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Rare inherited bleeding disorders

Inherited bleeding disorders


Summary table



Half life


Dosing frequency

Target level


3 d

PCC 20-30 U/kg

SD plasma 15-20 ml/kg




36 h

SD plasma 15-20 ml/kg

Can give platelets




4-6 h

Recombinant VIIa (15-30 mcg/kg)

FVII concentrate

PCC (20-30U/kg)

Doses 2hly (rVIIa)

Prophylaxis every 3d



8 h

rVIII concentrate (Advate)

Increment x Wt


Treatment BD

Prophylaxis x3/wk

30-50 Joint / muscle / epistaxis

50-100 Surgery / lifethreatening bleeds


18 h

rIX concentrate (Benefix)

Increment x Wt x 0.9

Treatment OD

Prophlyaxis x2 /wk

Same as for fVIII


20-40 h

PCC (20-30U/kg)

SD plasma (15-20 mL/kg)





52 hours

FXI concentrates (15-20 Ukg)


>45 for major surgery

<70 for thrombotic risk


11-14 d

Factor XIII concentrate (10 U/kg prophylaxis ./ 10-20U/ kg severe bleeds)




2-4 d

Fibrinogen concentrate 20-40 mg/kg

Cryoprecipitate (1-2 adult doses)


>1 mg/dL


Factor II - Prothrombin deficiency (1 per 2million / 0.02%)

§   AR, rarest of the rare disorders

§   Two forms hypoprothrombinaemia (no cases of complete deficiency described) and dysprothombinaemia (discrepancy between function and antigen)

§   Cases described with levels ranging from 4-13%

§   Undetectable levels not described

§   Prolonged PT and APTT

§   Bruising and haematomas /mucosal and GI bleeding / intracranial bleeding

§        Haemarthrosis rare

§        Acquired causes include vitamin K, liver disease, LA, warfarin

§   Treatment

§        SD plasma (15-20 mL/kg)

§        PCC (20-30 U/kg)

§        Repeat doses not normally required (t1/2 = 3 days)

§        Target level 20-30


Factor V deficiency (1 per million / 0.6%)

§        AR

§        75% type I (ie factor and Ag both deficient) 25% type II (low function / normal Ag)

§        Joint bleeding in 25%

§        Epistaxis and menorrhagia common

§        GI / CNS bleeding rare

§        Prolonged PT and APTT but normal TT

§        Always need to check factor VIII levels

§        Alloantibody formation NOT uncommon following treatment with FFP (treated with large doses of FFP and IVIg)

§        Autoantibodies may also occur

§        Platelet factor V relatively protected form antibody neutralisation, therefore platelets may be an effective treatment.

§        Treatment

§        SD plasma (15-20 mL/kg)

§        Pooled SD preferred to MB single as factor levels more consistent

§        Need to check levels after FFP

§        Platelets

§        rVIIa

§        Target level

§        above 15iu/dL


Factor VII (2 per million / 1.3%)

§        Most common AR coagulation disorder (1:300,000)

§        Severity of symptoms correlates poorly with antigen levels (30% asymptomatic)

§        Homozygotes have bleeding akin to haemophilia (joint bleeds reported, severe (<2) – CNS bleeding common)

§        Circulates at 10mmol/L / 0.5 mg/L

§        Some association with thrombosis

§        PT prolonged (APTT, TT and Fib normal)

§        Factor VII padua – factor VII and PT results which vary according to the thromboplastin used

§        Human thromboplastin preferred as more likely to represent in vivo levels

§        VII levels measured using 1 stage functional assay

§        Can measure antigen using ELISA but this is not recommended as first line

§        Most patients have true (type 1) deficiency but cases of functional deficiency have been described

§        Probably relates to the fact that only trace amounts of VIIa are needed to initiate coagulation in vivo (probably as little as 0.05%)

§        Need to exclude acquired causes

§        Vitamin K deficiency, dietary fat, hypertriglyceridaemia, obesity, diabetes, sex hormones Over 100 mutations described in the gene encoding factor VII (Chr 13)

§        Management

§        Consider trial of vitamin K

§        Recombinant VIIa (15-30 mcg/kg) treatment of choice – dosed every 2-3h initially

§        Factor VII concentrate can be used (virally inactivated) – 8-40u/kg 4-6 hourly

§        PCC (20-30 U/kg) or SD FFP – not recommended if alternatives available

§        Fibrin glue

§        Tranexamic acid

§        Prophylaxis

§        Has been used succesffuly 3x / week

§        Target level

§        >15


Factor X deficiency (1 per million / 0.5%)

§        AR

§        Either due to quantitative or qualitative deficiencies

§        Homozygotes severe bleeding (heteros may be asymptomatic)

§        Haematomas / haemarthosis in 2/3 patients

§        Several cases of GI bleeding or bleeding from umbilical stump

§        Haematuria common (in contrast to all other deficiencies)

