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HIS > HIS29 Inherited And Acquired Bleeding Disorders II > Flashcards

HIS29 Inherited And Acquired Bleeding Disorders II Flashcards

1
Q

Case 1:

  • 70 yo male
  • Hyperlipidaemia, Dementia
  • Spontaneous bruises / Haematoma over left thigh, both upper limb
  • No bleeding history
  • CT: Huge muscle haematoma over left thigh
  • About few days of onset
  • No drug history
  • APTT prolong
  • PT, platelet, WBC normal
  • Hb drop of 2g from baseline (∵ bleeding)
  • LRFT normal
A

Type of bleeding:
- Deep-seated bleeding

Inherited / Acquired:
- Acquired

Haemostatic system affected:
- Coagulation factor / Severe vWF deficiency

Complaint:
- Isolated prolong APTT
—> Only Intrinsic pathway affected
—> Factor 8, 9, 11, 12, Contact factor deficiency / inhibitor, Lupus anticoagulant
—> Heparin effects eliminated

Problem:

  • Which exact coagulation factor
  • Deficiency vs Inhibitor
  • Lupus anticoagulant? —> Cause ***thrombosis in-vivo rather than bleeding (in-vitro) —> can be ruled out

Investigation:

  1. 1:1 Mixing test
    - APTT —> 80.5
    - APTT control —> 28.3
    - APTT 1:1 mix —> 39.7
    - APTT 1:1 mix, 37oC, 1 hour —> 83.6

—> ***APTT corrected at first then back to prolong —> Factor 8 inhibitor

  1. Factor assay: Factor 8c <1 (50-200) (grossly reduced)

Diagnosis: Acquired Haemophilia A (Acquired Factor 8 inhibitor)

Summary: Acquired clotting defect with clinical deep-seated bleeding tendency + Isolated APTT
—> Think of acquired Factor 8 inhibitor

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2
Q

1:1 Mixing test

A

Distinguish between Factor deficiency and Presence of inhibitor

4 measurements:

  • APTT of patient
  • APTT of normal person (control)
  • APTT 1:1 mix (immediate mixing)
  • APTT 1:1 mix, 37oC, 1 hour

Factor deficiency:
Normal pool plasma replace missing clotting factor
—> final mixed concentration must be >=50% (normal 100%, patient 0%)
—> as long as >30%
—> normal APTT (APTT correctable by normal plasma)

Presence of Inhibitor (i.e. Ab):
Inhibitors continue to destroy clotting factor in normal pool control plasma
—> APTT continue to prolong (no correction)

Immediate inhibitor (i.e. no correction of APTT at all):

  • Lupus anticoagulant
  • Factor 9 inhibitor (very rare)

Delayed acting (i.e. corrected APTT after immediate mixing, after 1 hour go back to prolonged APTT):
- Factor 8 inhibitor
—> showed time-dependent effect

Summary:
Mixing test
—> Correction of PT/APTT
—> Yes —> Deficiency
—> No —> Inhibitor (If no throughout (keep住長): Lupus anticoagulant; If yes then no (短—>長翻): Factor 8 inhibitor)
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3
Q

Acquired Haemophilia A (Acquired Factor VIII inhibitor)

A
  • Production of ***AutoAb in adult life
    —> inactivate Factor 8
  • Both sexes affected equally (inherited Haemophilia A: Male predominant)
  • Middle age
  • Association with other autoimmune conditions, malignant disease, certain drugs, pregnancy has been recognised

Treatment:

  1. Treat acute bleeding immediately (can be severe)
  2. ***Immunosuppressants to eradicate inhibitor

Prognosis:

  • Significant morbidity
  • Significant mortality esp. if delayed treatment (41%)
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4
Q

Case 2:

  • 59 yo man
  • COPD, chronic smoker
  • Haemoptysis
  • CXR: Right upper zone patchy haziness, hyperinflation, no pneumothorax
  • Sputum Acid Fast Bacilli ++++ —> TB
  • No drug history
  • No clinical bleeding, bruising / prolong bleeding from venepuncture site
  • No abnormal bleeding history
  • No family history
  • LRFT normal
  • PT prolong
  • INR prolong
  • APTT prolong
  • Hb 23.3
  • Hct 0.699
  • WCC normal
  • Plt normal
A

