Blood coagulation exists to halt excessive blood loss. It is paradoxical that surgery and trauma simultaneously represent major risk factors for both hemorrhagic and thrombotic complications. Kearon and Hirsh  estimated that surgery and trauma increase the baseline risk of thrombosis up to a hundred-fold, whereas patients with mild hemophilia who have never bled from stresses of everyday life may bleed vigorously following surgical procedures . A detailed historical review of this subject is available for the interested reader .
SURGERY FOR PATIENTS WITH CONGENITAL HEMOSTATIC DEFECTS
Currently, hemophiliacs can and do undergo any and all surgical procedures as dictated by their medical condition. As their diagnoses are established, diagnostic confusion is all but eliminated and their general care is under that of hematologists who frequently do and are encouraged to serve as their primary care providers. Adequate levels of their genetically absent factor allow the operator to do whatever would be done in a similar procedure in a patient without hemophilia. Details of such surgery are available . A notable exception includes those hemophilia patients who have or are suspected to have an inhibitor. In this clinical scenario, it is generally not advised to perform elective surgery. Consultation with a center having experience and resources to treat these patients is in order.
PROPHYLAXIS AGAINST THROMBOSIS
Prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism in surgical patients is thoroughly reviewed in a 2012 consensus . In general, prophylaxis should be more aggressively used in hospitalized patients. Prophylaxis is safer and more effective than generally held while the toll of venous thromboembolism (VTE) without prophylaxis is usually significantly underestimated. The role of mechanical and similar adjuncts in prophylaxis against VTE verifies their use . Westrich  demonstrated that intermittent pneumatic compression (IPC) devices in total knee replacement surgery were more effective than low molecular weight heparin (LMWH) and far more effective than aspirin alone in reducing both DVT and pulmonary embolism. However, they did note only a 33% compliance rate with patients for whom IPC was prescribed. Others have demonstrated not only the effectiveness of IPC and similar devices but the additive effect of this mechanical methodology with pharmacologic prophylaxis .
There remains a reticence on the part of some surgeons citing concern of possible additional risk for hemorrhage as a result of employing VTE prophylaxis. For many indications, IPC is probably effective . However, several analyses of VTE prophylaxis in neurosurgical patients [8–10] have indicated that not only is chemical prophylaxis itself well tolerated, but when combined with IPC, it adds to the efficacy of VTE prophylaxis either without any additional risk of hemorrhage [9,10] or with such a small amount of increased risk that such risk of hemorrhage is easily absorbed by the decrease in overall morbidity and mortality from VTE . Additionally, successful employment of VTE prophylaxis avoids the concern for much higher and longer dosage of therapeutic anticoagulation should a VTE occur.
PREOPERATIVE HEMOSTATIC TESTING
Approximately 3% of all surgical procedures will be accompanied by a degree of hemorrhage deemed by the surgeon to be excessive. In their large meta-analysis of more than 50 randomized double-blinded studies comparing low-dose heparin with placebo in DVT prophylaxis, Collins et al.  noted that among the 7486 controls receiving placebo, 3.3% of patients were judged to have bled excessively by the surgeon, and that 0.1% succumbed to bleeding.
Three papers [12–14] rendered a similar rate of hemorrhage among patients who are undergoing surgical procedures during studies of appropriateness of preoperative hemostatic testing. Of 4499 patients, 2% were deemed to bleed excessively. The sensitivity of hemostatic screening tests in these 4499 patients was 18%, the specificity was 90%, the positive predictive value was 3%, and the negative predictive value was 98%. There was no correlation between results of these preoperative screening tests for hemostatic competence and surgery-related hemorrhage. Of the 85 patients who bled [12–14], 70% had completely normal tests. Of the 435 patients who had abnormal tests, only 15 bled, implying that 97% of patients potentially identified as those likely to bleed did not bleed.
Multiple studies continue to support the agreed upon conclusion that obtaining routine preprocedural coagulation study is without merit. That abnormal hemostasis exists and may be identifiable is irrefutable, but repeated studies fail to document the role of preoperative laboratory testing in identifying such patients because those with abnormal hemostasis are best discovered by a thorough history and physical examination. This is true for general surgical patients , those undergoing tonsillectomy and adenectomy [16–18], cataract surgery , and neurosurgical procedures .
