2. Haemostasis and Haemorrhagic disorders.pptx

Haemostasis and Haemorrhagic disorders Dr. B. MULENGA 2024  Haemostasis Maintain blood in a fluid, clot-free state Process by which blood clots form at sites of vascular injury A balance between blood clotting and bleeding If deranged; a. Haemor...

Haemostasis and Haemorrhagic disorders Dr. B. MULENGA 2024  Haemostasis Maintain blood in a fluid, clot-free state Process by which blood clots form at sites of vascular injury A balance between blood clotting and bleeding If deranged; a. Haemorrhagic disorders (excessive bleeding) b. Thrombotic disorders (Excessive clot formation) Steps in haemostasis Vasoconstriction Primary haemostasis Secondary haemostasis Thrombus and antithrombotic events  Vasoconstriction Immediate response Mediated by; Reflex neurogenic mechanisms Endothelin (Endothelia derived vasoconstrictor) Transient effects Short lived  Primary Haemostasis Formation of a platelet plug Once endothelium is disrupted, pro-coagulant factors are exposed such as; von-Willebrand factor (vWF) Collagen These factors activate platelets The activated platelets change from small rounded discs to flat plates with spiky protrusions and start releasing factors that recruit other platelets This results in the formation of a platelet plug  Secondary Haemostasis Involves deposition of fibrin Mediated by tissue factor (TF), released from subendothelial cells, smooth muscle cells and fibroblasts This tissue factor is exposed after vascular injury It activates factor VII setting in motion what is called coagulation cascade The end results is the activation of thrombin Thrombin then cleaves circulating fibrinogen into insoluble fibrin Fibrin creates a meshwork that activates platelets and acts as a stabilizer to the platelet plug formed in primary haemostasis Clot stabilization and resorption The platelet plug and insoluble fibrin undergoes further contraction to form a permanent plug Counter-regulatory mechanism mediated by tissue plasminogen activator (t-PA) are set into motion to limit further clotting at the site of injury This eventually leads to clot resorption and tissue repair  Role of endothelial cells Endothelial cells are central to haemostasis They maintain the balance between thrombosis and antithrombosis, this determines whether the thrombus is formed, propagate or dissolute Normal endothelial cells are antithrombotic They produce anticoagulants that prevent platelet aggregation, coagulation and promote fibrinolysis However, after injury or activation, endothelial cells become prothrombotic Factors that activate endothelial cells include; Trauma Microbial agents Pro-inflammatory mediators Haemodynamic forces Exogenous toxins like smoking (tar)  The role of platelets Come from megakaryocytes in the bone marrow Round disc shapes, with α-Granules and Dense (or δ) granules Activated by collagens and vWF  Sequence of platelet activation 1. Platelet adhesion a. facilitated by Gp1a/IIa that binds collagen 2. Platelets rapidly change shape a. Glycoprotein IIb/IIIa binds fibrinogen b. Negatively charged phospholipids binds calcium ions 3. Secretion (release reaction) of granule contents a. Mediated by thrombin and ADP. Binds to protease-activated receptor-1 (PAR-1), b. Produce thromboxane A2 a potent aggregator of platelets (principle action of aspirin) 4. Platelet aggregation a. Due to Glycoprotein IIb/IIIa that forms a reversible plug b. Aggregates of cells include Platelets, red blood cells and leukocytes  Coagulation cascade A major component of secondary haemostasis A series of enzymatic reactions that leads to formation of thrombin It can be likened to “relay” in athletics It consists of; Enzymes (activated coagulation factors) Substrates (inactive proenzyme form of a coagulation factor) Cofactors (a reaction accelerator) Some reactions depend on calcium ions Vitamin K acts as a cofactor in some reactions (II, VII, IX and I) Its divided into extrinsic and intrinsic (based on laboratory experiments) Clotting in vessels TF = Tissue factor VII = Factor seven VIIa = Factor seven active IX = Factor nine IXa = Factor nine active VIIIa = Factor eight active X = Factor ten Clotting in the laboratory Intrinsic pathway ( Factors above 7) Extrinsic pathway (Factor 7 only) Common pathway (Factors of 10, X, V, II and I)  Clinical application of the coagulation cascade Prothrombin time (PT) assay assesses the function of the proteins in the extrinsic pathway (factors VII, X, V, II [prothrombin], and fibrinogen). Tissue factor is added to blood together with calcium ions and phospholipids Partial thromboplastin time (PTT) assay screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen) Ground glass (negatively charged substance) is added to blood together with calcium ions and phospholipids  Importance of thrombin 1. Converts fibrinogen into fibrin 2. Activates factor XIII that helps in cross-linking with fibrin 3. Platelet activation 4. Pro-inflammatory effects 5. Procoagulant ( this prevents clots from extending beyond the site of injury)  Factors That Limit Coagulation 1. Simple dilution 2. Absence of negatively charged phospholipids beyond the injured site 3. Factors expressed by adjacent intact endothelium (Most important) a. Plasmin, it breaks down fibrin into dimers (so called D-dimers) b. Tissue thromboplastin (t-PA), a principle activator of plasmin  Antithrombotic role of endothelium 1. Platelet inhibitory effects Shields platelets from activators such as vWF and collagen 2. Anticoagulant effects Produce anticoagulant factors such as; Thrombomodulin, endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor 3. Fibrinolytic effects t-PA that activates plasmin.  