Coagulation Defects

Anesthesiology Clin 24 (2006) 549–578

Coagulation Defects Doreen E. Soliman, MD*, Lynn M. Broadman, MD Division of Pediatric Anesthesiology, University of Pittsburgh Medical Center and Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA

The understanding of the coagulation process has evolved over the past decade from one in which platelets and the triggering of one of two very separate protein cascade systemsdthe intrinsic and extrinsic pathwaysdwould ultimately produce clot formation, to the present understanding that places more emphasis upon the final common pathway and the proteolytic systems that result in the degradation of formed clots and the prevention of unwanted clot formations. This new understanding now also places emphasis upon a variety of defense systems that include: tissue repair, autoimmune processes, arteriosclerosis, tumor growth, the spread of metastases, and defense systems against micro-organisms [1]. More importantly, this article sheds light upon some of the most common bleeding disorders and their diagnosis and management. Finally, the authors’ goals are to provide clinicians with a simple guide on how to best manage patients afflicted with congenital or acquired clotting abnormalities during the perioperative period, present a brief overview of the methods of testing and monitoring the coagulation defects, and discuss the appropriate pharmacologic or blood component therapies for each disease. The coagulation process The coagulation process involves the following four phases: (1) initiation (endothelial damage and response in the form of platelet adherence and plug formation); (2) acceleration (protein activation and further cellular activation); (3) control (feedback mechanisms to control coagulation); and (4) lyses (breakdown of clots, initiation of healing and recannulization) [2]. Coagulation is a subset reaction of tissue injury and inflammation, and is the end result of interactions between platelets, white cells, and endothelial * Corresponding author. E-mail address: [email protected] (D.E. Soliman). 0889-8537/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.atc.2006.05.009 anesthesiology.theclinics.com

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cells at the site of tissue injury [2]. Vessels less than 30 to 50 microns in diameter react to injury by simply instituting serotonin-, epinephrine-, norepinephrine-, and thromboxane-mediated vasoconstriction [2]. Endothelial cells control vascular tone through nitric oxide release [2,3], which is also a potent antiplatelet agent, and endothelin, a potent vasoconstrictor. Endothelin is a 21-amino acid polypeptide that is produced by endothelial cells and plays a role in the control of blood pressure by regulating vascular tone. Endothelial cells also prevent blood from clotting, and secreted prostaglandins inhibit platelet formation and white cell binding. With tissue injury, endothelial cells are transformed into a procoagulantactivated state. Exposed collagen stimulates platelet adhesion, and the endothelial cells, through either direct damage or by ischemia and reperfusion, quickly decrease their release of nitric oxide and prostaglandins [2]. Platelets begin to adhere at the site of injury, while von Willebrand’s multimers are simultaneously formed at the same site and begin to adhere to both exposed collagen and dysfunctional endothelial cells. Platelets have ligands that are not expressed at rest; however, when stimulated, these glycoprotein ligands are displaced to the exterior of the cell, the von Willebrand factor (vWF) binds at the glycoprotein (GP)-Ib binding site, and the GP-IIb/IIIa receptor binds fibrin molecules [2]. Coagulation is a platelet-mediated and platelet surface ligand-mediated event. Many protein reactions occur on the surface of activated platelets [2]. Platelets that are adherent to vascular collagen release dense and alpha granules that contain a host of factors involved in the aggregation process and coagulation cascade. Activated platelets can also adhere to one another and thereby undergo conformational changes that allow for the formation of the initial platelet plug. Control of primary hemostasis is also maintained by balancing thromboxane A2, a potent vasoconstrictor and an agent that promotes platelet aggregation [4], and prostacyclin, which is a potent vasodilator and inhibitor of platelet aggregation [3]. The plasma proteins involved in the coagulation process are all synthesized in the liver. Factors II, VII, IX and X are the vitamin K-dependant factors, and circulate in an inactive form. Traditionally the clotting cascade is divided into intrinsic and extrinsic pathways. More recently the tissue factor pathway has been described. This pathway is regulated by the tissue factor pathway inhibitor (TFPI) [5]. Another reaction that takes place on the surface of platelets provides an increase in thrombin activity. Thrombin is the activator in the conversion of fibrinogen to fibrin. As protein cascade activation occurs, feedback to normal endothelial cells also occurs, leading to the release of both protein C and proteins through thrombomodulin activation [2]. Thrombomodulin is an endothelial cell protein that binds protein C and thrombin. Activated protein C and protein S inactivate Factors V and VIII, leading to the downregulation of the protein cascades. Thrombin also triggers the release of tissue plasminogen activator (TPA) from normal endothelial cells, which in turn

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converts plasminogen to plasmin. It is this increased level of plasmin that goes on to regulate the progress of coagulation (Fig. 1) [2]. Coagulation function is assessed by several techniques, including clotbased, chromogenic, and color assays. Clot-based assays are used to assess the global function of the clotting process, whereas chromogenic tests measure the level and function of specific factors [6]. Monitoring of coagulation Clot-based assays Clot-based assays are used both in the investigation of bleeding abnormalities and in the monitoring of anticoagulation therapy in which fibrinclot formation is the desired end point. Prothrombin time Prothrombin time (PT) is performed by adding thromboplastin reagent that contains tissue factor to an aliquot of plasma. Tissue thromboplastin is either obtained by extracting it from human, rabbit, or bovine brain, or alternatively from lung and placenta [7]; however, more recently it is obtained via recombinant techniques. The thromboplastin factor and calcium are added to plasma and the clotting time is measured. The normal PT ranges from 10 to 14 seconds, and it is used to monitor warfarin therapy. Unfortunately, the thromboplastin reagents used in the performance of this test have varying sensitivities because of the different sources from which the tissue factor has been derived. This leads to the production of

Fig. 1. Schematic representation of the reactions of blood coagulation and the protein anticoagulant system. (From Dahlpack B. Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases. J Intern Med 2005;257:214; with permission.)

