Introduction to Hemostatis
Coagulation is now thought to be a cell-based process occurring on the surface of endothelial/subendothelial cells and platelets, rather than the two-pathway plasma-based process traditionally described [Roberts et. al. Anesthesiology 100: 722, 2004; Schenone et. al. Curr Op Hematol 11: 272, 2004]. Native anticoagulants include heparin sulfate proteoglycans (increase antithrombin and thrombomodulin activity), nitric oxide, prostacyclin, and tPA.
Activation of Coagulation Process at Injury Site
When an injury occurs, subendothelial cell tissue factor is exposed to circulating blood which contains factor VII, forming a VIIa-TF complex which cleaves and activates IX and X, Xa then activates V (prothrombin: activates more Xa, also separates vWF from VIII, triggering a burst of feed-forward activity). Platelets begin adhering to the injury site and when activated release thromboxane (a vasoconstrictor). Furthermore, the platelet surface binds prothrombinase complexes which also activate factor V (which cleaves prothrombin to thrombin). Thrombin then cleaves fibrinogen into fibrin which traps platelets and red blood cells.
Native Attenuation of Coagulation
Coagulation is stopped by inhibitor proteins and anticoagulant proteases, including:
- serine protease inhibitors (serpins, including antithrombin, heparin cofactor II, alpha-2-macroglobulins which trap circulating coagulation factors, and tissue factor pathway inhibitor)
- anticoagulant proteases
Following an injury, the endothelium activates tissue plasminogen activator (TPA) which activates plasminogen (normally inhibited by circulating plasminogen activator inhibitor type 1) – the resulting plasmin is then capable of lysing fibrin
Utility of the Clinical Screen
While traditionally considered to be informative, the preoperative clinical history may not be a useful measure of bleeding risk. Suchman’s study from 1986, which analyzed over 12,000 patients, showed that “low risk” patients had a 0.22% risk of bleeding, and “high risk” patients had a 1.7% risk of bleeding [Suchman AL et. al. JAMA 256: 750, 1986]. Similarly, Houry’s study from 1995, of over 2300 patients showed a 3.9% difference in bruising (8.7% for high risk vs. 4.8% for low risk), but smaller differences in hematomas (4% vs 3%), reoperation for hemorrhage (1.2% vs. 0.48%), and deaths related to hemorrhage (0.21% vs. 0.13%) [Houry S et. al. The French Associations for Surgical Research Am J Surg 170: 19, 1995]
Usefulness of Laboratory Values
The utility of PTT and INR has recently come into question. There is minimal data to support the use of laboratory tests as a predictive variable prior to initiating invasive diagnostic procedures, including central vein cannulation, femoral angiography, bronchoscopy, and even liver and kidney biopsies [Segal J, Dzik WH; Transfusion 45: 1413, 2005]. From a teleological perspective, one would suspect that PTT and INR values are of limited use, as “normal” values are based on the general population and not surgical patients who do or don’t bleed [Eckman MH et. al. Ann Intern Med 138: W15, 2003]
Conducted by recalcifying plasma (which is usually citrated), then adding tissue thromboplastin (to activate factor X) to initiate coagulation. Addresses factor VII (but X, V, prothrombin, and fibrinogen must be present as well).
Data discouraging the routine use of PT/INR for preoperative evaluation in patients with no predisposing conditions emerged in the 1970s, starting with Eisenberg’s study of 301 VA surgical patients, which showed < 1% risk of PT/INR abnormalities in patients with a questionnaire negative for signs or symptoms of liver disease or coagulopathy. [Eisenberg JM et. al. Clin Chem 22: 1644, 1976]
Darcy et. al. prospectively studied 1,000 consecutive patients undergoing femoral artery puncture and found that abnormal results of coagulation tests were not correlated with an increased occurrence of hemorrhagic complications, although bleeding complications occurred more often in patients with platelets < 1.0 x 10(11) (p = 0.002). Hematomas occurred in 8.1% (10 of 123) of patients with any abnormal coagulation test results and 9.7% (85 of 877) of patients with normal test results (NS). [Darcy MD et. al. Radiology 198: 741, 1996]
The largest studies addressing preoperative INR and subsequent management changes in Munro’s review were Charpak [Charpak Y et. al. Can J Cardiol 2: 134, 1986] and Manning [Manning SC et. al. Int J Pediatr Otorhinolaryngol 13: 237, 1987] (> 900 preoperative labs in each) in which INR produced management changes in 0.8% and 2.9% (no differentiation between routine and indicated for either study) of patients, respectively.
