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Subject: Pathology Topic: CP-Blood Coagulation Lecturer: Dr.

Pascual Transcriptionist: Editor: Pages: 12

BLOOD COAGULATION Functions: Maintain blood in a fluid, clot-free state in normal vessels Rapid and localized hemostatic plug at the site of injury Abnormalities of clot formation may take two main forms: Failure to clot normally Failure to prevent excessive clotting Regulated by three general components: 1.Vascular wall 2. Platelets 3. Coagulation cascade
Diagrammatic presentation of normal homeostatic process

A.VASOCONSTRICTION: Shows that there is a site of injury, and in a period of arteriolar vasoconstriction occurs mostly as a result of neurogenic mechanisms and is improved by the secretion of local factors such as endothelin (a potent endothelium-derived vasoconstrictor). B.PRIMARY HEMOSTASIS: Shows that there is adhesion of platelets at the site of endothelial injury, and dramatic change in shape (from small rounded disks to flat plates with markedly increased surface area) and the release of secretory granules such as adenosine diphosphate (ADP) and thromboxane A2 (TXA2). Next, there will be recruitment of additional platelets (aggregation) to form a hemostatic plug primary hemostasis. C. SECONDARY HEMOSTASIS: At the endothelial injury, tissue factors are also exposed; such that are factor III and thromboplastin, a membrane-bound procoagulant glycoprotein synthesized by endothelium. It acts in conjunction with factor VII as the major in vivo pathway to activate the coagulation cascade leading to culminating thrombin generation. Remember: thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork deposition; also induces further platelet recruitment and granule release. As a result, the formation of fibrin polymerization as the secondary hemostasis sequence. D. ANTITHROMBOTIC COUNTER REGULATION: Here it shows the fibrin polymerization and platelet aggregation form a solid permanent plug to prevent for further additional damage or hemorrhage. Moreover, there is a release of counter-regulatory mechanisms, such as of tissue plasminogen factor (t-PA, a fibrinolytic product) and thrombomodulin (blocks coagulation cascade) to limit the formation of further increase of the hemostatic plug to the injury site.

SY 2011-2012

ENDOTHELIUM
Endothelial cells have the ability to restrain many aspects of normal hemostasis (stopping of blood flow). It can facilitate as antithrombotic and prothrombotic, whether there can be a thrombus formation, propagation or dissolution occurs. It has antiplatelet effect, anticoagulant and fibrinolytic effects wherein they inhibit the coagulation cascade discussed above, on the other hand it also has a procoagulant entity, in which the platelet factors (vWF), and antifibrinolytic affects are activated therefore, there will be an inhibition of t-PA (which can limit the increase of hemostatic plug at the injury site). Here are some factors that affect the endothelium per se: Antithrombotic properties: Antiplatelet effects Anticoagulant effects Fibrinolytic effects Prothrombotic properties: Platelet effects Procoagulant effects Anti-fibrinolytic effects Antithrombotic properties Antiplatelet effects During coagulation, platelets are activated and endothelial cells are stimulated by several factors such as thrombin and cytokines to produce endothelial prostacyclin (PGI2) and Nitric Oxide (NO), both of these are vasodilators and inhibitors of platelet aggregation thus, there will be no platelet adhesion to the surrounding uninjured endothelium and so the inactivated platelets. Endothelial cells also elaborate ADPase, further inhibits platelet aggregation. Anticoagulant effects They are mediated by membrane-associated, heparin-like molecules and thrombomodulin. Both of them act indirectly, the former are cofactors that allow antithrombin III to inactivate thrombin, factor X and several other coagulation factors. The letter binds with thrombin; converting it from a procoagulant to an anticoagulant capable of activating the anticoagulant protein C, this in turn inhibits clotting through proteolytic cleavage of factors Va and VIIIa; and requires protein S, synthesized by endothelial cells, as a cofactor. Fibrinolytic effects t-PA is synthesized by endothelial cells and promotes fibrinolytic activity to clear fibrin deposits from the endolethelial surfaces. Prothrombotic properties Platelet effects Whenever injury is encountered, it always result to platelet adhesion, may it be through vWF, which is an essential cofactor for binding platelets to collagen and other surfaces for both circulating and collagen bound, is synthesized largely by endothelium. If there is a loss of the endothelium it exposes the deposited vWF and allows the circulating vWF to also bind to the basement membrane Procoagulant effects Cytokines [e.g. tumor necrosis factor (TNF) or interleukin-1 (IL-1)] and bacterial endotoxin all induces endothelial cell production of tissue factor. It activates the extrinsic clotting pathway. Anti-fibrinolytic effects Again, endothelial cells produce plasminogen activator inhibitors (PAIs) that depress fibrinolysis.

