Coagulation‎ > ‎

Acquired coagulopathies

Acquired coagulopathies

Bleeding and liver disease


Haemostatic defects

§        Impaired coagulation

§        Reduced synthesis of clotting proteins

§        FV and FVII (INR) are sensitive indicators

§        vWF synthesised in megas and ECs – levels rise

§        FVIII synthesized in liver, but usually rises in liver failure

§        Vitamin K deficiency

§        Poor nutrition

§        Obstructive biliary disease

§        Malabsorption of fat soluble vitamins

§        Platelets

§        Hypersplenism

§        Failure to clear platelet inhibitors

§        Eg FDPs

§        Immune destruction

§        Platelet survival reduced in cirrhosis

§        Platelet associated IgG esp in hep C and AI hepatitis

§        Decreased production

§        low TPO production

§        alcohol reduces production by megas and hastens platelet destruction

§        viral infections inhibit megakaryopoiesis

§        Platelet dysfunction

§        Reduced GP1b on platelet surface

§        DIC

§        Procoagulants from hepatic cells

§        Endotoxins in portal circulation

§        Reduced clearance of activated clotting factors

§        Reduced AT and protein C

§        Elevated cytokines

§        Intercurrent events

§        Systemic fibrinolysis

§        Reduced hepatic synthesis of alpha2-antiplasmin

§        Failure to clear fibrinolytic enzymes

§        tissue plasminogen activator

§        Abnormal fibrinogen

§        Increased sialic acid

§        Inhibits polymerization of fibrin


§   HELLP/ pre-eclampsia

§        1% subcapsular haematoma

§        Catastrophic hepatic haemorrhage and rupture can occur

§        Liver transplant

§        Excessive bleeding

§        Severe portal hypertension

§        Previous RUQ surgery

§        Brisk rise in tPA and fall in PAI -1 during anhepatic and reperfusion stages, with reciprocal fall in fibrinogen

§        Alos get a prolonged APTT immediately after reperfusion secondary to release of a heparin-like substance

§        Peritoneal-venous shunts

§        DIC due to infusion of procoagulants from the ascetic fluid into the venous circulation

§        Limit by

§        Removal of ascetic fluid prior to shunt insertion

§        Temporarily occluding the shunt

§        Having the patient sit up





Renal disease and coagulopathy


Platelet vascular interactions are impaired

§        Guandinosuccinic acid accumulates in renal failure

§        Stimulates NO release – impaired platelet adhesion, aggregation and vascular reactivity

§        Severe anaemia – bleeding time is inversely proportional to the haematocrit

