Coagulation Disorders PDF

Bleeding disorders Coagulation disorders Hyperemia and Congestion Ø Hyperemia: Active accumulation of blood within vessels, such as would occur in vasodilation due to acute inflammation. Ø Congestion: Passive accumulation of blood within vessels, such as would occur in the lungs due to left-sided he...

Bleeding disorders Coagulation disorders Hyperemia and Congestion Ø Hyperemia: Active accumulation of blood within vessels, such as would occur in vasodilation due to acute inflammation. Ø Congestion: Passive accumulation of blood within vessels, such as would occur in the lungs due to left-sided heart failure, or in the liver and extremities due to right-sided heart failure. Ø Acute passive congestion: Passive congestion that developed recently. PASG 61310 Pathophysiology I L27 April 4th, Spring 2024 Ithaca College, Physician Assistant Program Ø Chronic passive congestion: Passive congestion that has been occurring over time and is often Dr. Elena Mueller, PhD Ø Hyperemia and acute passive congestion: Blood vessels are dilated by red blood cells; to associated with hemosiderin-laden macrophages and organ damage. Morphology of hyperemia and congestion differentiate the two would require knowledge of the scenario in which it is occurring. Ø Chronic passive congestion: A condition due to multiple episodes of acute passive congestion. Red blood cells break down, leaving hemosiderin and stimulate mild inflammation, which results in scarring. Chronic passive congestion of the lung o Cause: Left-sided heart failure, which causes blood to back up into the lungs because the left ventricle is not pumping the blood out as quickly or as efficiently as it should. o Gross morphology of chronic passive congestion of the lung: Darkly pigmented, heavy and firm lungs. o Microscopic morphology of chronic passive congestion of the lung: Hemosiderin in macrophages (“heart failure cells”) and fibrosis of the alveolar septae Arrows point to hemosiderin-laden macrophages, also called “heart-failure cells”. Chronic passive congestion of the liver o Cause: Right-sided heart failure, which causes blood to back up into the liver because the right ventricle is not pumping the blood out as quickly or as efficiently as it should. o Mechanism: In this condition, passive congestion of the blood with sinusoidal dilation is associated with a component of hypoxic injury. The sinusoidal dilation and hypoxic injury lead to atrophy and sometimes necrosis of the centrilobular hepatocytes. o Gross morphology: Nutmeg liver (shrunken and congested centrilobular areas with raised, tan portal areas). o Microscopic morphology: Atrophy of the centrilobular hepatocytes associated with sinusoidal dilation. Fibrosis may be present around the central veins. In cases of severe heart failure or shock caused by other conditions, the centrilobular hepatocytes are frankly necrotic. Hemorrhage Basic description: Leakage of blood from vessels. Types of hemorrhage 1.Petechiae 1. Gross morphology: Pinpoint hemorrhages. 2. Causes: Include platelet dysfunction and increased vascular pressure. 2.Purpura Nutmeg 1. Gross morphology: Larger than petechiae and usually raised. 2. Causes: Commonly associated with vasculitis. 3.Ecchymoses 1. Gross morphology: Larger than purpura (> 1.0 cm). 2. Causes: Trauma. Hemorrhage Hematoma: A space-occupying hemorrhage. Hemothorax, hemopericardium, and hemoperitoneum: Hemorrhage within the pleural cavity, the pericardial sac, or the peritoneal cavity, respectively Complications of hemorrhage o the location of the hemorrhage is important. o a cut in the skin that causes 250 mL of blood loss is usually not clinically significant o the average blood donation is about 450 mL, o a 5-mL hemorrhage in the brainstem can be fatal. o Loss of 40% or more of blood volume, or about 2000 mL, is fatal Hemostasis and Thrombosis Ø Basic description of hemostasis: Physiologic coagulation of blood with the purpose of preventing bleeding. Ø Basic description of thrombosis: Pathologic coagulation of blood resulting in the formation of a solid mass within a chamber of the heart or within a blood vessel. Thrombus Factors predisposing to thrombus formation (Virchow triad) Ø Stasis of blood (e.g., due to congestive heart failure, obesity, immobilization). Stasis is a particularly common predisposing condition in patients who develop venous thrombi. Ø Hypercoagulability: Hypercoagulable states may contribute to the development of thrombi in any location, and include hereditary conditions as well as various acquired