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laboratory results that are not comparable from one institution to another. Therefore, the international normalized ratio (INR) has been developed to standardize anticoagulant monitoring, because it takes into account the different sensitivities of the various thromboplastin reagents. Patients will have a prolonged PT whenever a deficiency in the levels of any of the following clotting factors exists: Factors VII, IX, X, fibrinogen, and prothrombin (II). The test is most sensitive to alterations in Factor VII levels, however. Factor VII has a very short half-life (7 hours), so it is the first vitamin K-dependent factor to be depleted when warfarin therapy is instituted. Therefore, any increases in the PT on the first and second days after therapy has been instituted are the result of decreased levels of Factor VII. The reverse is also true when warfarin therapy is stopped. Unfortunately, when one institutes warfarin therapy, protein C levels also fall because of the very short half-life of protein C. This can actually counter the early effects of Factor VII depletion, and can lead to the presence of a hypercoagulable state during the first 24 hours following the institution of warfarin therapy [8]. This hypercoagulable state can also be magnified by surgery, which in and of itself produces a hypercoagulable state [9]. Activated partial thromboplastin time The activated partial thromboplastin time (aPTT) measures clotting time by adding surface activators such as kaolin, Celite, or silica and phospholipid to citrated plasma, thereby activating the contact Factors XII, XI, and prekallikrein. The normal aPTT ranges between 22 to 40 seconds. The aPTT may be prolonged whenever deficiencies exist in any of the following clotting Factors: II, V, VIII, IX, X, or fibrinogen. The aPTT is also prolonged with heparin therapy, whenever thrombin inhibitors have been administered, and when fibrin degradation products are present [6]. Thrombin clotting time To conduct the thrombin clotting time (TCT) test one adds an excessive amount of thrombin to plasma. The TCT is prolonged with heparin therapy, whenever thrombin inhibitors have been administered, when fibrinogen levels are low, and when a dysfibrinogenemia is present. Dysfibrinogenemia is a rare cause of congenital hypercoagulability, which is prevalent in 1% of young adults who have unexplained thromboses [10]. Thrombin time may also prove to be useful during the monitoring of hirudin, bivalirudin, and low molecular weight heparin (LMWH) therapies. With these aforementioned medications the INR and aPTT may be normal or prolonged, but the TCT will be prolonged if adequate therapeutic levels have been achieved [6]. Thromboelastography The coagulation process involves initiation and propagation of clot formation. The conventional coagulation tests PT and aPTT only evaluate

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the initial phase of clot formation, and both of these tests are performed on platelet-poor plasma (PPP); however, clot formation also involves other components, such as platelets and fibrinogen. Thromboelastography (TEG) provides continuous coagulation profiles during all phases of clot formation, and produces a more accurate picture of the in vivo coagulation process [11]. Thromboelastography may be used to evaluate hypocoagulable states, hemophilia, rare coagulation disorders, anticoagulant therapy, coagulopathies secondary to dilution, hypercoagulable states (arterial and venous thrombosis), the monitoring of clinical efficacy during hemostatic interventions, and coagulation problems during liver transplantation [12]. Platelet function In the past the gold standard for monitoring platelet function was the bleeding time (BT); however, there is increasing evidence that the BT is not a very reliable test, because the results are very operator-dependent and may be quite variable from one institution to another, even when different technicians within the same institution perform the test [13]. BT is also rather insensitive to many mild platelet defects. Platelet function analyzer-100 Platelet function analyzer (PFA)-100 is a relatively new global test of high shear-dependant platelet adhesion and aggregation. The PFA-100 test simulates in vivo platelet adhesion and aggregate. This instrument uses small aperture cartridges that contain either collagen/ADP (CADP)- or collagen/ epinephrine (CEPI)-coated membranes. Citrated blood is aspirated under high shear forces from the sample reservoir through a capillary tube into the membrane, with the instrument monitoring the drop in flow rate through the aperture as platelets begin to aggregate and adhere to the membrane, thereby occluding the aperture. This occlusion of the aperture usually occurs within 1 to 3 minutes and is called the closure time (CT). The instrument will record a result of less than 300 seconds if the CT is very prolonged [14]. There are several advantages to using the PFA-100. It is noninvasive, simple, and easy to perform, and it only requires 0.8 mL of blood per cartridge. It is very sensitive in detecting the platelet defects associated with von Willebrand disease (vWD). The PFA-100 is also sensitive enough to detect and help diagnose acquired platelet defects caused by common over-thecounter drugs such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), and dietary factors [15]. For example, excessive cocoa ingestion can prolong CT [15]. The PFA-100 can also be used to monitor pro-hemostatic therapies such as desmopressin (DDAVP) administration and platelet transfusions. It is also used to monitor antiplatelet therapy with aspirin and other NSAIDs. Finally, the PFA-100 has the capability of being used as a point-of-care test for detecting and managing hemostatic defects.

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One of the limitations of this test is the inflexibility of the system. At the present time only two cartridge systems are available. The test requires a buffered citrate blood sample, and transport through hospital vacuum transport systems may adversely influence the PFA-100 test results [16]. Most importantly, the results of the PFA-100 should be interpreted in the context of either a simultaneously or a recently drawn full blood count. Platelet counts less than 80,000 or a hematocrit that is below 30% will produce prolongation of the CT, even if there are no platelet abnormalities [17]. Finally, the PFA-100 is more reliable and produces more reproducible results than bleeding times [18] Table 1 illustrates the patterns of coagulation results and possible diagnoses. Table 1 Patterns of coagulation results; possible diagnoses Test results

Possible diagnosis

Prolonge aPTT PT/fibrinogen/platelets normal

von Willebrand diseasea Factor VIII deficiency Factor IX deficiency Factor XI deficiency

Prolonged PT aPTT/fibrinogen/platelets normal

Warfarin ingestion Early vitamin K deficiency Early liver dysfunction Factor VII deficiency

Prolonged PT and aPTT Fibrinogen/platelets normal

Over warfarinisation Severe vitamin K deficiency Over heparinisation Factor X, Factor V, or prothrombin deficiency Acquired inhibitors

Prolonged PT and aPTT Decreased fibrinogen Normal or low platelets

Severe liver dysfunction Dysfibrinogenaemia/afibrinogenaemia Disseminated intravascular coagulation (including meningococcal sepsis)

a von Willebrand disease subtype 2B is associated with reduced platelets; aPtt is not always prolonged. From Thomas AE. The bleeding child; is it NAI? Arch Dis Child 2004;89:1164; with permission.

