NU608 Disorders of Hemostasis PDF

1 We experience frequent small capillary tears and occasional large blood vessel cuts. While unable to control large vessel bleeding without external support, the body is able to stop small vessel bleeding through the process of hemostasis. Hemostasis is the process the body uses to prevent excessiv...

1 We experience frequent small capillary tears and occasional large blood vessel cuts. While unable to control large vessel bleeding without external support, the body is able to stop small vessel bleeding through the process of hemostasis. Hemostasis is the process the body uses to prevent excessive hemorrhage following tissue injury. While hemostasis is frequently thought of as occurring in phases… remember that the biochemical reactions are simultaneous and interrelated. Effective hemostasis is dependent on three interrelated systems: 1. Blood vessel integrity 2. Platelets 3. Coagulation factors Vascular Phase: that of blood vessel integrity The first line of defense against bleeding is the blood vessel wall, also known as the vascular phase. When blood vessel integrity is interrupted there’s immediate vasoconstriction to divert flow away from the injury. Vasoconstriction triggers release of chemical messengers that that promotes the vasoconstriction and sets into motion the second event in hemostasis…an attempt by the platelets to plug the rent in the vessel through the formation of a platelet plug. This is a series of reactions taken by the platelets when they are exposed to the damaged vascular endothelium. 2 Second stage of hemostasis: Platelet Plug Formation Normally, the undamaged endothelium secretes prostacyclin PGI2), which prevents platelet activation and platelets from sticking to the blood vessel wall. Following injury/damage to the endothelium there’s immediate vasoconstriction and release of subendothelial collagen from the damaged vessel. In the presence of collagen the platelets are activated  their normal disc shape swell and become spherical with hair-like projections (see picture of this on next slide) This allows the platelets to stick together better The damages endothelium releases the mediators, serotonin and thromboxane A2, which further enhances vasoconstriction. And, then platelets start to fill the endothelial gap. We now have platelet adhesion  platelets start to stick to the vessel wall This adhesion occurs in the presence of a plasma clotting factor 8 and von Willebrand factor (vWB), a plasma protein The ability of the platelets to adhere on contact to the damages vascular wall requires the presence the Von Willebrand factor which is synthesized by the vascular endothelial cells & megakaryocytes (platelets) Following adhesion you have platelet aggregation  plts start to stick to each other. They secrete ADP, thromboxane A2, epinephrine, and platelet activating factor which act to recruit more plts to the area. Here’s some trivia…Plavix…which many people are on works by decreasing platelet aggregation – Plavix is actually an ADP receptor blocker – it prevents the mediator ADP from recruiting more platelet to come More trivia – ASA decreases the platelets ability to secrete thromboxane A2 – thereby decreasing their ability to aggregate. The plts in the plug then release a mediator known as PF3 (plt factor 3)  a phospholipid found in the plt membranes which helps accelerate the clotting cascade if it is needed to help control the bleeding which then helps deposit fibrin strands with the platelet plug. (This process of plt plug formation starts within 5-15 seconds of an injury. And, a plt plug is usually formed within 3 to 5 minutes of injury. Plt plugs seal the many minute ruptures that occur daily in the microcirculation, particularly in the capillaries.) Bleeding time is a lab value that looks at the effectiveness of this platelet plug formation. Bleeding time refers to the length of time bleeding occurs after a standardized puncture wound to the skin. Bleeding time is measured in minutes and indicates the functioning status of the platelets, specifically the effectiveness of the platelet plug. Bleeding time should not exceed 15 minutes (normal: 3 to 9.5 minutes) for a forearm stick. 3 Picture of activated platelets with the hair-like projections – makes it easier for them to “attach” to each other. 