Disorders of Coagulation and Fibrinolysis Two Major Etiologic Groups 1.

INHERITED DISORDERS affect one hemostatic component Intrinsic Pathway Disorders: this pathway brings about activation of Factor X 3 Proteins in Plasma begin this pathway: - Factor XII - Prekallikrein (Fletcher) - High Molecular Weight Kininogen (HMWK; Fitzgerald) Contact Phase of Coagulation : interrelated roles of these proteins -Contact point in time when plasma hemostatic components and tissues/artificial surfaces meet, after which a chain of rxn ensues. - Product of contact phase: Activation of Factor XI, carries the intrinsic pathway forward Factor XII, Prekallikrein, HMWK, Factor XI: four plasma contact factors; synthesized in liver - deficiency of any one of the first 3: hemostatically competent and asymptomatic appear to bypass contact activation schemes, generating fibrin by other means. Intrinsic system is markedly slowed by defective contact phase only when tested in vitro. - roles of four proteins are interdependent - proteins are structurally related First 3 contract factors have roles in fibrinolytic system, in activation of factor VII, and in bodys response to systemic infectious agents. -Intrinsic pathway Disorders - Extrinsic and Common Pathway Disorders - Postcoagulation Stabilization Defects

LF: APTT- prolonged, corrected by both adsorbed plasma and aged serum : Factor assay: specific factor deficiency & activity levels one-stage prothrombin time & bleeding time not affected Therapy: no single specific blood component exists : Fresh whole blood, fresh plasma, fresh frozen plasma :Plasma concentrations: raised to 20% - 30% of normal activity to protect patient E. Factor X Activation Phase Disorders Factor VIII:C and IXa = intrinsic pathway and factor VIIa in extrinsic, in conjunction w/ lipid and calcium : required for activation of factor X deficiency of factors needed for activation by intrinsic pathway cause serious bleeding disorders, occur frequently F. Factor VIII:C Deficiency (Hemophilia A, Classic Hemophilia) recorded in antiquity Royal Dss : Queen Victoria of England (carrier), condition spread through Europes Royal families described in 1803 85% of diagnosed congenital bleeding disorders are Hemophilia A, estimated @5 cases/100T population sex-linked disorder : X chromosome by carrier woman to son, Carrier women produce normal daughters who carry defect. Sons of affected men are unaffected, but daughters are obligatory carriers 1/3 of new cases occur spontaneously: mutations or variability in expression of X chromosomes: causing skipped generations

milder form of Hemophilia than VIII:C deficiency; Px not as prone to hemorrhages in GIT, abdomen, CNS, urinary tract severely deficient factor IX px: clinically indistinguishable fr classic hemophila 3 variants (based on antigenic reactivity of Factor IX): o CRM+ : antigen reacts w/ specific antibody (cross material positive) o CRM- : antigen undetable (cross material negative) o CRMR : reduced- antigen reactivity reduced but detable LF: APTT : prolonged in moderate to severe deficiency, corrected w/ aged serum, not w/ adsorbed plasma APTT: w/in normal limits (mild cases), Px may exhibit severe bleeding w/ trauma and surgery Specific factor IX assay: diagnosis & to assess activity levels during therapy Therapy: commercial concentrate products or human single-donor plasma units