Coagulation disorders von Willebrand disease vWD is the most common inherited bleeding disorder in humans, and is present in 1% to 2% of the population [19]. The defect is the result of an inherited quantitative or qualitative abnormality of the vWF. The vWF is a central component of primary hemostasis, in that it acts as an adhesive link between platelets and the injured walls of blood vessels. Initially vWF

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binds to platelets at the glycoprotein GP-Ib receptor, and then subsequently at the GP-IIb/IIIa receptor site on the exposed subendothelial surface. It also affects secondary hemostasis by acting as a carrier for Factor VIII through the formation of noncovalent bonds with this not very well-understood clotting factor. Mature vWF is composed of repeating subunits that are assembled into multimers, with these multimers forming filamentous structures the length of the diameter of a platelet. The size of vWF multimers directly relates to their function. The presence of large multimers at the site of vascular lesions, especially under conditions of high shear stress, is critical for primary hemostasis [20]. More specifically, vWF mediates platelet adhesion by serving as a bridge between tissue and the platelets, binding the exposed collagen at the site of vascular injury to the platelet membrane GP-Ib-V-IX complex [21]. The vWF is secreted by two pathways: a constitutive one that is directly related to its synthesis, and a regulated one that involves its storage and release by secretagogues [22]. The von Willebrand factor is stored in the Weibel-Palade bodies, which are found in the endothelial cells, and a-granules, which are found in megakaryocytes. Constitutive, secreted vWF is derived from the endothelial cells, and it circulates freely in plasma; none of this circulating vWF is derived from the megakaryocytes [22]. The large vWF multimers contained in storage granules are not found in the circulating blood of healthy adults, but can be found in the blood of neonates. The controlled release of vWF at the time of injury and physiologic regulatory mechanisms both limit excessive thrombus formation. Furthermore, vWF levels are regulated through proteolysis or depolymerization. Proteolysis is facilitated and controlled by ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin), a metalloproteinase that cleaves vWF. Mutations in this protease have been associated with thrombus formation in the small arterioles of afflicted individuals [23]. The vWF gene corresponds to approximately 180 kilobases [24], which are located on the short arm of chromosome-12 [25]. Expression of the vWF gene is restricted to endothelial cells and megakaryocytes [26]. Classification of von Willebrand disease Type 1 von Willebrand disease. Type 1 vWD is the most common form of the disease [27,28]. It involves a partial quantitative deficiency of vWF. Factor VIII, Plasma von Willebrand factor antigen (vWF:Ag), and ristocetin cofactor (vWF:Rco) are a measure of vWF-mediated platelet agglutination [20]. Ristocetin is an antibiotic that was formerly used in the treatment of severe staphylococcal infections, which were resistant to other antibiotics. When concentrations of these cofactors are reduced, one observes mild to moderate mucosal bleeding. The inheritance pattern of Type I vWD is autosomal dominant, with incomplete penetrance, and it is found in about 1% of the general population [29].

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Type 2 von Willebrand disease. Type 2 vWD involves qualitative alterations in the structure and function of vWF [29,30]. Type 2A is associated with decreased platelet-dependent function, and the vWF:Rco activity may be disproportionately low when compared with vWF:Ag levels [20]. Inheritance of this defect follows an autosomal dominant pattern [31]. Type 2B is associated with qualitative variations in the vWF, which results in the production of vWF that has an increased affinity for the platelet GP-Ib receptor [20]. This qualitative variation in the vWF causes spontaneous binding of large vWF multimers to platelets, which ultimately leads to the clearance of both platelets and vWF from the plasma afflicted individuals. The remaining smaller multimers are less reactive. In Type 2B disease, vWF:Ag, vWF:Rco, and Factor VIII activity are quite variable and may even be normal [20]. Inheritance of this defect also follows an autosomal dominant pattern [32]. Type 2M (multimer) disease is attributed to the presence of qualitative variants with decreased vWF-platelet-dependent function, despite a normal quantity of high molecular weight vWF multimers [20]. The vWF:Rco is low compared with vWF:Ag. Once again, inheritance follows an autosomal dominant pattern [33]. Type 2N (Normandy) is caused by qualitative variations in the vWF that cause it to have a decreased affinity for Factor VIII [20]. Type 2N may resemble mild to moderate forms of hemophilia A, and one finds the vWF:Rco, vWF:Ag, and multimer distribution all to be normal. Inheritance is autosomal recessive [20]. Type 3 is the least common and most severe type of vWD, characterized by a complete absence of vWF in plasma or storage organelles [20]. Multimers are absent and Factor VIII activity is markedly reduced [20]. Inheritance is autosomal recessive (Table 2) [19,20]. Distribution of von Willebrand disease types A number of studies in 1980 determined that type 1 was the most prevalent type of vWD, being found in 70% to 80% cases of vWD, and that type 2 was only found in 20% to 30% of cases, whereas type 3 was found to be quite rare, with an incidence of 1% to 3% of afflicted patients [34]; however, more recent studies conducted in 1999 suggest that Type 2 and the Type 2 subsets are in fact the most common forms (2A followed by 2M, 2B, and 2N) [35]. Acquired von Willebrand disease Acquired forms of vWD are associated with lymphoproliferative disease, tumors, autoimmune disease, hypothyroidism, cardiac and valvular defects, and medications such as valproic acid [36]. These acquired forms of vWD usually resolve once treatment of the underlying disease has been instituted, or alternate medications have been employed.

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Table 2 Phenotypic classification and genetic transmission of von Willebrand disease Phenotype

Mechanism of disease

1

Partial quantitative deficiency of von Willebrand factor (and Factor VIII) Qualitative defects of von Willebrand factor

2 A B M N 3

Defective platelet-dependent von Willebrand factor functions, associated with lack of larger multimers Heightened platelet-dependent von Willebrand factor functions, associated with lack of larger multimers Defective platelet-dependent von Willebrand factor functions, not associated with multimer defects Defective von Willebrand factor binding to Factor VIII Severe or complete deficiency of von Wille-brand factor and moderately severe Factor VIII deficiency

Genetic transmission Autosomal dominanta Autosomal dominantb

Autosomal recessive

a

This mode of transmission is sometimes not evident because of reduced penetrance and varied expressivity. b Rare cases are characterized by autosomal recessive transmission. From Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med 2004;351:686, with permission.

