Acquired abnormalities of platelets are much more common than acquired defects and may be quantitative or qualitative, although some patients have both types of defects. Quantitative defects may be a result of failure of production, shortened survival, or sequestration. Failure of production is generally a result of bone marrow disorders such as leukemia, myelodysplastic syndrome, severe vitamin B12 or folate deficiency, chemotherapeutic drugs, radiation, acute ethanol intoxication, or viral infection. If a quantitative abnormality exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized. The etiologies of both qualitative and quantitative defects are reviewed in Table 4-1.
Table 4-1Etiology of platelet disorders ||Download (.pdf) Table 4-1 Etiology of platelet disorders
Failure of production: related to impairment in bone marrow function
B12 or folate deficiencies
Chemotherapy or radiation therapy
Acute alcohol intoxication
1) Idiopathic thrombocytopenia (ITP)
2) Heparin-induced thrombocytopenia
3) Autoimmune disorders or B-cell malignancies
4) Secondary thrombocytopenia
Disseminated intravascular coagulation (DIC)
Related to platelet thrombi
Therapeutic platelet inhibitors
Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagulation, or disorders characterized by platelet thrombi such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Immune thrombocytopenia may be idiopathic or associated with other autoimmune disorders or low-grade B-cell malignancies, and it may also be secondary to viral infections (including HIV) or drugs. Secondary immune thrombocytopenia often presents with a very low platelet count, petechiae and purpura, and epistaxis. Large platelets are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh positive. Both gamma globulin and anti-D immunoglobulin are rapid in onset. Platelet transfusions are not usually needed unless central nervous system bleeding or active bleeding from other sites occurs. Survival of the transfused platelets is usually short.
Primary immune thrombocytopenia is also known as idiopathic thrombocytopenic purpura (ITP). In children, it is usually acute in onset, short lived, and typically follows a viral illness. In contrast, ITP in adults is gradual in onset, chronic in nature, and has no identifiable cause. Because the circulating platelets in ITP are young and functional, bleeding is less for a given platelet count than when there is failure of platelet production. The pathophysiology of ITP is believed to involve both impaired platelet production and T cell–mediated platelet destruction.10 Management options are summarized in Table 4-2.11 Treatment of drug-induced immune thrombocytopenia may simply entail withdrawal of the offending drug, but corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count. Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia. It is an immunologic event during which antibodies against platelet factor 4 (PF4) formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.12 The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a re-exposure, the decrease in count may occur within 1 to 2 days. HIT should be suspected if the platelet count falls to less than 100,000 or if it drops by 50% from baseline in a patient receiving heparin. While HIT is more common with full-dose unfractionated heparin (1%–3%), it can also occur with prophylactic doses or with low molecular weight heparins. Interestingly, approximately 17% of patients receiving unfractionated heparin and 8% receiving low molecular weight heparin develop antibodies against PF4, yet a much smaller percentage develop thrombocytopenia and even fewer develop clinical HIT.13 In addition to the mild to moderate thrombocytopenia, this disorder is characterized by a high incidence of thrombosis that may be arterial or venous. Importantly, the absence of thrombocytopenia in these patients does not preclude the diagnosis of HIT.
Table 4-2Management of idiopathic thrombocytopenic purpura (ITP) in adults ||Download (.pdf) Table 4-2 Management of idiopathic thrombocytopenic purpura (ITP) in adults
The diagnosis of HIT may be made by using either a serotonin release assay (SRA) or an enzyme-linked immunosorbent assay (ELISA). The SRA is highly specific but not sensitive, so a positive test supports the diagnosis but a negative test does not exclude HIT.12 On the other hand, the ELISA has a low specificity, so although a positive ELISA confirms the presence of anti-heparin-PF4, it does not help in the diagnosis of clinical HIT. A negative ELISA, however, essentially rules out HIT.