afibrinogenemia prolonged in all lab tests duration that depend on fibrin formation hypofibrinogenemia tests on fibrin formation, may or may not be prolonged, platelet counts normal thrombin time, variable PT and APTT Addition of reagent fibrinogen: correct prolonged endpoints POST COAGULATION STABILIZATION DEFECTS A. Factor XIII (Fibrin Stabilizing Factor) Deficiency CF: rare, symptoms: similar to mild hemophilia syndrome incompatible w/ pregnancy unless replacement therapy provided w/out gestation avoid aspirin products LF: inadequate crosslinking of fibrin: results in unstable & friable clot w/ excessive red cell fall out fibrin clots incubated w/ 5M Urea or 1% monochloroacetic acid dissolve rapidly, if adequate controls for excessive fibrinolysis are included: test is relatively specific condition cannot be evaluated in presence of heparin immunologic procedures: measure quantities of factor XIII exist ACQUIRED DISORDERS OF COAGULATION AND FIBRINOLYSIS A. Hepatic Dss liver dss: causes decreased synthesis of coagulation, lysis and inhibitory proteins, impaired clearance of activated hemostatic components neonatal liver profile: display decreased levels of plasma contact factors due to: hepatic immaturity lack sufficient levels of plasminogen and antithrombin III have unique fetal fibrinogen that doesnt behave in same manner as adult show decreased levels of Vit K dependent factors Adult parenchymal liver dss: cirrhosis, hepatitis, infiltrative liver dss (neoplasm) affect synthetic capacity of organ prolonged PT: sign of worsening dss bec of depression of Vit K dependent clotting factor synthesis, prro dietary intake, or Vit K malabsorption LF: screening tests: monitor hemostatic status PT, APTT, TCT, bleeding time, platelet count, fibrinogen levels and fibrin spilt products Therapy: infusion of fresh plasma: bolster circulating levels of procoagulants & minimize hemorrhagic risks commercial prothrombin complex concentrates: not used in liver dss bec of depressed levels of inhibitory antithrombin III availabiltity -

CF: Severity of bleeding diathesis is tied to degree of deficiency : 1% activity of Factor VIII:C most severely affected 2-5% - moderately affected 5% - mildly affected CF: Patients who maintain activity above 6%: clinically silent until traumatized or submitted to surgical procedures w/out prophylactic preparation : Activity level remains fairly constant throughout life LF: APTT screening test used; prolonged APTT corrected by fresh adsorbed plasma, NOT SERUM : Factor VIII:C assay- ID deficiency & characterize ability levels :Combined factor VIII:C and VII:Cag assays: det obligatory carriers Therapy: replacement of factor VIII:C by infusion of cryoprecipitate products done to arrest bleeding : Criteria for prophylactic infusions: cost, availability, home/hospital settings, age, status of joints, frequency of bleeding episodes, risk of hepatitis/AIDS psychological adjustment of patients and family members : Factor Assays are used to monitor therapeutic process: activity levels of 10-20%: stop bleeding into muscles 20-30% : stop deeper joint bleedings, hematomas 50-80% : GIT bleeding, dental extractions, surgery :IgG Ab (w/ Kappa light chains and y4 heavy chains) present in 10% of severely affected px, esp those who fail to respond to infusions of factor VIII:C FACTOR VIII:C and FACTOR VIII:vWF 2 distinct but related components: compromises Factor VIII/vWF (Factor VIII complex) Serves as cofactor in activation of Factor X to Xa Thrombin : required to modify structure of Factor VIII:C in order for it to fulfill role in accelerating proteolytic action of Factor IXa on Factor X -

H. Factor X (Stuart-Prower Factor) Deficiency 1959, Inherited as autosomal incompletely recessive trait uncommon in general population CF: symptoms highly variable possible of mult factor deficiencies must be eliminated when making diagnosis LF: prolonged PT, APTT and Prothrombin utilization abnormality Specific factor X assay: diagnostic PT corrected by aged serum, NOT by adsorbed plasma Therapy: uses frozen plasma components or prothrombin complex concentrates 10-40% of normal: considered for hemostasis I. Factor V Deficiency (Owrens dss) 1944, Norway, Professor Owren Adsorbed normal plasma, added to patients plasma corrected prolonged PT CF: less than 10% of normal results in hemorrhagic diathesis Deficiencies of platelet born factor V (platelet factor 1), may cause abnormal bleeding time, seem to precipitate more clinical problems than decrease in plasma factor V levels Platelet aggregation studies normal LF: PT and APTT prolonged If PT is corrected w/ adsorbed normal plasma: factor V deficiency Possibility of mult factor deficiencies must be considered Specific factor assay: diagnostic Therapy: fresh frozen plasma aspirin products avoided when there is platelet involvement