To contrast with the dozen or so studies reaching exactly the same conclusions, we are not aware of any study offering contradictory evidence or opinion. Accordingly, the statistical weight garnered by this unanimous thrust is so considerable that further studies of the general population seem without merit. This conclusion was arrived at in five of five overviews [21–25] on this subject.
When the cause of persistently prolonged partial thromboplastin times (PTTs) of unknown cause  was determined, 67% of patients were not at actual risk for hemorrhage because the nature of the process leading to the prolongation (bad laboratory sample, laboratory error, lupus anticoagulant, and prelaboratory variability) would not be expected to result in postoperative hemorrhage. However, the other 33% were at very clear risk to bleed; moreover, 81% of these 33% had already given a clear, positive history of a hemorrhagic diathesis even before the nature of their laboratory abnormality was determined. There was a lack of correlation between the degree of prolongation of the PTT and the risk of bleeding, a conclusion made by others ; the risk of bleeding rather is a function of the cause of the PTT prolongation, not the degree of prolongation.
Hemostatic tests should be ordered much less frequently than they customarily are. They are indicated in patients who answer affirmatively to any of the questions in Table 1. Others have stated that indications of screening tests should include malabsorption, trauma, a history of active hemorrhage, a history of chemotherapy or radiotherapy, purpura, anemia, or the prior use of anticoagulants . Some  have added patients with liver disease and operations characteristically associated with a blood loss of greater than 1500 ml. It would seem rational to include those patients refusing to accept blood or blood product infusion.
INVASIVE PROCEDURES IN PATIENTS WITH ABNORMAL ROUTINE COAGULATION TESTS, TO INCLUDE THOSE WITH CHRONIC LIVER DISEASE AND THE MISUSE OF FRESH FROZEN PLASMA
Those practicing invasive procedures often assume a proven relationship between in-vitro routine coagulation tests and the adequacy of in-vivo hemostasis. There is little evidence to support this stance; nonetheless, many physicians view coagulation tests to be touchstones of physiology. Multiple examples exist of abnormal hemostasis with normal routine coagulation tests as well as normal hemostasis in patients with substantially prolonged tests .
In severe chronic hepatic disease, most routine coagulation tests are severely altered, but most visceral bleeding is from structural causes (ulcers, tumors, or varices) or due to hemodynamic rather than hemostatic defects. Mannucci's group has shown that total thrombin generation (probably the best laboratory predictor of physiologic hemostasis) is actually normal in those with cirrhosis, despite severe alteration in conventional coagulation tests .
In the last several years there has been an evidence-based total reversal of our concept of the ‘coagulopathy of chronic liver disease’. The majority of human proteins are made by the liver and nearly all of the coagulation factors (the notable exception being factor VIII) and nearly all of the anticoagulant factors such as protein C, protein S, antithrombin III, and plasminogen are hepatically produced. An appreciation of how the prothrombin time (PT) and PTT are done shows us that the in-vitro coagulation that is assayed by these tests does not take into account the parallel decrease of the anticoagulant proteins. Accordingly, the PT and PTT are measuring only one side of the coagulation equation as severe depletions of protein C, protein S, antithrombin III, and plasminogen have no in-vitro way to reveal their absence. This had often been termed ‘autoanticoagulation’ by liver disease, such that it was once believed that patients with severe liver disease were highly prone to hemorrhage but actually protected from thrombosis. In truth, the risk of thrombosis in patients with severe liver disease is vastly underrated. In severe, ambulatory chronic liver disease, all the coagulation and anticoagulation factors are typically in the range of 25–35% of normal. This has been termed ‘rebalanced coagulation’ [31,32▪▪], which can be revealed by viscoelastic studies such as thromboelastography (TEG) [33–35]. Appreciation of this conundrum will allow treaters to not only consider thrombosis in such patients, but actually employ antithrombotic therapy in selected cases.