The initial treatment of suspected HIT is to stop heparin and begin an alternative anticoagulant. Stopping heparin without addition of another anticoagulant is not adequate to prevent thrombosis in this setting. Alternative anticoagulants are primarily thrombin inhibitors. The most recent guideline by the American College of Chest Physicians recommends lepirudin, argatroban, or danaparoid for patients with normal renal function and argatroban for patients with renal insufficiency.14 Because of warfarin’s early induction of a hypercoagulable state, warfarin should be instituted only once full anticoagulation with an alternative agent has been accomplished and the platelet count has begun to recover.
These are also disorders in which thrombocytopenia is a result of platelet activation and formation of platelet thrombi. In thrombotic thrombocytopenic purpura (TTP), large vWF molecules interact with platelets, leading to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAMtS13, which cleaves the large vWF molecules.15 TTP is classically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic signs or symptoms. The finding of schistocytes on a peripheral blood smear aids in the diagnosis. Plasma exchange with replacement of FFP is the treatment for acute TTP.16 Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lymphocytes, has shown promise as an immunomodulatory therapy directed against patients with acquired TTP, of which the majority are autoimmune mediated.17
Hemolytic uremic syndrome (HUS) often occurs secondary to infection by Escherichia coli 0157:H7 or other Shiga toxin-producing bacteria. The metalloproteinase is normal in these cases. HUS is usually associated with some degree of renal failure, with many patients requiring renal replacement therapy. Neurologic symptoms are less frequent. A number of patients develop features of both TTP and HUS. This may occur with autoimmune diseases, especially systemic lupus erythematosus and HIV infection, or in association with certain drugs (such as ticlopidine, mitomycin C, gemcitabine) or immunosuppressive agents (such as cyclosporine and tacrolimus). Discontinuation of the involved drug is the mainstay of therapy. Plasmapheresis is frequently used, but it is not clear what etiologic factor is being removed by the pheresis.
Sequestration is another important cause of thrombocytopenia and usually involves trapping of platelets in an enlarged spleen typically related to portal hypertension, sarcoid, lymphoma, or Gaucher’s disease. The total body platelet mass is essentially normal in patients with hypersplenism, but a much larger fraction of the platelets are in the enlarged spleen. Platelet survival is mildly decreased. Bleeding is less than anticipated from the count because sequestered platelets can be mobilized to some extent and enter the circulation. Platelet transfusion does not increase the platelet count as much as it would in a normal person because the transfused platelets are similarly sequestered in the spleen. Splenectomy is not indicated to correct the thrombocytopenia of hypersplenism caused by portal hypertension.
Thrombocytopenia is the most common abnormality of hemostasis that results in bleeding in the surgical patient. The patient may have a reduced platelet count as a result of a variety of disease processes, as discussed earlier. In these circumstances, the marrow usually demonstrates a normal or increased number of megakaryocytes. By contrast, when thrombocytopenia occurs in patients with leukemia or uremia and in patients on cytotoxic therapy, there are generally a reduced number of megakaryocytes in the marrow. Thrombocytopenia also occurs in surgical patients as a result of massive blood loss with product replacement deficient in platelets. Thrombocytopenia may also be induced by heparin administration during cardiac and vascular cases, as in the case of HIT, or may be associated with thrombotic and hemorrhagic complications. When thrombocytopenia is present in a patient for whom an elective operation is being considered, management is contingent upon the extent and cause of platelet reduction. A count of greater than 50,000/μL generally requires no specific therapy.
Early platelet administration has now become part of massive transfusion protocols.18,19 Platelets are also administered preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia. One unit of platelet concentrate contains approximately 5.5 × 1010 platelets and would be expected to increase the circulating platelet count by about 10,000/μL in the average 70-kg person. Fever, infection, hepatosplenomegaly, and the presence of antiplatelet alloantibodies decrease the effectiveness of platelet transfusions. In patients refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)-compatible platelets coupled with special processors has proved effective.