4 Bleeding that cannot be controlled by a platelet plug triggers circulating plasma protein coagulation factors to create a network of fibrin. It’s the formation of the fibrin strand that’s the basis of the clot. As the fibrin strands contract, it pulls together the endothelium and healing occurs. It’s the formation of the fibrin strand that is the third mechanism of hemostasis. Clotting (the formation of the fibrin plug) takes place in three essential steps: 1. A prothrombin activator is formed in response to damage 2. This activator then catalyzes the conversion of prothrombin into thrombin 3. Thrombin then acts as an enzyme to convert fibrinogen into the fibrin threads which form the clot 5 This is a flow map of what the previous slide was “saying” You have a prothrombin activator, which is either the intrinsic or extrinsic pathway. It is formed in response to injury and acts on prothrombin. PROTHROMBIN  is a protein that circulates in the bloodstream It is split into smaller compounds through the action of the extrinsic or intrinsic pathway Prothrombin is normally formed in the liver & requires Vit K for its production THROMBIN  is the smaller compound that prothrombin was broken up into thrombin is the most powerful procoagulant protein in the body…it acts as an enzyme on fibrinogen to become fibrin monomer. FIBRINOGEN  is a plasma protein (formed in the liver) and circulates in the bloodstream thrombin breaks fibrinogen into FIBRIN MONOMERS  which then change into the fibrin threads IT’S THE FIBRIN THREADS form the basis of the clot. This clot is initially weak but with the addition of F13 (fibrin stabilizing factorwhich is an enzyme released by plts within the clot) …the threads become crosslinked and strong, like a mesh FINALLY…the fibrin clot is the end product of hemostasis. 6 Picture of clot forming…fibrin threads have encased RBC’s within them 7 Picture of clot after it has stabilized …upper left corner….picture of the clot after the threads have cross-linked and formed a “mesh” 8 Frightening…isn’t it, just hearing the words “clotting cascades” … but we have to mention them 9 The prothrombin activator is either the coagulation factors involving the intrinsic or extrinsic pathways. There are two basic pathways in which prothrombin activator is formed. Which pathway that is used depends on the triggering mechanism for clotting. Under most physiologic conditions, coagulation occurs first through the extrinsic pathway; activation of the extrinsic pathway then turns on the more powerful intrinsic pathway. Both pathways ultimately merge at factor X  this merging of the intrinsic & extrinsic pathway at factor X is known as the final common pathway and this is what is ultimately responsible for converting that prothrombin into thrombin. Extrinsic Pathway  begins with direct trauma to the vascular wall or to the tissues. The extrinsic pathway to becomes activated when tissue factor (also known as tissue thromboplastin) is released into the circulation from the damaged tissue or vascular walls. This is through activation of clotting factor VII (remember this…that Factor 7 is associated with extrinsic pathway) Can produce clot within 15-20 seconds. Tissue thromboplastin found in most tissue with high amounts in brain, lung, bone marrow, kidney & placenta. Initiation of the intrinsic pathway  more complex of the two pathways. Activated when blood comes into contact the exposed collagen of the damaged intravascular endothelium. Produces clot within one to six minutes post initiation This is through the activation of clotting factor XII (also known as Hageman factor)  remember that also Lack of any of these clotting factors could interfere with coagulation predisposing the patient to bleeding 10 Hemostasis is counterbalanced with FIBRINOLYSIS  it’s the process of breaking the clot up Purpose of fibrinolysis: To prevent inappropriate clotting To re-establish patience once healing has occurred…Clots will start to lyses within 24 to 72 hrs There are several proteins that function as physiologic anticoagulants and are responsible for maintaining a normal balance between hemostasis and thrombosis: Endothelium: the smooth lining of the endothelium discourages platelet aggregation & clot formation and several anticoagulant substances (meadiators) are released by endothelium: Prostacyclin  immune system mediator causing 11 vasodilatation and decreases platelet aggregation Thrombomodulin  binds with thrombin to render it inactive t-PA (tissue plasmin activator)  part of fibrinolytic system  yep! that’s the clot buster used in the ER’s 11 The body also has several endogenous proteins that function as anticoagulants: As activated coagulation factors drift away from the site of clot formation, they are inactivated by these anticoagulant