PLATELETS Ultrastructure Glycocalyx: Outer membrane surface rich in glycoproteins o Glycoprotein Ib and Factor IX: receptor for vWF o Glycoprotein IIb and IIIa: fibrinogen Exposed by: Stimulation of thrombin ADP o Glycoprotein Va: receptor for thrombin Kinetics Maturation Megakaryoblast (progenitor cells) Mature megakaryocyte Mature Megakaryocyte o Platelet fields: clusters of pink granules in the cytoplasm o Individual platelets are shed from cytoplasm into marrow sinuses then released into the vascular lumen o mature megakaryocyte = 2000 7000 platelets o Normal circulation life: 7 10 days o Removed by macrophage in the liver and spleen or by active use in coagulation mechanisms Clinical findings of Patients with Platelet Abnormalities typically presents with: Skin and mucosal bleeding patterns Petechiae Ecchymoses Epistaxis Menorrhagia Patients who present with immediate postsurgical bleeding such as: Hemarthrosis, deep muscle, joint, intracerebral or retriperitoneal bleeding, and delayed postsurgical bleeding (1 4 hours after) suggest a defect in the COAGULATION CASCADE rather than a PLATELET ABNORMALITY. Platelets Normal/Range Values: 150-450 x 109/L 150,000 450,000/mm3 5-20 /OIF on peripheral smear

Abnormalities of Platelets can either be QUANTITATIVE or QUALITATIVE Quantitative - abnormal platelet count Qualitative - abnormal platelet function - can be surface membrane defect or a granule defect QUANTITAVE THROMBOCYTOPENIA decrease in the number or circulating platelets

Defective production in the bone marrow 1. Decrease number of megakaryocytes due to: congenital disorders acquired disorders (radiation, alcohol, thiazide diuretics, chloramphenicol, cancer chemotherapy) marrow replacement by malignant cells (*MYELOPHTHISIC ANEMIA) 2. Ineffective platelet production due to: hereditary thrombocytopenia Megaloblastic anemia problem in B12/folate deficiency -> derrangement of DNA synthesis -> ineffective production of platelets Erytholeukemia (Di Gugliemos syndrome) - an acute myelocytic leukemiaFAB classification, M6 Paroxysmal Nocturnal Hemoglobinuria (PNH)
From the book: PNH blood cells are deficient in three GPI-linked proteins that regulate complement . activity: (1) CD55- decayaccelerating factor (2)CD59 - membrane inhibitor of reactive lysis; a potent inhibitor of C3 convertase that prevents the spontaneous activation of the alternative complement pathway -most important factor (3) C8 binding protein

A. Disorders of the Distribution and Dilution of platelets in the circulation Splenic pooling: splenomegaly, hypersplenism * platelets are removed by macrophages in the spleen Hypothermia: vascular shunting Dilution in the circulation: transfused stored blood B. Disorders that result in Destruction of platelets 1. Combined consumption of both platelet and coagulation factors e.g. DIC and its causes 2. Isolated consumption of platelets
From the book: DISSEMINATED INTRAVASCULAR COAGULATION (DIC)- an acute, subacute, or chronic thrombohemorrhagic disorder characterized by the excessive activation of coagulation, which leads to the formation of thrombi in the microvasculature of the body.

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) caused by vascular wall dysfunction -> excessive deposition of platelet aggregates in renal and cerebral vessels Vascular endothelial cell damage, increase in PAF, deficiency of PAF-inhibitor, decrease PGI2, absence of t-PA FEMALE more affected than males Px will present w/ : microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, fever, renal disease *mnumonic ni doc: FAT RN (fat nurse) Fever, Anemia Thrombocytopenia- Renal, Neurologic HEMOLYTIC UREMIC SYNDROME Symptoms similar to TTP but less pronounced neurologic symptoms and more pronounced renal symptoms FRAT fever, renal disease, anemia, thrombocytopenia VASCULITIS HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) Associated with pregnancy or delivery common in pre-eclamptic or eclamptic patients Microangiopathic hemolysis 3. Immune destruction of platelets a.) IDIOPATHIC (IMMUNOLOGIC) THROMBOCYTOPENIC PURPURA (ITP) -type 2 hypersensitivity reaction Acute ITP children 2-6 years of age sudden onset of thrombocytopenia following viral infections (rubella, chickenpox, CMV, and toxoplasmosis Lasts for 2-6 weeks with a spontaneous remission in 80% of patients Platelet count <20,000/mm3 Viral attachment and antigen alteration of platelet membrane proteins -> platelet autoantibodies (most often IgG) Chronic ITP adults 20-40 years old Female > male Insidious onset: can last for months to years Platelet count: 30,000 80,000/mm3 Tx: splenectomy (to decrease the number of macrophages in the spleen)