Qualitative Platelet Defects
Impaired platelet function often accompanies thrombocytopenia but may also occur in the presence of a normal platelet count. The importance of this is obvious when one considers that 80% of overall strength is related to platelet function. The life span of platelets ranges from 7 to 10 days, placing them at increased risk for impairment by medical disorders and prescription and over-the-counter medications. Impairment of ADP-stimulated aggregation occurs with massive transfusion of blood products. Uremia may be associated with increased bleeding time and impaired aggregation. Defective aggregation and platelet dysfunction are also seen in patients with thrombocythemia, polycythemia vera, and myelofibrosis.
Drugs that interfere with platelet function include aspirin, clopidogrel, prasugrel, dipyridamole, and GP IIb/IIIa inhibitors. Aspirin, clopidogrel, and prasugrel all irreversibly inhibit platelet function. Clopidogrel and prasugrel do so through selective irreversible inhibition of ADP-induced platelet aggregation.20 Aspirin works through irreversible acetylation of platelet prostaglandin synthase.
There are no prospective randomized trials in general surgical patients to guide the timing of surgery in patients on aspirin, clopidogrel, or prasugrel.21 The general recommendation is that approximately 5 to 7 days should pass from the time the drug is stopped until an elective procedure is performed.22 Timing of urgent and emergent surgeries is even more unclear. Preoperative platelet transfusions may be beneficial, but there are no good data to guide their administration. However, new functional tests are becoming available that may better demonstrate defects in platelet function and may serve to guide the timing of operation or when platelet transfusions might be indicated.
Other disorders associated with abnormal platelet function include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease. In the surgical patient, platelet dysfunction of uremia can often be corrected by dialysis or the administration of DDAVP. Platelet transfusion may not be helpful if the patient is uremic when the platelets are given and only serve to increase antibodies. Platelet dysfunction in myeloproliferative disorders is intrinsic to the platelets and usually improves if the platelet count can be reduced to normal with chemotherapy. If possible, surgery should be delayed until the count has been decreased. These patients are at risk for both bleeding and thrombosis. Platelet dysfunction in patients with monoclonal gammopathies is a result of interaction of the monoclonal protein with platelets. Treatment with chemotherapy or, occasionally, plasmapheresis to lower the amount of monoclonal protein improves hemostasis.
Disseminated Intravascular Coagulation (DIC)
DIC is an acquired syndrome characterized by systemic activation of coagulation pathways that result in excessive thrombin generation and the diffuse formation of microthrombi. This disturbance ultimately leads to consumption and depletion of platelets and coagulation factors with the resultant classic picture of diffuse bleeding. Fibrin thrombi developing in the microcirculation may cause microvascular ischemia and subsequent end-organ failure if severe. There are many different conditions that predispose a patient to DIC, and the presence of an underlying condition is required for the diagnosis. For example, injuries resulting in embolization of materials such as brain matter, bone marrow, or amniotic fluid can act as potent thromboplastins that activate the DIC cascade.23 Additional etiologies include malignancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snake bites, illicit drugs, transfusion reactions, transplant rejection, and sepsis.24 In fact, DIC frequently accompanies sepsis and may be associated with multiple organ failure. As of yet, scoring systems for organ failure do not routinely incorporate DIC. The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut et al who showed that activated protein C was effective in septic patients with DIC.25 The diagnosis of DIC is made based on an inciting etiology with associated thrombocytopenia, prolongation of the prothrombin time, a low fibrinogen level, and elevated fibrin markers (FDPs, D-dimer, soluble fibrin monomers). A scoring system developed by the International Society for Thrombosis and Hemostasis has been shown to have high sensitivity and specificity for diagnosing DIC as well as a strong correlation between an increasing DIC score and mortality, especially in patients with infections.26
The most important facets of treatment are relieving the patient’s causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding, hemostatic factors should be replaced with FFP, which is usually sufficient to correct the hypofibrinogenemia, although cryoprecipitate, fibrinogen concentrates, or platelet concentrates may also be needed. Given the formation of microthrombi in DIC, heparin therapy has also been proposed. Most studies, however, have shown that heparin is not helpful in acute forms of DIC, but may be indicated in cases where thrombosis predominates, such as arterial or venous thromboembolism and severe purpura fulminans.