PT ↑, APTT ↑

Hb 23.3, Hct 0.699: Erythrocytosis (Polycythaemia due to chronic hypoxaemia from COPD)

—> Repeat test with appropriate citrate level —> Normal clotting time

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5
Q

Citrate bottle

A 
Trisodium citrate (0.109M) as anticoagulant in citrate bottle
—> bind Ca to prevent clotting

Most tubes collect blood (2.7 mL):anticoagulant (0.3 mL) in 9:1 ratio (fixed)

When Hct increased (e.g. Polycythaemia)
—> Actual plasma volume ↓ (if collect fixed amount of blood)
—> ↑ Anticoagulant to Plasma ratio
—> more Ca in plasma being bound away by Citrate
—> Falsely prolong clotting time

Recommended amount of citrate for different level of Hct
—> ↓ Citrate volume for ↑ Hct

Summary:
Correct ***blood:citrate ratio is very important when taking blood for clotting sample
—> falsely prolong clotting time if inadequately filled

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6
Q

Common pre-analytical pitfalls to affect clotting results

A
  1. Wrong patient, wrong specimen
  2. Heparin contamination during blood taking
  3. Haemolysed specimen
  4. Incorrect blood:citrate ratio
  5. Delay in transport (degradation of clotting factors)

—> If in doubt, repeat clotting profiles before treatment

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7
Q

Case 3:

  • 51 yo male
  • hypertension history
  • RUQ pain 3 months ago, Acute cholecystitis, treated with Cefuroxime, Metronidazole
  • Elective Cholecystectomy arranged
  • clinically well, no bleeding
  • Hb, WCC, Plt normal
  • LFT normal
  • RFT normal
  • APTT ↑↑
  • PT normal
  • INR normal
  • Heparin contamination excluded
  • No bleeding history
  • No family history
  • No drug history
  • Uneventful knee surgery for ACL repair previously
A

Complaint:
- Isolated ↑↑ APTT
—> Only Intrinsic pathway affected
—> Factor 8, 9, 11, 12, Contact factor, Lupus anticoagulant

1:1 mixing test:
- APTT fully correctable during immediate mixing and incubation after 1 hour
—> Factor deficiency

No bleeding tendency despite grossly prolong APTT
—> Not likely to be Factor 8, 9, 11 deficiency (highly associate with clinical bleeding)

Implication:
- Factor 12 / Contact factor deficiency

Further investigation:
- Factor assay:
—> Factor 8, 9, 11: normal
—> Factor 12: markedly ↓↓

Diagnosis:
- Severe Factor 12 deficiency

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8
Q

Factor XII deficiency

A

Deficiency of contact factors (Factor 12, Prekallikrein, Kallikrein, High MW Kininogen)
—> Prolonged APTT

Contact factors:
Function at step of initiation of intrinsic clotting pathway (In-vitro!!!) by reagent used to determine APTT
—> markedly prolong if contact factors absent

  • **NOT associated with bleeding tendency
  • **NO major role in normal physiological haemostasis
  • Orientals have common polymorphism in Factor XII gene causing deficiency
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9
Q

Pre-op assessment of bleeding risks

A

Routine testing of clotting profile pre-operatively (esp. elective surgery) for assessment of bleeding risks is **NOT recommended
—> **Poor predictive value to predict bleeding risks by PT / APTT

In-vitro (only Plasma) vs In-vivo coagulation (***also involves Platelets + Endothelium)

  • In-vitro tests do NOT accurately reflect in-vivo coagulation response
  • ***LOW sensitivity to clinically significant bleeding disorder (e.g. vWD, Factor 13 deficiency)
  • cause delay in surgical treatment
Therefore:
- CBC (platelet count)
- Bleeding symptoms
- Drugs history
- Family history of bleeding disorder
- Past bleeding episode under haemostatic challenge (e.g. tooth extraction, menstruation)
—> ***Higher predictive value!!!
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10
Q

Bleeding disorder cannot be detected by CBP, PT, APTT, TT, Fibrinogen tests
Pre-class quiz:
- 6 yo boy
- very severe post-op bleeding after simple knee surgery
- CBP normal
- PT, APTT, TT, Fibrinogen normal