proteins. Antithrombin III – is the most important of these as it is the major inhibitor of the coagulation system it is a glycoprotein synthesized in liver and endothelial cells it binds to and inactivates thrombin Protein C & S - these are two vitamin K dependent proteins that inactivate activated factors 5 and 8. Require thrombin to be present for activation Deficiencies predispose infants to thrombosis rather than hemorrhage. FDP (fibrin degradation products)  act as anticoagulants but are normally removed from the circulation by the liver as soon as they are formed. Heparin  doesn’t dissolve the clot but prevents further expansion of the clot. It  affinity of Antithrombin III to thrombin when heparin binds to Antithrombin III Produced by the basophils 12 This is just a flow map showing where antithrombin and heparin act to prevent clot formation…it thrombin is inactivated then it can’t act on fibrinogen, breaking it down to become the fibrin threads…if no thrombin then no fibrin…if no fibrin then no clot 13 And what about the clot that was needed and now the site has healed …what happens? The injured/damaged tissue & endothelium will start to leak small amounts of t-PA into the clot after several days. T-PA cleaves plasminogen (another plasma protein) into plasmin. Plasmin is a strong proteolytic enzyme that breaks down (degrades) the fibrin clot back into fibrin threads which are then removed and normally cleared by liver. WBC phagocytizes remaining clot. 14 Above is a list of the clotting factors and below are some “trivia” about them…never know when Jeopardy might have a category on hemostasis Trivia #1 all clotting factors (except 8 &13) are made in liver. F8 is synthesized by the endothelium F13 made by plts - functions to strengthen fibrin threads. Trivia #2  Factors 2- 7 - 9 - 10 (the one’s in pink on the slide) require vitamin K for synthesis….they are known as the vitamin K dependent clotting factors Hepatitis, liver dz, short gut affects production & absorption of Vit K so patients with these disorders will be prone to bleeding disorders Most common cause of Vit K deficiency clotting factors is HAF in combination with antibiotics that destroy normal gut flora Trivia #3  Look at what factor 4 is... Calcium  needed in all but two steps Trivia #4  What about factor 6.... not listed (at one time there was a #6 but then they found that it really wasn’t a clotting factor so it was stripped of it’s title) Trivia #5  deficient levels of factor 8 is associated with class hemophilia (also called hemophilia A). Remember it’s an x-linked inherited disease so only males are affected. Trivia #6 (not only for Jeopardy but for the next Quiz –hint! hint!) remember we said Von Willebrand Factor circulates with Factor 8 as a co-factor. vWB is a glycoprotein produced by the endothelial walls & plts - it complexes with antihemophilia factor and circulates jointly as F8* vWb disease is the most common bleeding disorder It affects both sexes equally Also known as pseudohemophilia because it is marked by low levels of F8 But there is also abnormal plt aggregation and abnormalities in the way small blood vessels constrict Treated with cryoprecipitate (which contains vWB factor) but also DDAVP which is vasopressin (also known as ADH)  encourages release of vWb from the endothelium 15 PT (prothrombin time)  measure of extrinsic pathway (F7). PTT (partial thromboplastin time)  measure of intrinsic pathway (measures all except F7 & F13). FSP product of clot lysis. When elevated excessive clots exist and are lysing. But...if hepatic dysfunction (for whatever reason) is present you can have elevated levels (as liver clears FSP). D-dimer assay  the test that is most specific for DIC. Now considered the gold standard test for DIC. Fibrin clots dissolve in fragments….so the presence of fibrin monomer D is specific for fibrin proteolysis. Measures degradation from cross-linked fibers. This test is also used in patients with suspected thrombi – such as pulmonary emboli 16 So…now some alterations in hemostasis Platelets disorders can be problems with number of platelets (quantitative) Thrombocytopenia  is low platelet count (count less than 150,000) Thrombocythemia (also known as thrombocytosis)  is count over 600,000 Usually not clinically significant unless count over one million This increases the risk of intravascular clotting Usually secondary to increased production by the bone marrow … or problems with the structure and/or function of the platelet (qualitative) Abnormalities here usually result in prolonged bleeding