b) POST TRANSFUSION PURPURA - antiplatelet antibodies produced by recipient of platelet transfusions c) DRUG-INDUCED ANTIBODY FORMATION : Quinidine and Heparin (mechanism : drug attaches to platelet membrane surface -> alter platelet membrane protein -> develop Abs against platelets -> thrombocytopenia corrected after withdrawal of drug ) II. THROMBOCYTOSIS Bleeding or thrombotic complications Increase in circulating platelet count 2 types: Essential Thrombocytosis commonly occurs with inc.levels of other hematopoietic cells Result of primary bone marrow disorder Often caused by a clonal proliferation that affects all hematopoietic cells Increased bleeding tendencies because of possible accompanying functional abnormalities Seen in Hodgkins disease, polycythemia vera (very high RBC count), myelofibrosis, chronic myelogenous leukemia, AML- M7 type (acute megakaryocytic) Secondary Thrombocytosis- occurs in assoc. with massive blood loss Iron deficiency anemia assoc. with chronic blood loss Chronic inflammatory disease Rebound thrombocytosis occurs after platelet depletion through a massive blood loss Post-splenectomy no sequestration of platelets so values will increase QUALITATIVE 1. Surface membrane defects BERNARD SOULIER DISEASE Functions disorder which may appear similar to ITP Decrease in platelet vWF receptor (glycoproteins 1b and IX) Bernard-soulier Vs Von Willebrand disease
Bernard-Soulier Disease vW FACTOR vW RECEPTOR (glycoproteins 1b and 9) normal decrease Von Willebrand Disease decrease normal

GLANZMANNS THROMBASTHENIA Platelets are normal in number and appearance Decrease in surface glycoproteins IIb and IIIa and a reduction in numbers of available fibrinogen binding sites End result: disorder of platelet-platelet interaction *platelets are able to recruit other addtional platelets to the hemostatic plug but it
cannot form a permanent plug because you it doesnt have binding sites for FIBRINOGEN

2. Abnormalities in granular fraction of platelets DENSE GRANULES Hermansky-Pudlak Syndrome- decreased number of platelet dense granules Chediak Higashi Syndrome: - autosomal dominant - presence of giant lysosomes in the cytoplasm of ALL precursor blood cells --> dense granule destruction Wiskott-Aldrich Syndrome: sex linked, decreased in the number of dense granules characterized by : eczema ,thrombocytopenia and immunodeficiency ALPHA GRANULES (Gray Platelet Sydrome) -aggregation and release properties diminished 5

3. Deficiencies of thromboxane generation: deficiency of cyclo-oxygenase enzyme 4. Acquired QUANTITATIVE THROMBOCYTOPENIA Di Guglielmos Syndrome Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome Vasculitis HELLP Idiopathic (Immunologic) Thrombocytopenic Purpura THROMBOCYTOSIS Essential Thrombocytosis Hodgkins Disease Polycythemia Vera Myelofibrosis Chronic myelogenous Leukemia AML M7 Secondary Thrombocytosis Iron Deficiency Anemia Chronic Inflammatory Disease Rebound Thrombocytosis Splenectomy QUALITATIVE Surface membrane defetcs 1. Bernard-Soulier Disease 2. Glanzmanns Thrombasthenia

Abnormalities in granular fractions of platelets Dense Granules: 1. Hermansky-Pudlak Syndrome 2. Chediak-Higashi Syndrome 3. Wiskott-Aldrich Syndrome Alpha Granules: Gray Platelet Syndrome