Clinical manifestations Mucocutaneous bleeding is the most common symptom found in patients who have previously undiagnosed vWD. Easy bruising, epistaxis, gingival bleeding, gastrointestinal bleeding, and menorrhagia are also common manifestations. Significant hemostatic challenges may be encountered during common surgical procedures such as circumcision, tonsillectomy, and dental procedures, if simple prophylactic measures such as the administration of DDAVP are not instituted before the onset of surgery. Hematological investigations If the anesthesiologist suspects that a patient who presents for elective surgery may have undiagnosed vWD, it is prudent to cancel the case and obtain a hematology consult. This consult, coupled with one or more of the following tests, may help make the diagnosis and then guide the institution of the most appropriate perioperative therapeutic plan. Some of the tests that should help make or exclude the diagnosis of vWD are: ristocetin cofactor activity, vWF antigen levels, vWF multimer, BT, ristocetin-induced platelet aggregation (RIPA), Factor VIII coagulant activity, and a platelet count [37]. Laboratory tests for the diagnosis of von Willebrand disease Bleeding time. BT assesses the formation of the platelet plug. The template BT has been widely used for several decades to assess platelet function, but the test is not specific for vWD. The BT is prolonged in symptomatic vWD,

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however. But more importantly, in light of newer, better and more specific tests, BT no longer plays a role as a screening test in the diagnosis of vWD [38]. Platelet function analyzer-100. The PFA-100 test is not specific for vWD, but it has become a useful screening tool for the global assessment of platelet dysfunction. The PFA-100 test is discussed in detail above in the coagulation monitoring section [39]. Ristocetin cofactor activity. The ristocetin cofactor activity (Rco-Ag) assay is the most sensitive and specific test for vWD [28]. The test quantitates the ability of plasma vWF to agglutinate platelets in the presence of ristocetin, via vWF GP-Ib, Factor IX, and Factor V interactions. Ristocetin is an antibiotic that induces a structural change in vWF resembling that which occurs in vivo during vascular injury. To perform this test one mixes the patient’s plasma with normal formalin-fixed platelets in the presence of ristocetin. An aggregometer measures the vWF activity by assaying the ability of any given patient’s plasma to promote platelet aggregation. The results are expressed as a percentage of the activity of a normal pooled plasma standard, which generally ranges from 50% to 150%. This test is widely used to assess the functional activity of vWF [40]. Ristocetin-induced platelet aggregation. The RIPA test is similar to the measurement of ristocetin cofactor activity, except that the patient’s own platelets are used and the concentrations of ristocetin vary [28]. The platelet aggregation as a function of ristocetin concentration is compared with normal controls. Hyper-responsiveness to RIPA is characteristic for the presence of type 2B vWD [41]. Plasma von Willebrand factor antigen. vWF:Ag is an ELISA (enzyme-linked immunoabsorbent assay) using polyclonal rabbit anti-vWF antibody) [28]. Normal levels range between 50 and 200 U/dL [28]. This test is quite specific for the detection of qualitative defects in vWF, as well as deficiencies in vWF production. Factor VIII activity. The normal values for Factor VIII activity range from 50 to 100 U/dL [28]. Factor VIII levels are markedly decreased in both type 2 N and type 3 disease [29]; however, in type 1 and type 2 disease the Factor VIII levels are only mildly to moderately decreased [29]. von Willebrand factor multimer analysis. Agarose gel electrophoresis is used to assess vWF multimer structure [29,42]. Patient plasma is fractionated on an agarose gel, and vWF multimers are visualized with a radioisotope labeled polyclonal anti-vWF antibody [29,43]. The vWF multimers are

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divided into low, intermediate, and high molecular weight fractions. The loss of high and intermediate molecular weight multimers is characteristic for vWD types 2A and 2B [20]. Thrombocytopenia Thrombocytopenia is commonly found in type 2B vWD, but it is also frequently present in several situations/conditions in which no hematological pathology exists [44]. Treatment of von Willebrand disease Desmopressin. DDAVP is a synthetic analog of the antidiuretic hormone vasopressin [45]. It increases both Factor VIII and vWF levels by triggering the release of these proteins from storage sites into plasma. The recommended preoperative prophylactic dose of DDAVP involves the intravenous administration of 0.3 mcg/kg of DDAVP that has been diluted with 50 to 100 mL saline [46]. This mixture is then infused over 20 to 30 minutes. DDAVP can increase both the Factor VIII and vWF levels by a factor of three to five above baseline levels in just 30 minutes [46]. These effects last 8 to 10 hours [47]; moreover, the infusion of DDAVP can be repeated every 12 to 24 hours if necessary [46]. Some patients may not be responsive to DDAVP therapy. Therefore, one must obtain a hematology consult to help guide the most appropriate therapy for any given von Willebrand patient before elective surgery (Table 3). The intranasal dose of DDAVP is 300 mcg and it is used for home treatment [46,47]; however, the intranasal uptake of DDAVP can be quite variable, so this route of administration is not recommended for prophylaxis before elective surgery [48]. Tachyphylaxis can occur with repeated therapy [49–51]. DDAVP therapy may precipitate flushing, tachycardia, and headache, because of the vasomotor effects of the drug; however, more serious and pathologic side effects such as hyponatremia and seizures may result from the antidiuretic effects of DDAVP. Therefore, it is prudent to monitor serum sodium levels whenever one intravenously administers DDAVP. In addition, the use of DDAVP is not recommended in children younger than 3 years of age [52]. Because of their small size and relatively large fluid intake in relation to their total plasma volume, small children may be at greater risk of developing hyponatremia and subsequent seizure activity following the administration of DDAVP. Also, other risk factors may exist in young children that may put them at increased risk of developing hyponatremia. These risk factors include oral or intravenous intake of hypotonic solutions in the context of an inability to excrete free water, concomitant liver disease, postoperative inappropriate antidiuretic hormone release (SIADH), the administration of multiple doses of DDAVP, and vomiting (particularly postoperative vomiting triggered by the use of narcotics) [53–55].

