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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
Q

Treatment of Autoimmune thrombocytopenic purpura?

A
  • Observation (spontaneous recovery)
  • Immunomodulatory therapy: e.g. Anti-CD20
  • TPO

**platelet transfusion alone is ineffective **

26
Q

Pathogenesis of Alloimmune thrombocytopenia and 3 possible causes?

A

HLA antibodies/ alloantibodies directed against donor platelets

  1. Neonatal alloimmune thrombocytopenia
  2. Post-transfusion purpura
  3. Platelet refractoriness
27
Q

Pathogenesis of Neonatal alloimmune thrombocytopenia?

A

Feto-maternal incompatibility for human platelet antigen (HPA)

> > sensitization of mother

> > maternal alloantibody crosses placenta

> > thrombocytopenia in foetus

28
Q

Pathogenesis of Post-transfusion purpura?

A

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
Q

What type of platelet disorder results from hypersplenism?

A

Abnormal pooling in spleen (sequestration) = numerical disorder

30
Q

What type of platelet disorder results from massive blood transfusions?

A

Dilutional = numerical disorder

31
Q

List some inherited vs acquired platelet Functional disorders?

A

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
Q

List some drugs that cause functional platelet disorders

A

1) Cyclo-oxygenase inhibitor (targets thromboxane A2): aspirin
2) ADP receptor antagonists: clopidogrel
3) Glycoprotein IIb-IIIa inhibitors: abciximab

33
Q

Pathogenesis of uraemia causing plt dysfunction? Is the coagulation screening test normal?

A

High urea conc. in blood&raquo_space; 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
Q

Treatment options for uraemia?

A

 Increasing the haematocrit through red cell transfusion / erythropoietin therapy

 Peritoneal / haemodialysis

35
Q

Genetic defect, inheritance of Von Willebrand DIsease?

A

Quantitative / qualitative defect/deficiency of von Willebrand factor (VWF)

chromosome 12, autosomal dominant / recessive

36
Q

What is the commonest hereditary bleeding disorder?

A

Von Willebrand Disease (VWD)

37
Q

2 functions of VWF?

A
  1. Carries factor VIII, prevents its rapid degradation in plasma
  2. Mediates platelet adhesion (GP Ib) to collagen in the subendothelial matrix
38
Q

Pathogenesis of VWD?

A

Defective platelet adhesion + reduced factor 8 = Mucocutaneous bleeding + coagulation-type bleeding

39
Q

Clotting test results for VWD?

A

Low factor 8 = intrinsic pathway affected

Isolated APTT

40
Q

List some functional assays for VWD?

A

VWF ristocetin cofactor (RiCof) assay: agonist for agglutination

Factor VIII-binding assay

41
Q

Why is mild VWD so easily underdiagnosed?

A
  • Subtle bleeding history
  • No definite family history
  • VWF levels vary too much physiologically e.g. after exercise
42
Q

List 2 disorders with combined coagulation and platelet abnormalities.

A

Parenchymal liver disease

Acute disseminated intravascular coagulation (DIC)

BOTH COMMON**

43
Q

Outline the functions of the liver in coagulation.

A

-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
Q

Coagulation test results in parenchymal liver disease?

A

 Prolongation of PT and APTT

 Probably prolonged TT

45
Q

Outline how parenchymal liver disease leads to coagulation abnormality?

A
  • 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
Q

Pathogenesis of disseminated intravascular coagulation (DIC)?

A
  1. Tissue thromboplastin enters bloodstream&raquo_space; directly activates coagulation
  2. Severe vascular endothelial injury&raquo_space; directly activates platelets&raquo_space; generate thrombin&raquo_space; fibrin
  3. Widespread intravascular coagulation&raquo_space; secondary fibrinolysis&raquo_space; Microthrombi formation&raquo_space; consume clotting factors and platelets
47
Q

List some primary conditions that cause DIC?

A
  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
Q

Coagulation results of DIC?

A

Microthrombi consume F8, 5, fibrinogen:

Prolong PT, APTT, TT
Low Fibrinogen
Increase Fibrin degradation product = D-dimer

49
Q

Treatment of DIC?

A

Supportive therapy – transfusion of platelet and fresh frozen plasma

treat underlying disorder

50
Q

Coagulation result for superwarfarin poisoning?

A

Unexplained increased APTT and PT, normal TT and fibrinogen

Without drug history or liver diseases

Present with deep-seated bleeding

51
Q

What test is done to differentiate between factor deficiency and inhibitor?

A

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
Q

What factor deficiency does NOT result in bleeding tendency/ symptoms and results in isolated aPTT increase?***

A

Factor 12***
everything is normal except high aPTT
common polymorphism in HK

53
Q

Factor 13 deficiency coagulation test results?

A

CBP normal, PT, APTT, TT and fibrinogen are all normal

54
Q

Difference in inhibiting speed between Lupus anticoagulant and Factor 8 inhibitor?

A

Immediate acting: • Lupus anticoagulant

Delayed acting: • Factor VIII inhibitor

55
Q

Explain how Hct (haematocrit) levels influence the clotting time in standard citrate bottles?

A

Trisodium citrate act as anti-coagulant by chelating Ca in the bottle:

Hct increased (e.g. chronic hypoxia)&raquo_space; 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
Q

Give examples of immediate acting and delayed acting coagulation inhibitors in mixing test?

A

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
Q

Define the cause and treatment of Acquired Haemophilia A?

A

production of autoantibodies which inactivate factor VIII

Treat acute bleeding + eradicate inhibitor by immunosuppressants

58
Q

Epidemiology of Acquired Haemophilia A?

A

association with other autoimmune conditions, malignant disease, certain drugs, and pregnancy

Middle age, both sexes

59
Q

List 5 pre-analytic variables that affect the accuracy of clotting test results?

A
  • Wrong patient, wrong specimen
  • Heparin contamination during blood taking
  • Haemolysed specimen
  • Incorrect blood:citrate ratio
  • Delay in transport
60
Q

In-vitro coagulation texts e.g. aPTT, PTT are useful for pre-operative assessment of bleeding risks. T or F? Explain.

A

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
Q

What questions would you ask a patient to assess bleeding risk pre-op?

A

Proper and structured history on bleeding symptoms

relevant drugs

family history

past bleeding episode under haemostatic challenge (eg: tooth extraction, surgery)

62
Q

Which types of bleeding disorder CANNOT be identified by routine in-vitro coagulation tests e.g. aPTT, TT… etc?

A

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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