An acquired hypofibrinogenic state in the surgical patient can be a result of pathologic fibrinolysis. This may occur in patients following prostate resection when urokinase is released during surgical manipulation of the prostate or in patients undergoing extracorporeal bypass. The severity of fibrinolytic bleeding is dependent on the concentration of breakdown products in the circulation. Antifibrinolytic agents, such as ε-aminocaproic acid and tranexamic acid, interfere with fibrinolysis by inhibiting plasminogen activation.
Polycythemia, or an excess of red blood cells, places surgical patients at risk. Spontaneous thrombosis is a complication of polycythemia vera, a myeloproliferative neoplasm, and can be explained in part by increased blood viscosity, increased platelet count, and an increased tendency toward stasis. Paradoxically, a significant tendency toward spontaneous hemorrhage also is noted in these patients. Thrombocytosis can be reduced by the administration of low-dose aspirin, phlebotomy, and hydroxyurea.27
Coagulopathy of Liver Disease
The liver plays a key role in hemostasis because it is responsible for the synthesis of many of the coagulation factors (Table 4-3). Patients with liver disease, therefore, have decreased production of several key non-endothelial cell-derived coagulation factors as well as natural anticoagulant proteins, causing a disturbance in the balance between procoagulant and anticoagulant pathways. This disturbance in coagulation mechanisms causes a complex paradigm of both increased bleeding risk and increased thrombotic risk. The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolongation of the prothrombin time and international normalized ratio (INR). The etiology of thrombocytopenia in patients with liver disease is typically related to hypersplenism, reduced production of thrombopoietin, and immune-mediated destruction of platelets. The total body platelet mass is often normal in patients with hypersplenism, but a much larger fraction of the platelets is sequestered in the enlarged spleen. Bleeding may be less than anticipated because sequestered platelets can be mobilized to some extent and enter the circulation. Thrombopoietin, the primary stimulus for thrombopoiesis, may be responsible for some cases of thrombocytopenia in cirrhotic patients, although its role is not well delineated. Finally, immune-mediated thrombocytopenia may also occur in cirrhotics, especially those with hepatitis C and primary biliary cirrhosis.28 In addition to thrombocytopenia, these patients also exhibit platelet dysfunction via defective interactions between platelets and the endothelium, and possibly due to uremia and changes in endothelial function in the setting of concomitant renal insufficiency. Hypocoagulopathy is further exacerbated with low platelet counts because platelets help facilitate thrombin generation by assembling coagulation factors on their surfaces. In conditions mimicking intravascular flow, low hematocrit and low platelet counts contributed to decreased adhesion of platelets to endothelial cells, although increased vWF, a common finding in cirrhotic patients, may offset this change in patients with cirrhosis.29 Hypercoagulability of liver disease has recently gained increased attention, with more evidence demonstrating the increased incidence of thromboembolism despite thrombocytopenia and a hypocoagulable state on conventional blood tests.30,31 This is attributed to decreased production of liver-synthesized proteins C and S, antithrombin, and plasminogen levels, as well as elevated levels of endothelial-derived vWF and factor VIII, a potent driver of thrombin generation.32,33 Given the concomitant hypo- and hypercoagulable features seen in patients with liver disease, conventional coagulation tests may be difficult to interpret, and alternative tests such as thromboelastography (TEG) may be more informative of the functional status of clot formation and stability in cirrhotic patients. Several studies imply that TEG provides a better assessment of bleeding risk than standard tests of hemostasis in patients with liver disease; however, no studies have directly tested this, and future prospective trials are needed.34
Table 4-3Coagulation factors synthesized by the liver ||Download (.pdf) Table 4-3 Coagulation factors synthesized by the liver
Vitamin K–dependent factors: II (prothrombin factor), VII, IX, X
Factors XI, XII, XIII
Protein C and protein S
Before instituting any therapy to ameliorate thrombocytopenia, the actual need for correction should be strongly considered. In general, correction based solely on a low platelet count should be discouraged. Most often, treatment should be withheld for invasive procedures and surgery. Platelet transfusions are the mainstay of therapy; however, the effect typically lasts only several hours. Risks associated with transfusions in general and the development of antiplatelet antibodies in a patient population likely to need recurrent correction should be considered. A potential alternative strategy involves administration of interleukin-11 (IL-11), a cytokine that stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitors.26 Most studies using IL-11 have been in cancer patients, although some evidence exists that it may be beneficial in cirrhotics as well. Significant side effects limit its usefulness.35 A less well-accepted option is splenectomy or splenic embolization to reduce hypersplenism. In addition to the risks associated with these techniques, reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are mixed following insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Therefore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure.
