Clotting Cycle & Bleeding Disorders PDF

Chapter Eight: The Clotting Cycle & Bleeding Disorders Lacerations, burns, abrasions and punctures. Pressure, ischemia, vascular occlusion, and surgery. These are just a few of the things that can lead to a wound, which is defined as “an acute injury to intact skin.” And while there are many possibl...

Chapter Eight: The Clotting Cycle & Bleeding Disorders Lacerations, burns, abrasions and punctures. Pressure, ischemia, vascular occlusion, and surgery. These are just a few of the things that can lead to a wound, which is defined as “an acute injury to intact skin.” And while there are many possible inciting causes, the healing sequence of all acute wounds follow the same ordered path, which starts the moment after there is a breach in the skin. A wound leaves an actual physical gap in the epidermis that immediately fills with blood, causing a leak. The blood amazingly carries with it almost everything it needs to not only stop the leak, but also to fill the gap. It contains platelets to form a plug and clotting factors to change that plug into a fibrin mesh. It is helped in this by the endothelium of the small blood vessels within the wound, which clamp down to stem the flow of blood, causing fluid stasis. The vessels can only hold the fluid back for about 5 to 10 minutes, hopefully giving the factors in the stagnant blood time to bind together. This process is as precise as it is orderly, involving many proteins, cells, factors, and cytokines, that all must work together for the wound to eventually close. If any part of the process breaks down, an acute wound can become a chronic one. Chronic wounds become arrested in one of the five stages of wound healing —hemostasis, inflammation, epithelialization, fibroplasia, and maturation. If a wound does stop healing, it cannot progress further. Here, we will consider the initial stage of wound healing — hemostasis — by first looking at platelets and platelet disorders before moving on to their job in the wound-healing work environment. Then we will focus on the clotting cascade and how disruptions to that system can cause bleeding disorders. Most common cause of clotting: Stasis Most common cause of venous clots: Stasis Most common cause of arterial clots: Endothelial injury. Exposure of the BM. Most common cause of genetic venous clots: Factor V Leiden Defect 210 The Clotting Cycle & Bleeding Disorders Hemostasis: creation of a blood clot following injury to blood vessel A. Has two phases: Primary hemostasis and secondary hemostasis B. Has three steps: Vasoconstriction; formation of platelet plug; and formation of fibrin clot Vasoconstriction Also known as: Vascular spasm, vascular contraction Main participant: Smooth muscle cells of endothelium Trigger: Local sympathetic contraction of muscle cells Main job: Stop blood loss Formation of platelet plug Also known as: Primary hemostasis Main participant: Platelet cells Trigger: Exposure of subendothelial collagen Main job: Create temporary plug Formation of fibrin clot (coagulation) Also known as: Secondary hemostasis Main participant: Protein clotting factors Trigger: Exposure of tissue factor and collagen surface Main job: Create stable clot PLATELETS Platelets (Thrombocytes) are the first cells to respond in primary hemostasis — a.k.a. wound healing. They create a temporary clot called a platelet plug. These cells originate in the bone marrow from megakaryocytes and are stimulated by Thrombopoietin. Platelets survive in circulation for 4 to 7 days and are responsible for bleeding from the skin and mucosal surfaces. Deficiency leads to petechiae, purpura, ecchymoses and mucosal bleeding. Normal count: 150,000 to 350,000 platelets/microL Thrombocytosis: More than 350,000 platelets/microL Thrombocytopenia: Less than 150,000 platelets/microL Definitions Petechiae: dot sized hemorrhage Purpura: palpable hemorrhage Ecchymoses: bruise Striae: bruises that follows skin lines 211 The Clotting Cycle & Bleeding Disorders Thrombocytosis • Slight increase in platelet count • Thrombocythemia: platelet count more than two standard deviations above normal • MCC of clot formation is stasis of blood, NOT thrombocytosis • Can be primary or secondary o Primary is also called essential  Essential thrombocythemia is one of the four types of myeloproliferative diseases o Secondary is also called reactive  Reactive thrombocytosis is caused by another current condition such as anemia, neoplasm, autoimmune disease inflammation or infection  Platelet count returns to normal when we treat the associated condition