Bleeding and Clotting Disorders PDF

Platelets, blood coagulation and haemostasis Bleeding and Thrombotic disorders Objectives Review the hemostatic response Describe the clinical and laboratory evaluation of bleeding disorders Outline the clinical features and laboratory features of some specific bleeding disorders Def...

Platelets, blood coagulation and haemostasis Bleeding and Thrombotic disorders Objectives Review the hemostatic response Describe the clinical and laboratory evaluation of bleeding disorders Outline the clinical features and laboratory features of some specific bleeding disorders Define thrombosis and thrombophilia Outline the pathogenesis of thrombosis Describe the clinical and laboratory evaluation of deep venous thrombosis and pulmonary embolism The normal hemostatic response It is a response to vessel wall injury. The five major components involved are: Vascular wall Platelets Coagulation factors Coagulation inhibitors Fibrinolytic proteins These carry out the processes of clotting, regulation of clotting and eventual fibrinolysis Central to healing and repair. Haemostatic response Vasoconstriction Immediate vasoconstriction of the injured vessel and reflex constriction of adjacent small arteries and arterioles slows blood flow to the area of injury. This vascular reaction prevents exsanguination. The reduced blood flow also allows activation of platelets and coagulation factors. Haemostatic response Platelet reactions (primary clot) Following a break in the endothelial lining, there is an initial adherence of platelets (via GP1a and GP1b receptors) to exposed connective tissue, mediated by VWF. Collagen exposure and release and activation of tissue factor produced at the site of injury cause the adherent platelets to release their granule contents. Released ADP causes platelets to swell and aggregate. Additional platelets from the circulating blood are drawn to the area of injury (platelet aggregation) forming a primary platelet plug which covers the exposed Primary haemostatic plug formation Haemostatic response Fibrin formation (secondary clot) Vascular injury initiates the coagulation cascade by releasing tissue factor (extrinsic cascade) Platelet aggregation and release reactions accelerate the coagulation process by providing abundant membrane phospholipid (intrinsic cascade). This results in generation of thrombin which converts soluble plasma fibrinogen into fibrin The fibrin component of stabilizes the loose primary platelet plug and after a few hours the entire haemostatic plug is transformed into a solid mass of crosslinked fibrin. Haemostatic response Physiological limitation of blood coagulation TFPI synthesized in endothelial cells inhibits Xa and VIIa and tissue factor. Antithrombin directly inactivates thrombin. Heparin cofactor II, also inhibits thrombin. α2‐Macroglobulins, α2‐antiplasmin, C1 esterase inhibitor and α1‐ antitrypsin also exert inhibitory effects. Protein C and Protein S are inhibitors of coagulation cofactors V and VIII. They destroy these factors thus preventing further thrombin generation. In addition, activated protein C enhances fibrinolysis. At the periphery of a damaged area of tissue, blood flow rapidly achieves dilution and dispersal of activated factors before fibrin formation has occurred. Haemostatic response Fibrinolysis Fibrinolysis (like coagulation) is a normal haemostatic response to vascular injury. Plasminogen is converted to plasmin by activators the most important of which is tissue plasminogen activator (TPA) from endothelial cells. Plasmin then digests fibrin to fibrin degradation products thus breaking up the clot. Tissue plasminogen activator is inactivated by plasminogen activator inhibitor (PAI). Circulating plasmin is inactivated by α2‐antiplasmin and α2‐ macroglobulin. Assessment of bleeding disorders Bleeding occurs when there is a disruption in blood vessel walls. In healthy individuals, if the endothelial defect is not too large, exposed subendothelial proteins interact with coagulation factors and platelets to form clots. Petechiae are the result of blood leakage from a small number of blood vessels. Bruising is when a hematoma forms under the skin as the result of vascular damage. History The age and sex of the patient should be considered when evaluating those with abnormal bruising and bleeding. Inherited bleeding disorders often