Rare Coag Disorders (BSH 2014, Green Top 2017)
Intro
Guidance and data based on EN-RBD registry data
Prevalence 1 in 1 million in general
Defects can be qualitative or quantitative, with variable lab-clinical correlation
Consider prophylaxis when combo of low level + bleeding history
TXA usually sufficient for mild cases / minor surgery
Fibrinogen (Factor I) deficiency
Inheritance - AD(hypo/dys) / AR(afib)
Prevalence - 1 in 1 million
Factor half-life - 4 days
PT - Prolonged
APTT - Prolonged
TT - Prolonged
Other tests - Reptilase time prolonged, Clauss FGN low, FGN antigen normal or low
Treatment - FGN concentrate (Riastap) 50-100mg/kg —> raises FGN by 1-1.5g/l
Target level - >1.0-1.5g/l
Prophylaxis - If <0.1g/l + bleeding history. Twice weekly dosing.
Pregnancy - Keep >1.0 in pregnancy, >1.5 at delivery.
Notes - Dysfibrinogenemia can be haemorrhagic or thrombotic
Prothrombin (Factor II) deficiency
Inheritance - AR
Prevalence - 1 in 2 million
Factor half-life - 60 hours
PT - Prolonged
APTT - Prolonged
TT - ?
Other tests - 1-Stage FII and Antigen to separate hypo- from dys-
Treatment - PCC 20-30 u/kg —> raises level by 0.4-0.6. Repeat after 48 hours if needed
Target level - >0.2iu/ml
Prophylaxis - If <0.01iu/ml + bleeding history. Weekly dosing
Pregnancy - PCC for bleeding, labour or prior to CS if <0.2iu/ml, aiming for 0.2 – 0.4
- Maintain >0.2 for three days using 48-hourly PCC
Notes - SD-FPP is alternative
Factor III = Tissue Factor
Factor IV = Calcium
Factor V deficiency
Inheritance - AR
Prevalence - 1 in 1 million
Factor half-life - 16-36 hours
PT - Prolonged
APTT - Prolonged
TT - Normal
Other tests - Remember to check FVIII
Treatment - SD-FFP 15-25ml/kg 12 hourly —> raises level by 0.15iu/ml
Target level - >0.2 iu/ml
Prophylaxis - If <0.05iu/ml + bleeding history. Twice weekly dosing
Pregnancy - SD-FFP in labour. 15ml/kg 12 hourly to keep >0.2iu/ml
Antibodies - Can develop. Use FVIIa, high dose FFP or IVIg
- Beta-lactam antibiotics. Usually resolves on cessation of drug
Notes - 80% in plasma, 20% in platelets. Produced in hepatocytes.
- rFVIIa is an alternative
Factor VI = Activated Factor V
Factor VII deficiency
Inheritance - AR
Prevalence - 1 in 500,000
Factor half-life - 4-6 hours
PT - Prolonged
APTT - Normal
TT - Normal
Treatment - rFVIIa 15-30 microg/kg, 4-6 hourly
Target level - level of limited value
Prophylaxis - If <0.01iu/ml + bleeding history. 40-60 microg/kg, 3x per week
- Treat to the age of 6-12 months even if no bleeding history
Pregnancy - Treat at delivery if <0.2iu/ml or previous bleeding history
- Maintain >0.2 for 3-5 days after CS
- Levels rise in pregnancy.
Notes - 99% circulates as inactive zymogen.
- Weak lab/clinical correlation.
Factor VIII – Haemophilia A, see elsewhere
Factor IX – Haemophilia B, see elsewhere
Factor X deficiency
Inheritance - AR
Prevalence - 1 in 1 million
Factor half-life - 20-40 hours
PT - Prolonged
APTT - Prolonged
Other tests - APTT / RVVT based FX level can detect rare variants
Treatment - PCC 20-30u/kg —> raises level by 0.4-0.6iu/ml. Repeat after 24 hrs if need
Target level - >0.2iu/ml
Prophylaxis - If <0.02iu/ml + bleeding history. 2-3x per week, aim trough >0.02iu/ml
Pregnancy - Consider antenatal prophylaxis if history of severe bleeding
- PCC at time of delivery if <0.3iu/ml, aim for >0.4iu/ml, then >0.3 for 3 days
- Levels rise in pregnancy
Notes - Acquired FX def: AL Amyloid, Infection, Drugs, Malignancy
- High purity FX concentrate or SD-FFP are alternatives
Factor XI deficiency
Inheritance - AD/AR
Prevalence - 1 in 1 million
Factor half-life - 52 hours
PT - Normal
APTT - Prolonged or Normal (levels 0.5-0.7)
Other tests - 1-stage APTT based assay
Treatment - FXI concentrate 10-20iu/kg —> raises level by 0.2-0.4iu/ml
Pregnancy - FXI concentrate at delivery if <0.15iu/ml
Antibodies - Look for antibodies if level <0.1 and prev factor exposure
Notes - higher prevalence in Ashkenazi Jews (hetero 8%, homo 0.5%)
- 65% asymptomatic. Spontaneous bleeding is uncommon.
