MLAB 1227: Coagulation Keri Brophy-Martinez Coagulation Disorders: Secondary Hemostasis Part Two

Acquired Coagulation Disorders Two or more factors generally affected, more complicated Bleeding from multiple sites More common than hereditary disorders Classification 1.DIC 2.Primary Fibrinogenolysis 3.Liver Disease 4.Vitamin K Deficiency 5.Acquired Pathologic Inhibitors

1. DIC: Disseminated Intravascular Coagulation Consumption Coagulopathy ◦ As fibrin is formed, clotting proteins and naturally occurring inhibitors and platelets are consumed faster than they are made ◦ Thrombo-hemorrhagic disorder  Clotting and lysing occurring in blood vessel, at the same time ◦ Life threatening ◦ Bleeding is the most apparent characteristic ◦ Initiating events are thrombotic, where material enters circulation ◦ Occurs due to lack of the negative feedback mechanism ◦ Affects young and elderly

DIC: Triggers  Obstetric – usually due to major tissue damage such as retained dead fetus, abruptio placentae, or placenta previa  Acute leukemias – Promyelocytic – increase number of granules released into circulation as cells break down  Intravascular hemolysis – ex: transfusion reaction  Massive trauma (especially crushing injuries), burns, surgical procedures  Heat stroke  Snake venoms  Septicemias and infections – viral, bacterial, rickettsial, fungal, protozoan (especially gram negative that release endotoxins)  Tumors – foreign tissues and cells  Prosthetic devices – heart valves, aortic balloon, peritoneal shunting  Vascular disease – damaged endothelial lining

Course of DIC

DIC: How Does It Occur? Step 1: Out of control clotting ◦ Causes widespread fibrin deposits in vessels of tissues and organs ◦ Subsequent event: Hemorrhage  Clotting proteins consumed at a high rate  Causes multiple factor deficiencies, especially fibrinogen group  Platelets caught in thrombi and removed

DIC: How Does It Occur? Step 2: Triggers Fibrinolytic system to remove fibrin ◦ Results in:  Circulating degradation products (FDPs) that interfere with platelet function & normal clot formation  Degradation of Factor V & VIII

DIC: How Does It Occur? Step 3: Uncontrolled plasmin and thrombin enter circulation ◦ Why?  Inhibitors such as AT have been depleted

DIC: How Does It Occur? Step 4: Appearance of Symptoms ◦ Bleeding from multiple sites ◦ Petechiae ◦ Purpura ◦ Occlusions in organs ◦ Oozing from needle puncture sites ◦ Shock

Lab Features of DIC Platelet count: decreased ◦ (40-75 x 10 9 /L) PT: increased PTT : increased Fibrinogen: decreased FDP /D-dimer: positive ◦ **Most helpful in diagnosis AT : decreased RBC fragments: present

DIC Treatment ◦ Goal is to treat the underlying condition  Remove the triggering process – treat with antibiotics, antineoplasms, remove dead tissue, treat the diseases or conditions ◦ Heparin – to prevent or limit further coagulation ◦ Replace factors, platelets = give FFP

2. Primary Fibrinogenolysis Similar to DIC Plasminogen is inappropriately activated to plasmin Plasmin circulates overwhelming the antiplasmin inhibitors and degrading fibrinogen and factors V,VIII, XIII No thrombin is generated Liver disease is a common trigger

3. Liver Disease Affects all proteins made in the liver that function in fibrin formation, fibrinolysis and inhibition. Patients show minimal bleeding, except in severe cases Lab features ◦ Increased  PT,PTT ◦ Decreased  Platelets

4. Vitamin K Deficiency Liver cells able to make precursor protein but the calcium binding site is nonfunctional Causes ◦ Malabsorptive syndromes  Sprue  Obstruction in biliary tract  Ingestion of vitamin K inhibitors- like warfarin ◦ Antibiotic therapy  Kills off normal flora in gut which made vitamin K

5. Acquired Pathologic Inhibitors Develop in patients with certain disease states and others with no underlying conditions Circulating anticoagulants which may develop against any clotting factor Classed as immunoglobulins ◦ Either IgG or IgM ◦ Can be alloantibodies or autoantibodies

Types of Inhibitors 1. Directed towards a single coagulation factor ◦ Seen in patients with inherited factor deficiencies that have had replacement therapy for bleeding complications ◦ Less commonly seen in healthy people and those taking certain drugs ◦ Rare, except Factor VIII & IX ◦ How do we find them?  Interfere with clotting factor activity  PTT prolonged, other tests normal  Mixing study: test will still be prolonged

Types of Inhibitors 2. Lupus Inhibitor/Anticoagulant ◦ Seen in patients with autoimmune diseases, drug reactions, but also in normal patients ◦ Autoantibodies interfere with phospholipid- dependent reagents used in PTT tests ◦ Patients have no bleeding problems (though some have an increase risk of thrombosis) ◦ In vitro, any coag test using a phospholipid reagent will be falsely prolonged (PT, PTT) ◦ Coag studies must be performed using reagents that do not contain phospholipids

Comparison of Acquired Disorders TestDICPrimary Fibrinogenolysis Severe Liver Disease Vitamin K Deficiency Factor Inhibitor Lupus Anticoagulant Platelet Count DecNormalDecNormal PTInc Normal, except VII inhibitor Normal APTTInc FibrinogenDec Normal D-dimerIncNormal Plasminogen Dec Normal-decNormal Antithrombin DecNormalDecNormal Blood Smear FragmentsNormal Macrocytes Targets, acanthocytes Normal

References McKenzie, Shirlyn B., and J. Lynne. Williams. "Chapter 32." Clinical Laboratory Hematology. Boston: Pearson, Print.