manifest in infancy or early childhood. Women are more likely to report bleeding because of menses and childbirth, even in the absence of a bleeding disorder. The patient should be asked to describe the type of bleeding or bruising (i.e., epistaxis, menorrhagia, or hematomas) and the circumstances surrounding the bleeding (e.g., trauma, dental procedures, surgery). Severity can be assessed based on previous treatment with blood products or anti bleeding medical or surgical intervention. Family history is important for potential inherited bleeding disease Drug history Previous medical history – malignancy, infection, pregnancy loss, menstrual history, kidney and liver failure Physical examination Information about the origin of bleeding. Spontaneous hemarthroses, muscle hemorrhages, or retroperitoneal bleeding may indicate hemophilia Mucocutaneous bleeding (e.g., petechiae, epistaxis, gingival bleeding, gastrointestinal or genitourinary bleeding) suggests a platelet disorder. Hepatomegaly suggests liver failure, whereas splenomegaly may suggest underlying malignancy. Laboratory evaluation Blood count and blood film examination As thrombocytopenia is a common cause of abnormal bleeding, patients with suspected bleeding disorders should initially have a blood count including platelet count and blood film examination. Patient with thrombocytopenia may need bone marrow evaluation Screening tests of blood coagulation The prothrombin time (PT) measures factors VII, X, V, prothrombin and fibrinogen. The activated partial thromboplastin time (APTT) measures factors VIII, IX, XI and XII in addition to factors X, V, prothrombin and fibrinogen PT/INR APTT Thrombin time Other tests Specific factor assays Quantification of other proteins such as fibrinogen, VWF Platelet aggregometry measures the fall in light absorbance in plasma as platelets aggregate. PFA‐100 test measures platelet function PFA-100 Platelet aggregometry Bleeding disorders  Abnormal bleeding may result from: 1 Vascular disorders; 2 Thrombocytopenia; 3 Defective platelet function; or 4 Defective coagulation. The pattern of bleeding is relatively predictable depending on the aetiology. Vascular and platelet disorders tend to be associated with bleeding from mucous membranes and into the skin. In coagulation disorders the bleeding is often into joints or soft tissue Vascular bleeding disorders Group of conditions characterized by easy bruising and spontaneous bleeding from the small vessels. The underlying abnormality is either in the vessels themselves or in the perivascular connective tissues. Bleeding is mainly in the skin causing petechiae, ecchymoses or both. In some disorders there is also bleeding from mucous membranes. Tests of haemostasis are usually normal. Vascular defects may be inherited or acquired. Inherited vascular disorders Hereditary haemorrhagic telangiectasia is an uncommon disease is transmitted as an autosomal dominant trait. The genetic defect is usually in an endothelial protein such that they are fragile and cause bleeding seen as dilated microvascular swellings in the skin, mucous membranes and internal organs. Ehlers–Danlos syndromes is a hereditary collagen abnormality with purpura resulting from defective platelet adhesion, hyperextensibility of joints and hyperelastic friable skin. Patients may present with superficial bruising and purpura following minor trauma. Bleeding and poor wound healing after surgery may be a problem. Acquired vascular defects Simple easy bruising is a common benign disorder which occurs in otherwise healthy women, especially those of child‐bearing age. Senile purpura caused by atrophy of the supporting tissues of cutaneous blood vessels is seen mainly on dorsal aspects of the forearms and hands Purpura associated with infections may cause purpura. Scurvy. In vitamin C deficiency defective collagen may cause perifollicular petechiae, bruising and mucosal haemorrhage Steroid purpura. associated with long‐term steroid therapy or Cushing’s syndrome, is caused by defective vascular supportive tissue. Thrombocytopenia Abnormal bleeding associated with thrombocytopenia or abnormal platelet function is characterized by spontaneous skin purpura and mucosal haemorrhage and prolonged bleeding after trauma The main causes of thrombocytopenia are Failure of production Increased destruction Redistribution Failure of platelet production