Note also that the likelihood of actually “correcting” a mildly abnormal INR (1.8 or less) with FFP, based on a retrospective audit of 1091 transfusions at Massachusetts General Hospital, is less than 1% (although there is a 15% chance that the INR will return halfway to normal) [Abdel-Wahab OI et al. Transfusion 46: 1279, 2006]
Conducted by recalcifying plasma (which is usually citrated), then adding phospholipids to initiate coagulation. Addresses VIII, IX, XI, and XIII (but X, V, prothrombin, and fibrinogen must be present as well).
The futility of routine PTT testing (as with PT/INR) was also first proposed in the late 1970’s [Eisenberg JM et. al. Clin Chem 22: 1644, 1976; Robbins JA et. al. Med Clin North Am 63: 1145, 1979; Robbins JA et. al. Ann Intern Med 90: 796, 1979]. PTT does not seem to affect surgical mortality in patients with no clinical risk factors – in a study of 3242 surgical patients (2291 of whom were clinically low-risk), bleeding complications were similar in low-risk patients regardless of PTT. In the clinically low-risk group, 0.15% of 1951 patients with normal test results died of bleeding complications, whereas none of 340 with abnormal test results died of hemorrhagic complications. [Houry S et. al. The French Associations for Surgical Research Am J Surg 170: 19, 1995]
The largest studies addressing preoperative PTT and actual management changes (as mentioned in in Munro’s review) were Charpak [Charpak Y et. al. Can J Cardiol 2: 134, 1986] and Manning [Manning SC et. al. Int J Pediatr Otorhinolaryngol 13: 237, 1987] (> 900 preoperative labs in each), in which PTT produced management changes in 0.7% and 2.9% (no differentiation between routine and indicated for either study) of patients, respectively.
Conducted by recalcifying plasma and adding thrombin. Prolonged clotting suggests fibrinogen < 100 mg/dL, abnormal fibrinogen, or the presence of anticoagulants such as heparin.
Activated Clotting Time (ACT)
Whole blood is added to celite or kaolin. Used to monitor heparin in the OR (especially at levels where the PTT ceases to be of use).
None of the studies reviewed by Munro which examined the impact of routine platelet counts found a single patient in which management had been altered by the test result [Rohrer MJ et al. Ann Surg 208: 554, 1988; Narr BJ et. al. Mayo Clin Proc 66: 155, 1991]. Furthermore, in Charpak’s study of selectively ordered platelet counts (i.e., not routine), management was altered in only 1.7% of cases. [Charpak Y et. al. Can J Cardiol 2: 134, 1986]
A retrospective study of 958 consecutive children with ALL who underwent a diagnostic and therapeutic LPs showed that of the 5223 LPs evaluated, 29 were performed at PLT < 10,000/mm3, 170 at PLT 11-20,000/mm3, and 742 at PLT 21-50,000/mm3. No serious complications (defined as any neurologic, infectious, or hemorrhagic problems related to the procedure) were encountered in the study, regardless of the platelet count [Howard et. al. JAMA 284: 2222, 2000]. Furthermore, platelet activation can occur during a difficult draw, resulting in clumping and an artificially-decreased platelet count.