§        Lowered platelet counts and MPV



§        Dialysis

§        Accelarted dialysis schedules improve bleeding time

§        Correction of anaemia

§        Improve platelet function

§        DDAVP

§        Tachphylaxis, so can’t be used long-term regularly

§        Improve platelet-vascular interactions

§        Conjugated oestrogens

§        Longer half-life, thus better than DDAVP


Collagen disorders and Bleeding


Ehlers-danlos syndrome

§        Types I-X

§        Type IV

§        Most clinically important

§        Reduced type III collagen

§        Stabalises blood vessels and skin

§        COL3A1 gene on chromosome 2

§        Directs synthesis of type III procollagen

§        Thin skin with prominent venous pattern

§        Thin lips, prominent eyes and a sharp nose

§        Cigarette paper scarring

§        Small joint hyperextensibiltiy

§        Common cause of death is arterial rupture or dissection

§        Diagnosis is skin biopsy


Osteogenesis imperfecta

§        COL1A1 on choromosome 7

§        COL1A2 on chromosome 17

§        Change in type 1 procollagen

§        Brittle bones and blue sclerae


Marfan syndrome

§        Fibrillin gene (FBN1) on chromosome 15

§        AD

§        Skeletal deformities, ocular lens dislocation and CVS manifestations

§        Connective tisssues are often friable







Bleeding and cancer



§        Marrow suppression

§        Malignancy

§        Chemotherapy

§        Radiation

§        ITP

§        Malignancy/ treatment

§        MAHA

§        Gastric/ breast carcinoma

§        Therapy

§        Mitomycin C, cisplatin, bleomycin, CsA

§        No abnormality of vWF cleaving protease

§        Often fatal

§        Plasmapheresis much less effective



§        Mucous producing adenocarcinomas of the GI tract or lung

§        In children – disseminated neuroblastomas

§        Probably triggered by TF expression on malignant cells

§        Tumour cell lysis can expose blood to more procoagulant activity

§        Eg. Surgery, chemotherapy


Primary fibrinolysis

§        Prostate cancer

§        Malignant cells express plasminogen activator

§        tPA or urokinase

§        Occasionally APL

§        Express annexin II – accelerated tPA

§        Release proteases (elastin) which reduces fibrinogen

§        Also express TF

§        Produce IL-1, stimulates synthesis and expression of TF on endothelial cells and monocytes

§        ATRA promotes terminal differentiation and reduces TF expression

§        May be found concurrently with DIC


§        Bleeding and lymphoproliferative disorders


Acute lymphoblastic leukaemia

§        DIC in 5-10%

§        T-cell > B-cell

§        Increases after induction because of L-asparaginase

§        Inhibits protein synthesis and hence the formation of clotting factors (or their inhibitors) by the liver

§        Bleeding occurs few days after completion of course, and thrombosis may occur later because of reduced anti-thrombin levels

§        Predeliction for the CNS



§        ITP

§        Usually responds to standard treatment

§        Treatment of the CLL doesn’t always improve ITP

§        Aquired vWD

§        CLL, B-cell lymphoma or myeloma

§        Anti-von willebrand factor antibodies

§        Often IgG

§        Adsorption of plasma von willebrand factor onto the surfaces of neoplastic cells

§        DDAVP or VWF concentrates

§        IVIG/ plasma exchange/ splenectomy


Myeloma/ Amyloid

§        Risk factors for bleeding

§        IgA K PP

§        High protein levels

§        Increased viscosity

§        Thrombin inhibitors

§        Prolonged thrombin and reptilase time

§        Heparin-like ACs

§        Don’t prolong reptilase time

§        Correct with addition of protamine

§        Factor X deficiency

§        Adsorption of factor X onto amyloid fibrils

§        Chronic systemic fibrinolysis

§        Increased plasminogen activators and reduced PAI

§        Adsorption of alpha2 AP onto amylod fibrils




Avoid epidural anaesthesia


Von Willebrands disease

§        Type 1

§        Associated with substantial increase in vWF complex as pregnancy proceeds

§        Bleeding at time of delivery is uncommon

§        Bleeding can occur following abortion as levels don’t significantly increase until 2nd trimester

§        Document levels in 3rd trimester

§        Can treat with DDAVP +/- concentrate

§        Type 2b is associate with worsening thrombocytopenia

§        2a and 2b

§        Document levels at 36 weeks

§        Treat with concentrate

§        Type 3 likely to need treatment

§        Expect no rise, and document levels at 36 weeks

§        DDAVP

§        Concerns about fluid retention, inducing contractions


Platelet defects

§        Pseudo-vWD

§        Defect in GP1b receptor on platelets, results in increased platelet binding of normal vWF

§        Thrombocytopenia

§        Platelet count falls, as increased VWF in pregnancy binds more platelets

§        Treatment

§        Platelets NOT DDAVP or concentrate


Haemophilia A and B

§        Factor 8 levels rise during pregnancy

§        Factor 9 rises only slightly or remains constant

§        Replacement therapy should be considered if levels not risen before delivery



§        Factor V, XI and XIII don’t rise significantly during pregnancy

§        Dysfibrinogenaemic bleeding may worsen during pregnancy because of increased production of the abnormal molecule