Invasive procedures such as bronchoscopy, endoscopy, lumbar punctures, paracentesis, and the insertion of lines for central venous access are part of modern medical practice. Although many patients needing these procedures have abnormal routine coagulation studies, published data underscore the safety and acceptable outcomes of such procedures in cancer patients, transplant patients, and patients in ICUs. There is no published evidence for increased risks of procedure-related hemorrhage. There is also no controlled study that indicates at what levels the PT, PTT, and platelet count actually represent contraindications to invasive procedures or the use of prophylactic infusion of blood products reduces the risk of procedural-related hemorrhage [36–40].
Far too many clinicians believe that fresh frozen plasma (FFP) is highly efficacious when used, particularly preoperatively, for invasive procedures in patients who have abnormal preoperative PTs and/or PTTs. Obviously, if the preoperative blood tests are due to therapeutic anticoagulant agents, attention should be paid to its effective reversal. However, by far the most common cause of such prolongations of the PT and PTT is chronic liver disease, whereby you will see an in-vitro correction of the laboratory values by 1:1 mixing with normal plasma. The usual clinical practice has held that providing 2–4 units of FFP before an invasive procedure not only will correct the PT and PTT, but will also result in less bleeding. Müller et al. [41▪] are the latest in a long line who published evidence showing that FFP infusion has not only no efficacy, but only occasionally corrects the slightly abnormal coagulation tests. There is also no evidence that such a maneuver results in less bleeding than not transfusing FFP. In the past, this practice was tolerated but there is increasing evidence that the use of FFP is associated with a poorer outcome (with particular reference to transfusion-related acute lung injury). A reasoned analysis of the risk:benefit ratio shows that this practice should be abandoned. Müller et al. [41▪] observed 81 patients with International Normalized Ratios (INRs) in the 1.5–3.0 range who were not on anticoagulant therapy; the vast majority had chronic liver disease. The patients underwent procedures such as central venous line placement, tracheostomy, chest tube placement, or draining of various abscesses or fluid collections. Patients were randomized between receiving FFP (12 ml/kg) with a mean infusion of 3 units FFP per patient, and with proceduralists operating in a blinded fashion. There was no difference in either major or minor bleeding between the two groups. The INR decreased in only half the patients. Clearly, this practice needs to be curtailed [42,43].
MASSIVE TRANSFUSION PROTOCOLS IN TRAUMA
Replacement therapy with massive blood transfusions following trauma has undergone total re-examination. This is in large part based on the four decades long held theory that blood replacement should not be done using whole blood, but by progressively adding crystalloids, FFP, red blood cells, plasma, and lastly, platelet transfusion as the patient's blood volume approaches being totally replaced. Newer methods to include earlier use of all blood products are now referred to as ‘massive transfusion protocol’ although more discoveries are needed in this area [44▪]. Many have opined that classic coagulation laboratory tests used, such as the PT and PTT, were promulgated to identify congenital hemophilia  and not designed to direct transfusion decisions. These are static tests and if not done at the point of care, they often consume an unacceptably long time to guide healthcare decisions . Indeed, others have shown that viscoelastic laboratory evaluations with devices such as TEG or rotational thromboelastometry (ROTEM) better guide transfusion compared with standard laboratory tests. TEG and ROTEM do admittedly take into account hypofibrinogenemia and hyperfibrinolysis . Much work is anticipated in this area and it is suspected that the study of such patients will result in the earlier use of plasma, platelets, and red cell replacement in a 1:1:1 ratio in patients who are expected to experience massive transfusion, thus emulating reconstituted whole blood more rapidly than using the various components of blood incrementally.
CONTRIBUTIONS AND WORRIES BROUGHT ABOUT BY THE NEW TARGET-SPECIFIC ORAL ANTICOAGULANTS
There are now several target-specific oral anticoagulants (TSOACs) approved by the U.S. Food and Drug Administration. Although the introduction of these medications has offered the practicing clinician more options for chronic anticoagulation therapy, their use has presented both new questions and newer ways to look at old problems [47▪▪].