Platelet Function Analysis
Requires a hematocrit of 35% and a normal platelet count to run this assay. A prospective study of 255 CABG patients by Cammerer et. al. showed that both modified computerized thromboelastography and platelet function analysis (PFA) post-bypass were predictive of postoperative blood loss in routine cardiac surgery, although the preoperative values were not of use (p > 0.05) – the negative predictive value of both tests (82% for angle alpha) was more useful than the positive predictive values [Cammerer U et. al. Anesth Analg 96: 51, 2003; FREE Full-text at Anesthesia & Analgesia]
Measures four variables: 1) factor-dependent clot time 2) fibrinogen/platelet-dependent clot time 3) clot strength and 4) degree of clot lysis. Cammerer et. al. found thromboelastography to be superior to PFA in their study of 255 CABG patients [Cammerer U et. al. Anesth Analg 96: 51, 2003; FREE Full-text at Anesthesia & Analgesia]
Conducted by making a 9 mm long x 1 mm deep incision, inflating a blood pressure cuff to 40 mm Hg proximal to the lesion, blotting excess blood every 30 seconds and then measuring time to cessation of bleeding. This test is unpopular because of the potential for scarring as well as its inaccuracy in the perioperative period. Barber’s study of 1800 perioperative patients showed that among patients in whom bleeding time was measured (pooled group including measurements made as indicated and as a routine test), 2.3% of measurements led to a change in management [Barber A et. al. Am J Med 78: 761, 1985]
Excerpts from MGH FFP transfusion article
(from MGH Transfusion article: The assumption that coagulation test variables predict the risk of bleeding has been challenged.1-3 Numerous studies evaluating bleeding following central venous line placement, 4,5 liver biopsy,6 thoracentesis,7 paracentesis,7 and lumbar puncture8 have all revealed no correlation between the risk of bleeding and mild abnormalities in preprocedure PT, partial thromboplastin time (PTT), or platelet (PLT) values
Munro J et. al. Health Technology Assessment 1(12): 1, 1997
Munro et. al. identified 23 studies of preoperative clotting tests which reported useful outcome data, all of which were case-series. The results from routine tests could be distinguished from those for indicated tests for ten of the studies, in which the percentage of tests which lead to a change in management was 0.8% or less in all studies. By contrast, in studies of routine and indicated tests (i.e., including those in which the test is indicated), up to 5.3% of tests produce a change in management. PT is abnormal in up to 4.8% of routine preoperative tests, and PTT is abnormal in up to 15.6% of routine preoperative tests.
Nine of the 23 papers explicitly addressed whether preoperative tests had any predictive value for intraoperative or postoperative bleeding, and in all nine either there was no association or the positive predictive value was so low that it was clinically useless.
“PT is abnormal in up to 4.8% of routine preoperative tests, and rarely leads to change in management of patients. • PTT is abnormal in up to 15.6% of routine preoperative tests, and rarely leads to change in management of patients. The evidence reviewed does not support a policy of routine preoperative testing for bleeding disorders in all patients, and conversely provides no evidence that such a policy would be harmful. Benefits would probably only occur in the small proportion (< 1%) of patients who have an abnormal test result and for whom management is altered [Munro J et. al. Health Technology Assessment 1(12): 1, 1997]”
Fisher NC, Mutimer DJ. Central venous cannulation in patients with liver disease and coagulopathy—a prospective audit. Intensive Care Med 1999;25:481-5.
DeLoughery TG, Liebler JM, Simonds V, Goodnight SH. Invasive line placement in critically ill patients: do hemostatic defects matter? Transfusion 1996;36:827-31.
Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981;26:388-93.
McVay PA, Toy PT. Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities. Transfusion 1991;31:164-71.
The ASA Practice Guidelines for perioperative blood transfusion and adjuvant therapies recommend that “a visual assessment of the surgical field should be jointly conducted by the anesthesiologist and surgeon to determine whether excessive microvascular bleeding (i.e. coagulopathy) is occurring” [Anesthesiology 105: 198, 2006]
Generally speaking, coagulation factor levels of ~ 25% of normal or platelet counts < 50,000/uL are associated (but not proven to cause) with intraoperative bleeding. [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier: China p. 335, 2007].
Von Willebrand’s (1-2% of the population) is the most common genetic disorder leading to a hypocoagulable state. vWF binds to platelets and factor VIII, and vWF deficiency exists in three types – type I (quantitative deficiency, 70% of cases), type II (qualitative, 25% of cases), and type III (undetectable levels of vWF and VIII, 1-5% of cases). Treatment is usually with DDAVP, FFP (20-25 mL/kg), or intermediate-purity factor VIII. DDAVP is contraindicated in type 2B vWF (because of transient decrease in platelets) as well as in patients with unstable CAD, as vWF multimers can cause platelet aggregation.
Hemophilia A and B (VIII and IX) are less common hereditary hypocoagulopathic disorders. Mild VIII deficiency can be treated with cryoprecipitate as well as DDAVP at 0.3 ucg/kg (to release vWF and VIII) and antifibrinolytics (ex. tranexamic acid 10-15 mg/kg IV q8-12h or e-aminocaproic acid 50-60 mg/kg q4-6h). Coagulant activity should be maintained to at least 50% of normal prior to surgery.
Thrombocytopenia is most commonly caused by HIT (5% of patients receiving heparin), but is also common in pregnant patients (HELLP syndrome) and in patients with splenomegaly. Platelet function can also be caused by NSAIDs, uremia, fibrinogen-fibrin split products, or high levels of circulating proteins.
