Inherited bleeding disorders
Summary table
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 ./ 10-20U/ kg 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 |
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