Subject: Surgery Topic: Bleeding Disorder Lecturer: Dr.

Ocampo Date of Lecture: 1st sem Transcriptionist: Miu Editor: Pinay Pages: 6

(Since wala ng marecover na recording of docs lecture, kukunin ko na lng sa Robbins and Schawartzs ung discussion ng mga pictures. Ill try my best to explain itPinay) Coagulation Cascade

One should already know this cascade since this is discussed to the nth time. -Maebritt MECHANICS OF HEMOSTASIS the process by which cellular and plasma components interact in response to vessel injury in order to maintain vascular integrity and promote wound healing initial response to vascular injury (primary hemostasis) - recruitment and activation of platelets, adhere to the site of injury plasma proteins, cellular components generate thrombin further activation of platelets and converts fibrinogen to fibrin monomers that polymerize into a fibrin clot release of plasminogen activators that induce clot lysis and tissue repair.

Basically pare-pareho lng ung mga pictures sa taas, gusto lng nya sabihin satin na after injury, there is a characteristic hemodynamic response that will happen on the vessel wall. Hemostatsis will prevent or limit the blood loss from the injured vessel. There are for physiologic events that participate in the hemostatic

SY 2011-2012

process: vascular constriction, platelet plug formation, fibrin formation, and fibrinolysis. Vascular constriction is the initial response to vessel injury. It is more pronounced in vessels with medial smooth muscles and is dependent on local contraction of smooth muscle. The extent of vasoconstriction varies with the degree of vessel injury. Platelet Plug Formation aids in cessation of bleeding when vascular disruption occurs. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere. This process requires vWF which binds to glycoprotein I/IX/V on the platelet membrane. After adhesion, they will recruit other platelets from the circulating blood to seal the disrupted vessel (Primary hemostasis). Heparin does not interfere with this reaction, and thus hemostasis can occur in the heparinized patient. Adenosine diphosphate and serotonin are the principal mediators in platelet aggregation. Arachidonic acid released from the platelet membranes is converted by COX to PGG 2 (prostaglandin G2) and then to PGH2 (Prostagalndin H2), which in turn, is converted to TXA2. TXA2 has potent vasoconstriction and platelet aggregation effects. It may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2), which is a vasodilator and acts to inhibit platelet aggregation. Platelet COX is irreversibly inhibited by aspirin and reversibly blocked by NSAIDs but not affected by COX-2 inhibitors. In the second wave of platelet aggregation, a release reaction occurs in which several substances, including ADP, calcium, serotonin, TXA2, and - granule proteins are discharged. Fibrinogen is a required cofactor for this process, acting as a bridge for the glycoprotein IIb/IIIa receptor on the activated process. Thrombospondin is also released, which stabilizes fibrinogen binding to the activated platelet. Laboratory

Must know in the LAB: Activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) assesses intrinsic and common pathways. Thrombin clot time (TCT) assesses common pathway (fibrinogen to fibrin). Prothrombin time (PT) and PIVKA asseses extrinsic and common pathways. Mnemonic accdg sa Patho dept: PiTT Partial (intrinsic) thromboplastin time PeT Prothrombin (extrinsic) time BLEEDING DISORDERS IN SURGERY May be congenital or acquired; acquired defects more common Review of the clotting mechanisms; coagulation pathway

Vitamin K Deficiency Needed for the reaction that attaches a carboxyl group to glutamic acid Vitamin K dependent factors prothrombin (II), Factors VII, IX, X and proteins C and S Common causes inadequate dietary intake, malabsorption, lack of bile salts, obstructive jaundice, biliary fistula, antibiotics, parenteral alimentation Antibiotics cephalosporin, quinolones, doxycycline, trimethoprim-sulfa Clinical Features: Prolongs the prothrombin time, activated partial thromboplastin time Treatment Vitamin K injections, transfusion of FFP

Warfarin works by inhibiting VKOR (Vit. K epoxide reductase), an enzyme that recycles oxidized Vit. K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins mainly prothrombin and factor VII. By decreasing the activity of your Vit. K, it lenghtens the time it takes for a clot to form. Individuals at risk for developing blood clots take warfarin (Coumadin) to lengthen the usual time it takes for a clot to form, resulting in a prolonged PT. Anti-coagulant drugs Warfarin blocks the synthesis of Vitamin K dependent factors

 Prolongs the prothrombin time, activated partial thromboplastin time Treatment administration of Vitamin K and FFP Heparin blocks the activation of Factor X by binding with AT-III and Thrombin All coagulation tests are affected esp. aPTT and PT Treatment protamine sulfate