Laboratory Evaluation of Platelets *check for quantitative abnormalities FIRST 1. Platelet count Normal Values : 150,000 400,000/mm3 5-20 platelets/ oil immersion field on peripheral smear 2. Bleeding time Indicator of platelet abnormality in number or function Abnormal if platelet count is less than 100,000/mm3 and prolonged in cases of Glanzmanns thrombasthenia, uremia and myeloproliferative syndromes, aspirin intake, vonWillebrand disease
PROCEDURE: Use of spring lancet producing a 5mm long and 1.0mm deep cut Normal values: 2-8 minutes 3.Torniquet test

Demonstrate capillary abnormality due to intrinsic defect in the capillary walls (capillary fragility) or to some type of thrombocytopenia 4.Clot retraction Begins 1 hr. and completes by 24 hrs. (a firm clot with 50% serum and 50% clot) Deficient clot retraction in all types of thrombocytopenia and in Glanzmanns thrombasthenia COAGULATION CASCADE Intrinsic Pathway Triggered by damage to the endothelial lining of blood vessel When blood comes in contact with certain foreign bodies Evaluated by activated Partial Thromboplastin Time (aPTT) Extrinsic Pathway Triggered by tissue thromboplastin (Factor III) Released by damage endothelial and body tissues Evaluated by Prothromin Time (PT)

Mnemonics: Intrinsic = pItt Extrinsic = pEt

The figure shows the intrinsic &extrinsic pathways and the final common pathway. Intrinsic pathway It starts with the activation of Factor XII (Hageman factor) to Factor XIIa with the help of High molecular weight Kininogen (HMWK) collagen. At the same time, Prekallikrein becomes Kallikrein. Factor XIIa then activates Factor XI to XIa which then activates Factor IX to Factor IXa. At the same time Factor VIII, with the help of Thrombin (IIA), activates Factor VIIIa. Factor s IXa and VIIIa, together with Calcium, activates Factor X to Factor Xa. Factor Xa activates Factor II to Factor IIa with the help of activated Factor Va and Calcium. Thrombin (Factor IIa) activates Fibrinogen, with the help of Calcium, to Fibrin. At the same time, it activates Factor XIII to Factor XIIIa. Finally, Factor XIIIa cross-links Fibrin to form Fibrin Polymer. Extrinsic Pathway It starts with the tissue injury with the release of Tissue Factor (Thromboplastin) which activates Factor VII to VIIa. Factor VIIa, with the help of Calcium, also activates Factor X to Xa. And the process goes on.. (Final common pathway) Factor Xa activates Factor II to Factor IIa with the help of activated Factor Va and Calcium. Thrombin (Factor IIa) activates Fibrinogen, with the help of Calcium, to Fibrin. At the same time, it activates Factor XIII to Factor XIIIa. Finally, Factor XIIIa cross-links Fibrin to form Fibrin Polymer.

COAGULATION FACTORS AND FACTOR DEFICIENCIES Factor I (Fibrinogen) Glycoprotein synthesized by the liver Acute phase reactant o Increases in response to trauma or to onset of a variety of illnesses Plays the final major step in coagulation Decreased in severe liver disease Sources: fresh frozen plasma or cryoprecipitate Factor II (Prothrombin) Proenzyme synthesized by the liver Vitamin K dependent factor Maybe decreased in severe liver diseases Deficiency: Autosomal recessive, extremely rare Factor III (Tissue Factor) Factor IV (Calcium) Factor V (Labile Factor) Synthesized by the liver Found in plasma but not in serum Very unstable, must be frozen to maintain activity Deficiency: also called parahemophilia Associated with bruising and soft tissue hemorrhage Factor VII (Stable Factor) Synthesized by the liver Vitamin K dependent factor Present in both serum and plasma Deficiency: Autosomal recessive; large hemorrhages into joint, body cavity, intracranial and intramuscular sites; delayed post-surgical bleeding Factor VIII (von Willebrand Factor complex/Antihemophilic Factor) Found in plasma but not in serum o Formed by 2 subunits VIII:C (antihemophilic factor) Synthesized by the liver and is genetically controlled on the X-chromosome

Factor VIII:R (vWF/ factor VIII-related protein) Synthesized by endothelial cells, megakaryocytes and platelets Has effect on platelet adhesion and platelet aggregation Deficiency: von Willebrand disease Classic Hemophilia Sex-limited recessive trait Female carriers and males have clinical diseases Severe bleeding following trauma Bleeding into joints (hemarthrosis), mouth, urinary tract, GIT and intracranial hemorrhage Depressed factor VIII:C activity; normal vWF; PT and BT are normal; aPTT abnormal

