HEMA2 LEC WK 7: Coagulation Disorders Quantitative and Qualitative PDF

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Summary

COAGULATION DISORDERSOUTLINE Coagulation Disorders a. Disorders of fibrinogen and related disordersb. Acquired disorders of fibrinogenc. Inherited extrinsic and common pathway hemorrhagic disordersCOAGULATION DISORDERS● If you lack or have defective clotting factors, you will end up not activating t...

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COAGULATION DISORDERS OUTLINE 1.

Coagulation Disorders a.

Disorders of fibrinogen and related disorders

b.

Acquired disorders of fibrinogen

c.

Inherited extrinsic and common pathway hemorrhagic disorders

COAGULATION DISORDERS ● If you lack or have defective clotting factors, you will end up not activating them and have basic clinical manifestation of BLEEDING ● Hyperthrombotic states ○ End point: No lysis of Clot will end up with lots and lots of THROMBOSIS ○ This is a separate lecture

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Figure 1. Balance of hemostasis. Coagulation and fibrinolytic systems are in perfect balance as long as positive and negative influences are equal. PLATELETS AND COAGULATION FACTORS drive the clotting process, while PLASMIN ACTIVATORS drive the opposing fibrinolytic system. Both systems are held in check by regulators and inhibitors. Table 1. REFER TO FIGURE 1: ● BALANCE OF HEMOSTASIS is regulated by several factors. It is a balance between COAGULATION and FIBRINOLYSIS ● The process of hemostasis maintains BLOOD in its normal form (LIQUID) ○ Blood should be in an INTACT BLOOD VESSEL ○ It should flow normally ■ AXIAL FLOW ● central flow at the core of the blood stream wherein the cells are located ● Platelet, WBC and RBC are located ● Rapid Flow ■ LAMINAR FLOW ● at the periphery, devoid of any cell ● Purpose is to protect the lining epithelium (ENDOTHELIAL LINING OF THE BLOOD VESSEL) ● Slow flow ● Within the blood are the COAGULATION FACTORS and PLATELETS ○ Will activate the coagulation ○ Primary Hemostasis: Involves platelets ○ Secondary Hemostasis: Involves coagulation Factors

COAGULATION ● End product: FIBRIN ○ Formation of Fibrin within the blood vessel is basically a THROMBUS FORMATION, which is not normal so fibrinolytic system is activated ● To have normal hemostasis, you have to maintain the normal flow with no barriers ● INHIBITORS OR REGULATORS ○ Antithrombin III ○ Protein C ○ Heparin cofactor II FIBRINOLYTIC ● Lyse the Fibrin formed or clot ● Plasmin is activated by t-PA ● REGULATORS/INHIBITORS ○ t-PA inhibitor ○ A2- antiplasmin

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SUMMARY OF THE DISCUSSION

Figure 2. Coagulation disorder algorithm AT-III: antithrombin III; DIC: disseminated intravascular coagulation Table 2. REFER TO FIGURE 2: DISORDERS OF FIBRINOGEN (Factor I)

CONGENITAL DEFICIENCIES OF INTRINSIC AND EXTRINSIC PATHWAYS

ACQUIRED DISORDERS

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● HEREDITARY (Primary) ○ Afibrinogenemia (absence; quantitative) ○ Hypofibrinogenemia (decreased; quantitative) ○ Dysfibrinogenemia (qualitative defect of fibrinogen) ■ Has normal amount of fibrinogen but the function is abnormal or non-functional ■ Will still end up with bleeding ○ Decrease in Factor XIII (Deficiency) ■ Factor XIII does not belong to any of the 3 pathways ■ It is at the end-point, it only stabilizes the clot ■ It is an autonomous factor and it cannot be determined by any of the tests used in the 3 pathways; it has a separate ASSAY ● ACQUIRED (Secondary) ○ DIC ○ Primary Fibrinolysis ○ Liver Disease ■ Important because the LIVER is the main processing zone of the body, it metabolizes proteins, lipids and carbohydrates ■ Also produces majority of the clotting factors