Renal Failure Renal disease and uremia can result to reversible bleeding disorder related to platelet dysfunction; uremic metabolites; impaired synthesis of factors; protein loss Decrease in aggregation and adhesiveness of platelets ***Renal failure blood disorders but mechanism or exact cause is unknown Causes later): 1. 2. 3. 4. 5. of Bleeding Disorder (will be discussed in detail Hepatic Failure, Renal Failure, Thrombocytopenia Hypothermia, DIC Treatment desmopressin treat the uremia Thrombocytopenia Normal 150-450,000 cubic/mm If patient has >100,000 cubic/mm = thrombocytopenia 40,000-100,000 no spontaneous bleeding but may bleed during injury or surgery 10-20,000 spontaneous bleeding and severe Disorder may be due to failure of production, sequestration increased destruction increased use of platelets and dilution

Hepatic Failure The liver plays a key role in hemostasis because it is responsible for the synthesis of many coagulation factors. The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolongation of the PT. Secondary to liver disease - major hepatic trauma - cirrhosis - biliary obstruction Impairs synthesis of all coagulation factors except VIII (because it is stored in the endothelium, but accdg to Patho dept/lec last sem it is synthesized in the liver) Can be further impaired by thrombocytopenia and platelet dysfunction Thrombocytopenia (will be discussed more later) decreased production due to splenic sequestration, anti-platelet antibodies and viral hepatitis.

Clinical Sign: Petechiae, purpura and ecchymoses Defects in platelets often manifests as: spontaneous bleeding into the skin mucosal bleeding and extensive bleeding after surgery massive GI bleeding or intracranial hemorrhage Causes of Thrombocytopenia: Drug-induced quinidine, sulfa preparations, H2 blockers, antidiabetic agents, rifampicin and heparin Post-transfusion purpura, alcohol-induced thrombocytopenia, immunologic disorders, malignancies Treatment directed to correct the underlying cause Platelet concentrates Corticosteroids for those due to marrow failure

Clinical Features: Low serum fibrinogen levels, prolonged PT, increased aPTT, slightly elevated thrombin time Hypersplenism, reduced production of thrombopoietin, and immune-mediated destruction of platelets. Treatment desmopressin improves bleeding time, FFP to correct the inadequate coagulation factors

*Contributing factors post transfusion purpura *Repeated platelet use reduces effectivity due to development of platelet alloantibodies *Corticosteroids have no proven value *Affect the prostaglandin metabolism in the platelet *They become dysfunctional throughout their 7 day life when exposed to aspirin effect is 3-4 days

**The coagulopathy noted in hypothermic trauma patients has been variously theorized to be caused by enzyme inhibition, platelet alteration, or fibrinolytic processes, but no study has examined the possibility that all three processes may simultaneously contribute to coagulopathy, but are perhaps triggered at different levels of hypothermia. Hypothermia inhibits fibrinogen synthesis, whereas acidosis accelerates fibrinogen degradation, leading to a potential deficit in fibrinogen availability. In addition, coagulation complications caused by acidosis cannot be immediately corrected by pH neutralization alone. Treatment terminate the procedure quickly, pack bleeding areas, close the incision and rewarm the patient; damage control surgery Warm all intravenous fluids and blood products

Hypothermia Most common; least recognized in surgical patients especially in massive transfusion Exacerbated by open chest and abdominal cavities accelerating heat loss Activity of the coagulation system decreases with decreasing temperature Dec in temp will increase in fibrinolytic activity, thrombocytopenia, impaired platelet function, decrease in collagen-induced platelet aggregation and increased affinity of hemoglobin to oxygen

The lethal triad which can lead to bleeding 1. Acidosis 2. Coagulopathy 3. Hypothermia Treatment: Crystalloid and PRBC Administration Continued administration of FFP, platelets, and other blood products can worsen hypothermia with continued bleeding. Warming intravenous fluids before they are given can ameliorate hypothermia. Care must be taken not to heat RBCs above 40C because shortened survival or acute hemolysis can result. Hemorrhage accounts for 90% of deaths after abdominal injury, and half of these deaths are secondary to a recalcitrant coagulopathy. Disseminated Intravascular Coagulation A syndrome rather than a disease Hemorrhagic disorder which can have a sequelae of microvascular thrombosis leading to end organ failure and death Systemic thrombohemorrhagic disorder with laboratory evidence of coagulant activation, fibrinolytic activation, inhibitor consumption and end organ dysfunction DIC is commonly found in hemolysis, massive transfusion, amniotic fluid embolism, placental disruption, retained fetus, gram negative and positive sepsis, viremia, burns, crush injury, tissue destruction, leukemia, malignancy, liver disease, inflammatory and autoimmune diseases

Hypothermia and bleeding usually occur in a patient who receives large-volume resuscitation during an extensive surgical procedure or in the perioperative period. Temperatures as low as 30C to 34C can be associated with coagulopathy even if levels of factors and platelets are normal. Hypothermia and bleeding occur during large volume resuscitation during surgery. Coagulopathy occurs even with even if factor levels and platelet levels are normal

Pathogenesis 1. Activated coagulation and fibrinolytic systems; thrombin and plasmin are in circulation

2. 3.