Decreased production or increased destruction of coagulation factors as well as vitamin K deficiency can all contribute to a prolonged PT and INR in patients with liver disease. As liver dysfunction worsens, so does the liver’s synthetic function, which results in decreased production of coagulation factors. Additionally, laboratory abnormalities may mimic those of DIC. Elevated D-dimers have been reported to increase the risk of variceal bleeding. The absorption of vitamin K is dependent on bile production. Therefore, liver patients with impaired bile production and cholestatic disease may be at risk for vitamin K deficiency.
Similar to thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophylaxis for invasive procedures and surgery. Treatment of coagulopathy caused by liver disease is usually done with FFP, but because the coagulopathy is usually not a result of decreased levels of factor V, complete correction is not usually possible. If the fibrinogen is less than 200 mg/dL, administration of cryoprecipitate may be helpful. Cryoprecipitate is also a source of factor VIII for the rare patient with a low factor VIII level.
Traditional teaching regarding trauma-related coagulopathy attributed its development to acidosis, hypothermia, and dilution of coagulation factors. Recent data, however, have shown that over one third of injured patients have evidence of coagulopathy at the time of admission.36 More importantly, patients arriving with coagulopathy are at a significantly higher risk of mortality, especially in the first 24 hours after injury. In light of these findings, a dramatic increase in research focused on the optimal management of the acute coagulopathy of trauma (ACoT) has been observed over the past several years. ACoT is not a simple dilutional coagulopathy but a complex problem with multiple mechanisms.37 Whereas multiple contributing factors exist, the key initiators to the process of ACoT are shock and tissue injury. ACoT is a separate and distinct process from DIC, with its own specific components of hemostatic failure. Brohi et al have demonstrated that only patients in shock arrive coagulopathic and that it is the shock that induces coagulopathy through systemic activation of anticoagulant and fibrinolytic pathways.38 As shown in Fig. 4-5, hypoperfusion causes activation of TM on the surface of endothelial cells. Thrombin-TM complexes induce an anticoagulant state through activation of protein C and enhancement of fibrinolysis. This same complex also limits the availability of thrombin to cleave fibrinogen to fibrin, which may explain why injured patients rarely have low levels of fibrinogen.
Illustration of the pathophysiologic mechanism responsible for the acute coagulopathy of trauma. PAI-1 = plasminogen activator inhibitor 1; TAFI = thrombin-activatable fibrinolysis inhibitor.
Acquired Coagulation Inhibitors
Among the most common acquired coagulation inhibitors is the antiphospholipid syndrome (APLS), which includes the lupus anticoagulant and anticardiolipin antibodies. These antibodies may be associated with either venous or arterial thrombosis, or both. In fact, patients presenting with recurrent thrombosis should be evaluated for APLS. Antiphospholipid antibodies are very common in patients with systemic lupus but may also be seen in association with rheumatoid arthritis and Sjögren’s syndrome. There are also individuals who will have no autoimmune disorders but develop transient antibodies in response to infections or those who develop drug-induced APLS. The hallmark of APLS is a prolonged aPTT in vitro but an increased risk of thrombosis in vivo.