Haemorrhagic disorders 1. Defects of primary haemostasis (platelet defects or von Willebrand disease) a. Present with petechiae (1 – 2mm) b. Purpura (>3mm) c. Epistaxis (nose bleeds) d. Gastrointestinal bleeding e. Excessive menstruation (menorrhagia) f. Intracerebral haemorrhage (most feared) 2. Defects of secondary haemostasis (coagulation factor defects) Often presents with deep tissue bleeding such as; Muscle or joint Bleeding into joints know as haemarthrosis is characteristic of haemophilia Also may present with Intracerebral haemorrhage 3. Generalized defects involving small vessels Purpura Ecchymosis (simply bruise) are 1-2 cm in size When palpable these are called haematomas Examples of conditions include vasculitis, vascular amyloidosis, scurvy Petechiae and Intracerebral haemorrhage Disseminated Intravascular Coagulation (DIC)  Disseminated Intravascular Coagulation (DIC) Disseminated Intravascular Coagulation (DIC) Acute, subacute, or chronic thrombohemorrhagic disorder Characterized by excessive activation of coagulation and formation of thrombi in the microvasculature It occurs as a secondary complication of many disorders, sometimes localised to a specific organ or tissue DIC can present with signs and symptoms relating to tissue hypoxia and infarction caused by microthrombi, haemorrhage due to depletion of factors required for haemostasis and activation of fibrinolytic mechanisms, or both  Mechanisms Triggering DIC Release of Endothelial Injury Role of TNF Procoagulants Injuries that cause TNF induces Placenta in endothelial cell endothelial cells to obstetric necrosis expose express tissue factor complications Tissues injured by Tissue factor, on their cell surfaces trauma or burns. vWF and and to decrease the Mucus released collagen, leading expression of from certain to the activation of thrombomodulin, adenocarcinomas platelets and the tilting the checks and may also act as a coagulation balances that govern procoagulant by pathway. haemostasis towards directly activating coagulation. factor X. Common Associations and Triggers of DIC Obstetric Complications Procoagulants derived from the placenta, dead retained foetus, or amniotic fluid may enter the circulation. Malignant Neoplasms Acute promyelocytic leukaemia and adenocarcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC. Sepsis Endotoxins can inhibit endothelial expression of thrombomodulin directly or indirectly by stimulating immune cells to make TNF, and also can activate factor XII. Major Trauma In massive trauma, extensive surgery, and severe burns, the major trigger is the release of procoagulants such as tissue factor.  Consequences of DIC Widespread Fibrin Deposition This leads to ischaemia of the more severely affected or more vulnerable organs and a microangiopathic haemolytic anaemia, which results from the fragmentation of red cells as they squeeze through the narrowed microvasculature. Consumption of Platelets and Clotting Factors This leads to a haemorrhagic diathesis. Plasmin not only cleaves fibrin, but it also digests factors V and VIII, reducing their concentration further. Activation of Plasminogen This also contributes to the haemorrhagic diathesis. In addition, fibrin degradation products resulting from fibrinolysis inhibit platelet aggregation, fibrin polymerisation, and thrombin.  Morphology of DIC Organ Morphological change Brain Microinfarcts with haemorrhage Heart Thrombi in small vessels Lungs Fibrin thrombi in alveolar capillaries, pulmonary oedema, hyaline membranes Kidney Glomerular thrombi, microinfarcts, possible cortical necrosis Adrenals Fibrin thrombi, possible massive haemorrhage (Waterhouse-Friderichsen syndrome) Spleen and Thrombi in small vessels Liver  Clinical Features of DIC Onset The onset of DIC may be fulminant, as in sepsis or amniotic fluid embolism, or insidious and chronic, as in cases of carcinomatosis or retention of a dead foetus. Common Presentations Clinical presentations can include microangiopathic haemolytic anaemia; dyspnoea, cyanosis, and respiratory failure; convulsions and coma; oliguria and acute renal failure; and sudden or progressive circulatory failure and shock. Acute vs Chronic DIC Acute DIC, associated with obstetric complications or major trauma, is dominated by a bleeding diathesis. Chronic DIC, such as occurs in cancer patients, tends to present with thrombotic  Diagnosis of DIC Diagnosis is based on clinical observation and laboratory studies Including measurement of fibrinogen levels, platelets, PT and PTT, and fibrin degradation products, particularly D-dimers Prognosis and Treatment of DIC Prognosis The prognosis is highly variable and largely depends on the Underlying disorder Treatment Approach The only definitive treatment is to remove or treat the inciting cause. Management requires meticulous maneuvering between the Scylla of thrombosis and the Charybdis of bleeding diathesis. Controversial Interventions Administration of anticoagulants or procoagulants has been advocated in specific settings, but not without controversy.