Surgical Conditions Which Affect Bleeding
Surgical conditions which can increase the risk of bleeding include hypothermia, acidosis, and anemia. [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier: China p. 335, 2007]
Spontaneous hypercoagulable states can be found in malignancies, kidney disorders, diabetes, CAD, sepsis, and in the face of vascular damage or stasis. Cardiac causes include artificial valves as well as arrhythmias.
Factor V Leiden
The most common hereditary hypercoagulable state is caused by Factor V Leiden deficiency, which occurs in approximately 4-8% of the population. Other causes include deficiency of antithrombin, protein C or S, or prothrombin (20210), as well as the MTHFR mutation (and consequent elevated homocysteine). Additionally, factor XII deficiency causes a hypercoagulopathic state.
Disseminated Intravascular Coagulation (DIC)
DIC is, at least initially, a hypercoagulable state (which ultimately leads to a hypocoagulable state as factors are depleted). It is detectable during the hypocoagulable state, when INR and PTT are elevated, as are D-dimers (which remain elevated for days). Treatment is removal of stimulus if known, followed by replacement of deficient products. Despite the fact that DIC begins as an initially hypercoagulable state, there is no evidence that transfusion of products is deleterious [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier: China p. 335, 2007]. Heparin is not useful unless coagulation is overt.
Coumadin, with its narrow therapeutic range and time to steady-state (peak plasma concentrations are achieved in 90 minutes, but anticoagulant effect takes several days), should always be treated with caution.
Unfractionated heparin has two advantages over LMWH: immediate onset and reversibility with protamine. It is the anticoagulant of choice after cardiac, vascular, and neurointerventional procedures. For cardiac cases 300-400 U/kg is normally given, leading to an ACT > 400 seconds (the safe threshold for going on cardiopulmonary bypass). Note that aprotinin artificially shortens the kaolin-activated ACT, thus the ACT must be 600 seconds to come off of bypass if aprotinin/kaolin are used (celite-based ACTs are not affected). In other cases (vascular, neurointerventional), heparin is usually given in simple 3000-5000 U boluses until ACT is 2x baseline. Beware that boluses of heparin can drop SBP due to decreased SVR. Heparin resistance is usually caused by excessive heparin binding proteins or insufficient antithrombin – in the latter case, administration of FFP (which contains AT) will be therapeutic. HIT type 1 occurs in 5-25% of patients (usually 1-2 days after starting heparin), is non-IgG mediated, and self-limited. HIT type 2 is less common (usually 5-10 days after starting heparin), IgG mediated, and fatal in ~ 25% of cases.
LMWH activates antithrombin and inactivates factor Xa, but is unable to inhibit thrombin directly (as UFH does). Its onset is in 20-60 minutes, and is more predictable. In obese, renal failure, or neonatal patients, anti-factor Xa levels have to be monitored.
Fondaparinux is a pentasaccharide that activates antithrombin. It has a longer half-life than LMWH and can be given SQ qday. Risk of bleeding in long term therapy, however, is higher than for LMWH.
Direct thrombin inhibitors (argatroban, melagatran, hirudin, and bivalirudin) are mostly given IV, although ximelagatran is given PO. Key to their use is understanding that all direct thrombin inhibitors significantly elevate the risk of bleeding and cannot be reversed. Argatroban, uniquely for this class, can be monitored via ACT or PTT (bivalirudin and hirudin cannot).
Tissue plasminogen activators contraindicate surgery or puncture of non-compressible vessels for ten days.
Platelet function normalizes within 3 days of discontinuation of NSAIDs. [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier: China p. 335, 2007]
Thienopyridine derivatives (namely clopidogrel) inhibit ADP-induced platelet aggregation and prevent fibrin from binding to platelets. Platelets take ~ 7 days to normalize after cessation of clopidogrel, although some believe that normalization can take as many as 10 days (ticlopidine, for instance, requires 14-21 days).
GPIIB/IIIA antagonists (abciximab, eptifibatide, and tirofiban) prevent fibrinogen and vWF from binding to the platelet GPIIB/IIIA receptor. Platelets normalize 24-48 hours after discontinuing abciximab.
