Coagulopathies & Treatment
The most common cause of intraoperative coagulopathy is thrombocytopenia (decrease in platelet count) secondary to hemodilution. Blood loss that is replaced by crystalloid volume will progressively dilute platelet numbers as well as platelet entrapment on the surfaces of the extracorporeal circuit. Associated with bypass is platelet migration to the spleen and reticuloendothelial system (approximately 33%) which will be rapidly returned to the circulation after bypass. This phenomenon assures that platelet loss cannot be arithmetically calculated based solely on blood loss.
Stress causes the release of fibrinogen from hepatic stores. The dilutional effects seen with platelets are therefore mimicked in the plasma protein changes. For normal activity, most plasma protein procoagulants are required in only 30% of their normal concentrations because of the fact that they function as enzymes rather than consumable proteins. Low fibrinogen levels (<150 mg/dl) can contribute to coagulopathy. It is important therefore, to assure that fibrinogen levels exceed that threshold. Surgery in general, causes most patients to become more hypercoagulable. That response is nonspecific and appears to occur within the first hour of surgery/anesthesia.
Hypothermia while being a common problem associated with all operations, is an inseparable aspect of cardiopulmonary bypass that has a profound impact on most enzyme systems, and the coagulation cascade. Pro-thrombin times (PT) and partial thromboplastin (aPTT) times are prolonged and platelets become nonfunctional as the body temperature is lowered (usually to 28¡ C). For cardiac surgery hypothermia has some therapeutic benefits. It will allow for lower pump flows (subsequently less blood trauma), better myocardial protection, better organ protection, and reduction of oxygen consumption; implying a reduction in basal metabolic rate.
Metabolic acidosis results from low flow states, and subsequent inadequate tissue/organ perfusion. Acidosis inhibits both the clotting mechanism and platelet function. Rapid infusion of large quantities of blood products can exacerbate acidosis due to the low pH content of old stored blood, as well as the citrated dextrose used as an anticoagulant preservative.
Acid citrate dextrose (ACD) is the most commonly used preservative for whole blood in the United States. Administered in large quantities, the citrated blood will bind with circulating ionized calcium, and may deliver the patient into a profound (reduction of 50%) hypocalcemic state. The primary impact of this condition is on the cardiovascular system and results in hypotension.
In terms of clinical management, treatment of coagulopathy focuses on monitoring preoperative, intraoperative, and postoperative laboratory values pertaining to the patient’s coagulation profile. Therapy is guided in accordance to clinical need and by measured values deviating from acceptable ranges. Typically tests for coagulation function, or suspected coagulopathy can be categorized as screening tests or specific tests applied according to the nature and clinical circumstances of the bleeding. These screening tests include the activated partial thromboplastin time (aPTT), the prothrombin time (PT), the thrombin clotting time (TCT), platelet count, and bleeding time. Tests for the coagulation pathway can also be subdivided according to which function of the hemostatic mechanism they are measuring: coagulant, platelet function, fibrinolytic, or endothelial.
Tests specific to coagulation function are: PT, aPTT, fibrinogen, Fibrin degradation products (FbDP), ATIII, heparin cofactor II (HCII), protein C, fibrinopeptide A (FPA), thrombin antithrombin complex (TAT), kallikrein-kinen, and compliment.
Tests for platelet function include: Count, agglutination, aggregation, thrombo elastogram (TEG), platelet factor 4 (PF4), glycoproteins, platelet activating factor (PAF), prostaglandin F (PGF), and thromboxane B2 (TxB2).
Fibrinolytic pathway tests include: Euglobin lysis, plasminogen, antiplasmin, tissue plasminogen activator (TPA), plasminogen activator inhibitor (PAI), D-dimer, fibrinogen degradation products (FgDP), and FbDP.
Tests of endothelium are: TxB2, TPA, von Willebrand factor (vWF), growth factors, PGF, PAI, and leukotrine C4(LtC4) (Melvin et al. 1989).
In the event of suspected coagulopathy (usually evidenced as diffuse uncontrolled bleeding) it is essential to discriminate the cause, and consider the possibility of disseminated intravascular bleeding (DIC). Specific tests used to rule out (or differentiate as to the type of) DIC are platelet count, fibrinogen, ATIII, FDP, and D-dimer.
DIC is a condition where spontaneous clotting has consumed the majority of procoagulatory factors, or circulating plasminogen levels are exhausted (either condition can be the precursor for the other). There are three recognized classifications of DIC, based on whether or not thrombin and/or plasmin is generated in the episode.
Type I DIC (secondary fibrinolysis) is the most common (80-90%) and reflects the generation of thrombin and activation of plasmin. Type II DIC (consumptive coagulopathy) reflects progression of DIC to the point where plasminogen has been exhausted, and uncontrolled clotting occurs. Type III DIC (primary fibrinolysis) is characterized by almost exclusive activation of plasmin without concurrent thrombin formation. The treatment for this type is to use an agent that blocks the conversion of plasminogen to plasmin.
If the assessment can be made as to the potential cause of coagulopathy (which clotting factor is involved, factor versus inhibitor depletion), then effective management of the problem can be started using blood products such as fresh frozen plasma (FFP), and cryoprecipitate, platelet rich plasma (PRP) for treatment of factor depletion.
Antifibrinolytics (Amicar ¨, tranexamic acid, and para-amino-benzoic acid), platelet enhancers, and protease inhibitors are drug therapies currently in clinical use for the treatment of coagulopathy.
Amicar ¨ (Epsilon-aminocaproic Acid)
Amicar ¨ is the first representative of a new family of drugs, the antifibrinolytic agents The relationship between it’s chemical structure, and its antifibrinolytic action is well established. It was initially proposed for the treatment of fibrinolysis associated with prostate and cardiac surgery. A major concern of the administration of Amicar ¨ is the possibility of excessive coagulation because of impaired fibrinolysis, leading to subsequent tissue or organ ischemia. (Verstraete, 1985)
Antifibrinolytics bind to plasminogen and plasmin to block fibrinolytic enzymes from binding with lysine residues of fibrinogen (appendix G). Excretion occurs renally with concentrations 75-to 100-fold those of plasma. Plasma half-life is approximately 80 minutes.
Aprotinin is a naturally occurring antifibrinolytic agent, and is a 58 residue protein derived from beef lung. Similar to Amicar ¨, aprotinin inhibits plasmin and plasminogen and additionally inhibits kallikrein (the contact activation protein which enhances factor XII activation
Cryoprecipitate contains 2 or more times the concentration of fibrinogen contained in plasma as well as increased levels of factor V and factor VIII. Each unit however, contains only 50 ml, thus conceivably requiring several units of cryoprecipitate to be administered in order to achieve target ranges (>150 mg/dl) for depleted fibrinogen levels. This represents exposure to multiple donors and implies an increased risk to the recipient.
Desmopressin acetate (DDAVP) is a synthetic analog of vasopressin and like ADH, epinephrine, and insulin, releases a variety of hemostatically active substances from vascular endothelium. It is administered in doses of 0.3 µg/kg by intravenous, intranasal, or subcutaneous routes. It has a half life of 55 minutes, (with clinical effects lasting from 5 to 6 hours) and results in an approximate fourfold increase in circulating levels of factor VIII, prostacycline, t-PA, and von Willebrand factor (vWF). The overall effect of desmopressin is hemostatic and it has been used to treat uremia, cirrhosis, platelet disorders, and mild or moderate cases of hemophilia A (von Willebrand’s disease).
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