4. 5. 6. 7. 8.

Thrombin cleaves Fibrinopeptides A and B from fibrinogen fibrin monomers Soluble fibrin clots cause microvascular thrombosis with entrapment and depletion of platelets Simultaneous degradation with plasmin Decreased levels of fibrinogen and increased fibrin degradation products Inhibition of normal coagulation by delaying polymerization of fibrin Weak fibrin clots are formed fibrin products interposing (X,Y,D,E fragments) Plasmin degrades factors V, VIII, IX, XI; activates the complement system

With the activation of the coagulation and fibrinolytic systems, both thrombin and plasmin are in circulation. Thrombin cleaves fibrinopeptides A and B from fibrinogen, converting it to fibrin monomers. These monomers form soluble fibrin clots, causing microvascular thrombosis with entrapment and depletion of platelets. Simultaneous degradation of these factors by plasmin occurs. Depressed levels of fibrinogen and elevated levels of fibrinogen degradation products (fibrin-split products) result. These degradation products inhibit the normal coagulation of blood by delaying polymerization of fibrin. Fibrin degradation products may also interpose themselves between fibrin and polymers, forming a weak fibrin clot. The fibrin degradation products include X, Y, D, and E fragments; platelet dysfunction is attributable to the latter two fragments. Plasmin also degrades factors V, VIII, IX, and XI and activates the complement system. These changes produce the clinically observed changes characteristic of DIC. Types of DIC Low grade DIC minimal symptoms and minimal laboratory abnormalities Fulminant DIC life threatening bleeding and coagulation abnormalities producing end-organ dysfunction and death

Three mechanism of DIC When DIC begins accelerated clotting (characteristic of DIC) which usually results in excess thrombin which in turn causes fibrinolysis with excess fibrin formation and fibrin degradation products Activation of fibrin stabilizing factor (F13), consumption of platelet and clotting factors and eventually hemorrhage.

Disorders associated with DIC include hemolysis, massive transfusion, amniotic fluid embolism, placental abruption, retained fetus, gram-negative and grampositive sepsis, viremia, burns, crush injury and tissue destruction, leukemia, malignancy (especially metastatic), liver disease, and miscellaneous inflammatory and autoimmune conditions, including vasculitis. Laboratory abnormal PT and aPTT levels, decreased fibrinogen abnormal platelet counts, fibrin degradation products and d-dimer levels elevated fragmented RBCs on smear, thrombin, antithrombin levels decreased; coagulation factor fragments elevated; plasminogen and antiplasmin inhibitors decreased

modalities, mortality from DIC remains high and closely related to the underlying disorder.

--------------------End of Transcription--------------Hello sa section B! Happy aral!

Laboratory abnormalities in DIC are variable and related to the many diseases that are associated with this condition. Common abnormalities include abnormal PT and aPTT levels with depressed fibrinogen levels and abnormal platelet counts. Levels of fibrin degradation products and D-dimer are elevated. The peripheral smear reveals fragmented RBCs, but this finding is not specific. Because of the continued activation of coagulation, thrombin/antithrombin complexes will be formed. Levels of thrombin/antithrombin and AT-III are depressed. Fragments of coagulation factor degradation are elevated, including F1.2 and FpA. Because of the activation of the fibrinolytic system, plasminogen and 2 -antiplasmin inhibitor levels are decreased. Treatment 1. 2. 3. 4. 5. 6. 7. Low grade DIC treat the underlying proble Fulminant DIC controversial; most crucial is treatment of the main problem Heparin Antithrombin concentrates Blood products - fibrinogen, RBCs platelets, ATIII concentrates Crystalloid and colloid volume expanders Fibrinolysis E-aminocaproic acid with heparin

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The treatment of the underlying condition is critical to the successful management of DIC. Also important is the treatment of the thrombotic intravascular process that causes end-organ failure. Therapy with heparin is begun if treatment of the underlying pathology does not ameliorate DIC after 6 to 8 hours. Intravenous heparin is administered in doses of 80 to100 units/kg every 4 to 6 hours. Higher doses of heparin may be needed if the patient does not respond. Antithrombin concentrates administered to attain a serum level of 125% of normal have been useful in some patients. Continued bleeding may be related to depletion of components, but random administration of blood products, especially those containing fibrinogen, may exacerbate the syndrome. Washed RBCs, platelets, AT-III concentrate, and crystalloid and colloid volume expanders may be used. If other therapeutic measures are unsuccessful, inhibition of fibrinolysis may be employed. -Aminocaproic acid may be given along with heparin. Despite improved diagnostic and therapeutic