§        Most mutations in the catalytic domain (Chr 13)

§        Complete absence not seen – unlikely to be compatible with life

§        Acquired causes

§        Vit K, liver disease, amyloid, MM, PP

§        PT and APTT prolonged

§        Several different assays available for measuring levels – the one stage PT or APTT based assay is sufficient (may vary with the type of thromboplastin used)

§        If level >10 and no bleeding do not need treatment

§        Management – no consensus – options include:

§        Trial of vitamin K

§        SD plasma (15-20 mL/kg)

§        PCC (20-30U/kg)

§        Antifibrinolytics

§        Fibrin glue

§        rVIIa has been used to treat acquired X deficiency in amyloidosis

§        Target level

§        > 20



Factor XI deficiency (1 per million / 3.3%)

§        Usually parallel reduction of functional activity and antigen (majority in Ashkenazi Jews – 8% heterozygosity)

§        Can show AD inheritance because it exists as a dimer

§        Two groups of patients severe deficiency (<1%) and mild deficiency (6-30%) but both have similar rates of bleeding.

§        Spontaneous bleeding rare, usually in response to trauma / surgery. Muscle haematomas and haemarthrosis in 25%, but most have mild-moderate bleeding.

§        Possible explanation is that the APTT does not measure the important in vivo interaction between XI and platelets.

§        Eg.discrepancy between platelet specific expression and plasma levels

§        Noonans often associated with a partial factor XI deficiency

§        Diagnosis

§        Lower limit of normal around 70 U (50 is too low)

§        A normal APTT doesn’t exclude

§        Management

§        Measure vWF levels, as mild disease can affect bleeding phenotype

§        Level <20

§        Need prophylaxis prior to surgery

§        FXI concentrates (15-20 Ukg)

§        treatment of choice but only available on a named patient basis

§        Half life  52 hours

§        Check daily levels

§        SD plasma (15-20 mL/kg)

§        Fibrin glue

§        rVIIa

§        Avoid tranexamic acid with FXI due to thrombotic risk.

§        Target level

§        > 45iu/dL for major surgery but usually aim for around 70 in practice

§        Some concerns that XI is prothrombotic so try to prevent going over 70

§        Level 20-70

§        More difficult – depends on prior bleeding history and surgery

§        Factor XI concentrate for major surgery

§        Watch and wait for vaginal delivery (avoid epidural – unless been given FXI concentrate with documented response)

§        C. Section dependent on previous bleeding history

§        Inhibitors can rarely occur – can use rVIIa to treat



Combined Factor V and VIII (1 per million / 0.3%)

§        AR

§        Due to mutations in LMAN1 and MCFD2 (15%)  – Chr 18

§        Deficienct protein ERGIC 53 (endoplasmic reticulum golgi intermediate compartment) which has a major role in intracellular trafficking

§        FV and FVIII are synthesized normally but have abnormal passage through the cell and impaired release

§        Levels usually between 4 and 14%

§        Appt usually more prolonged than the PT

§        Bleeding symptoms usually mild and mucosal– epistaxis / menorrhagia / bleeding after dental extractions

§        Management

§        SD plasma (15-20 mL/kg) to keep V level >20

§        rFVIII to keep VIII level >30 or >50 for minor and major procedures respectively

§        For epidural – Fv > 15, FVIII >50

§        Other combinations include VitK related, VII and IX and deletion of Chr13 (VII and X)



Fibrinogen deficiency (1 per million / 0.2%)

§        Fibrinogen is a dimer composed of 2 identical sub units

§        Present in cytoplasmic alpha granules of platelets

§        Parent molecule for fibrin and also supports platelet aggregation by bridging between GPIIb IIIa

§        Also has roles in inflammation and wound healing

§        Half life 4 days

§        Afib/ hypofib/ dysfib/ hypodysfib

§        Afibrinogenaemia

§        APTT / PT/ TT unrecordable

§        Unmeasurable fibrinogen with both clottable (eg. Clauss) and immunoreactive assays

§        (cf dysfibrinogenaemia in which there is low claus / normal antigen)

§        Derived fibrinogen should not be used

§        AR

§        Severe bleeding like haemophilia

§        Umbilical stump, haematoma, haemarthrosis, mucosal

§        Excessive blood loss following surgery around 30% of the time

§        May have difficulties with recurrent miscarriages (fibrinogen may be important for implantation)

§        Treatment

§        Virally inactivated fibrinogen (not cryoprecipitate unless an emergency as not virally inactivated)

§        Aim to keep FI level >1 until haemostasis secure

§        Then > 0.5 until wound healing achieved

§        Formula Dose = desired increment (g/L) x plasma volume (weight x 0.07 x (1 – haematocrit))

§        Half life 3-5d

§        Little evidence for primary prophylaxis

§        Should supplement levels during pregnancies

§        Hypofibrinogenaemia

§        AR or AD

§        Low level of normal fibrinogen

§        TT the most sensitive test

§        Dysfibrinogenaemia

§        Most common

§        Discrepancy between functional and immunoreactive assay

§        Can also have severe thrombotic episodes (perhaps explained by the intravascular formation of platelet aggregates due to increased generation of thrombin unimpeded by fibrin formation.