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Table 3 Summary of recommended treatment according to the phenotypes of von Willebrand disease Type

Treatment of choicea

Alternative therapy

1

Desmopressinb

2A

Factor VIII-von Willebrand factor concentrates Factor VIII-von Willebrand factor concentrates Factor VIII-von Willebrand factor concentrates Factor VIII-von Willebrand factor concentrates Factor VIII-von Willebrand factor concentrates Recombinant Factor VIII

Factor VIII-von Willbrand factor concentrates Desmopressin

2B 2M 2N 3

In patients without alloantibodies In patients with alloantibodies

None Desmopressin Desmopressin Platelet concentrates Recombinant activated Factor VII

a

Adjuvant therapy with antifibrinolytic amino acids is recommendeded, together with firstchoice or alternative therapies in all types of von Willebrand’s disease. The recommended oral or intravenous dosage of a aminocaproic acid is 50 to 60 mg per kilogram of body weight every 4 to 6 hours; the recommended dose of tranexamic acid is 10 to 15 mg per kilogram every 8 to 12 hours. b Indications for desmopressin cannot be assumed unless a test infusion has shown that Factor VIII and von Willebrand factor levels rise adequately for that given bleeding episode or hemostatic challenge. From Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med 2004;351:691; with permission.

Unfortunately, children under 3 years of age who are afflicted with vWD may require surgery. Therefore, the authors provide the following guidelines for the management of children under the age of 3 who require DDAVP therapy:  Normal saline is the intravenous fluid of choice, and hypotonic solutions should be avoided during the first 24 hours following the administration of DDAVP [52].  Fluid intake should be restricted to 66% of maintenance requirements [52].  Serum sodium and osmolality levels should be measured and monitored before the administration of the drug and every 6 hours for 24 hours following the institution of intravenous DDAVP therapy [52,56]. Replacement therapies. Individuals who are unresponsive to DDAVP, a condition which may be found in about 15% of patients afflicted with vWD, may show a favorable response to the intravenous administration of plasma-derived blood products containing both Factor VIII and vWF concentrates [57]. The intravenous administration of either cryoprecipitate or fresh frozen plasma (FFP) may be employed to institute such backup treatment

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protocols. Cryoprecipitate (CRYO) contains 5 to 10 times more Factor VIII and vWF than FFP [58]; therefore, large amounts of FFP will be required if FFP is used in lieu of CRYO. This in turn limits the usefulness of FFP in the management of vWD. Virucidal techniques have never been applied to either FFP or cryoprecipitate because such techniques would deactivate the very proteins that are an essential part of the clotting cascade, thus, they both carried and still carry the risk of transmitting blood-borne infections such as HIV and hepatitis B and C [58–60]. The recent advent of virally inactivated Factor VIII/ vWF concentrates has played an important role in the treatment/management of vWD. Humate-P, an intermediate-purity Factor VIII/vWF concentrate, is now widely used in the treatment management of vWD (Table 4) [61]. Adjunct therapies for the management of von Willebrand disease Antifibrinolytic amino acid therapies. Antifibrinolytic amino acids can be administered either intravenously, orally, or topically to control mild forms of vWD-associated bleeding. Epsilon-aminocaproic acid (50–60 mg/kg every 4 to 6 hours) [58] and tranexamic acid (20–25 mg /kg every 8 to 12 hours) [58] have been used in conjunction with DDAVP therapy and plasma product infusions to control bleeding during both major and minor surgeries. Antifibrinolytic agents interfere with the lyses of newly formed clots. These agents can

Table 4 Average recommended dosages of Factor VIII (coagulant activity) and von Willebrand factor (ristocetin cofactor activity) for patients with phenotypes of von Willebrand disease associated with severely reduced factor levels (10% or less of normal levels) Type of hemorrhage

Dose (IU/kg)a

Frequency of infusions

Target

Major surgery

50

Daily

Minor surgery

40

Daily or every other day

Dental extraction

30

Single dose

Spontaneous bleeding episode

25

Daily

Delivery and puerperium

40

Daily before delivery and in the postpartum period

Trough Factor VIII level O50% of normal level until healing is complete (usually, 5–10 days) Trough Factor VIII level O30% of normal level until healing is complete (usually, 2–4 days) Factor VIII level O50% of normal level for 12 hr Factor VIII level O30% of normal level until bleeding stops (usually, 2–4 days) Factor VIII level O50% of normal levels for 3–4 days

a

In children, all doses should be increased by 20 percent to account for the greater plasma volume. (For instance, instead of receiving a dose of 40 to 50 IU per kilogram, a child would receive 48 to 60 IU per kilogram). From Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med 2004;351:689; with permission.

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be used alone for the treatment of mild forms of mucosal bleeding, but they are more likely to be used either as an adjunct to DDAVP replacement therapy or in conjunction with plasma product infusions before major or minor surgical procedures. In a recent large study the researchers examined the use of topically applied antifibrinolytic agents during dental procedures in patients who have hereditary bleeding disorders [62]. The patients who received locally applied antifibrinolytic agent had only a 1.9% incidence of bleeding complications. This incidence is comparable to that found in normal healthy individuals. This topical application of antifibrinolytic agents has been shown to improve local hemostasis, and in fact to decrease the need for systemic antifibrinolytic and factor replacement therapies [63,64]. Fibrin glues. These glues can help achieve local hemostasis. Estrogens. Both synthetic and natural estrogens increase the level of plasma vWF. Unfortunately, the response to estrogen therapy is quite variable and unpredictable, and for this reason estrogens are not widely used in the management of vWD [46]; however, oral contraceptives containing estrogen may be useful in reducing the severity of menorrhagia in women who have vWD [46]. This treatment modality does not significantly increase either Factor VIII or vWF levels, but it does decrease the vascularity of the endometrium [58]. Treatment of patients who have alloantibodies to von Willebrand factor Anti-vWF alloantibodies develop after multiple transfusions in 10% to 15% of patients who have type 3 vWD, and the repeated infusion of vWF concentrates can produce life-threatening anaphylactic reactions. Plasma exchange and plasma immunoadsorption are therapeutic options for patients who have developed alloantibodies or who have had a previous anaphylactic reaction to CRYO or huminate-P. The infusion of either recombinant Factor VIII devoid of vWF or recombinant activated Factor VIIa may be beneficial in controlling bleeding in such patients [65–68]. Hemophilia The hemophilias are a group of inherited bleeding disorders caused by the deficiency of certain blood coagulation factors. The most common factor deficiencies found in patient’s afflicted with hemophilia are Factors VIII (type A) and IX (type B) [69]. Both are X-linked conditions [70]; therefore, the most severe forms of these two diseases occur almost exclusively in males. Hemophilia A is an X-linked recessively inherited bleeding disorder resulting from deficiency of Factor VIII. It affects 1 in 5000 males in the United States [71]. A family history of the disease is an indication for referral to a hematologist; however, one-third of hemophilia cases are the result

