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MBBS II HIS > L29 - Inherited & Acquired Bleeding Disorders > Flashcards

L29 - Inherited & Acquired Bleeding Disorders Flashcards

1
Q

Genetic defect, Inheritance of Haemophilia A

A

factor 8 gene defect = quantitative deficiency of Factor 8

X-linked recessive: male affected or spontaneous

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2
Q

Genetic defect, Inheritance of Haemophilia B

A

Defect in the factor 9 gene = deficiency of factor 9

X-linked recessive, rarer than haemophilia A

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3
Q

Clinical presentation of Haemophilia A/B

A
  1. Haemarthrosis (recurrent bleeding in major joints, cause progressive joint destruction)
  2. Severe deep seated bleeding (subcutaneous, muscles, intestines, Intracranial**)
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4
Q

Dx of Haemophilia A/B? How to differentiate?

A

isolated prolongation of APTT

Diff. by clotting factor assay:
 Haemophilia A: low factor 8 clotting activity
 Haemophilia B: low in factor 9 clotting activity

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5
Q

Treatment of Haemophilia A/B?

A
  • Coagulation factor replacement from donor/ recombinant (expensive)

(Replacement therapy ineffective due to alloantibodies/ inhibitors)

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6
Q

Compare the coagulation test results between factor 7,10 and 12 deficiency?

A

Factor 7 = extrinsic pathway = Isolated PT

Factor 10 = common pathway = prolong both aPTT and PT

Factor 12 = Instrinsic pathway = Isolated aPTT

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7
Q

Coagulation test result for fibrinogen deficiency?

A

Both intrinsic, extrinsic and common pathway affected

Prolong PT, APTT, TT

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8
Q

2 most common acquired bleeding disorders?

A

Vitamin K deficiency

Vitamin K antagonism

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9
Q

Physiological function of Vit. K in coagulation?

A

Activated by binding to Calcium ions:
- gamma-carboxylation of glutamic acid residues at the amino-terminal domain of the vitamin K dependent clotting factors (II, VII, IX & X)

  • Natural inhibitors of coagulation (Protein C, protein S)
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10
Q

List some causes of Vit K deficiency?

A
  • Cholestatic, Biliary tract disease&raquo_space; impaired bile secretion = malabsorption of VitK
  • Poor nutrition
  • After broad-spectrum antibiotics&raquo_space; kill intestinal flora, cant make Vit. K
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11
Q

Coagulation results of Vit K deficiency? List 2 sources of Vit. K?

A

Factor 2,7,9,10 affected
» PT and APTT prolong

  • Intestinal flora
  • Absorbed from food in upper small intestines with bile
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12
Q

Give 2 most common cause of Vitamin K antagonism? Give 1 very rare cause of Vit. K deficiency?

A 
Oral anticoagulants (i.e. Warfarin)
Superwarfarin poisoning

Haemorrhagic disease of the newborn (very uncommon)

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13
Q

MoA of warfarin?

A

Competitive inhibitors of the vitamin K epoxide reductase enzyme complex &raquo_space; less recycling of Vit. K&raquo_space; reduction in the activation of factor II, VII, IX, X (Vit K dependent factors)

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14
Q

Coagulation result of Vit. K antagonism?

A

Prolong PT and APTT, Normal TT

Factor 2,7,9,10 affected

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15
Q

Which coagulation factors are used to monitor oral anticoagulant therapy?

A

factors VII, X, V, II & fibrinogen

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16
Q

How is INR calculated? Why is it needed?

A

Prothrombin Time in an individual will vary with the type of thromboplastin used

International Sensitivity Index (ISI) corrects for the sensitivity of thromboplastin by calibrating against a reference: ratio of the patient’s PT to the mean normal PT raised to the power of the ISI

(Patient’s PT / Mean normal PT)^ ISI

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17
Q

What is INR used for?

A

Use for warfarin monitoring/ titration ONLY!

DO NOT use it to monitor other new oral anti-coagulants!
DO NOT use to monitor DIC!

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18
Q

2 classes of numerical disorder of platelets? Which is more common?

A

Acquired thrombocytopenia (common)

Inherited (uncommon) – hereditary thrombocytopenias

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19
Q

List 3 hereditary thrombocytopenias?

A

 Bernard-Soulier syndrome
 Wiskott-Aldrich syndrome
 May-Hegglin anomaly

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20
Q

Isolated thrombocytopenia is rarer than pancytopenia. T or F?

A

True

Isolated thrombocytopenia is rare unless amegakaryocytic

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21
Q

List 2 conditions due to increased peripheral consumption of platelets?