Thrombotic Microangiopathy vs. Microangiopathic Hemolytic Anemia Thrombotic Microangiopathy • Main cell involved: platelets • Causes: tiny clots • Endothelium injury causes platelets to form clots in microvasculature. The microthrombi are composed of platelets and von Willebrand factor. • Main types they want you to know: o Thrombotic thrombocytopenia purpura; can be hereditary or acquired; involves vWF-esterase deficiency (Adam TS13) o Hemolytic-uremic syndrome o DIC Microangiopathic Hemolytic Anemia (MAHA) • Main cell involved: RBCs • Causes: tiny clots tear passing red blood cells • Endothelium injury causes fibrin mesh in microvasculature, which fragment RBCs. These fragmented RBCs are called schistocytes. MAHA is a subtype of hemolytic anemia. • Main types they want you to know: o Thrombotic thrombocytopenia purpura: can be hereditary or acquired o Hemolytic-uremic syndrome o DIC 212 The Clotting Cycle & Bleeding Disorders o Prosthetic heart valve Bottom line: • All thrombotic microangiopathy can cause microangiopathic hemolytic anemia • Not all microangiopathic hemolytic anemia are caused by thrombotic microangiopathy • Example: Prosthetic heart valve can cause microangiopathic hemolytic anemia Thrombocytopenia • Deficiency leads to petechiae, non-palpable purpura and mucosal bleeding • MCC is virus, followed by drugs MCC: (1) viral infection (2) drugs • Can be asymptomatic to life threatening • Most concerned about spontaneous bleeding • Associated with many disorders: alcoholism, pregnancy, neoplasm, malnutrition, chronic liver disease, bone marrow disorders. • Here we will consider: Thrombocytopenia due to platelet consumption, autoimmune reaction, infection, medication, and congenital platelet disorders Thrombocytopenia due to platelet consumption • Thrombotic microangiopathy • Endothelium injury causes platelets to form clots in microvasculature • Platelets are consumed when thrombi are created, causing low platelet count • Seen in disseminated intravascular coagulation, thrombocytopenic purpura, and hemolytic uremic syndrome Thrombocytopenia due to autoimmune reaction • Immune thrombocytopenia is the current preferred name. However, it has had other names: idiopathic thrombocytopenic purpura; immune thrombocytopenic purpura; and autoimmune thrombocytopenic purpura • Note: Do not confuse “immune thrombocytopenia” (ITP) with “thrombotic thrombocytopenic purpura” (TTP), which is when ADAMTS13 — a protease that cleaves von Willebrand factor — is impeded • Antibodies made against antigens on platelets 213 The Clotting Cycle & Bleeding Disorders • • • Can occur on its own or another condition can trigger the body to make antibodies against platelets If triggered by infection, patients do not remember being sick Patients are often asymptomatic Thrombocytopenia due to infection • Infections can cause thrombocytopenia via bone marrow suppression, hypersplenism or platelet consumption • Thrombocytopenia is common in acutely ill patients due to sepsis (48%) • Patients remember having symptoms of illness including fever, rash, etc. • Type of infection—most often viruses: o Parvovirus B-19 o Hepatitis C o Hepatitis E • 90% resolve without problems in children • 90% remain chronic in adults • Can precede SLE in adolescent females • Treat with steroids • Remember, do not transfuse platelets into a destructive process o Exception: If patient is about to go into surgery or if count goes below 10,000 platelets/microL Thrombocytopenia due to medication • Drugs that can cause low platelets: (1) AZT (2) Vinblastine (3) Chloramphenicol (4) Benzene Heparin-induced thrombocytopenia (HIT) • HIT is an autoimmune reaction that occurs in about 5% of individuals who take heparin • It is independent of the dose or method of heparin given • IgG attacks heparin after it forms a complex with Platelet Factor 4, which is released from platelets during platelet aggregation. HIT-2 usually occurs 3 to 10 days after initiating heparin therapy. • IgG activates platelets, causing arterial and venous thrombosis • HIT-1 occurs due to platelet clumping; occurs on day 1 or 2. Simply follow the platelet levels. 