● If there is any deficiency in the clotting factors, the clotting mechanism will not progress and you cannot end up with fibrin ○ You will instead end up with BLEEDING ● All are HEREDITARY (acquired from the genes of the parents) ● Contact Factors ○ Involves PF XII, PK, & HMWK ● VIII Deficiency may induce either: ○ Hemophilia A (most common) ■ Deficiency in factor VIII:C (coagulant component) ○ Von Willebrand Disease ■ Deficiency in Factor VIII:R (receptor component) **may affect each other in the 2 types of Factor VIII deficiency** ● Factor IX deficiency or Hemophilia B ● Factor X deficiency ● Factor VII deficiency ● Factor V deficiency ● Factor II deficiency ● There is no such thing as Factor III deficiency or the tissue factor because it is found in all over the body ● CALCIUM is PF IV, it has a different metabolic pathway and is not produced in the liver

● Acquired Factor VIII deficiency ○ Pregnancy: temporary deficiency ○ Autoimmune: SLE ■ May dampen or decrease the function and production of Factor 8 ● Factor X deficiency ○ Due to amyloidosis ● Factor XIII ○ Has something to do with ISONIAZID ● Lupus-like Anticoagulant ○ In-relation to factor 8 ● Vitamin K deficiency ○ Affects the vitamin K dependent factors (2, 7, 9, 10) ● HEPARIN ○ Heparin therapy may affect the clotting factors ○ Heparin is a parenteral anticoagulant ○ Coagulation test to assess heparin therapy is APTT *Warfarin and Coumadin are oral anticoagulants and is monitored by PT

All will lead to BLEEDING, be it acquired or hereditary Table 3. DISORDERS OF FIBRINOGEN AND RELATED DISORDERS HEREDITARY DISORDERS OF FIBRINOGEN AEtiology

Clinical Features

DYSFIBRINOGENEMIA

/ HYPO- FIBRINOGENEMIA

Quantitative deficiency due to lack of synthesis by the liver A- Absence Hypo- Decreased amount of production AR trait

Qualitative abnormality due to the change in the structure and function

AFIBRINOGENEMIA: Severe Spontaneous hemorrhages (umbilical, mucosal, GIT, and intracranial regions)

Posttraumatic or postoperative bleeding of MUCOSAL TISSUES

FACTOR XIII DEFICIENCY AR trait

AR Trait Moderate-to-severe bleeding spontaneous bleeding,

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● Greater degree of lack of FIBRINOGEN= greater degree of BLEEDING ● This is the most severe ● UMBILICAL CORD: A newborn with the umbilical cord clamped is still prone to bleeding may be seen by the pediatrician as a sign of afibrinogenemia HYPOFIBRINOGENEMIA: Bleeding symptoms correlate with fibrinogen concentration ● Less severe Laboratory Findings

Treatment

Prolonged BT ● Fibrinogen bridges do not form- Platelet aggregation defect ○ Adhesion is by vWF, collagen, and GP Ia ○ Link fibrinogen to induce aggregation is by: GP IIb ○ A- and Hypo- will prolong bleeding time due to lack of AGGREGATION or it was inhibited ■ Adhesion can still occur ○ Platelets can also produce fibrinogen ● Fibrinogen has 2 components ○ Fibrinogen as a class(?) of proteins (factor I) ○ Fibrinogen factor in your platelet Decreased fibrinogen Prolonged PT, aPTT, & TT ● If PT is prolonged but aPTT is normal, it is an extrinsic pathway deficiency ● Prolonged aPTT: intrinsic pathway ● Both prolonged: Common pathway deficiency ● Multiple deficiencies may occur in LIVER DISEASES ● TT: normal if the fibrinogen is not affected

Severity: Afibrinogenemia> Dysfibrinogenemia (if posttraumatic)> Hypofibrinogenemia

DISTINCT FEATURES ● Delayed wound healing ● Unusual scar formation; ● Increased incidence of spontaneous abortion

Fibrinogen levels may be normal ● Normal to slight decrease but most likely normal ● The problem is the function not the production Bleeding time is usually normal

APTT, PT, TT tests normal ● Cannot be tested by the usual screening tests 5.0 M UREA TEST abnormal ● Normal fibrin clot will not be dissolved in 5 M urea after 24 hrs incubation ● Clot deficient in factor XIII will be dissolved after 24 hrs ● 5.0 M Urea Test- only test to determine Factor XIII Enzymatic and immunologic studies can be done

Treatment for fibrinogen problems: ● Handled by Blood Banking ● REPLACEMENT THERAPY with Cryoprecipitate or FFP to raise the blood fibrinogen level higher than 60 mg/dL. ○ Cryoprecipitate has a large amount of fibrinogen *Questions in the test will not focus on the treatment