§        Need thrombophilia screen

§        Identification of the mutation may help identify the clotters

§        35% asymptomatic, 26% haemorrhage, 21% thrombosis

§        Treatment

§        Haemorrhage – fibrinogen concentrate (>1 above baseline), TA with caution

§        Thrombus – LMWH

§        Three genes involved FGA, FGB and FGG with mutations in all three being implicated – Chr 4

§        Acquired hypofibrinogenaemia in liver disease, ascites, DIC, L-asparaginase, thrombolysis

§        Cryoprecipitate 5-10 bags or fibrinogen concentrates 20-40mg/kg



Factor XIII deficiency (1 per million / 0.5%)

§        Normal APTT/ PT/ TT

§        It is activated by thrombin and functions to cross link a and b fibrin chains resulting in a stronger clot, with increased resistance to fibrinolysis.

§        Screening test = clot solubility test

§        Test plasma is clotted and exposed to a chemical challenge which lyses the clot if insufficienct FXIII cross-linking has occurred.

§        Thrombin/ acetic acid rather than urea recommended (more sensitive)

§        Inaccurate and insensitive

§        2 activity assays / 1 ELISA kit

§        Levels of factor XIII are usually immeasurable (no cases of a qualitative defect have been described)

§        Most severe bleeding tendency of all coagulation deficiencies – umbilical cord (80%) or CNS (30%)

§        Delayed wound healing

§        Usually diagnosed early in life

§        Reduced fertility – should continue prophylaxis throughout pregnancy

§        Management

§        Prophylaxis started as soon as diagnosis made due to high risk of intracerebral bleeding (plasma levels of 2-5% are sufficient to prevent bleeding)

§        Long half life (11-14 d) so can infuse cryoprecipitate or concentrates monthly

§        Develop soft tissue / joint bleeding / GI bleeding / intraperitoneal bleeding at time of ovulation

§        Mild bleeding once prophylaxis initiated

§        Factor XIII concentrate (10 U/kg prophylaxis ./ 10-20Ukg severe bleeds) but also cryo (2-3 bags) / SD plasma (3mL/kg)

§        Target

§        Normal levels

§        Inhibitors may occur and bleeding may be severe but there is no consensus on management

§        Acquired in liver disease, leukaemia, DIC, malignancy, P falciparum, Rh arthritis, HSP

§        Pregnancy

§        Prophylaxis throughout with trough levels >3



Inhibitors of fibrinolysis


Alpha-2 Antiplasmin deficiency

Plasminogen is activated to plasmin by t-PA and urokinase which break-up fibrin

Alpha-2 antiplasmin is primary inhibitor of plasmin

§   Normal APTT/PT

§   Inhibits plasmin

§   Severe bleeding in homozgote

§        Intramedullary haematoma of the long bones

§        Acquired in liver disease, nephritic syndrome, amyloid, DIC, thrombolysis, by-pass, malignancy

§        Treat with tranexamic acid


Plasminogen activator inhibitor-1 deficiency

§   Normal APTT/PT

§   Inhibits t-PA

§   Responds to tranexamic acid

§   Acquired auto antibody has been reported in amyloid




Contact factor deficiencies

§   Factor XII (Hageman factor), prekallikrein (Fletcher factor) and high molecular weight kininogen (Fitzgerald factor)

§   Isolated prolonged APTT (often 2x APTT in severe haemophilia) with no bleeding diathesis


General recommendations

1. Avoidance of blood-borne infections

§   Solvent detergent FFP

§   Virally inactivated factor concentrates (Fibrinogen, PCC, VII, XI and XIII) – should be used if SD plasma not available or concerns about fluid overload.

§   No concentrate available for factor V

2. Prenatal diagnosis

§   Feasible in couples who already have affected children

§   Discourage consanguineous marriage



Ehlers-Danlos syndrome

§   Inherited connective tissue disorders

§   Joint, skin and tissue hyperextensibility

§   6 major types – depending on the clinical picture – skin biopsy is occasionally necessary

§   Classical (skin laxity / hypermobility)

§   Hypermobility (joint hypermobility and dislocation)

§   Vascular (Arterial / intestinal / uterine fragility)

§   Kyphoscoliosis (also prone to arterial rupture and have marfanoid habitus)

§   Arthochalasia (severe joint hypermobility with dislocations – often bilateral hip dislocations in babies)

§   Dermatosparaxis (skin hypermobility)


§   Management

§   No specific management of bleeding

§   Tranexamic acid may be helpful

§   Advise surgeon – likely to need extra sutures, which may need to be left in for longer

§   Cardiologist / opthamology follow up