time 17 Clinical reason for seeing Thrombocytopenia pseudothrombocytopenia (agglutinated plts)  just a bad lab sample, or lab stick causing the plts to “clump” – aggregate - giving a false low reading massive PRBC transfusion (>10 units/24hr)  due to dilutional affect  RBC’s being replaced but not platelets congenital conditions  certain congenital conditions are known to be associated with low counts…such as Down’s syndrome sepsis (bacterial, viral, fungal) drug-induced  see next slide immune mediated  which we learned about in the hypersensitivity reaction section, ITP 18 Certain drugs we take or give our patients can affect the platelets. The drugs listed on this slide are known to affect platelet function and can lead to prolonged bleeding times in some patients. Aspirin (ASA) affects platelet function (decreases ability of plt to aggregate). A single dose of aspirin affects the platelets for the entire lifespan of the platelet (9-10 days). It will increase bleeding time d/t irreversible inhibition of the cycloxygenase enzyme. This is the basis for taking ASA for it’s “anticlotting” effects to help prevent MI Ibuprofen (Advil or Motrin) also causes a decrease in platelet ability to aggregate but it’s effects are reversible in that the effects only last for the halflife of the drug and not the entire lifespan of the plt 19 20 DIC occurs when release of tissue factor & cytokines results in excessive activation of coagulation & fibrinolysis. DIC is a unique condition characterized by the formation of multiple blood clots throughout the microvascular. Eventually, the components of the blood clotting cascade and the platelets are used up, and hemorrhages begin to occur at all bodily orifices, at sites of injury or venous punctures, and throughout the organ systems. DIC is never a primary condition…it is a symptom of some other triggering event! 21 Due to some triggering event there is rapid consumption of plts and clotting factors...the circulating levels of these factors are inadequate for hemostasis and hemorrhage then follows. There’s massive fibrin formation occurring  widespread small thrombi in the microcirculation leads to tissue damage, necrosis and shock Microangiopathic hemolytic anemia occurs secondary to mechanical fragmentation of RBC…RBC fragments known as schistocytes appear Because of the small thrombi present.... fibrinolysis is stimulated to dissolve the clots. Breakdown product of clot lysis has anticoagulant effect It’s a vicious cycle you have a paradoxical clinical situation with thrombosis & hemorrhage developing simultaneously While hemorrhage is the predominant clinical manifestation the concomitant development of the microvascular thrombi is the more irreversible of the two events! The most important issue in treatment of DIC is stopping the triggering event! If the triggering event is not treatable or reversible then no matter how vigorous the blood abnormalities are treated.... the patient will die. Once removed, the liver can restore coagulation factors within 24-48 hours The important thing to remember.... DIC is a syndrome that occurs secondary to a variety of triggering events. So, what are these triggering events? 22 Endothelial damage Infection  particularly when due to gram negative. Endotoxin stimulate the generation of tissue thromboplastin by the endothelium Combines with Factor 7 to initiate clotting via the extrinsic pathway Viral  produces circulating antigen-antibody complexes that activate F12 (Hageman factor) and initiates the intrinsic pathway Hypoxia & acidosis Ischemic & vascular changes shock, hemangiomas, conditions that promote vascular stasis such as polycythemia Overwhelming inflammation (as in SIRS) d/t release of mediators can initiate the clotting cascade 23 Release of tissue factor (thromboplastin) into circulation Tissue destruction crush injuries, tissue necrosis, burns Head injury  hemorrhagic strokes, intracerebral or intraventricular hemorrhage (IVH) Surgery  with the tissue manipulation that is required (especially abdominal surgery) there is large release of tissue factor so post-op patients can be at risk for developing DIC  as we saw in our case study patient Release of tissue procoagulants as seen in some malignancies Placental disorders…such as placenta abruption (premature separation of the placenta from the uterus)…Placenta is a rich source of tissue thromboplastin …One of the most common causes of DIC is abruption…and DIC is one of the most common causes of maternal mortality in OB 24 Direct activation of clotting cascade at Factor