Causes of thrombocytopenia in pregnancy

§        Immune

§        ITP

§        10% risk of baby having passively acquired thrombocytopenia

§        SLE

§        Evan’s

§        Thyrotxicosis

§        LPD

§        Gestational thrombocytopenia

§        5%

§        No history of ITP

§        No increased risk of neonatal thrombocytopenia

§        No special management

§        Plts <50, ITP is more likely

§        Infections

§        Drugs

§        Others

§        TTP

§        Preeclampsia/ eclampsia/ HELLP

§        Chronic hepatitis

§        DIC
massive blood transfusion

§        Bone marrow hypoplasia/ malignant disease

§        Megaloblastic anaemia


Post-partum aquired haemophilia

§        Weeks to a year or more after delivery

§        IgG


Congenital heart disease

§        Platelet dysfunction

§        Mild thrombocytopenia due to shortened survival

§        Mild defects in platelet aggregation

§        HMW vWF multimers reduced in acyanotic heart disease and severe pulmonary hypertension

§        Coagulation

§        PT and APTT frequently prolonged

§        Often corrects if amount of AC reduced to correct for the often elevated haematocrit

§        Reduced synthesis due to liver congestion

§        Clinical manifestations usually mild

§        Surgical bleeding is unpredictable

§        Severe hypoxia, increased risk of haemorrhage

§        Cardiac by-pass in neonates often causes marked haemodilution of clotting factors depending on what machine prepped with

§        Platelet function usually improves post-operatively

§        Suggesting causality either cardiac lesion, erythrocytosis or hypoxia


Cardiac surgery

§        Platelet dysfunction

§        Thrombocytopenia and platelet activation with granule discharge from bypass circuit

§        Hypothermia

§        Pre-op anti-platelet drugs

§        Heparin

§        Monitored by the ACT – protamine

§        Haemodilution, plts <50, hypothermia, aprotinin (due to kallikrein inhibition) all also prolong ACT

§        Protamine also an AC

§        Systemic fibrinolysis

§        Aprotinin now withdrawn due to renal failure

§        Tranexamic acid

§        reduce blood loss by 30-50%

§        Defective surgical haemostasis

§        Haemodilution

§        Rarely a problem in adults cf. children

§        Other problems

§        Topical bovine thrombin can be used

§        Antibodies to bovine thrombin or bovine factor V

§        Cross-react with human thrombin/ factor V

§        Bleeding several weeks later

§        Protamine toxicity

§        NPH insulin contains protamine

§        Can develop antibodies – IgG or IgE

§        Pulmonary hypertension, hypoxia and DIC on exposure during by-pass


Acquired Haemophilia

§        Autoantibody usually against factor VIII

§        A2, A3 or C2 domains

§        Rarely FV inhibitors – usually transient

§        0.2-1 per 1 million per year

§        Indirectly associated with death about 20% of the time

§        Aetiology

§        50% no underlying cause

§        10% pregnancy

§        40% assoc with AI disease, malignancy, drugs

§        Different bleeding pattern to congenital haemophilia – more soft tissue

§        Time and temperature dependant, so APTT may initially correct, but needs to be incubated for 1-2 hours at 37 C

§        Non-linear (complex) type 2 kinetics in contrast to congenital haemophila inhibitors which have 1st order kinetics (inactivation proportional to their concentration)

§        Rapid inactivation at first which then slows as the Ag:Ab complex dissociates or displays some FVIII activity

§        Plateau at measurable levels

§        Treatment of bleeding

§        DDAVP

§        Porcine FVIII

§        Cross reactivity and anamnesis in 15%

§        No longer commercially available

§        Activated prothrombin complex concentrates

§        FEIBA/ Autoplex

§        FEIBA is plasma derived

§        Recombinant VIIa

§        Binds to activated platelets and supports thrombin generation

§        Treatment of inhibitor

§        Extracorporeal removal

§        plasmapheresis

§        Long-term immunosupression

§        Steroids (30%), cyclophosphamide or combination (60-70%)

§        IVIG (30%) – likely only transient response

§        CsA esp effective in patients with SLE

§        Encouraging results with rituximab


Vitamin C deficiency

§        Prolonged bleeding time

§        APTT, PT, Platelet aggregation N

§        DD – collagen/ vascular defect