Whereas the VKA or TSOAC agents treat more or less the same disease, there remain questions regarding the safety of the TSOAC agents for each indication. By having both a test (INR) with which one can monitor dosing and as VKA usage can be reversed by several methods (to include FFP, vitamin K administration, or 4-factor prothrombin complex concentrates), it was conceivable that VKAs might prove safer than TSOACs for which there is neither a test to monitor nor an agent to reverse its effects.
Three recent articles have approached this question [47▪▪,48,49]. Using the ARISTOTLE trial, Hylek et al. studied the anticoagulation of patients with atrial fibrillation with the intention of reducing stroke. The rate of major hemorrhage in the apixaban group had an incidence of 2.13% per year compared with 3.09% per year amongst those patients in the warfarin-treated group (hazard ratio 0.69, P < 0.001) and is consistent with the notion that patients undergoing apixaban treatment bled at a statistically significant lower rate than those treated with warfarin. Equally or more important is that amongst those who did sustain bleeding, apixaban-treated patients experienced only half as much fatal bleeding (even with no reversing agents available) than did those patients who were treated with warfarin and its reversing agents. This decrease in the crude rate of fatal bleeding was also seen in all phase III studies comparing a TSOAC with conventional therapy, and is partly explained by the approximately 50% relative-risk reduction in the often fatal intracranial bleed [47▪▪].
CONSULTATION ON PATIENTS WITH INTRAOPERATIVE OR POSTOPERATIVE HEMORRHAGE
Nearly all reviews of intraoperative and early postoperative bleeding  point out that 75–90% of all such bleeding is structural in nature, such as an undone ligature, failed clamp, or partially secured vessel. It is vital to work with the surgeon because the cause of bleeding must be either surgical or hemostatic failure. Early in the consultation process, it is advisable to have personnel draw blood samples for routine available coagulation tests. Too frequently laboratory samples are adulterated by supportive infusions or transfusions. Therefore, the very sample that one needs for critical decision-making must not be suspect from the beginning. Assessment of all patients experiencing substantial hemorrhage usually includes a PT, PTT, thrombin time (TT), platelet count, and measurements for D-dimer. If the PT, PTT, and TT are all prolonged with decreased plasma fibrinogen levels, decreased platelets, and positive assays for D-dimers, disseminated intravascular coagulation (DIC) is very high on the list for hemorrhage. If the D-dimers are elevated but with the PT, PTT, and platelet count fairly well preserved yet with a very long TT, hyperfibrinolysis is strongly suggested. Conversely, if the TT is the sole test that is relatively the most prolonged, the culprit more often than not is excessive heparin either systemically administered or possibly from a contaminated sample from an intravenous line containing heparin. It must be recalled that neither LMWH nor pentasaccharides in their usual dosage prolong the PT, PTT, or TT so their involvement cannot be eliminated by those tests being normal . However, accidental, surreptitious, or suicidal use of LMWH and/or newer TSOACs can result in confusion from rather prolonged standard coagulation tests and these possibilities must be considered [52,53].
The coagulation laboratory can set up a 1:1 mixture of patient plasma with normal plasma to repeat the PT, PTT, and TT if any of these tests are abnormal upon initial testing. If the 1:1 mixture results in a previously abnormal test becoming normal, it strongly suggests a deficiency that can occur either congenitally, because of vitamin K deficiency or warfarin therapy, or from severe liver disease. Should the 1:1 mixture not correct the abnormal test(s), then an inhibitor, to include heparin, D-dimers, or spontaneous acquired inhibitor, is strongly suggested. Although the use of TEG does not traditionally fit into hematologists’ thinking, it clearly is one of the more rapid ways to detect hyperfibrinolysis, especially in situations that are characterized by hyperfibrinolysis. Increasingly, two older standby antifibrinolytic drugs have enjoyed a renewed popularity and efficacy in managing hyperfibrinolysis. These are tranexamic acid and epsilon-aminocaproic acid, which have resulted in considerable decreases in blood loss and transfusion requirements when used in the appropriate setting [54,55].
