used for determination of factor levels.
    Levels >2% will allow normal haemostasis.
  • Treatment: prophylactic FXIII concentrate monthly or at trauma.
42
Q

Acquired deficiencies of FII, FV, FVII, IX and X

A
  • Factor II - Autoantibody due to lupus- type anticoagulant.
  • Factor V - transient after surgery, transfusion or aminoglycoside antibiotics.
  • Factor VII - Very rare.
  • Factor IX - very rare associated with post partum and SLE.
  • Factor X - Amyloidosis
43
Q

FVIII acquired deficiencies

A
  • Development of inhibitors due to treatment or autoantibodies found in adults, postpartum women, immunological disorders and older patients >50 yrs. Evenly distributed between the sexes. - Presentation occurs with large haematomas
  • Treatment: involves immunosuppressants (prednisone, cyclophosphamide) and Novoseven for bleeds.
44
Q

Liver disease

A
  • Prothrombin Time increases due to a decrease of extrinsic coag factors synthesised in the liver.
  • As liver damage increases the APTT will also be affected.
  • Also affects fibrinogen synthesis
45
Q

Vitamin K deficiency

A
  • affects production of Vit K dependent factors (FII, FVII, FIX, FX) causing an increase in the Prothrombin Time.
  • Can be common in premature babies and patients with malabsorption conditions
46
Q

Advantages of automation

A
  • Reduces human error
  • CTS reduces health and safety risks
  • Large volume of work
  • Reduction in assay time
47
Q

Prothrombin time (PT)

A
  • measure efficiency of EXTRINSIC pathway – FVII, FV, FX, FII or FI.
  • Due to presence of excess TF, coag activation is independent from FVIII and FIX and less influenced by AT3/heparin.
  • Add thromboplastin and calcium to citrated plasma. The time to clot formation is recorded.
  • Normal range 13-20secs
48
Q

Commonest causes of disorder for PT

A
  • warfarin therapy

- liver disease

49
Q

Activated Partial Thromboplastin Time (APTT)

A
  • assesses intrinsic pathway and common terminal sequence
  • phospholipid added to initiate coag as well as surface
  • normal range 27-40secs
  • deficiency of FXII, FXI, FVIII, FX, FV, FII or FI
  • commonest causes of disorder: Haem B, Haem A
50
Q

Thrombin time (TT)

A
  • assesses common terminal sequence
  • sensitive to fibrinogen (I) or thrombin inhibition (IIa)
  • commonest causes of disorder: disseminated intravascular coagulation (DIC) and heparin therapy
51
Q

Fibrinogen

A
  • based on addition of an excess of thrombin to platelet poor plasma
  • fibrinogen concentration becomes rate-limiting factor and clotting time is a function of fibrinogen concentration
  • increased concentration = shortened clotting time
  • Not affected by heparin up to 1 U/ml, bilirubin to 21mg/dl, Hb to 375mg/dl.
  • May be affected by degradation products
52
Q

Further testing

A
  • Once abnormal coag results have been found, second line tests can be done to investigate the cause.
  • Thrombin Time (TT).
  • Reptilase Time (RT)
  • Protamine Time.
  • Correction Tests.
  • D-Dimer assay.
  • Factor Assays.
  • Dilute Russel Viper Venom Test.
  • Lupus anticoagulant
53
Q

Factor assays

A
  • Patients plasma mixed with factor deficient plasma and the appropriate test repeated. - Time taken to clot can be read from graph to determine patient factor level
  • Intrinsic factors: FVIII, FIX, FXI, FXII
  • Extrinsic factors: FII, FV, FVII, FX
54
Q

Anticoagulant therapy

A
  • Agents inhibiting platelet function e.g aspirin.
  • Warfarin.
  • Heparin.
  • Thrombin Inhibitors.
  • FXa inhibitors.
  • Thrombolytic agents e.g. streptokinase
  • Natural Inhibitors of Coagulation
55
Q

Warfarin

A
  • Inhibits the vit K-dependent posttranslational modification of coag factors.
  • Before release into circulation gamma carboxylation occurs converting ~10 glutamic acid residues in N-terminal regions to gamma-carboxyglutamates (Gla).
  • catalysed by a carboxylase requiring O2, CO2 and reduced form of vit K (vit KH2). - Vit KH2 is oxidised to vitamin K epoxide which is recycled by vitamin K epoxide reductase and vitamin K reductase.
  • Warfarin inhibits both, limiting the degree of carboxylation
56
Q

International Normalised Ratio (INR)

A
  • Monitored using the PT test.
  • used for monitoring dose.
  • INR is calculated according to; INR = PR^ISI
  • PR is Prothrombin Ratio (clotting time of patient/ mean normal clotting time)
  • ISI is the International Sensitivity Index which is a lot specific correction factor established against the WHO reference preparation.
57
Q

Heparin

A
  • complexes with Anti-Thrombin III to inhibit thrombin and increase clotting time.
  • ATIII complexed to heparin is 1000-fold more efficient at binding thrombin due to a conformational change
  • Other serine proteases are inactivated by the Heparin-ATIII complex – FXa
  • Chromogenic Anti-Xa assays measure effect of low molecular weight heparins e.g. Tinzaparin, Fragmin, Danaparoid and Orgaran.
  • Some ranges given as 0.3-0.6 U/ml.
58
Q

Direct Oral Anticoagulants

A
  • Thrombin inhibitor: Dabigatran (14-17hrs), PT^, APTT^, TT^
  • Xa inhibitors: Rivaroxaban (7-11hrs), Apixaban (8-15hrs)
    PT^, APTT^, TT not affected

AP0509 Component 2 Exam (21 decks)

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