Anticoagulation and Bleeding
Spontaneous bleeding can be a complication of any anticoagulant therapy whether it is heparin, low molecular weight heparins, warfarin, factor Xa inhibitors, or new direct thrombin inhibitors. The risk of spontaneous bleeding related to heparin is reduced with a continuous infusion technique. Therapeutic anticoagulation is more reliably achieved with a low molecular weight heparin. However, laboratory testing is more challenging with these medications, as they are not detected with conventional coagulation testing. However, their more reliable therapeutic levels (compared to heparin) make them an attractive option for outpatient anticoagulation and more cost-effective for the inpatient setting. If monitoring is required (e.g., in the presence of renal insufficiency or severe obesity), the drug effect should be determined with an assay for anti-Xa activity.
Warfarin is used for long-term anticoagulation in various clinical conditions including deep vein thrombosis, pulmonary embolism, valvular heart disease, atrial fibrillation, recurrent systemic emboli, recurrent myocardial infarction, prosthetic heart valves, and prosthetic implants. Due to the interaction of the P450 system, the anticoagulant effect of the warfarin is reduced (e.g., increases dose required) in patients receiving barbiturates as well as in patients with diets low in vitamin K. Increased warfarin requirements may also be needed in patients taking contraceptives or estrogen-containing compounds, corticosteroids, and adrenocorticotropic hormone (ACTH). Medications that can alter warfarin requirements are shown in Table 4-4.
Table 4-4Medications that can alter warfarin dosing ||Download (.pdf) Table 4-4 Medications that can alter warfarin dosing
↓ warfarin effect
↑ warfarin requirements
Barbiturates, oral contraceptives, estrogen-containing compounds, corticosteroids, adrenocorticotropic hormone
↑ warfarin effect
↓ warfarin requirements
Phenylbutazone, clofibrate, anabolic steroids, L-thyroxine, glucagons, amiodarone, quinidine, cephalosporins
Although warfarin use is often associated with a significant increase in morbidity and mortality in acutely injured and emergency surgery patients, with rapid reversal, these complications can be dramatically reduced. There are several reversal options that include vitamin K administration, plasma, cryoprecipitate, recombinant factor VIIa, and factor concentrates. Urgent reversal for life-threatening bleeding should include vitamin K and a rapid reversal agent such as plasma or prothrombin complex concentrate. In the elderly or those with intracranial hemorrhage, concentrates are preferred, whereas in situations with hypovolemia from hemorrhage, plasma should be used.
Newer anticoagulants like dabigatran and rivaroxaban have no readily available method of detection of the degree of anticoagulation. More concerning is the absence of any available reversal agent. Unlike warfarin, the nonreversible coagulopathy associated with dabigatran and rivaroxaban is of great concern to those providing emergent care to these patients.39
The only possible strategy to reverse the coagulopathy associated with dabigatran may be emergent dialysis. Unfortunately, the ability to rapidly dialyze the hemodynamically unstable bleeding patient or rapidly dialyze the anticoagulated patient with an intracranial bleed is challenging even at large medical centers. Recent data suggest that rivaroxaban, however, may be reversed with the use of prothrombin complex concentrates (four-factor concentrates only: II, VII, IX, and X).40 In less urgent states, these drugs can be held for 36 to 48 hours prior to surgery without increased risk of bleeding in those with normal renal function. Alternatively, activated clotting time (stand alone or with rapid TEG) or ecarin clotting time can be obtained in those on dabigatran, and anti-factor Xa assays can be obtained in those taking rivaroxaban.
Bleeding complications in patients on anticoagulants include hematuria, soft tissue bleeding, intracerebral bleeding, skin necrosis, and abdominal bleeding. Bleeding secondary to anticoagulation therapy is also not an uncommon cause of a rectus sheath hematomas. In most of these cases, reversal of anticoagulation is the only treatment that is necessary. Lastly, it is important to remember that symptoms of an underlying tumor may first present with bleeding while on anticoagulation.
Surgical intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without full reversal of the anticoagulant, depending on the procedure being performed.41 When the aPTT is less than 1.3 times control in a heparinized patient or when the INR is less than 1.5 in a patient on warfarin, reversal of anticoagulation therapy may not be necessary. However, meticulous surgical technique is mandatory, and the patient must be observed closely throughout the postoperative period.