TEG appeared to better predict bleeding and guide therapy than traditional coagulation tests. Although agreeing that point-of-care testing was of marginal diagnostic significance, studies [56,57] have pointed out that its use within a protocol for hemorrhage following heart surgery resulted in a more focused transfusion practice than in patients whose care was under clinical discretion using traditional laboratory testing, despite actually resulting in fewer transfused blood products.
Once laboratory studies are initiated, attention must be paid to the clinical features of hemorrhage. As Table 2 depicts, the nature of bleeding is very helpful. The concept that bleeding is due to a structural defect is greatly strengthened if there is bleeding from a single site while other potential sites are not bleeding. Clinical features that favor a basic hemostatic defect are multiple concurrent bleeding sites. Concomitant hemoglobinuria and hemoglobinemia strongly implicates transfusion reaction-induced DIC. Slow and persistent oozing, particularly several days after surgery, suggests a hemostatic defect.
Table 3 lists several hemostatic details that may or may not affect postoperative hemorrhage. Low-dose prophylactic use of heparin does not increase bleeding according to comprehensive meta-analyses . Recalling that perhaps 1% of the population may have low von Willebrand factor levels that do not fulfill criteria for von Willebrand disease (VWD) and whom are without a history of hemorrhage, it is highly possible that the challenge of surgery or the addition of aspirin or NSAIDs is enough to expose the underlying nature of that disorder. The division separating ‘low-normal’ from ‘high-VWD’ is not at this time firmly established . By far, the rarest abnormality is mild, previously undiagnosed hemophilia , which is characterized by a slow ooze that usually starts on postoperative days 1–3 and is rarely of a brisk or alarming nature initially. Characteristically, hemostasis in mild hemophiliacs undergoing surgery is surprisingly normal for the first day or so during high levels of wound-induced tissue factor generation.
Table 4 presents various causes of postoperative bleeding to consider. The differential diagnosis is, in part, a function of time from the operation. Hyperfibrinolysis characteristically is very brisk but usually of short duration and corrects itself. Thrombocytopenia that begins postoperatively and becomes worse, particularly if it is associated with new thrombosis, is highly suggestive of heparin-induced thrombocytopenia. Vitamin K deficiency of an acquired nature is surprisingly common in intensive care situations, particularly if the patient has been ill for some time and, therefore, malnourished from the onset and resulting in the depletion of vitamin K-dependent factors. One clinical hallmark of this situation is that the PT tends to prolong comparatively earlier than the PTT. Vitamin K deficiency is diagnosed by clinical suspicion and the response of the patient to vitamin K administration.
Table 5 offers several therapeutic options. Watching and waiting with the appropriate administration of red blood cells and fluid is often appropriate, particularly if the rate of bleeding seems to be decreasing. Re-exploration of the surgical site not only often will identify the bleeding site, but also may be therapeutic in itself because of the removal of thromboplastic as well as fibrinolytic agents released from large collections of clotted blood. If a specific bleeding site is found, therapy is obviously addressed toward its correction.
In desperate situations in which more traditional methods have failed and even without a specific diagnosis, many have employed the use of rFVIIa. Dosage is usually initially 40–90 μg/kg which may be repeated every 2 h for 6–8 h total if hemostasis is not achieved earlier. There is a risk of pathologic thromboses, particularly in older patients, without a clear mortality benefit and at a significant cost [59,60]. Prolonged repeated doses are generally not recommended.
The administration of 1-deamino-8-D-arginine vasopressin is effective for platelet dysfunction due to aspirin or NSAIDs. Administration of 0.3 μg/kg intravenously over 30 min every 12 h for 24–36 h is suggested.
The past three decades of research in the clinical sciences regarding hemostasis and surgery has supported a re-emphasis on the prevention of VTE, a major cause of morbidity and mortality in hospitalized surgical patients. Although perioperative hemorrhage is a natural risk to any procedure, there is an abundance of data confirming the robust risk:benefit ratio of antithrombotic prophylaxis, despite the increasingly complex comorbidities that exist in the modern-day surgical patient population. Careful attention to the patient's clinical history and presentation provides the best guarantee in predicting hemorrhagic complications, as well as identifying and successfully intervening in hemostatic failures.
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Conflicts of interest
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