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of point mutations, and therefore there is no antecedent family history of this disease [72]. Hemophilia also results from heterogonous mutations in the Factor VIII and IX genes. Approximately one-half of the severe cases are due to intron22 inversions [73]. For smaller deletions, insertions, or point mutations, the degree of severity depends upon the function of the affected domains. In about 4% of hemophiliacs, no mutation can be found [74]. The severity of the disease is defined by the plasma level of Factor VIII. The level of Factor VIII ranges from greater than 5% to less than 40% of normal in the mild form, 1% to 5% in the moderate form, and less than 1% in the severely affected individuals [75]. Clinical presentation of hemophilia Unexplained bruising or bleeding in young males should raise awareness in both parents and primary care physicians and precipitate Factor VIII and IX testing or referral to a specialist. The bruising and bleeding usually occurs at about 1 year of age when infants become more mobile; however, the mild to moderate forms of the disease can first present in adult life [76]. In cases in which a family history of hemophilia exists, male cord blood can be tested at birth for the level of Factor VIII [77]. Affected males suffer from joint and muscle bleeding and easy bruisability. Arthropathy secondary to recurrent hemarthrosis and chronic synovitis is the most common clinical manifestation of hemophilia [78]. Joint surface erosion secondary to chronic synovitis occurs in early childhood and progresses in late adolescence. The knee, elbow, ankle, hip, and shoulder are the most commonly affected joints. The most common orthopedic procedures performed during the management of hemophiliac arthritis are synovectomies, joint debridements, fusions, and joint arthroplasties [78]. Infection can occur in these children because of frequent intravenous self-administrations of clotting factors combined with immune suppression [79]. Finally, a coagulative disorder should be suspected any time spontaneous hemorrhage occurs in the central nervous system [80]. Tests and studies that may be helpful in making the diagnosis of hemophilia The hematological investigation in cases of nontraumatic bleeding should include a coagulation screen that consists of a PT, aPTT, Thrombin Clotting Time (TT), fibrinogen level, a platelet count, and a full blood count. Hemophilia A & B Isolated prolongation of the aPTT is found in both hemophilia A and B, whereas the fibrinogen level, PT, and platelet count all remain normal; however, Factors VIII and IX levels are low [81]. Unfortunately, in very mild cases of hemophilia the aPTT may remain within the normal range

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[81,82]. In such cases it will be necessary to perform a direct measurement of the factor levels to make the diagnosis. Treatment of hemophilia The development of viral-free blood products for the treatment of hemophilia has dramatically improved the prognosis for patients who must have regular access to these products. In 1965, Poole and Shannon [83] reported that a fraction of thawed plasma which contained Factor VIII could be used for the treatment of hemophilia. In the early 1970s, concentrates of both Factors VIII and IX were obtained from pooled plasma, and the median life expectancy of men who had severe hemophilia increased from 11 years to 56 years by the 1980s [84]. Unfortunately, in more recent times infection with HIV and hepatitis C from the transfusion of these Pooled plasma products has had a negative impact upon life expectancy and quality of life in men and boys afflicted with hemophilia [85–87]. Now the mainstay of treatment in both hemophilia A & B is factor replacement therapy [88]. Prophylaxis at an early age reduces the incidence of crippling arthropathies later in life. In cases of minor hemarthrosis or hematoma formations, Factor VIII levels should be raised to at least 20% to 30% of normal [89]. In major hemorrhage in the pharynx, retropharynx, retroperitoneum, or central nervous system, levels of 50% to 100% of normal are recommended [89]. In cases of elective dental extractions, the recommended factor levels one should attempt to obtain before the procedure are 25% to 50% of normal [89]. The biological half-life of Factors VIII and IX ranges from 15 to 20 hours. Replacement therapy is administered once daily for minor hemorrhage and two to three times daily for severe conditions [59,90–94]. In 1997, the National Hemophilia Foundation (NHF) estimated that the average annual cost for factor products (either recombinant or human plasma derived) used by an individual who had severe hemophilia ranged between $50,000 and $100,000, and for those patients who have severe forms of hemophilia, the costs of prophylaxis and emergent factor replacement therapy often exceed this range [95,96]. The average cost/dose for the Factor VIII products Humate-P, Alphanate, and Koate-HP are $3500, $2975, and $3220, respectively [97,98]. The duration of treatment depends upon the resolution of hemorrhage. Because of the high cost of recombinant Factor VIII and IX replacement therapies, prophylactic therapy is reserved for the pediatric population to prevent the development of crippling arthropathies [99]. Factor VIII and IX inhibitor antibodies Thirty to forty percent of patients who have severe hemophilia ultimately develop Factor VIII and IX antibodies [100,101]. The development of such antibodies is a function of the duration of treatment, the type of concentrate