214 The Clotting Cycle & Bleeding Disorders Platelets — how they create the platelet plug 1. Vasoconstriction: This temporary vasoconstriction is responsible for the lucid interval in the epidural hematoma Formation of the platelet plug Three steps Step 1: Platelet adhesion to injured vessel Step 2: Platelet degranulation Step 3: Platelet aggregation 2. Step 1: Platelet adhesion (A) Injury causes exposure of the vascular sub endothelium, which has collagen fibrils • Collagen provides surface for platelets to adhere to (B) Von Willebrand (vWF) factor binds to collagen • vWF is made in endothelial cells — inside Weibel-Palade bodies — and platelets — inside alpha-granules • Defective vWF causes Von Willebrand disease (see below) • Defective ADAMTS13, the enzyme which breaks up vWF, causes thrombotic thrombocytopenic purpura (see below) (C) Glycoprotein receptor GpIb on platelet binds to Von Willebrand factor • Defective GpIb causes Bernard-Soulier Syndrome (see below) Step 2: Platelet degranulation (A) Adhesion causes platelets to activate and undergo conformational change, and dump contents of their granules: thromboxane A2, ADP, and Ca2+ • Thromboxane A2 (TXA2) promotes platelet aggregation • ADP helps expose glycoprotein receptor GpIIb/IIIa on platelet so it can bind fibrinogen and provides energy for the clumping process. • Ca2+ is needed by clotting factors to create fibrin clot Step 3: Platelet aggregation (A) (B) Receptor GpIIb/IIIa binds circulating coagulation protein fibrinogen • Each platelet has 40,000 to 80,000 copies of GpIIb/IIIa on its surface • Defective GpIIb/IIIa causes Glanzmann thrombasthenia (see below) Fibrinogen can bind to GpIIb/IIIa receptors on two different platelets, linking them together Result: Platelet plug is formed 215 The Clotting Cycle & Bleeding Disorders PROSTAGLANDIN ACTION Prostacyclin (PGI1) Inhibits platelet aggregation; vasodilation Prostaglandin E2 Vasodilation (leading to fever, inflammation) Decreases gastric acid secretion Increases gastric mucus secretion Prostaglandin F2α Bronchoconstriction; vasoconstriction; uterus contraction Thromboxane (TXA 2) Promotes platelet aggregation; vasoconstriction Disorders of Platelet Plug Formation Platelet disorders with decreased number of platelets. Glycoprotein receptor defects. Bernard-Soulier Syndrome • • • • • • Also called giant platelet syndrome Autosomal recessive inheritance Characterized by large platelets, thrombocytopenia, and prolonged bleeding time Patients bleed excessively and bruise easily Defective glycoprotein GpIb receptor on platelet Without GpIb receptor, platelets cannot bind to Von Willebrand factor Glanzmann Thrombasthenia • • • • • • Autosomal recessive inheritance Rarely, can be acquired, with autoantibodies to glycoprotein GpIIb/IIIa receptor Characterized by normal size platelets, normal platelet count but prolonged bleeding time without platelet aggregation Patients have mucocutaneous bleeding Defective glycoprotein GpIIb/IIIa receptor on platelet Without GpIIb/IIIa receptor, fibrinogen cannot bridge platelets and cause aggregation 216 The Clotting Cycle & Bleeding Disorders Von Willebrand disease • • • • • • • Most common inherited bleeding disorder Has three major types and several subtypes Autosomal dominant genetic mutation leads to a decrease in von Willebrand factor Von Willebrand factor anchors platelets to endothelium and acts as carrier for factor VIII Since a decrease in vWF can cause a decrease in factor VIII levels, there can be an elevation in PTT, while PT and platelet counts are normal Patients can become symptomatic at any age Usual presentation includes childhood nosebleeds that lasted longer than 10 minutes; long bleeding time following dental procedures; heavy menstrual periods for women; and easy bruising Ristocetin used to test for von Willebrand disease and Bernard-Soulier syndrome If ristocetin is added to blood without vWF or its receptor GpIb, the platelets will not clump • • • • Treatment in mild bleeding: Desmopressin (DDAVP) causes Weibel–Palade bodies in endothelial cells to release vWF and factor VIII As an ADH analog, DDAVP can also be used to treat central diabetes insipidus Moderate bleeding: cryoprecipitate Severe bleeding: FFP Thrombotic Thrombocytopenic Purpura (TTP) • • • • • • Can be inherited or acquired Both involve ADAMTS13, which breaks up vWF Initially vWF is released as a macromolecule then broken down into “normal” size by the enzyme ADAMTS13 In inherited TTP, the gene mutation causes ADAMTS13 deficiency In acquired TTP, antibodies are made against ADAMTS13 Treat with plasmapheresis 217 The Clotting Cycle & Bleeding Disorders Anti-Platelet Drugs Antiplatelet drugs decrease platelet aggregation and stop clot formation Types: ADP-receptor blockers; phosphodiesterase inhibitor; glycoprotein GpIIb/IIIa receptor inhibitors; and COX inhibitors, both irreversible and reversible (A) ADP-Receptor Blockers • • • • • Names: Clopidogrel, ticlopidine, ticagrelor, prasugrel ADP interacts with P2Y12 receptor on platelets, which