Factor IX (Plasma Thromboplastin Component) X-linked recessive trait Hemophilia B or Christmas Disease Produces a hemophilia-like syndrome Found in plasma or serum Vitamin K dependent factor

Factor X (Stuart Factor) Present in serum and plasma Part of intrinsic and extrinsic pathways Vitamin K dependent factor Factor XI (Plasma Thromboplastin Antecedent) Autosomal recessive trait Present in serum and plasma Mild bleeding Factor XII (Hageman Factor) Surface contact activator for intrinsic pathway Does not cause clinical bleeding Patients with factor XII deficiency have increased incidence of myocardial infarction and thrombosis Factor XIII (Fibrin Stabilizing Factor) Autosomal recessive trait Bleeding noted in newborns: umbilical stump bleeding Also associated with intracranial hemorrhage, soft tissue hemorrhage, recurrent spontaneous abortions, delayed bleeding and poor wound healing aPTT, PT and BT normal Diagnosis: 5M Urea clot dissolution time o Measure time it takes for a clot to dissolve in urea o Normal: clot dissolves in 24 hours o In Factor XIII deficiency; clot dissolves faster than 24 hours o High Molecular Weight Kininogen (HMWK / Fritzgerald Factor) Part of Kallikrein system; affects Factor XII Also plays a role in inflammatory response Deficiency is rare and no clinical bleeding is induced Prekallikrein (Fletcher Factor) Deficiency does not predispose to clinical bleeding Key Facts regarding Coagulation Factors 9 of the 13 coagulation factors are proenzymes that must be activated o Exceptions: Fibrinogen (not an enzyme) Factor III (tissue factor ) it is a complex rather than a single protein Factor IV (calcium) Vitamin K is essential for post-translational carboxylation of factors II, VII, IX, X Many of the coagulation factors are decreased at birth and do not reach adult levels for several months. The PT and aPTT cannot be used in newborns Fibrinogen or platelets are at normal levels at birth, and factor VIII:C and VIII:Ag are elevated at birth Factor VIII:Ag and Fibrinogen are acute phase reactants (i.e., they are elevated in any condition associated with inflammation) LABORATORY EVALUATION OF COAGULATION Specimen Collection (aPTT and PT) Whole blood anticoagulated with sodium citrate (citrate binds to calcium and prevents coagulation) 9:1 blood:citrate ratio is required o A ratio less that 9:1 may falsely increase results Specimen must be assayed as soon as possible and the plasma must be kept cold to avoid factor deterioration Activated Partial Thromboplastin Time (aPTT) Reference Value: 25-35s; ratio: < 1.2

Used in detecting intrinsic pathway abnormalities before prothrombin to thrombin stage Sensitive to effects of heparin Principle: citrated blood is mixed with a negatively charged activator, a partial thromboplastin as a phospholipid source and Calcium. Time to form fibrin clot is measured Prothrombin Time Reference value: 11-13s; % activity: 70-120; INR: <1.15 Uses: 1. Monitors extrinsic pathway 2. Monitor anticoagulant therapy with Coumadin or Warfarin 3. Liver Funtion test indicates defect in extrinsic coagulation system (Factors II, V, VII, X). this can be affected by high heparin blood volumes. Principle: citrated blood is mixed with tissue factor and Calcium to replenish Calcium bound by the citrate). Time to form fibrin clot is measured. Mnemonics: from PET to PWET. Since warfarin is added. Thrombin Time Reference value: 10-20s Used for abnormalities in the fibrinogen or fibrin stage of coagulation Principle: Commercially prepared thrombin reagent is added to citrated plasma and time required for clot formation is measured Prolonged TT can be observed in patients receiving therapeutic heparin, increased fibrin degradation products and in patients with any disorder of hypofibrinogenemia. Plasma Fibrinogen (Quantitative fibrinogen assay) Principle: o A measured amount of commercially prepared thrombin reagent is added to citrated plasma o Clotting time measured and compared with clotting times of plasma fibrinogen standards (contg known amount of fibrinogen) o Clotting time (seconds) plotted against mg/dL of fibrinogen Low values may be due to high titers of fibrinolysins or DIC RV: 200-400 mg/Dl