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used in the treatments, and the factor mutations found in these patients. Several treatment modalities have been described for the management of patients who have high titers of Factor VIII and IX antibodies. Immune tolerance induction (ITI) is such a treatment option. With ITI, patients receive daily Factor VIII or IX infusions until responsiveness is restored, and then the factor is administered every other day [102]. Other treatment strategies include plasmapheresis, cyclophosphamide administration, and immune absorption [102–104]. Prothrombin complex concentrates that contain Factors II, IX, X, and VII have also been shown to be effective [105]. Recombinant Factor VIIa (rFVIIa) (NovoSeven) may be used in patients who have congenital or acquired hemophilia, and those in whom inhibiting antibodies toward Factors VIII or IX have formed [105–108]. In such patients, where there is risk of death caused by uncontrollable bleeding during emergency surgery or in limb-threatening hemorrhages such as hemarthroses and muscle hematomas, treatment should be aimed at bypassing inadequate levels of Factors VIII and IX and the other factors contained in the intrinsic pathway, and should instead rely upon rFVIIa infusions to bind directly or in conjunction with tissue factor to negatively charged phospholipids exposed on the surface of activated platelets [109,110]. Unfortunately, thrombotic events have been reported with the use of rFVIIa [111]. Gene therapy Replacement therapy is not a cure, and at the present time, only gene therapy carries the promise of an ultimate cure for patients afflicted with hemophilia. Unfortunately, at this time insertion of genes that produces sufficient quantities of functional clotting factors only temporarily brings the disease under control [112]. This is because of the instability of the transferred gene, and additional periodic gene replacement therapies are still required to keep the disease in check; however, such gene replacement therapy can and does modify the severity of the disease, and does decrease the total cost of care [113]. Hypercoagulable states Hypercoagulable states (thrombophelias) consist of a group of disorders that predispose one to thrombosis. They may be either inherited or acquired, and the thrombus formation can occur in either arteries or veins [8]. Acquired hypercoagulable disorders Many clinical situations predispose patients to thrombosis, either by activating the coagulation system, inhibiting the fibrinolytic system, or initiating platelet activation. The following are some common conditions/situations or medical therapies that may produce hypercoagulable states: smoking, heparin-induced thrombocytopenia (HIT syndrome), antiphospholipid syndrome, pregnancy, oral contraceptives, diabetes mellitus, polycythemia

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vera, hyperfibrinogenemia, malignancy, sepsis, trauma, hyperthermia, immobility, and newly initiated warfarin therapy (the first 24 hours of therapy) [8,114]. Both protein C and Factor VII have a half-life of about 8 hours. When one initiates oral anticoagulant therapy with warfarin, protein C is rapidly depleted, causing a transient hypercoagulable state for about 48 hours, or until the other vitamin-K-dependant coagulation factors are reduced to anticoagulant levels. Therefore, large loading doses of warfarin should be avoided, and anticoagulant therapy with warfarin should be initiated by also administering concomitant intravenous doses of low- dose heparin for 2 to 4 days, in order to prevent the development of the hypercoagulable state [115]. Congenital hypercoagulable syndromes Congenital abnormalities of procoagulant and anticoagulant proteins predispose patients to venous thromboembolism as well as arterial thrombosis. Some of the more common congenital hypercoagulable syndromes/ conditions are Factor V Leiden mutation, protein C or S deficiencies, antithrombin deficiency, hyper-homocystinemia, increased Factor VIII levels, dysfibrinogenemia, increased Factor XI levels, increased plasminogen activator inhibitor levels, and decreased plasminogen activator [114]. Protein C deficiency. Protein C is an endogenous anticoagulant. It is synthesized in the liver. Activated protein C inactivates Factors V and VIII, and it also decreases Plasminogin Activator Inhibitor-I (PAI-I) activity, which in turn decreases the conversion of plasminogen to plasmin [8]. The activity of protein C is enhanced by the binding of thrombin to thrombomodulin on the endothelial cell surface. Protein C is decreased in renal, hepatic failure, and Disseminated Intravascular Coagulopathy (DIC) [116–118]. The disease is transmitted as an autosomal dominant trait. There are two types of protein C deficiencies. In Type I disease both protein C function and levels are low, and in Type II disease only the function is low [119,120]. Protein S deficiency. Protein S is a cofactor for protein C. As such, protein S enhances the rate of inactivation of activated coagulation Factor V by protein C. Independent of activated protein C (APC), protein S can reduce the degradation of Factors II and X. Protein S deficiency occurs in 1 of 500 individuals and it is inherited by variable penetrance. Types of protein S deficiency include  Type I, associated with low levels of total and protein S antigen, along with decreased APC cofactor activity. This is the most common type.  Type II, associated with normal levels of total and free protein S, but with low levels of APC.  Type III, associated with normal to low levels of total protein S, a low level of free protein S, and an elevated fraction of protein S bound to the C4-binding protein.

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Where levels less than 50% of normal are found, both protein C and S deficiencies will have clinical manifestations, and thrombotic events will usually occur over time. In protein C and S deficiency, anticoagulant therapy is initiated after an episode of thrombosis [121]. Factor V Leiden mutation This mutation occurs on the Factor V molecule, where glutamine is substituted for arginine at position 506 [8]. In this condition, Factor V is resistant to proteolytic degradation by APC. The diagnosis of Factor V Leiden can be easily made by the genetic screening of the DNA from white blood cells [122]. Patients who have Factor V Leiden mutation are at increased risk for the development of deep vein thrombosis in the lower extremities as well as the brain [123,124]. Patients heterozygous for the defect have a sevenfold increased risk for thrombosis, whereas homozygous individuals have a 20 fold increased risk [125]. Asymptomatic patients diagnosed with the Factor V Leiden mutation do not require anticoagulation; however, with recurrent thromboses, lifelong anticoagulation therapy is both necessary and life-saving [126,127]. Activated protein C resistance APC resistance is the most common cause of hereditary predisposition to venous thrombosis, and it accounts for 20% of initial events in unselected patients, 50% of events in patients predisposed to familial thrombosis, 60% of events in pregnant women, and 60% of patients who have normal levels of protein S, protein C, and antithrombin or antiphospholipid antibody levels [125]. Diagnosis of hypercoagulable states The existence of a hypercoagulable state is suggested whenever recurrent thrombotic events occur in any given patient. In addition, the presence of a hypercoagulable state may be implied by the failure of an arterial reconstruction, or whenever multilevel arterial thromboses occur. The coagulation and anticoagulation proteins are consumed during a thrombotic event; however, during the sentinel event, testing is still reliable for the Factor V Leiden mutation, anticardiolipin antibodies, and the prothrombin 20210A mutation [128]. Ideally, however, testing should take place 2 to 3 weeks after the thrombotic event, and with cessation of the anticoagulant therapy [129]. The following laboratory studies are recommended for patients who have suspected thrombophilia [8]:  A routine coagulation panel, including a complete blood count (CBC), platelets, PT, aPTT, and fibrinogen  Protein C assay and protein S antigen  Anticardiolipin antibody