ultimately leads GpIIb/IIIa receptor expression on platelet surface and platelet aggregation P2Y12 receptor antagonists for patients who cannot tolerate aspirin. Used to coat coronary stents placed to prevent thrombosis. Used with aspirin in patients with strong family history of heart disease Toxicity: o Ticlopidine — agranulocytosis and seizures o Clopidogrel—TTP (in first two weeks) (B) Phosphodiesterase Inhibitor • • • Names: Cilostazol, Dipyridamole Inhibits cyclic nucleotide phosphodiesterase, so it cannot break down cAMP builds up, which inhibits TXA2 while increasing prostacyclin Inhibition of TXA2 causes decrease in platelet aggregation, while increase of prostacyclin causes coronary vasodilation o Cilostazol—TTP (in first two weeks) o Dipyridamole—Vasodilates (potentiates adenosine) (C) Glycoprotein GpIIb/IIIa Receptor Inhibitors • • • Names: Abciximab, eptifibatide, tirofiban Bind to glycoprotein GpIIb/IIIa receptor on platelets, preventing binding of fibrinogen and thus aggregation Toxicity: bleeding, thrombocytopenia D) COX inhibitors • Major effect at thromboxane A2 or prostaglandin E2 218 The Clotting Cycle & Bleeding Disorders • • • • • Irreversible Thromboxane A2 inhibitor — Aspirin Inhibition lasts 8-10 days, until effected platelets leave circulation increases bleeding time; PT and PTT are normal Thromboxane A2 (TXA2) promotes platelet aggregation TXA2 is made from arachidonic acid, converted by enzyme cyclooxygenase-1 (COX-1 and COX-2) Aspirin irreversibly blocks COX via acetylation, stopping TXA2 production and thus platelet aggregation REMEMBER Cinchonism: thrombocytopenia, tinnitus, and hearing loss • • • • This is how aspirin works as a “blood thinner;” it is NOT an anti-coagulant, i.e. it does not stop formation of fibrin clot More correctly, aspirin is anti-platelet; stops formation of platelet plug Toxicity: bleeding in GI tract; increase risk of gastric ulcers; tinnitus; Reye syndrome if given to children with viral infection Overdose: o Early signs — hyperventilation and respiratory alkalosis, with notably increased depth of respiratory effort as salicylates directly stimulate the medullary respiratory center o Later signs — mixed primary respiratory alkalosis-primary metabolic acidosis with anion-gap o Possible hyperthermia o Salicylates uncouple oxidative phosphorylation in the mitochondria, which generates heat. 219 NSAID NOTES Ibuprofen MC over the counter Indomethacin Most potent treatment for gout (Contraindicated for renal disease or bone marrow problems) Closes PDA Phenylbutazon e Second in potency Naproxen Best for dysmenorrhea High sodium load Ketorolac Morphine-strength analgesic effect Ketoprofen Topical Diclofenac Topical Sulindac Contains sulfur The Clotting Cycle & Bleeding Disorders (E) Reversible Prostaglandin E2 Inhibition — NSAIDs (nonsteroidal anti-inflammatory drugs) • • • • • • No significant anti-platelet effect since platelets can replenish amounts of TXA2 Names: Ibuprofen, naproxen, indomethacin, diclofenac Reversible inhibitor of COX 1 and 2, decreasing prostaglandin E2 (PGE2) levels PGE2 is part of all signs of inflammation — redness, swelling and pain Causes arterial dilatation and microvascular permeability, increases blood flow leading to redness and edema Acts on sensory neurons as well as spinal cord and the brain, leading to pain Clotting Factors • • • Stop bleeding into cavities Intrinsic Pathway- involves bleeding because of internal illness. Most common: sepsis o Measure with partial thromboplastin time Extrinsic Pathway- involved bleeding due to trauma o Measure with prothrombin time Large Cavities • • • • • • • • Intracranial Mediastinum Pleural Pericardium Abdominal Pelvis Retroperitoneum Thighs Hemophilia A • • • • X-linked recessive Bleeding into cavities Check PTT This is a factor ACTIVITY deficiency Hemophilia A: Treatment • • Mild bleeding: DDAVP Moderate bleeding: cryoprecipitate 220 The Clotting Cycle & Bleeding Disorders • Severe bleeding: factor VIII concentrate Hemophilia B • • • • • • Factor IX deficiency X-linked recessive Low factor IX levels Elevated PTT Bleeding into cavities Treatment: FFP for all levels of bleeding Direct Thrombin inhibitors: • • • • Argatroban Lepirudin Bivalirudin Dabigatran Factor X Inhibitors • • • Rivaroxaban Apixaban Edoxaban REMEMBER Intrinsic: PTT Extrinsic: PT Common pathway: PTT and PT both elevated To Stop Passive Hemorrhage • • • • Tranexamic acid Activated Factor VII Activated prothrombin concentrate Activated Fibrinogen Complex Concentrate 221 The Clotting Cycle & Bleeding Disorders Figure 8.1 Coagulation Cascade 222