5M Urea clot dissolution time Assess factor XIII Measure time it takes for a clot to dissolve in urea Normal: clot dissolves in 24 hours In factor XIII deficiency: clot dissolves faster in 24 hours

Substitution tests / Mixing studies Adapted if primary tests like PT or APTT are abnormally prolonged and indicate factor deficiency Patients plasma + normal plasma or serum substitute, APTT or PT repeated Correction of original prolonged APTT or PT indicates that the deficient factor has been added to patients plasma by the substitution solution

FIBRINOLYSIS Enzymatic pathway of clot dissolution Plasminogen is adsorbed onto fibrin polymers within the clot T-Plasminogen activator, from surrounding endothelial cells, activates plasminogen into plasmin lyses fibrin into fibrin split products or fibrin degradation products D dimer

Fibrinolysins / Plasmin anticoagulants Naturally occurring or acquired enzymes that attack and destroy fibrinogen and fibrins PRIMARY FIBRINOLYSINS

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o Acquired o Attack fibrinogens o Eg: in malignancies, extensive surgeries SECONDARY FIBRINOLYSINS o Naturally occurring; Plasmins o Attack fibrin clot to produce FIBRIN SPLIT PRODUCTS TEST OF FIBRINOLYSINS o Clot lysis test; Fibrinogen assay; thrombin time; PT; APTT; tests for FDP

FIBRINOLYTIC DISORDERS: Disseminated Intravascular Coagulation (DIC) Release of tissue thromboplastin and unknown substances liberated into the blood stream and result in deposition of fibrin and fibrin precursor substances like fibrinogen Major Disorders Associated with DIC o Obstetric Complications Abruptio placentae; retained dead fetus; septic abortion; amniotic fluid embolism; toxemia with pregnancy o Infections Gram (-) sepsis; meningococcemia; rocky mountain spotted disease; histoplasmosis; aspergillosis; malaria o Neoplasms Carcinomas of pancreas, prostrate, lung and stomach; acute promyelocytic leukemia o Massive Tissue Injuries Acute intravascular hemolysis; snakebite; giant hemangioma; shock; heat stroke; vasculitis; aortic aneurysm; liver disease o S/Sx of bleeding: ARF; RF; tissue hypoperfusion and infarction o Laboratory tests: Thrombocytopenia; hyperfibrinogenemia; PT and APTT abnormalities; elevated FDP / DDimer

ANTICOAGULANT SYSTEMS Coumarin Anticoagulants Inhibits Vit. K utilization by liver cells affecting Factors II, VII, IX, X Use of coumarin (Warfarin sodium) for antithrombotic activity Monitoring of coumarin therapy by PT Therapeutic range of 1.3 to 1.5 times control value or around 15-20 sec. (N= 11-13 sec.) May also report INR International Normalized Ratio INR is used for long-term warfarin therapy after patients have been stabilized For standardization of all thromboplastin reagents which permits patients to have comparable results in any laboratory Heparin / Antithrombin III (AT-III) AT-III o Serine protease that binds to and inhibits thrombin o Requires heparin as an activator to produce effective anticoagulation o Synthesized by liver Heparin o Biologic substance extracted from porcine gastric mucosa and bovine lung tissues o Contains a CHO group that binds to AT-III and increase anti-coagulant effect o Monitoring of heparin therapy by APTT, TT o Therapeutic range is 1.5 2.5 times the APTT upper reference limit Protein C / Protein S System Protein C o Serine protease producing inactivation of Factor V and Factor VIII thereby inhibiting conversion of prothrombin to thrombin o Produced in the liver o Vitamin K dependent 11

o Must be activated by THROMBOMODULIN Protein S o Cofacor needed by Protein C for maximum effect o Synthesized by the liver o Vitamin K depended Immunologic Type Coagulation Factor Inhibitor Antiphospholipid antibody (APA) inhibitors of coagulation factor o Lupus anticoagulant (LAC) o Anticardiolipin Antibody (ACA) Are of IgG, M or A type antibody type inhibitors of coagulation factors Interfere with coagulation assays that use phospholipids reagents such as APTT o Effects of thrombosis, fetal death

INVESTIGATION OF A PATIENT WHO IS ACTIVELY BLEEDING History bleeding / purpura Bleeding time to test for platelet and capillary fragility abnormalities Peripheral blood smear platelet and RBC morphology APTT for intrinsic pathway abnormalities PT for extrinsic pathway abnormalities FDP (D-dimer) for DIC

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