Week 12

• Thrombosis

  Solid masses formed in the circulation from blood constituents, resulting in local vascular obstruction or distant embolization
• Pathogenesis of thrombosis

  • Myocardial infarction (MI)
  • Cerebrovascular disease (CVA)
  • Peripheral arterial disease (PVD)
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
• Thrombosis is more common with increasing age and associated with risk factors such as pregnancy or surgery
• Virchow's Triad

  Three components important in thrombus formation: (1) Slowing of blood flow (stasis), (2) Increased coagulability of the blood, (3) Vessel wall injury
• Arterial thrombosis

  • Pathogenesis: atherosclerosis of the arterial wall, plaque rupture and endothelial injury
  • Significant morbidity and mortality
• Ischaemic heart disease (IHD) is the leading cause of death worldwide, most common cause of death in men in UK (14.2%)
• Cerebrovascular disease is the third most common cause of death in women (7.5%) and fifth most common cause of death in men (5.6%)
• Venous thrombosis

  • Pathogenesis: increased systemic coagulability and stasis
  • Risk factors: hereditary vs acquired
• Approximately 1/3 of patients with DVT/PE have an identifiable heritable risk factor, but gene-environment interaction is crucial
• Venous thromboembolism (VTE)

  DVT + PE
• Annual incidence of VTE: 110-130 per 100,000 population, slightly more common in men than women
• Mortality of VTE: 1-5%, morbidity significant including post thrombotic syndrome and 30% recurrence within 10 years
• Deep vein thrombosis (DVT)


  • Unilateral thigh or calf swelling, pitting oedema, presence of collateral superficial non-varicose veins
  • Diagnosis: plasma D-dimers raised, compression Doppler ultrasound
• DVT algorithm

  1. Clinical probability score

  2. D-dimer

  3. Doppler US
• Pulmonary embolus (PE)

  • Presentation: shortness of breath, pleuritic chest pain
  • Diagnosis: CXR often normal, plasma D-dimers raised, ventilation perfusion (VQ) scan, CT pulmonary angiogram
• Thrombophilia

  Inherited or acquired disorders of the haemostatic system that predispose to thrombosis
• Hereditary risk factors for VTE

  • Factor V Leiden
  • Antithrombin deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Prothrombin G20210A variant
  • Dysfibrinogenaemia
  • Non-O ABO Blood group
  • DVT in close relative
• Factor V Leiden

  • Heterozygous state: 5-8x increased risk of VTE, only 10% will develop thrombosis
  • Homozygous state: 30-100x increased risk of VTE
  • Incidence in patients with VTE ~20-40%
• Factor V Leiden

  • Most common inherited cause of increased risk of venous thrombosis
  • Genetic polymorphism in Factor V gene
  • Less susceptible to cleavage by APC
• Antithrombin deficiency

  • Autosomal dominant
  • Variety of genetic lesions
  • Heterozygotes have marked tendency to venous thrombosis with first events in early adulthood
  • Arterial thrombi may occur
  • Antithrombin concentrates available
  • Occasionally used to prevent thrombosis during surgery or childbirth
  • Lifelong anticoagulation after first VTE
• Protein C deficiency

  • Autosomal dominant with variable penetrance
  • Heterozygotes have protein C levels 50% of normal
  • Homozygous deficiency: presents with severe DIC or purpura fulminans (dermal vessel thrombosis) in infancy
  • May develop skin necrosis on starting warfarin due to dermal vessel occlusion
  • Due to further reduction in protein C levels in the first day or two of therapy
• Protein S deficiency

  • Cofactor for protein C
  • Clinical features as for protein C deficiency
• Prothrombin allele G20210A

  • Point mutation in the prothrombin gene
  • Prevalence 2-3%
  • Increased plasma prothrombin levels
  • Increased thrombotic risk by 5x
• Hereditary or acquired risk factors for VTE

  • Raised plasma levels of factor VIII
  • Raised plasma levels of fibrinogen
  • Raised plasma levels of homocysteine
• Acquired risk factors for VTE

  • Acutely ill hospitalised patient
  • Pregnancy
  • Surgery
  • Major trauma
  • Malignancy
  • Pelvic obstruction
  • Age
  • Obesity
  • Stroke
  • Dehydration
  • Oestrogen therapy
  • Antiphospholipid syndrome
  • Myeloproliferative disorder
  • Heparin-induced thrombocytopenia
  • Hyperviscosity
  • Nephrotic syndrome
  • PNH
  • Behcets
• Hospital-acquired thrombosis occurs within 90 days of hospitalisation and causes ~50% of DVT/PE
• National strategy to reduce incidence of hospital-acquired thrombosis via universal patient risk assessment
• Oestrogen therapy

  • Increased plasma levels of II, VII, VIII, IX and X
  • Decreased antithrombin and TPA
  • Oral contraceptives: 5x increased risk VTE compared to non-use, dependent on dose of oestrogen
  • HRT: 2-5x increased risk of VTE
• Antiphospholipid syndrome

  Occurrence of venous and arterial thrombosis and/or recurrent miscarriage in association with laboratory evidence of persistent antiphospholipid antibody
• Antiphospholipid antibodies

  • Lupus anticoagulant
  • Anticardiolipin
  • b2-GPI-1 (glycoprotein 1)
• Antiphospholipid antibodies

  • Prolong APTT
  • Does not correct with 50:50 mix with normal plasma (ie evidence of inhibitor)
  • Confirmation of phospholipid-dependent nature of the inhibitor
  • DRVVT (dilute Russell's viper venom test)
  • Persistence confirmed in 2 samples at least 6 weeks apart
• Testing for heritable thrombophilia is not indicated in unselected patients presenting with VTE
• Testing for heritable thrombophilia may be useful in selected patients to determine recurrence risk
• When is testing for heritable thrombophilia indicated?

  • VTE under 40 years
  • More than 2 other symptomatic family members
• Investigations

  • FBC and ESR
  • Blood film (myeloproliferative disorder, leucoerythroblastic)
  • Clotting tests (PT, APTT, TT) with mixing studies
  • Anticardiolipin and anti-b2-GPI antibodies
  • Fibrinogen assay
  • DNA analysis (FV Leiden, PT G20210A)
  • Antithrombin, protein C and protein S (immunological and functional assays)
  • Plasma homocysteine
• Blood transfusion medicine


  The study of the practice of transferring blood or blood components from one person (the donor) to another (the recipient)
• Objectives of the study material

  • History of blood transfusion medicine
  • Blood groups and frequencies in different ethnic groups
  • Antibodies and antigens and relevance to transfusion
  • Blood collection and processing
  • Compatibility testing, antiglobulin test, ensuring patient safety
  • Complications of blood transfusion
  • Investigation of patient with suspected transfusion reaction
• Although some successes, blood transfusion fell into disrepute as deaths were common
• Blood groups first identified by Karl Landsteiner (A,B,O system)


  1901
• Storage was also a problem, anticoagulant and dextrose were added to prolong shelf life