- Do not combine FXI concentrate with TXA à thrombotic risk
- SD-FFP is alternative
Pregnancy - Levels do not usually increase in pregnancy. Check at booking, 3rd trimester
- Increased risk of PPH, highest if blood group O & bleeding phenotype
- TXA alone usually sufficient.
- No neuroaxial anaes. if: very low level, or bleeding phenotype at any level
- Women with non-bleeding phenotype can be managed expectantly
- No special precaution required for baby unless at risk of homozygosity
Factor XII – Does not cause a bleeding disorder
Factor XIII deficiency
Inheritance - AR
Prevalence - 1 in 1 million
Factor half-life - 11-14 days
PT - Normal
APTT - Normal
TT - Normal
Other tests - Screening tests: 5-molar-urea test or Acetic acid test. Both are clot solubility assays
which are no longer recommended. Only detect severe deficiencies.
- Confirmatory tests: Ammonia release / Amine Incorporation / ELISA
- Genetic testing
Treatment - FXIII concentrate, FFP and Cryo are options
- (rFVIIa 10-40iu/kg has been used in severe bleeding in absence of FXIII concentrate)
Prophylaxis - If <0.1iu/ml + bleeding history.
- FXIII concentrate available. Alternative: rFVIIa 20-40iu/kg monthly, trough 0.1-0.2
Pregnancy - Levels fall in pregnancy. Increase rVIIa prophylaxis to 2-3x weekly
- FXIII plasma or recombinant concentrate also available, every 14-21 days
- Aim >0.2
- Prophylaxis vital to avoid miscarriage (FranceCoag Cohort BJH 2019)
Notes - Classic presentation: Umbilical bleeding a few days after birth seen in 80%
- Acquired FXIII def: Isonizaid, Valproate, HSP, IBD, Gut GVDH, cardiac bypass, pregnancy
- FXIII protein composed of A subunit (active) and B subunit (carrier protein)
Factor V+VIII deficiency
Inheritance - AR. LMAN1 (Lectin, Mannose binding 1) and MCFD2 (Multiple Coagulation Factor
Deficiency 2) gene mutations
Prevalence - 1 in 2 million
PT - Prolonged
APTT - Prolonged
Treatment - SD-FFP 15ml/kg. Supplementary rFVIIa 20-40iu/kg or desmopressin
Target level - FV >0.15, FVIII >0.5
Pregnancy - SD-FFP 15-20ml/kg 12 hourly for 3 days at labour if FV level <0.2
- & maintain FV >0.2 for three days after CS
- FVIII rises in pregnancy, FV does not.
Antibodies - Yes. Treat with high dose FFP or IVIg
Notes - Usually mild-moderate phenotype
- rFVIIA is alternative or combination for SD-FFP
- Could use platelet transfusion, contains plt-type FV
Vit K-dependent Coag Factor Deficiency (VKDCFD)
Inheritance - AR
Prevalence - <30 families worldwide
PT - Prolonged
APTT - Prolonged
Treatment - PCC in bleeding / surgery
Prophylaxis - Oral Vit K 15mg daily. IV if not responding
Pregnancy - PCC at labour for 3 days
- FVII and FX rise in pregnancy.
Combined FVII + FX Deficiency
PT - Prolonged
APTT - Prolonged
Notes - Often associated with developmental delay
Hypofibrinolysis
Test - Euglobulin Clot Lysis Time (ECLT) becomes prolonged
Causes - Low testosterone state increases PAI-1 levels
- e.g. Kleinfelters (XXY). Hormone replacement corrects the abnormality.