states. Ø Endothelial damage: Endothelial damage plays a major role in many arterial thrombi. Thrombus Thrombus Hereditary conditions predisposing to thrombosis (primary hypercoagulable states) Acquired states predisposing to thrombosis (secondary hypercoagulable states) o Myocardial infarct o tissue damage (e.g., surgery, trauma, burns) o cancer o prosthetic cardiac valves o disseminated intravascular coagulation (DIC) o heparin-induced thrombocytopenia o anti-phospholipid antibody syndrome. Ø Factor V Leiden mutation: A mutation in the factor V gene removes the cleavage site for protein C from factor V; therefore, protein C is no longer able to cleave activated factor V. The incidence of factor V Leiden mutations is 2–15% of the Caucasian population. Ø Prothrombin gene mutation: Causes an elevated level of prothrombin. Patients with the prothrombin gene mutation have a threefold risk of having venous thromboses. The incidence is 1–2% of the general population. Thrombus Embolus Ø An embolus is a substance that forms within or enters the vascular system at one site and is carried through the blood stream to another area of the body, where it lodges in a blood vessel and produces its effects (usually infarcts) Complications of thrombi: Occlusion of the blood vessel, which leads to ischemia. Ischemia causes cell injury and cell death (necrosis). The region of necrotic cells is referred to as an infarct. Platelets Ø Platelets normally circulate freely, suspended in plasma, in an unactivated state. Ø The roles of platelets are to (1) contribute to regulation of blood flow into a damaged site by induction of vasoconstriction (vasospasm); (2) initiate platelet–platelet interactions (adhesion and aggregation) and attachment to injured endothelium, resulting in formation of a platelet plug to stop further bleeding; (3) release granules that activate the coagulation (or clotting) cascade to stabilize the platelet plug; and (4) initiate repair processes, including clot retraction and clot dissolution (fibrinolysis) and release of growth factors. Ø If a thrombus breaks free from where it forms and goes to another part of the body, it becomes a thromboembolus Ø Substances besides thrombi, such as cardiac valvular vegetations, foreign bodies, fat, and air, can also embolize Platelets Ø The normal platelet count ranges from 150,000 to 400,000/mm3. Ø Thrombocytopenia (abnormally low numbers of platelets) develops if the platelet count drops below 100,000/mm3, and an individual may experience longer than normal clotting times. Ø Spontaneous major bleeding episodes do not generally occur unless the platelet count falls below 20,000/mm3. Ø If platelet numbers are elevated (thrombocytosis), the risk for spontaneous blood clots (thrombosis), stroke, or heart attack is increased. Platelet Adhesion, Activation, and Aggregation Normal hemostasis. Step 1 After vascular injury, neurohumoral factors induce transient vasoconstriction to limit blood flow to the affected site. 1. Endothelial injury exposes the underlying basement membrane ECM; platelets adhere to the ECM primarily through the binding of platelet GpIb receptors to VWF. 2. Adhesion leads to platelet activation, an event associated with secretion of platelet granule contents, including calcium (a cofactor for several coagulation proteins) and ADP (a mediator of further platelet activation); dramatic changes in shape and membrane composition; and activation of GpIIb/IIIa receptors. 3. The GpIIb/IIIa receptors on activated platelets form bridging cross-links with fibrinogen, leading to platelet aggregation. 4. Concomitant activation of thrombin promotes fibrin deposition, cementing the platelet plug in place. Normal hemostasis. Step 2 o Platelets bind via glycoprotein Ib (GpIb) receptors to von Willebrand factor (vWF) on exposed extracellular matrix (ECM) and are activated, undergoing a shape change and granule release. o Shape change from smooth discs to spiky “sea urchins” with greatly increased surface area. o Released adenosine diphosphate (ADP) and thromboxane A2(TxA2) induce additional platelet aggregation through platelet GpIIbIIIa receptor binding to fibrinogen, and form the primary hemostatic plug. o Shape change leads to translocation of phosphatidylserine to the membrane surface. It can bind calcium and serves as nucleation site for the assembly of coagulation factor complexes Normal hemostasis. Step 3 Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug Normal hemostasis. Step 4 Coagulation Factors Coagulation occurs via the sequential enzymatic