This is usually part of a generalized bone marrow failure Selective megakaryocyte depression may result from drug toxicity or viral infection. Rarely it is congenital. Increased destruction of platelets – Chronic idiopathic thrombocytopenic purpura (ITP) It is the most common cause of thrombocytopenia without anaemia or neutropenia. It is usually idiopathic but may be seen in association with other autoimmune diseases such as systemic lupus erythematosus (SLE). Platelet autoantibodies result in the premature removal of platelets from the circulation by macrophages of the reticuloendothelial system, especially the spleen The normal lifespan of a platelet is 10 days but in ITP this is reduced to a few hours. Total megakaryocyte mass and platelet turnover are increased Clinical features The onset is often insidious with petechial haemorrhage, easy bruising and, in women, menorrhagia. Mucosal bleeding (e.g. epistaxes or gum bleeding) occurs in severe cases Chronic ITP tends to relapse and remit spontaneously. Diagnosis The platelet count is usually 10–100 × 109/L. The haemoglobin concentration and white cell count are typically normal unless there is iron deficiency anaemia because of blood loss. The blood film shows reduced numbers of platelets, those present often being large. There are no morphological abnormalities in the other cell lines. The bone marrow shows normal or increased numbers of megakaryocytes. Acute idiopathic thrombocytopenic purpura This is most common in children. In approximately 75% of patients the episode follows vaccination or an infection such as chickenpox or infectious mononucleosis. Spontaneous remissions are usual but in 5–10% of cases the disease becomes chronic. The diagnosis is one of exclusion. Treatment is with steroids and/or intravenous immunoglobulin, especially if there is significant bleeding. Thrombocytopenia Thrombocytopenia is associated with many viral and protozoal infections Post transfusion purpura occurs approximately 10 days after a blood transfusion, and has been attributed to antibodies in the recipient developing against human platelet antigen‐1a (HPA‐1a) on the transfused platelets. Redistribution Increased splenic pooling Due to splenomegaly Massive transfusion syndrome Platelet count rapidly falls in blood stored for more than 24 hours. Patients transfused with massive amounts of stored blood, such as more than 10 units over a 24‐hour period, frequently show abnormal clotting and thrombocytopenia. Disorders of platelet function Disorders of platelet function are suspected in patients who show skin and mucosal haemorrhage despite a normal platelet count and normal levels of VWF. These disorders may be hereditary or acquired. Hereditary disorders Thrombasthenia (Glanzmann’s disease) - Autosomal recessive disorder which causes failure of primary platelet aggregation. Bernard–Soulier syndrome is autosomal recessive disease due to mutations in the GPIb gene, the platelets are larger than normal. There is defective adherence to exposed sub‐endothelial connective tissues. Acquired disorders Antiplatelet drugs Aspirin therapy is the most common cause of defective platelet function. It causes inhibition of cyclo‐oxygenase with impaired thromboxane A2 synthesis hence impairment of the release reaction and aggregation. Myeloproliferative and myelodysplastic disorders Intrinsic abnormalities of platelet function occur in many patients with essential thrombocythaemia, other myeloproliferative and myelodysplastic diseases. Uraemia This is associated with various abnormalities of platelet function. Coagulation disorders Hereditary coagulation disorders Hereditary deficiencies of each of the coagulation factors have been described. Haemophilia A (factor VIII deficiency), haemophilia B (Christmas disease, factor IX deficiency) and von Willebrand disease (VWD) are the most frequent; the others are rarer. Haemophilia A Haemophilia A is the most common of the hereditary clotting factor deficiencies. The inheritance is sex‐linked. The defect is an absence or low level of plasma factor VIII. Clinical features Infants may develop profuse post‐circumcision haemorrhage or joint and soft tissue bleeds and excessive bruising when they start to be active. Recurrent painful joint bleeding (haemarthroses) and muscle haematomas dominate the clinical course of severely affected patients and, if inadequately