A

Thrombocytopenia unlikely
—> ∵ CBP normal

Bleeding disorder cannot be detected by CBP, PT, APTT, TT, Fibrinogen tests:

  1. vWF deficiency (all parameters present normally —> need vWF assay)
  2. Platelet dysfunction (all parameters present normally —> need platelet function test)
    (Both unlikely ∵ NO other clinical bleeding e.g. Mucocutaneous bleeding)
    (unless very severe vWF deficiency —> Factor VIII deficiency —> affect APTT)
  3. Blood vessels problem (unlikely ∵ no bruising over skin)
  4. ***Factor XIII deficiency (In-vitro test only detect up to fibrin monomer stage rather than polymer!!!)
    —> need specialised test
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11
Q

Case 4:

  • 60 yo male
  • NPC received radiotherapy in 2000
  • Complicated by hormone deficiencies
  • Regular Fludrocortisone, Hydrocortisone, Testosterone replacement
  • Anti-HT
  • No anticoagulant
  • No bleeding history
  • No liver cirrhosis, other systems unremarkable
  • LL pain
  • Generalised bruising
  • Left thigh swelling
  • CT: huge muscle haematoma in left thigh
  • Hb ↓ (∵ bleeding)
  • Platelet normal
  • Clotting profile: PT ↑↑, APTT ↑↑, TT normal, Fibrinogen normal
  • Clotting result in 2012 normal —> acquired
A

Complaint:

  • Generalised bruising
  • Left thigh swelling

Type of bleeding:
- Deep-seated bleeding

Inherited / Acquired:
- Acquired

Haemostatic system affected:
- Coagulation factor / Severe vWF deficiency
—> Severe vWF deficiency —> unlikely ∵ it is congenital

Suggestion:
- Acquired Coagulation factor defect
—> most commonly due to ***liver cirrhosis (but not in this case)

1:1 mixing test:
- PT: correctable throughout
- APTT: correctable throughout
—> Factor deficiency

Liver cirrhosis: Unlikely
—> ∵ unremarkable P/E + TT / Fibrinogen normal (liver cirrhosis synthesise abnormal fibrinogen —> TT ↑, Fibrinogen ↓)

Causes:
Flowchart (from L28):
Prolong APTT —> Prolong PT —> Normal TT (i.e. NOT involve fibrinogen to fibrin)
1. Vit K deficiency / antagonists (Factor 2, 7, 9, 10)
2. Common pathway factor deficiency / inhibitors (Factor 2, 5, 10)
3. Multiple factor deficiencies involving multiple pathway

Further investigation:
- Factor assay:
—> Factor 2, 7, 9, 10 ↓↓
—> suggest presence of Vit K antagonists in body

Further history:
- NO warfarin history
—> but taking herbs before admission
—> toxicology lab for further investigations

Diagnosis:
- Superwarfarin poisoning (from rodenticides)

Treatment:
- High dose oral Vit K for long period of time to normalise clotting profile

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12
Q

Superwarfarin poisoning

A
  • Class of rodenticide to overcome warfarin resistance in rats
  • Long-acting
  • Fat soluble
  • Colourless, Tasteless, Odourless
  • t1/2: from weeks to months (very long)

Lab investigations:
- ↑ PT, APTT
- TT, Fibrinogen normal
- absence of liver disease / warfarin therapy
—> results same as Vit K antagonist (e.g. Warfarin)
—> ↓ Vit K dependent factors (Factor 2, 7, 9, 10)

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13
Q

Summary

A

Case 1:

  • 1:1 mixing test —> differentiation deficiency vs inhibitor
  • Acquired Haemophilia A

Case 2:

  • Polycythaemia —> High Hct —> falsely prolong clotting
  • Citrate:plasma ratio importance
  • Common pitfall of clotting test

Case 3:

  • Factor 12 deficiency —> NOT cause physiological bleeding —> Limitation of lab test
  • No need routine pre-op assessment of clotting file unless anticoagulant therapy previously
  • Higher predictive value: Structural bleeding history
Pre-class quiz:
- Factor 13 deficiency cannot be detected by lab test

Case 4:
- Pattern of Vit K dependent factors deficiency

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