conversion of a cascade of circulating and locally synthesized proteins. o Counterregulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a fibrinolytic product) and thrombomodulin, confine the hemostatic process to the site of injury. Tissue factor elaborated at sites of injury is the most important initiator of the coagulation cascade in vivo. At the final stage of coagulation, thrombin converts fibrinogen into insoluble fibrin that contributes to formation of the definitive hemostatic plug. Coagulation normally is restricted to sites of vascular injury by: q Limiting enzymatic activation to phospholipid surfaces provided by activated platelets or endothelium q Circulating inhibitors of coagulation factors, such as antithrombin III, whose activity is augmented by heparin-like molecules expressed on endothelial cells q Expression of thrombomodulin on normal endothelial cells, which binds thrombin and converts it to an anticoagulant q Activation of fibrinolytic pathways (e.g., by association of t-PA with fibrin) The Fibrinolytic System o Fibrinolysis is initiated by the binding of plasminogen to fibrin. o Although tissue plasminogen activator (t-PA) initiates intravascular fibrinolysis, urokinase plasminogen activator (u-PA) is the major activator of fibrinolysis in tissue (extravascular). o Plasmin digests the fibrin into smaller soluble pieces (fibrin degradation products). o u-PAR, Urokinase-like plasminogen activator receptor. o Platelet adhesion is mediated largely via interactions between the platelet surface receptor glycoprotein Ib (GpIb) and vWF in the subendothelial matrix. o Platelets also adhere to exposed collagen via the platelet collagen receptor Gp1a/IIa. Genetic deficiencies of vWF (von Willebrand disease) or GpIb (Bernard-Soulier syndrome) result in bleeding disorders von Willebrand factor (vWF) Ø Plasma contains a large, elongated protein called von Willebrand factor (vWF) that forms multimeric polymers with molecular masses as high as 15 million Daltons. Ø vWF binds to and transports factor VIII, the protein deficient in patients with classic hemophilia. Ø In addition, vWF fulfills a vital role in the formation of the primary platelet plug. Ø It has binding sites for collagen as well as for a glycoprotein complex on the surface of platelets, GPIbIX-V (referred to simply as the GPIb complex). Ø Under high shear stresses, such as occur within flowing blood, vWF “unwinds” to an extended conformation in which it can bind to both platelet GPIb complexes and to collagen exposed by damage to the blood vessel. Ø Thus, vWF is a kind of molecular “glue” that allows platelets to adhere to injured vessel walls. The coagulation cascade in the laboratory and in vivo Platelet activation. A) Dramatic change in platelet morphology following activation. B) Molecules on the surface of platelets that are either turned on or exposed upon activation and the substances released from activated platelets. Schematic illustration of the conversion of factor X to factor Xa, which in turn converts factor II (prothrombin) to factor IIa (thrombin). The initial reaction complex consists of a proteolytic enzyme (factor IXa), a substrate (factor X), and a reaction accelerator (factor VIIIa), all assembled on a platelet phospholipid surface. Calcium ions hold the assembled components together and are essential for the reaction. Activated factor Xa becomes the protease for the second adjacent complex in the coagulation cascade, converting prothrombin substrate (II) to thrombin (IIa) using factor Va as the reaction accelerator. The coagulation cascade in the laboratory and in vivo. (A) Clotting is initiated in the laboratory by adding phospholipids, calcium, and either a negatively charged substance such as glass beads (intrinsic pathway) or a source of tissue factor (extrinsic pathway). factor II (prothrombin) factor IIa (thrombin) (B) In vivo, tissue factor is the major initiator of coagulation, which is amplified by feedback loops involving thrombin (dotted lines). § The red polypeptides are inactive factors, the dark green polypeptides are active factors, and the light green polypeptides correspond to cofactors (reaction accelerators). § Factors marked with an asterisk (*) are vitamin K dependent as are protein C and S (not depicted). § Warfarin acts as an anticoagulant by inhibiting the γ-carboxylation of the vitamin K– dependent coagulation factors. § Vitamin K is an essential cofactor for the synthesis of all of these vitamin K–dependent clotting factors. reaction accelerator (factor VIIIa) Va: