14.1 Haemophilias A, B, and C are deficiencies of FVIII, FIX, and FXI, respectively. Haemophilias A and B exhibit sex-linked inheritance and are almost exclusively found in males, whereas haemophilia C is autosomally inherited.
14.2 Reduction in platelet adhesion and reduced FVIII levels.
14.3 Hereditary bleeding disorders are inherited and tend to be due to abnormality in one component of haemostasis. Acquired disorders are secondary to primary pathologies and often affect multiple areas of haemostasis.
14.4 Intrinsic pathway leads to activation of FX via the contact pathway and intrinsic tenase complex. Extrinsic pathway leads to activation of FX via FVIIa and tissue factor. Common pathway begins with the FXa generated from either of the above which activates prothrombin to thrombin in order to generate fibrin from fibrinogen.
14.5 Thromboplastin contains tissue factor to begin the extrinsic pathway and phospholipid as a cofactor but no contact activator. Calcium ions are also added to facilitate phospholipid-dependent reactions. Clotting times are prolonged in the presence of reduced levels of factors II, V, VII, and/or X such as in hereditary deficiencies. Acquired deficiencies due to reduced production in liver disease or vitamin K deficiency, or consumption in DIC. Autoantibodies. Anticoagulant therapy such as warfarin or DTIs.
14.6 Contact activator begins the intrinsic pathway and phospholipid as a cofactor but no tissue factor. Calcium ions are also added to facilitate phospholipid-dependent reactions. Clotting times are prolonged in the presence of reduced levels of factors II, V, VIII, IX, X, XI, XII, PK, and/or HMWK such as in hereditary deficiencies. Acquired deficiencies due to reduced production in liver disease or vitamin K deficiency, or consumption in DIC. Autoantibodies. Anticoagulant therapy such as warfarin, heparin, or DTIs. Some forms of VWD may have low FVIII. Lupus anticoagulants.
14.7 TT and RT will detect fibrinogen abnormalities. Elevated TT (and APTT) accompanied by normal RT suggests the presence of heparin. Some dysfibrinogenaemias will exhibit a discrepancy between TT and RT.
14.8 Thrombin time, reptilase time, Clauss fibrinogen assay, prothrombin time-derived fibrinogen, immunological assays (e.g. ELISA).
14.9 If only APTT elevated, any deficiency will be in the intrinsic pathway. The patient is male with a severe bleed so sex-linked haemophilia A or B are the most likely causes; investigations would therefore begin with FVIII and FIX assays
14.10 Serial dilutions of patient plasma are added to equal volumes of FIX-deficient plasma, which makes the patient’s FIX rate-limiting. APTTs are performed on each mixture and the clotting times are proportional to the amount of FIX present. Results are plotted on log–log graph paper and assessed in relation to the results of a standard plasma.
14.11 Equal-volume mixing tests on PT or APTT can suggest the presence of an inhibitor if an initially abnormal result does not correct upon the addition of normal plasma. This concept can be extended to incorporate an incubation phase to detect time-dependent inhibitors. The Bethesda assay progressively dilutes the inhibitor to find the dilution factor that leaves 50% residual activity in a plasma originally containing 100% of the factor being inhibited (after a 2-hour incubation at 37o PC).
14.12 Functional assays assess the binding properties of VWF for ristocetin (via platelet gpIb), collagen, and FVIII. Immunological assays measure the total amount of VWF irrespective of function. Electrophoresis of multimer subunits characterizes structural abnormalities.
14.13 Glanzmann’s thrombasthenia is characterized by defects in the GPIIbIIIa complex, and Bernard–Soulier syndrome is characterized by defects in the GPIb–IX–V complex.
14.14 Hermansky–Pudlak and Chediak–Higashi syndromes are complex congenital disorders characterized by albinism and platelet dense-body deficiency. Primary dense-body disorder exists as a separate clinical entity. Grey platelet syndrome is a deficiency of a-granules. Paris–Trousseau syndrome is characterized by sub-populations of platelets with dysfunctional giant a-granules and micromegakaryocytes. Quebec disorder is characterized by increased levels of platelet urinary plasminogen activator (u-PA), which activates platelet plasminogen that subsequently degrades a-granule contents.
14.15 Systemic disorders such as renal failure, liver disease, and DIC. Haematological disorders such as chronic myeloproliferative disorders, acute myeloid leukaemia, myelodysplastic syndromes, and paraproteinaemias. Numerous drugs and foodstuffs.
14.16 Platelet count, histogram assessment, and peripheral blood morphology. Bleeding time, PFA-100 and Impact-R analysers, and thromboelastography.
14.17 Light-transmittance aggregometry involves placing stirred platelet-rich plasma in a light path. A panel of agonists are added to separate aliquots to initiate platelet aggregation, which allows more light to be transmitted as it progresses. Graphical printouts are generated showing specific aggregation patterns that vary between normality and the different disorders. Electrical-resistance methods involve platelets aggregating in response to agonists and adhering to wires that have a current passing through them. The greater the aggregation response, the greater the change in resistance.