AR: Autosomal Recessive Fibrinogen: Part of the COMMON PATHWAY PT and APTT: Test for Common Pathway Prothrombin Time: Test for Extrinsic Pathway but since there is no deficiency in Factor 3, it is basically a Factor 7 test aPTT: Test for Intrinsic Pathway Thrombin Time: screening test for FIBRINOGEN BT (BLEEDING TIME): Screening Test for platelet activity and vascular integrity; qualitative test for the platelet Platelet Count: Quantitative test for platelets

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Table 4. ACQUIRED DISORDERS OF FIBRINOGEN DIC

Etiology

Extrinsic system activation: is affected due to a FACTOR III SURGE: ● Factor 3 came from all over the body usually from the TISSUES ● Hypofibrinogenemic states ○ Tissue will undergo necrosis ○ Necrotic tissue will release factor 3 ● Complicated Pregnancy ○ C-section ○ Placenta previa ○ Placental Abruption ● Metastatic carcinoma ○ Will induce cancer formation in different organs ○ Cancer will induce necrosis or cell death ○ Cells will release PF3 at necrosis and activate extrinsic pathway ● Promyelocytic leukemia ○ AML prone to DIC is M3 or Promyelocytic Leukemia ○ Principle: Tissue necrosis, prone to DIC, tissue factor is released and clotting mechanisms are activated

PRIMARY FIBRINOLYSIS

● ● ● ● ●

Cirrhosis Shock Metastatic Prostatic ca GUT injury฀ urokinase leaks from urine into tissues which will induce primary fibrinolysis

LIVER DISEASE

Decrease synthesis- basic problem ● Liver is not working well, no production of clotting factors

THERAPEUTIC HEPARIN ADMINISTRATION ● Used in post-surgical and cardiac patients ● Heparin is also used in cardiac surgery or open-heart surgery ○ Patient is subjected to blood-lung machine ● Heparin is a natural anticoagulant ○ Used to prevent clotting ● Given to patients with HYPERTHROMBOTIC STATES

Intrinsic system activation: ● damage or altered vascular endothelium:฀ collagen exposure ○ started by extrinsic factor damages ○ Times of necrosis: will cause damage to vascular endothelium ○ Collagen activates platelets and intrinsic pathway ● Product: Fibrin ● Result: Thrombosis all over the body ● Seen in the Following: ○ Infectious diseases ○ Ag-ab complexes ○ Liver disease ○ Snake venom poisoning- exposes collagen

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○ Massive trauma, or surgery Mechanism

CONSUMPTION COAGULOPATHY: depletion of platelets and plasma coagulation factors

(1) A decrease in FACTOR VII occurs first because factor VII has the shortest half-life of the coagulation factors. (2) In patients with severe liver disease, the PT usually is prolonged1; in later stages, the APTT will also be prolonged. (3) Severe liver disease often causes decreased fibrinogen production (hypofibrinogenemia) or an abnormal fibrinogen molecule (dysfibrinogenemia).

Events: Deposition of large amounts of fibrin throughout the microcirculation that results in a pathologic activation of coagulation pathways.

Clinical Features

Fatal or self-limiting; acute, or chronic

Similar to DIC

Prevents clotting ● Problem: sometimes the administration of heparin is not regulated which will result to BLEEDING ● Patients undergoing heparin treatment should be monitored for coagulation factor tests ○ aPTT- for heparin monitoring (parentetal) ○ PT- Oral anticoagulant therapy (warfarin and coumadin monitoring) Bleeding

PHYSIOLOGIC EFFECTS: ● Plasminogen activated systemically to plasmin฀ increase in plasma FDP. ● Peripheral Blood Smear ○ RBC fragmentation caused by damage from multiple thromboembolus ○ Schistocytes are formed because the RBC will pass through the thrombus which contain fibrin strands which will tear the RBC (fragmented) ■ Sign of DIC ● Usually happens to babies in the intensive care unit ● Die basically of BLEEDING Laboratory Findings

● Decreased platelet count ● Prolonged PT, APTT, and TT ○ Consumed all the PFs ● Elevated FDP or D-dimer ○ Monitoring COVID cases for THROMBOSIS, particularly D-dimer

