mlab 1227: coagulation keri brophy-martinez

1. Coagulation Disorders: Secondary Hemostasis MLAB 1227: CoagulationKeri Brophy-Martinez

3. Terms Quantitative: absence of a coagulation protein Qualitative: Present in plasma but functionally defective

4. Lab Diagnosis: General PT prolonged aPTT prolonged Platelets normal

5. Patient Presentation Coagulation Factor Disorders Platelet Disorders Bleed from ruptured arterioles Deep muscular & joint bleeding Delayed bleeding Ecchymoses Hematuria No petechiae Bleed from capillaries Superficial bleeding Acute bleeding Ecchymoses Hematuria Petechiae

6. Factor VIII Deficiency Hemophilia A � classical hemophilia Sex-linked recessive (carried by female, manifested in the male) causing a marked decrease in VIII:C (VIII:vWf is normal) Deficiency of factor VIII portion of VIII/vWf complex Patient has normal circulating vWf Accounts for 80% of all hemophiliacs Less than 5% Factor VIII activity Results in symptoms of Bleeding occurs with NO trauma or trivial injury Spontaneous bleeding into joints, causes extreme pain and destroys cartilage of knees, elbows, ankles Deep tissue hemorrhage � internally Hematuria CNS bleeding PTT is greatly prolonged ( normal platelet function tests)

7. Factor VIII Deficiency Von Willebrand's Disease � lack of or defective VIII:vWF Autosomal dominant � seen in both males and females Most common inherited blood disorder Mild to moderately low Factor VIII:vWF (5-15%). Factor VIII function is affected more than the quantity. Platelet abnormalities � adhesiveness and aggregation, bleeding times

8. Von Willebrand's Disease Clinical Features Lab Diagnosis Mild bleeding in mucosal & cutaneous tissues Easy bruising Hallmark is variability of symptoms PTT prolonged PT normal Platelet count normal BT abnormal

9. Factor IX Deficiency � Hemophilia B, Christmas Disease <20% of all hemophiliacs Sex-linked recessive No Factor IX function Clinically indistinguishable from hemophilia A � must do special coag tests to distinguish Can be acquired in coumadin therapy and liver disease

10. Factor XI Deficiency � Rosenthal's Disease or Hemophilia C <5% of all hemophiliacs Autosomal recessive Highest incidence in Jewish persons of Russian decent Mucosal bleeding Requires therapy only following childbirth or surgery

11. Congenital Disorders of the Other Factors The following factors are rarely deficient or defective to the extent that coagulation is slowed � I, II, V, VII, X, XII, XIII Very rarely seen Severity of bleeding dependent upon concentration of factor present PK and HMWK disorders do exist but patients do not have bleeding tendencies. Defective activation of the fibrinolytic system are seen;therefore an increased chance of thrombosis PTT results are often markedly prolonged in these asymptomatic patients.

12. Acquired Coagulation Disorders Two or more factors generally affected Bleeding from multiple sites Usually result from underlying disease � �acquired� Produced by a variety of conditions Liver Disease Impaired or abnormal synthesis of I, II, V, VII, IX and X, XI, XII, XIII, PK, HMWK (also AT III, the antiplasmins, plasminogen) Enhanced destruction (primary fibrinolysis) of these factors Vitamin K Deficiency � II, VII, IX and X (also Protein C and S) Absence of vitamin K renders calcium binding sites nonfunctional Sources are diet and intestinal bacterial flora At birth, deficiency exists due to decreased production of factors since the liver is immature and absence of normal intestinal flora DIC: see next slides Pathologic Inhibitors: see next slides

13. DIC: Disseminated Intravascular Coagulation Consumption Coagulopathy Coagulation Disorder Thrombo-hemorrhagic disorder 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

14. DIC: Disseminated Intravascular Coagulation Pathological syndrome Uncontrolled formation of fibrin clots in circulating blood Small and large vessel thrombosis with impairment of blood flow and possible organ damage (systemic) Activation of fibrinolytic system to break down the excessive clots. Large amounts of FDP formed due to large number of clots being broken down Consumption of factors and platelets resulting in hemorrhage Secondary complication of conditions which cause hyperactivation of the intrinsic or extrinsic coagulation systems

15. DIC Causes Extrinsic activation 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

16. DIC: Causes con�t Causes Intrinsic activation 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 Snake venoms

17. 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

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

19. DIC: How Does It Occur? Step 3: Uncontrolled plasmin and thrombin enter circulation Why? Inhibitors such as ATIII have been depleted

20. DIC: How Does It Occur? Step 4: Appearance of Symptoms Bleeding from multiple sites Petechiae Purpura Occlusions in organs Oozing from arterial lines, venipuncture sites

21. DIC No one specific test for DIC, but FDP is the most helpful Lab values platelet count: decreased PT: increased PTT : increased Fibrinogen: decreased FDP /D-dimer: positive RBC fragments: present ATIII : decreased

22. 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

23. Acquired Coagulation Disorders: 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 Not normally synthesized by the body, bind with the factors making them unavailable for use in the cascade

24. Types of Inhibitors Directed against 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

25. Types of Inhibitors Lupus Inhibitor/Anticoagulant Seen in patients with autoimmune diseases, drug reactions, but also in normal patients Antibodies do not bind coag factors, but interfere with phospholipid-dependent reagents used in coag lab tests Patients have no in vivo 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