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 à 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 à 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 à 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 à 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 à 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                  - rFVIIa 10-40iu/kg (pFXIII, FFP & Cryo also options)

Prophylaxis                - If <0.1iu/ml + bleeding history. 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

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.