Certain surgical procedures should not be performed in concert with anticoagulation. In particular, cases where even minor bleeding can cause great morbidity, such as the central nervous system and the eye, surgery should be avoided. Emergency operations are occasionally necessary in patients who have been heparinized. The first step in these patients is to discontinue heparin. For more rapid reversal, protamine sulfate is effective. However, significant adverse reactions, especially in patients with severe fish allergies, may be encountered when administering protamine.42 Symptoms include hypotension, flushing, bradycardia, nausea, and vomiting. Prolongation of the aPTT after heparin neutralization with protamine may also be a result of the anticoagulant effect of protamine. In the elective surgical patient who is receiving coumarin-derivative therapy sufficient to effect anticoagulation, the drug can be discontinued several days before operation and the prothrombin concentration then checked (a level >50% is considered safe).43 Rapid reversal of anticoagulation can be accomplished with plasma or prothrombin complex concentrates in the emergent situation. Parenteral administration of vitamin K also is indicated in elective surgical treatment of patients with biliary obstruction or malabsorption who may be vitamin K deficient. However, if low levels of factors II, VII, IX, and X (vitamin K–dependent factors) exist as a result of hepatocellular dysfunction, vitamin K administration is ineffective.
The perioperative management of patients receiving long-term oral anticoagulation therapy is an increasingly common problem. Definitive evidence-based guidelines regarding which patients require perioperative “bridging” anticoagulation and the most effective way to bridge are lacking. However, the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines do serve as best practice for these situations.44 A few clinical scenarios exist where the patient should be transitioned to intravenous heparin from oral anticoagulants. A heparin infusion should be held for 4 to 6 hours before the procedure and restarted within 12 to 24 hours of the end of its completion. The primary indication for this level of aggressiveness is patients with mechanical heart valves. Other indications include a recent (within 30 days) myocardial infarction, stroke, or pulmonary embolism. Situations such as thromboembolic events greater than 30 days prior, hypercoagulable history, and atrial fibrillation do not require such stringent restarting strategies.
Under normal conditions, homeostasis of the coagulation system is maintained by complex interactions between the endothelium, platelets, and coagulation factors. In patients undergoing cardiopulmonary bypass (CPB), contact with circuit tubing and membranes results in abnormal platelet and clotting factor activation, as well as activation of inflammatory cascades, that ultimately result in excessive fibrinolysis and a combination of both quantitative and qualitative platelet defects. Platelets undergo reversible alterations in morphology and their ability to aggregate, which causes sequestration in the filter, partially degranulated platelets, and platelet fragments. This multifactorial coagulopathy is compounded by the effects of shear stress in the system, induced hypothermia, hemodilution, and anticoagulation.45
While on pump, activated clotting time measurements are obtained along with blood gas measurements; however, conventional coagulation assays and platelet counts are not normally performed until rewarming and after a standard dose of protamine has been given. TEG may give a better estimate of the extent of coagulopathy and may also be used to anticipate transfusion requirements if bleeding is present.45
Empiric treatment with FFP and cryoprecipitate is often used for bleeding patients; however, there are no universally accepted transfusion thresholds. Platelet concentrates are given for bleeding patients in the immediate postoperative period; however, studies have shown that indiscriminate platelet therapy conferred no therapeutic advantage.46 It is in these patients where rapid coagulation testing is required to assist with directed transfusion therapy.47 Many institutions now use antifibrinolytics, such as ε-aminocaproic acid and tranexamic acid, at the time of anesthesia induction after several studies have shown that such treatment reduced postoperative bleeding and reoperation. Aprotinin, a protease inhibitor that acts as an antifibrinolytic agent, has been shown to reduce transfusion requirements associated with cardiac surgery.48 Desmopressin acetate stimulates release of factor VIII from endothelial cells and may also be effective in reducing blood loss during cardiac surgery. The use of recombinant factor VIIa has also been studied but with conflicting results between improved hemostasis and thrombotic events and mortality, and thus its use is often employed only as a measure of last resort.45,49
Significant surgical bleeding is usually caused by ineffective local hemostasis. The goal is therefore to prevent further blood loss from a disrupted vessel that has been incised or transected. Hemostasis may be accomplished by interrupting the flow of blood to the involved area or by direct closure of the blood vessel wall defect.