Patient Care Issues re: Hemostasis
How To Approach Anticoagulated Patients
Always take into account the reason that patients are on anticoagulant therapy to begin with. Patients who had a thromboembolic event within the last month are at highest risk for thromboembolic complications. Patients undergoing elective surgery should probably wait until at least 3 months of anticoagulant therapy have been completed prior to undergoing an operation. [Stoelting et. al. Basics of Anesthesia, 5th ed. Elsevier – China, p. 342, 2007] Patients who are coming off of coumadin are at risk for thrombosis for several reasons. First, they have some sort of predisposing hypercoagulable state (or they wouldn’t be on coumadin to begin with). Second, thrombin formation is abnormally high following cessation of coumadin therapy [Stoelting et. al. Basics of Anesthesia, 5th ed. Elsevier – China, p. 343, 2007]. Third, INR measurements are not entirely representative of the patient’s true coagulative state (i.e., there is some lag). Furthermore, as in all patients, plasminogen activator inhibitor type I levels increase postoperatively.
How to Assess Risk of Perioperative Venous Thrombosis
Orthopaedic surgery patients are at particularly high risk for thromboembolic complications, as are patients coming off of coumadin in order to undergo cardiovascular or abdominal operations. In high risk patients, Stoelting recommends converting to IV heparin perioperatively, and discontinuing UFH 6 hours prior to surgery (or LMWH 12 hours prior to surgery). Heparin can then be restarted 12 hours after surgery. One must always take into account the likelihood of perioperative bleeding. Postoperative heparin is given at maintenance doses only (i.e., no loading doses are used) [Stoelting et. al. Basics of Anesthesia, 5th ed. Elsevier – China, p. 343, 2007]
Patients at intermediate risk do not require preoperative heparinization. Low risk patients only require SQH or LMWH.
In patients who need immediate restoration of vitamin K activity, FFP (10-15 cc/kg IV) can be infused, however FFP is rarely able to normalize or even half-normalize INR below 1.85 [Abdel-Wahab et. al. Transfusion 46: 1279, 2006]. Prothrombin complex concentrate (which is normally dosed at 25-50 IU/kg) has been shown to be more effective [Makris et. al. Br J Haematol 114: 271, 2001] than FFP, but the high risk of perioperative thrombosis must be taken into account.
As stated in Murray’s “Critical Care Medicine,” the ASA recommendations for FFP are the following:
ASA recommendations for the administration of FFP
ASA recommendations for the administration of FFP (recommended dose = 10-15 cc/kg)
- Urgent reversal of warfarin (only requires 5-8 cc/kg). Note, however, the prothrombin complex concentrate (which is normally dosed at 25-50 IU/kg) has been shown to be more effective [Makris et. al. Br J Haematol 114: 271, 2001]
- Correction of known coagulation factor deficiencies for which specific concentrates are unavailable
- Correction of microvascular bleeding in the presence of INR > 1.5 (debatable efficacy, see below)
- Correction of microvascular bleeding in the presence of massive transfusion (> 1 blood volume)
Neuraxial Anesthesia (NAA)
The reader is referred to Horlocker TT et. al. Reg Anesth Pain Med 28: 172, 2003 for complete recommendations – highlights include the following:
Excerpts from Horlocker TT et. al. Reg Anesth Pain Med 28: 172, 2003
- NSAIDs are not a contraindication to neuraxial anesthesia
- Plavix should be discontinued 7 days prior to neuraxial anesthesia
- SQH is not a contraindication to NAA but platelets should be measured (risk of HIT-1)
- IV heparin should not be given if other coagulopathies are present, and held 1 hour after catheter placement, no restrictions before the procedure
if dosed every 12 hours
- NAA should wait 10-12 hours after last dose of once-daily LMHW, wait 24 hours after traumatic tap or if patient is receiving twice-daily dosing
- Warfarin should be stopped 4-5 days and INR should be normal prior to NAA
Approach to Intraoperative Bleeding
If coagulation factors are thought to be the cause of blood loss, FFP can be given. As a general rule, FFP is often transfused when one blood volume is lost, and platelets are often transfused after two blood volumes are lost [Stoelting et. al. Basics of Anesthesia, 5th ed. Elsevier – China, p. 345, 2007]. Prothrombin complex concentrate and recombinant Factor VIIa can be given if needed, but the former is highly thrombogenic (rFVIIa is less-so). Other considerations include cryoprecipitate (0.1 concentrate per kg), DDAVP, aprotinin (inactivates plasmin and plasminogen, carries a risk of anaphylaxis if reinfused within 6 months), e-aminocaproic acid, and tranexamic acid.