*All abnormal

● Prolonged PT or APTT ● Decreased fibrinogen ● Increased FDP or D dimer ● In contrast to DIC, usually demonstrates normal platelet count, and RBC morphology does not show fragmentation ● TEST TUBE SAMPLE from a patient will initially form a clot that dissolves in 1 to 2 hours

ACUTE USE: Prolong the APTT and TT CHRONIC USE: prolonged PT with ● Coagulation results must be distinguished from similar coagulopathies if the patient history is unknown. ○ This can be done with the reptilase-R time test (Refer to Table 5)

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○ Not diagnostic ○ Better to rely on the aforementioned tests Treatment

Varies with the cause

Treat etiology

Adjust dosage ● Wherein the aPTT hits a certain level, the doctors will decrease the amount of heparin

FFP-pooled platelet, cryoprecipitate, or low-molecular-weight heparin is used to treat the symptoms and break the cycle.

DIC- Disseminated intravascular Coagulation but is sometimes called DEFIBRINATION SYNDROME (consumes fibrinogen which will eventually end up with no fibrinogen) ● At the onset of DIC, expect for THROMBOSIS to happen because all clotting factors and platelets are activated ● If you do not check the cause of DIC, you will end up consuming the clotting factors and platelets ● The patient will not die due to thrombosis but rather due to BLEEDING because all clotting factors are consumed ● Also called Consumptive Coagulopathy FDP: Fibrin degradation products Schistocytes: it is a sign of DIC but it is not indicative of DIC; need to correlate with clinical findings 1 PT: is part of the Liver Function Tests not aPTT ● PT is more sensitive in determining Factor 7 Things to Remember: ● Remember the cause, what is activated, remember the end-product Table 5. COMPARISON OF THE THROMBIN AND REPTILASE* TIMES TO DISTINGUISH INHERITED FIBRIN THROMBIN TIME

REPTILASE TIME

DEFECT

Infinitely prolonged

Infinitely prolonged

Dysfibrinogenemia

Infinitely prolonged

Infinitely prolonged

Afibrinogenemia

Prolonged

Equally prolonged

Hypofibrinogenemia

Prolonged

Normal

Heparin Therapy

Prolonged

Slight to moderate

Fibrin degradation product (high levels)

● Reptilase activates fibrinogen in a manner similar to thrombin but is not sensitive to heparin and fibrin degradation product ● Comparison of thrombin time and reptilase time is dependent on the diagnosis ● Prolonged Thrombin time is a problem in the FIBRINOGEN

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INHERITED EXTRINSIC AND COMMON PATHWAY HEMORRHAGIC DISORDERS Factor deficiency F VII (stable factor)

F X (Stuart Prower)

Manner of Inheritance AR trait

AR trait

Clinical

Laboratory

Soft tissue bleeding not usually associated with a serious clinical bleeding history.

Prolonged PT only but a normal Stypven time

Soft tissue bleeding & chronic bruising

Prolonged PT & aPTT Normal TT and bleeding time

Normal APTT, TT, and bleeding time Prolonged PT

caused by quantitative and qualitative abnormalities F V (labile factor)

Rare; AR trait Owren dse

Mild to moderate bleeding symptoms The level of factor V activity in the patient’s plasma does not directly correlate to the patient’s clinical severity.

F II (prothrombin)

Rare; AR trait

Mild bleeding symptoms

Prolonged PT & aPTT Normal TT Approximately 1/3 of patients have an increased BT because of the platelet-related function of factor V of binding factor X to the platelet surface Prolonged PT & aPTT corrected in substitution testing only by fresh normal plasma Normal fibrinogen assay

This table indicates how to determine the particular clotting factor deficient ● Done through SUBSTITUTION STUDIES AR: Autosomal Recessive This table indicates how to determine the particular clotting factor deficient ● Done through SUBSTITUTION STUDIES ● Factors other than FIBRINOGEN usually only present MILD TO MODERATE BLEEDING SYMPTOMS SUBSTITUTION STUDIES ● To determine whether the problem is due to Factor Deficiency or due to an Inhibitor ○ If corrected: Factor Deficiency

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○ Not corrected: due to Inhibitors ● If the substitution studies did not give any conclusion as to what is the deficient factor ●

Specific Clotting Factor Determination can be done. However, it is EXPENSIVE

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