X (the common pathway) Hepatic disease  so your patients with liver disease, hepatitis, liver cancer, cirrhosis are at risk Acute pancreatitis  d/t mediator release Venomous snakebites  any poisonous snakes where you are? Where I work at All Children’s Hospital (in Florida) we see about 5-8 kids a year in our PICU who have been bitten by pygmy rattlesnakes 25 Combined or unclear triggering mechanisms Intravascular hemolysis Massive blood transfusions  probably d/t dilution effects, blood (RBC’s replaced) but not clotting factors Malignant hyperthermia  associated with risk for DIC but I’m not sure what the mechanism is ECMO (sort-of like the heart-lung bypass machine)  may be d/t trapping and destruction of clotting factors in the filters and tubing of the machine 26 The diagnosis of DIC is based on laboratory findings: Prolonged PT and PTT, decreased fibrinogen Decreased plts Increased FSP Increased d-dimers  now considered the gold standard for DIC Peripheral blood smear shows helmut shaped, schistocytes (fragmented RBC cells) 27 Treatment of DIC remains difficult and controversial but supportive care with blood components is considered the best treatment of DIC… FFP, Cryo, Plts. It’s controversial in that there are some (especially in the adult population there are more articles relating to this) that believe if we transfuse with blood products…we’re adding “fuel to the fire” by providing by the thrombin that will be broken down into the fibrin allowing for the microclots within the circulation. Goals of treatment are to: Eliminate underlying pathology Restore hemostasis Maintain organ viability Infusion of Antithrombin 3 concentrate is newer and still controversial in DIC  attempts to prevent thrombotic complications. Heparin therapy Heparin blocks thrombin formation thus blocking consumption of other clotting factors So … The most important issue in treatment of DIC is stopping the triggering event! 28 Thrombosis (fixed) vs embolus (moving)  either one there is blockage of blood flow within a vesse; Hypercoagulability predisposes individual to develop thrombi this can be hereditary or acquired. 29 Types of thrombosis can be arterial or venous: Arterial in which thrombi form under conditions of high blood flow and are composed mainly of plt aggregates held together with fibrin. Usually related to some type of endothelial cell trauma. Venous thrombosis tend to form in low flow conditions and tend to be mostly RBC’s with fibrin (few plts). Other etiologies of venous thrombosis seen with: Increased red cell mass and viscosity Small vascular caliber Low levels of proteins related to coagulation & fibrinolysis Triad of Virchow refers to three conditions or factors that lead to hypercoagulability: 1. There is injury to blood vessel endothelium (something leads to loss of blood vessel wall integrity) 2. Abnormalities of blood flow  especially turbulence or stasis  atherosclerotic plagues, cardiac valvular disease; hyperviscosity syndromes, sickle cell anemia 3. Hypercoagulability of blood  congenital conditions or acquired conditions that are related to deficiencies of the anticoagulants such as protein C & S, antithrombin III 30 Picture of pulmonary emboli 31 Protein C deficiency Associated with cerebral & ophthalmic thrombotic events Transient deficiency noted in neonates  renal vein thrombosis, umbilical thrombosis Treatment includes FFP, and ? monoclonal protein C concentrate Protein S deficiency Rare, autosomal dominant Present with “spontaneous thrombosis”, deep vein and pulmonary emboli. 32 Antithrombin III deficiency  can be autosomal dominant or acquired secondary to liver disease (remember liver produces protein C & S and antithrombin) Frequently presents during years 20 – 30 with healthy young adults developing MI, stokes or PE During pregnancy  typically present with DVT, pulmonary emboli Several reported cases in neonates myocardial infarction, aortic thrombi, cerebral thrombosis Factor V Leiden (activated protein C resistance) mutation  form of activated protein C resistance  normally inactivation of factor 5 (part of the common pathway) by protein C limits further production of thrombin. But Factor 5 Leiden is a mutation in a gene that codes for clotting factor 5 and factor 5 becomes resistant to degradation by Protein C Most common inherited thrombotic tendency in adults Increased risk of venous (but not arterial) thrombosis 33 In children, increased risk of stroke and catheter related thrombosis Incidence in neonates unknown 33 The end! Anybody need a drink…or some puppy kisses! 34