the reaction accelerator Based on assays performed in clinical laboratories, the coagulation cascade can be divided into the extrinsic and intrinsic pathways PTT assay The blood coagulation cascade in vitro. A fibrin clot can be formed by activation of either the intrinsic or extrinsic pathway. In the test tube, surface contacts trigger the intrinsic pathway. Key: diamonds = zymogens; circles = active enzymes and cofactors; pink rectangles = pro-cofactors; green rectangles = bimolecular complexes; F, fibrin; FG, fibrinogen; HMWK, high-molecular-weight kininogen; PT, prothrombin; T, thrombin; TF, tissue factor. Based on the effects of various factor deficiencies in humans, it is believed that, in vivo, o factor VIIa/tissue factor complex is the most important activator of factor IX and that o factor IXa/factor VIIIa complex is the most important activator of factor X PT assay Platelet function analysis (PFA) measures the ability of platelets to activate and aggregate. It also tests the function of vWF to assist platelet adhesion. Ø The prothrombin time (PT) assay assesses the function of the proteins in the extrinsic pathway (factors VII, X, V, II [prothrombin], and fibrinogen). In brief, tissue factor, phospholipids, and calcium are added to plasma, and the time for a fibrin clot to form is recorded. Ø The 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). In this assay, clotting of plasma is initiated by the addition of negatively charged particles (e.g., ground glass) that activate factor XII (Hageman factor) together with phospholipids and calcium, and the time to fibrin clot formation is recorded. The fibrinolytic system § Deficiencies of factors V, VII, VIII, IX, and X are associated with moderate to severe bleeding disorders § Prothrombin deficiency is likely incompatible with life. § In contrast, factor XI deficiency is only associated with mild bleeding § Individuals with factor XII deficiency do not bleed and in fact may be susceptible to thrombosis. § There is evidence from experimental models suggesting that in some circumstances factor XII may contribute to thrombosis. Factors That Limit Coagulation Ø Platelet inhibitory effects o normal endothelium also releases a number of factors that inhibit platelet activation and aggregation. Among the most important are § prostacyclin (PGI2); produced by COX-1 § nitric oxide (NO); endothelial nitric oxide synthase eNOS § adenosine diphosphatase (degrades ADP) Ø Anticoagulant effects. o Normal endothelium shields coagulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coagulation, § thrombomodulin, § endothelial protein C receptor § heparin-like molecules (bind and activate antithrombin III, which then inhibits thrombin and factors IXa, Xa, XIa, and XIIa) § tissue factor pathway inhibitor. Ø Fibrinolytic effects. o Normal endothelial cells synthesize t-PA, as already discussed, a key component of the fibrinolytic pathway. Factors That Limit Coagulation Coagulation must be restricted to the site of vascular injury to prevent deleterious consequences. 1. simple dilution; blood flowing past the site of injury washes out activated coagulation factors, which are rapidly removed by the liver. 2. the requirement for negatively charged phospholipids, which are mainly provided by platelets that have been activated by contact with subendothelial matrix at sites of vascular injury. 3. the most important counterregulatory mechanisms involve factors that are expressed by intact endothelium adjacent to the site of injury The mnemonic “PVC Pipes” P—Platelets a. Not enough (usually below 50,000/μL): may be because of decreased production, destruction, or sequestration. b. Not working: may be secondary to aspirin, NSAIDs, uremia, or genetic causes. V—vWD (type 1 is most common) results in decreased platelet adhesion and lack of stabilized factor VIII. C—Clotting factors (most commonly factors VIII and IX), vitamin K deficiency (vitamin K is required for factors X, IX, VII, II, and I), liver disease (manufactures clotting factors), and presence of factor inhibitors P—Pipes: vasculitis, scurvy (vitamin C deficiency), Ehlers–Danlos syndrome, hereditary hemorrhagic telangiectasias, steroids, and palpable purpura (sepsis, meningococcemia, Henoch–Schönlein purpura, drugs) Thrombocytopenia General characteristics § Mild thrombocytopenia (low platelets) is 100,000 to 150,000 per μL. § Moderate thrombocytopenia, where caution is needed for surgery or procedures, is 50,000 to 100,000 per μL. § Severe thrombocytopenia, where spontaneous bleeding can occur, is