treated, lead to progressive joint deformity and disability Prolonged bleeding occurs after dental extractions. Spontaneous haematuria and gastrointestinal haemorrhage, sometimes with obstruction resulting from intramucosal bleeding, can also occur. Laboratory findings Activated partial thromboplastin time (APTT) is prolonged Factor VIII clotting assay show reduced levels. The platelet function and prothrombin time (PT) are normal. Factor IX deficiency (haemophilia B, Christmas disease) The inheritance and clinical features of factor IX deficiency (Christmas disease, haemophilia B) are identical to those of haemophilia A The incidence is one‐fifth that of haemophilia A. The principles of replacement therapy are similar to those of haemophilia A. Bleeding episodes are treated with high‐purity factor IX concentrates. Laboratory findings The following tests are abnormal: 1 APTT; 2 Factor IX clotting assay. As in haemophilia A, the Platelet function and PT tests are normal. Von Willebrand disease In this disorder there is either a reduced level or abnormal function of von Willebrand factor (VWF) resulting from a wide variety of mutations in different parts of the gene. VWF is produced in endothelial cells and megakaryocytes. It has two roles : It promotes platelet adhesion to subendothelium and each other at high shear rates and it is the carrier molecule for factor VIII, protecting it from premature destruction. This explains the reduced factor VIII levels found in VWD.. Clinical features vWD is the most common inherited bleeding disorder. Usually, the inheritance is autosomal dominant. The severity of the bleeding is highly variable Women are more badly affected than men. Typically, there is mucous membrane bleeding (e.g. epistaxes, menorrhagia), excessive blood loss from superficial cuts and abrasions, and operative and post‐ traumatic haemorrhage. Haemarthroses and muscle haematomas are rare, except in type 3 disease. Laboratory findings 1. The platelet function tests (PFA‐100) is abnormal. 2. Factor VIII levels are low. 3. The APTT prolonged. 4. VWF levels are low. 5. The platelet count is normal Acquired coagulation disorders Vitamin K deficiency Fat‐soluble vitamin K is obtained from green vegetables and bacterial synthesis in the gut. Deficiency may present in the newborn because Vitamin K‐ dependent factors are low at birth and fall further in breast‐fed infants in the first few days of life contributing to a deficiency which causes haemorrhage, usually on the second to fourth day of life In later life, deficiency of vitamin K is caused by an inadequate diet, malabsorption or inhibition of vitamin K by vitamin K antagonist drugs such as warfarin. Diagnosis Both PT and APTT are prolonged. There are low plasma levels of factors II, VII, IX and X. Liver disease Multiple haemostatic abnormalities contribute to a bleeding tendency. Biliary obstruction results in impaired absorption of vitamin K and therefore decreased synthesis of factors II, VII, IX and X. Functional abnormality of fibrinogen (dysfibrinogenaemia). Decreased thrombopoietin production from the liver contributes to thrombocytopenia. Hypersplenism associated with portal hypertension results in thrombocytopenia. Disseminated intravascular coagulation due to impaired removal of activated clotting factors and increased fibrinolytic activity. Disseminated intravascular coagulation Widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets Occurs as a result of many disorders that release procoagulant material into the circulation The main clinical presentation is with uncontrolled bleeding  Pathogenesis Causes: Tissue factor (TF) release into the circulation from tumour cells Upregulation of TF In response to proinflammatory cytokines (e.g. interleukin‐1, tumour necrosis factor, endotoxin). Entry of procoagulant material into the circulation by severe trauma, amniotic fluid embolism, premature separation of the placenta, mucin‐secreting adenocarcinomas, acute promyelocytic leukaemia, liver disease, severe falciparum malaria, transfusion reactions and snake bites. Endothelial damage and collagen exposure (e.g. Gram‐negative and meningococcal septicaemia, septic abortion, severe burns ). Pathogenesis Increased activity of thrombin overwhelms its normal rate of removal – increased fibrin formation. Fibrinolysis is also stimulated by thrombi and the release of