A

Autoimmune thrombocytopenic purpura (AITP)

Alloimmune thrombocytopenia (rare)

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22
Q

Pathogenesis of Autoimmune thrombocytopenic purpura?

A

AutoAb (IgG) coat Megakaryocytes and Platelet glycoproteins

> > premature destruction by reticuloendothelial system in liver + inhibit platelet production in marrow

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23
Q

Aetiology of Autoimmune thrombocytopenic purpura?

A

Idiopathic

Secondary to other autoimmune diseases, malignancy (young women)

acute post-viral infection event (children)**

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24
Q

Dx of Autoimmune thrombocytopenic purpura?

A

Low platelet count

platelet glycoprotein-specific autoantibodies on platelets/serum

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25
Treatment of Autoimmune thrombocytopenic purpura?
- Observation (spontaneous recovery) - Immunomodulatory therapy: e.g. Anti-CD20 - TPO **platelet transfusion alone is ineffective **
26
Pathogenesis of Alloimmune thrombocytopenia and 3 possible causes?
HLA antibodies/ alloantibodies directed against donor platelets 1. Neonatal alloimmune thrombocytopenia 2. Post-transfusion purpura 3. Platelet refractoriness
27
Pathogenesis of Neonatal alloimmune thrombocytopenia?
Feto-maternal incompatibility for human platelet antigen (HPA) >> sensitization of mother >> maternal alloantibody crosses placenta >> thrombocytopenia in foetus
28
Pathogenesis of Post-transfusion purpura?
Transfusion of HPA-1a positive platelets into HPA-1a negative patients previously sensitized to HPA-1a >> HPA-1a antigen and corresponding antibody form immune complex = attack HPA-1a negative (donor) platelets >> severe thrombocytopenia
29
What type of platelet disorder results from hypersplenism?
Abnormal pooling in spleen (sequestration) = numerical disorder
30
What type of platelet disorder results from massive blood transfusions?
Dilutional = numerical disorder
31
List some inherited vs acquired platelet Functional disorders?
Acquired: 1) Drug-induced (anti-platelet)*** 2) Uraemia (common)*** Inherited (very rare): - Bernard-Soulier syndrome (defect glycoprotein receptor GP Ib) - Grey platelet syndrome: (deficiency of α-granules, or delta-granules- storage pool disease) - Glanzmann’s thrombasthenia (defect GP IIb-IIIa, fail aggregation)
32
List some drugs that cause functional platelet disorders
1) Cyclo-oxygenase inhibitor (targets thromboxane A2): aspirin 2) ADP receptor antagonists: clopidogrel 3) Glycoprotein IIb-IIIa inhibitors: abciximab
33
Pathogenesis of uraemia causing plt dysfunction? Is the coagulation screening test normal?
High urea conc. in blood >> uremic toxin to cause:  Platelet Dysfunction (Uraemia inhibit nitric oxide production)  Abnormal binding of Platelet to Vessel Wall Coagulation screening tests: usually normal mucocutaneous bleeding
34
Treatment options for uraemia?
 Increasing the haematocrit through red cell transfusion / erythropoietin therapy  Peritoneal / haemodialysis
35
Genetic defect, inheritance of Von Willebrand DIsease?
Quantitative / qualitative defect/deficiency of von Willebrand factor (VWF) chromosome 12, autosomal dominant / recessive
36
What is the commonest hereditary bleeding disorder?
Von Willebrand Disease (VWD)
37
2 functions of VWF?
1. Carries factor VIII, prevents its rapid degradation in plasma 2. Mediates platelet adhesion (GP Ib) to collagen in the subendothelial matrix
38
Pathogenesis of VWD?
Defective platelet adhesion + reduced factor 8 = Mucocutaneous bleeding + coagulation-type bleeding
39
Clotting test results for VWD?
Low factor 8 = intrinsic pathway affected Isolated APTT
40
List some functional assays for VWD?
VWF ristocetin cofactor (RiCof) assay: agonist for agglutination Factor VIII-binding assay
41
Why is mild VWD so easily underdiagnosed?
- Subtle bleeding history - No definite family history - VWF levels vary too much physiologically e.g. after exercise
42
List 2 disorders with combined coagulation and platelet abnormalities.
Parenchymal liver disease Acute disseminated intravascular coagulation (DIC) BOTH COMMON**
43
Outline the functions of the liver in coagulation.
-Synthesize All coagulation factors except VWF and F8 -Syn. natural anti-coagulants: Antithrombin (AT), Protein C & protein S, Plasminogen & α2-antiplasmin -Reticuloendothelial cells for fibrinolysis and clearance of coagulation intermediates
44