2. ACQUIRED DISORDERS differ in severity and complexity characteristically involve mult hemostatic components or pathways o Hepatic Dss o Vitamin K deficiency o Therapeutic Anticoagulation o Acquired Circulating Anticoagulant (inhibitory) substances o Massive Transfusion Effects o Artificial Surface Effects o DIC INHERITED DISORDERS OF COAGULATION Inherited Pathway Disorders: A. Factor XII (Hageman Factor) Deficiency: CF: Homozygous factor XII deficiency: no bleeding disorder; may be vulnerable to excessive clotting LF: Normal except for det of intrinsic system: prolonged APTT (corrected w/both adsorbed plasma and aged serum) : Factor XII assays confirm Therapy: No therapy is necessary; abnormality is in vitro phenomenon B. Prekallikrein (Fletcher Factor) Deficiency: CF: dont demonstrate clinical bleeding; vulnerable to thrombotic events LF: similar to factor XII deficiency; Px APTT results will shorten if plasma is incubated w/ surface-activating substances (kaolin) C. High Molecular Weight Kininogen (Fitzgerald Factor) Deficiency: absence results in poor contact-phase rxns, deficiency of kinin formation, and defective fibrinolysis rxns CF: autosomal recessive defect, does not produce clinical bleeding : APTT results mildly prolonged, other tests w/in reference limits D. Factor XI deficiency (Hemophilia C) 1st inherited disorder in intrinsic cascade: clinical bleeding syndrome is attributed Jewish population CF: mild bleeding syndrome responds well to therapy; silent until stressed by trauma or surgery : clinical syndrome: epistaxis, hematuria, menorrhagia :surgery/trauma: exaggerated bleeding

J. Factor II (Prothrombin) deficiency inherited as dysfunction or deficiency rare in general population CF: less than 50% activity exhibit mild bleeding aspirin: bleeding tendencies Therapy: fresh frozen plasma : usual choice K. Factor I (Fibrinogen) Deficiency rare Causes of defect in fibrin formation: afibrinogenemia: inherited lack of fibrinogen hypofibrinogenemia: inherited deficiency of fibrinogen dysfibrinogenemia: inherited production of dysfunctional fibrinogen molecule all inherited as autosomal traits CF: variation in severity of bleeding manifestations surgery & trauma presents risks: poor wound healing noted LF:

B. Vitamin K Deficiency One-Stage PT: used to asses levels of Vit K dependent coagulation factors in newborn C. Therapeutic Anticoagulation Heparin Coumarin Drugs D. Circulating Anticoagulant (Inhibitory Substances) anti lupus antibody fibrin spilt products anti factor VIII in hemophilia anticoagulant drugs abnormal immunoglobulins in mult myeloma and related dsss E. Massive Transfusion Effects transfusion of large quantities of blood leads to: excessive quantities of infused citrate donor product incompatible w/ recipients system deficient labile clotting factors or platelets in stored blood Bleeding Time: sensitive indicator of depressed platelet function in extensively transfused patients

G. Factor IX Deficiency (Hemophilia B, Christmas Dss) 1947, Pavlovsky: in vitro mixing of plasmas of 2 hemophilia patients = correction of recalcification time of both plasmas (results were not consistent w/ classic hemophilia) 1952, Hemophilia px who possessed Factor VIII in plasma, but whose serum did not contain another substance that require Vit K for synthesis and could be adsorbed into barium salts Factor was named thromboplastin component (PTC) or Christmas Factor surname of one index patient CF:

Artificial Surface Effects Consequences of exposing blood to artificial surfaces: formation of thrombi and emboli consumption of procoagulant proteins and platelets alteration of function of these proteins incitement of systemic syndromes (fever, vasoconstriction, bronchial constriction) when blood and artifact surface meet, plasma proteins, especially fibrinogen, coat exposed area. Platelets may or may not attach, spread, degenerate APTT, PT, platelet count, fibrinogen level, plasminogen level, antithrombin III assay, FSP determination and fibrin monomer titer may be used to evaluate & monitor effects of artificial surface w/in patients vascular system.