split products interferes with fibrin polymerization. The combined action of thrombin and plasmin causes depletion of fibrinogen and all coagulation factors. Intravascular thrombin also causes widespread platelet aggregation in the vessels causing thrombocytopenia. Clinical features These are usually dominated by bleeding, particularly from venepuncture sites or wounds. There may be generalized bleeding in the gastrointestinal tract, the oropharynx, into the lungs, urogenital tract and in obstetric cases, vaginal bleeding may be particularly severe. Less frequently, microthrombi may cause skin lesions, renal failure, gangrene of the fingers or toes or cerebral ischaemia. Laboratory findings The platelet count is low. Fibrinogen concentration is low. The thrombin time is prolonged. High levels of fibrin degradation products such as D‐dimers are found in serum and urine. The PT and APTT are prolonged. Blood film examination In many patients there is a ‘microangiopathy’) and the red cells show prominent fragmentation because of damage caused when passing through fibrin strands in small vessels. Thrombosis : pathogenesis and diagnosis  Thrombi are solid masses or plugs formed in the circulation from blood constituents. Their clinical significance lies in the ischaemia that results from local vascular obstruction or distant embolization. Thrombi are involved in the pathogenesis of myocardial infarction, cerebrovascular disease, peripheral arterial disease, deep vein thrombosis (DVT) and pulmonary embolism (PE). The term thrombophilia is used to describe inherited or acquired disorders of the haemostatic mechanism that predispose to thrombosis. Arterial thrombosis: Pathogenesis Atherosclerosis of the arterial wall, plaque rupture and endothelial injury expose blood to subendothelial collagen and tissue factor. This initiates the formation of a platelet nidus on which platelets adhere and aggregate. As well as blocking arteries locally, emboli of platelets and fibrin may break away from the primary thrombus to occlude distal arteries. Risk factors for arterial thrombosis (atherosclerosis). Positive family history Cigarette smoking Male sex ECG abnormalities Hyperlipidaemia Elevated CRP, IL6, fibrinogen, Hypertension lipoprotein‐associated phospholipase A2 Diabetes mellitus Lupus anticoagulant Gout Collagen vascular diseases Polycythaemia Behçet’s disease Hyperhomocysteinaemia Venous thrombosis: Pathogenesis and risk factors Virchow’s triad suggests that there are three components that are important in thrombus formation: 1 Slowing down of blood flow; 2 Hypercoagulability of the blood; 3 Vessel wall damage. Hereditary disorders of haemostasis Approximately one third of patients who suffer deep vein thrombosis (DVT) or pulmonary embolus (PE) have an identifiable heritable risk factor. Factor V-Leiden Protein C deficiency Protein S deficiency Antithrombin deficiency Hyperhomocysteinemia Acquired risk factors Hospital admission Post operative Pregnancy and post partum Immobility malignancy Chronic inflammation Hematological disease such as myeloproliferative disease Oestrogen therapy Venous thrombosis Deep vein thrombosis Clinical suspicion DVT is suspected in patients with a painful swollen limb. It is more common in those with previous DVT or superficial venous thrombosis, cancer or recent confinement to bed In the leg, unilateral thigh or calf swelling or tenderness, pitting oedema and the presence of collateral superficial non‐varicose veins are important signs. Plasma D‐dimer concentration The concentration of these fibrin breakdown products is raised when there is a fresh thrombosis. A negative result in emergency departments can be used to exclude DVT or PE. D‐dimer elevation occurs in cancer, inflammation, after surgery or trauma False positive. Diagnosis of venous thrombosis Compression ultrasound This is a reliable and practical method for patients with first suspicion of DVT in the legs and other sites It can be combined with spectral, colour or power Doppler (duplex) scanning which improves accuracy by focusing on individual veins. It does not distinguish between acute and chronic thrombi. Pulmonary embolus This usually present with shortness of breath and there may be pleuritic chest pain. PE should be particularly suspected in patients with signs or previous history of DVT, immobilization for more than 2 days or recent (