The oldest mechanical method of bleeding cessation is application of direct digital pressure, either at the site of bleeding or proximally to permit more definitive action. An extremity tourniquet that occludes a major vessel proximal to the bleeding site or the Pringle maneuver for liver bleeding are good examples. Direct digital pressure is very effective and has the advantage of being less traumatic than hemostatic or even “atraumatic” clamps.
When a small vessel is transected, a simple ligature is usually sufficient. However, for larger pulsating arteries, a transfixion suture to prevent slipping is indicated. All sutures represent foreign material, and selection should be based on their intrinsic characteristics and the state of the wound. Direct pressure applied by “packing” a wound with gauze or laparotomy pads affords the best method of controlling diffuse bleeding from large areas, such as in the trauma situation. Packing bone wax on the raw surface to effect pressure can control bleeding from cut bone.
Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue. Electrocautery generates heat by induction from an alternating current source, which is then transmitted via conduction from the instrument directly to the tissue. The amplitude setting should be high enough to produce prompt coagulation, but not so high as to set up an arc between the tissue and the cautery tip. This avoids thermal injury outside of the operative field and also prevents exit of current through electrocardiographic leads, other monitoring devices, or permanent pacemakers or defibrillators. A negative grounding plate should be placed beneath the patient to avoid severe skin burns, and caution should be used with certain anesthetic agents (diethyl ether, divinyl ether, ethyl chloride, ethylene, and cyclopropane) because of the hazard of explosion.
A direct current also can result in hemostasis. Because the protein moieties and cellular elements of blood have a negative surface charge, they are attracted to a positive pole where a thrombus is formed. Direct currents in the 20- to 100-mA range have successfully controlled diffuse bleeding from raw surfaces, as has argon gas.
Topical Hemostatic Agents
Topical hemostatic agents can play an important role in helping to facilitate surgical hemostasis. These agents are classified based on their mechanism of action, and many act at specific stages in the coagulation cascade and take advantage of natural physiologic responses to bleeding.50 The ideal topical hemostatic agent has significant hemostatic action, minimal tissue reactivity, nonantigenicity, in vivo biodegradability, ease of sterilization, low cost, and can be tailored to specific needs.51
In 2010, Achneck et al published a comprehensive overview of absorbable, biologic, and synthetic agents.52 Absorbable agents include gelatin foams (Gelfoam), oxidized cellulose (Surgicel), and microfibrillar collagens (Avitene). Both gelatin foam and oxidized cellulose provide a physical matrix for clotting initiation, while microfibrillar collagens facilitate platelet adherence and activation. Biologic agents include topical thrombin, fibrin sealants (FloSeal), and platelet sealants (Vitagel). Human or recombinant thrombin derivatives, which facilitate the formation of fibrin clots and subsequent activation of several clotting factors, take advantage of natural physiologic processes, thereby avoiding foreign body or inflammatory reactions.51 Caution must be taken in judging vessel caliber in the wound because thrombin entry into larger caliber vessels can result in systemic exposure to thrombin with a risk of disseminated intravascular clotting or death. They are particularly effective in controlling capillary bed bleeding when pressure or ligation is insufficient; however, the bovine derivatives should be used with caution due to the potential immunologic response and worsened coagulopathy. Fibrin sealants are prepared from cryoprecipitate (homologous or synthetic) and have the advantage of not promoting inflammation or tissue necrosis.53 Platelet sealants are a mixture of collagen and thrombin combined with plasma-derived fibrinogen and platelets from the patient, which requires the additional need for centrifugation and processing.
Topical agents are not a substitute for meticulous surgical technique and only function as adjuncts to help facilitate surgical hemostasis. The advantages and disadvantages of each agent must be considered, and use should be limited to the minimum amount necessary to minimize toxicity, adverse reactions, interference with wound healing, and procedural costs.