Coagulation test results in parenchymal liver disease?
 Prolongation of PT and APTT  Probably prolonged TT
45
Outline how parenchymal liver disease leads to coagulation abnormality?
- Impaired/ abnormal synthesis of clotting factors - Cholestasis reduce Vit K absorption > impair vitamin K-dependent clotting factors & inhibitors - Acquired dysfibrinogenaemia - Fail to clear products and intermediates from increased fibrinolysis - Thrombocytopenia due to increased splenic pooling, i.e., hypersplenism
46
Pathogenesis of disseminated intravascular coagulation (DIC)?
1. Tissue thromboplastin enters bloodstream >> directly activates coagulation 2. Severe vascular endothelial injury >> directly activates platelets >> generate thrombin >> fibrin 3. Widespread intravascular coagulation >> secondary fibrinolysis >> Microthrombi formation >> consume clotting factors and platelets
47
List some primary conditions that cause DIC?
1. Infections: Mainly septicaemia & some viral infections. 2. Malignancies: Acute promyelocytic leukaemia, metastatic carcinomas. 3. Obstetric conditions: Septic abortion, amniotic fluid embolism, abruptio placentiae 4. Massive tissue trauma: Extensive trauma or burns. 5. Extensive intravascular haemolysis: Usually from ABO incompatibility.
48
Coagulation results of DIC?
Microthrombi consume F8, 5, fibrinogen: Prolong PT, APTT, TT Low Fibrinogen Increase Fibrin degradation product = D-dimer
49
Treatment of DIC?
Supportive therapy – transfusion of platelet and fresh frozen plasma treat underlying disorder
50
Coagulation result for superwarfarin poisoning?
Unexplained increased APTT and PT, normal TT and fibrinogen Without drug history or liver diseases Present with deep-seated bleeding
51
What test is done to differentiate between factor deficiency and inhibitor?
1:1 mixing test If APTT is corrected ( as long as factor level above around 30%) = factor deficiency If APTT not corrected = inhibitor present
52
What factor deficiency does NOT result in bleeding tendency/ symptoms and results in isolated aPTT increase?***
Factor 12*** everything is normal except high aPTT common polymorphism in HK
53
Factor 13 deficiency coagulation test results?
CBP normal, PT, APTT, TT and fibrinogen are all normal
54
Difference in inhibiting speed between Lupus anticoagulant and Factor 8 inhibitor?
Immediate acting: • Lupus anticoagulant Delayed acting: • Factor VIII inhibitor
55
Explain how Hct (haematocrit) levels influence the clotting time in standard citrate bottles?
Trisodium citrate act as anti-coagulant by chelating Ca in the bottle: Hct increased (e.g. chronic hypoxia) >> actual plasma vol reduced => increased anti-coagulant to plasma ratio => bind/chelate more Ca+ in patient’s plasma => falsely prolong clotting time of patient’s plasma
56
Give examples of immediate acting and delayed acting coagulation inhibitors in mixing test?
Immediate acting: immediately increase aPTT after mixing: • Lupus anticoagulant • Factor IX inhibitor (very rare) Delayed acting: Increase aPTT slowly (over 1 hour) • Factor VIII inhibitor
57
Define the cause and treatment of Acquired Haemophilia A?
production of autoantibodies which inactivate factor VIII Treat acute bleeding + eradicate inhibitor by immunosuppressants
58
Epidemiology of Acquired Haemophilia A?
association with other autoimmune conditions, malignant disease, certain drugs, and pregnancy Middle age, both sexes
59
List 5 pre-analytic variables that affect the accuracy of clotting test results?
- Wrong patient, wrong specimen - Heparin contamination during blood taking - Haemolysed specimen - Incorrect blood:citrate ratio - Delay in transport
60
In-vitro coagulation texts e.g. aPTT, PTT are useful for pre-operative assessment of bleeding risks. T or F? Explain.
False: poor predictive value: In-vitro tests do NOT accurately reflect in-vivo coagulation + has Low sensitivity to clinically significant bleeding disorder (e.g. cannot detect VWD)
61
What questions would you ask a patient to assess bleeding risk pre-op?
Proper and structured history on bleeding symptoms relevant drugs family history past bleeding episode under haemostatic challenge (eg: tooth extraction, surgery)
62
Which types of bleeding disorder CANNOT be identified by routine in-vitro coagulation tests e.g. aPTT, TT... etc?
Blood vessel problems VWF factor deficiency Factor 13 deficiency >> present with bleeding but normal PT, aPTT, TT, CBC

MBBS II HIS (30 decks)

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