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 Factor V Leiden (functional and nucleic acid)  Lupus anticoagulant and homocystiene assay (HPLC)  Functional antithrombin assay [128] Screening for activated protein C resistance If the test for APC resistance is positive, one should also perform genetic testing for the presence of the Factor V Leiden mutation and the prothrombin gene mutation [8]. The following additional tests and studies may also help elucidate the etiology of the problem: functional assays for antithrombin levels, protein C and protein S levels; and an immunogenic assay for total and free protein S [130]. Other useful tests to ascertain the etiology of APC resistance are a clotting assay to determine if a lupus anticoagulant is present, an ELISA study to screen for antiphospholipid antibodies, and finally a measurement of plasma homocysteine levels [129]. Treatment of hypercoagulable states Patients who have a suspected hypercoagulable state are treated with warfarin for 6 months, or until they are thrombosis-free for 2 months [8]. At this point warfarin therapy may be discontinued, and therapy may be instituted with LMWH. This therapy should be continued for 2 weeks, at which time the patient should be retested for the continued presence of the hypercoagulable state [8]. If the problem persists, long- term anticoagulation is usually recommended. In addition, patients who develop a second thrombotic event or have other risk factors such as cancer also require longterm anticoagulation therapy. Family members of patients who have had recurrent thrombotic events should also be tested and offered counseling [131]. Inherited platelet disorders Congenital platelet disorders represent a group of qualitative and quantitative abnormalities that impair platelet function. Platelet disorders are suspected when patients demonstrate bleeding tendencies upon exposure to hemostatic challenges [132]. The mode of inheritance of these disorders ranges the gamut from X-linked to autosomal dominant and autosomal recessive patterns [132]. Laboratory studies To properly investigate the basis for platelet dysfunction, the whole blood picture should be assessed to determine if there is an accompanying anemia, another cytopenia, or an associated clotting factor deficiency [132]. Either BT or a CT may be obtained by using the PFA–100. Each has become a routine part of today’s assessment for platelet dysfunction. Closure time is more sensitive than BT in detecting congenital platelet disorders and aspirin-induced platelet dysfunction. Platelet aggregation tests also play an important part in the identification of conditions associated

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with defective signaling and secretion, and they are also used to diagnose rare platelet disorders [132]. Treatment of platelet disorders DDAVP, rFVIIa, and antifibrinolytic agents (tranexamic acid and epsilon-aminocaproic acid) have all been used in the treatment of inherited platelet disorders [133,134]. Bone marrow transplantation has become a more radical therapeutic option; however, bone marrow transplantation at this time is only offered to patients when other cytopenias are found to be present in association with significant platelet dysfunction, or when a profound thrombocytopenia exists [135]. Idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura (ITP), or immune thrombocytopenia, is a common hematologic disease that affects all age groups, but it is more commonly found in children. The diagnosis of ITP is generally made by excluding other causes of thrombocytopenia. In adults the typical presentation is in an otherwise healthy female who ranges in age from 18 to 40 [136]. These patients present with an isolated thrombocytopenia and a normal peripheral smear [136]. In the elderly, the gender disparity begins to disappear and the female to male ratio is about 1.7 to 1 [137]. Secondary immune thrombocytopenia can occur in cases of exposure to drugs, herbs, foods, or other substances (eg, quinine) [136]. Other conditions that may precipitate the onset of thrombocytopenia are systemic lupus erythematosus, antiphospholipid syndrome, B-cell malignancies (CLL), and HIV infections [138]. Clinical presentation. Patients who have platelet counts of less than 20,000  109/L usually present with petechiae that develop over several days; however, when the platelet count is less than 10,000  109/L at the time of presentation, symptoms are more severe and may include severe cutaneous bleeding, epistaxis, gingival bleeding, hematuria, and menorrhagia [136]. Intracranial hemorrhage (spontaneous or post-traumatic) and internal bleeding are rare phenomena, but can occur when platelet counts range between 10 and 20,000  109/L [136]. Of note is the fact that recombinant Factor VIIa has been successfully used to treat several cases of life-threatening intracranial hemorrhages in ITP patients [139]. The ongoing medical management of Idiopathic thrombocytopenic purpura. Medical management is generally initiated when platelet counts are less than 30,000. A meta-analysis of 17 studies of the age-adjusted risk of fatal hemorrhage at platelet counts less than 30,000  109/L found that the estimated rate of fatal hemorrhage was 0.4% in patients who were less than 40 years of age, 1.2% in patients who ranged in age from 40 to 60 years, and dramatically increased to 13% for patients older than 60 [140].

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Therapy must be individualized according to the signs and symptoms, tolerance to treatment, and patient preference; however, the basic guidelines shown in Box 1 are provided to help the anesthesia care team better understand how patients who have ITP are medically managed [136]. Splenectomy Splenectomy offers a treatment modality in which the patient requires fewer ongoing medical interventions, requires monitoring, and experiences a reduced interference with normal lifestyle. The optimum time to perform the elective splenectomy in the ITP patient remains controversial. Splenectomy is recommended if a course of more than 10 mg/d of prednisone is required for longer than 3 to 6 months to maintain a platelet count greater than 30,000  109/L [141]. On the other hand, some centers prefer to reserve splenectomies for patients whose platelet counts are found to be persistently lower than 20,000  109/L, or in whom intractable bleeding has developed [136]. Patients who present for elective splenectomy are made ready for surgery in accordance with the following guidelines. They receive IVIG, IV anti-D, or pulse doses of corticosteroids; these measures will usually boost the platelet count to acceptable levels before their splenectomy. Prophylactic platelet transfusions are not recommended [136]. Moreover, such transfusions are definitely not recommended [136]. Elective splenectomy in the ITP patient may be performed either as an open or laparoscopic procedure, but mortality rates are much lower if the surgery can be done laparoscopically (0.2% for laparoscopic versus 1% for open procedures) [142]. Splenic radiation is recommended as an alternative form of therapy in ITP patients who have hypersplenism and in whom surgery is not an option because they are considered to be high-risk surgical candidates [143]. The post-splenectomy ITP patient is very prone to developing infection, and many of these infections may be life-threatening. Overwhelming bacterial sepsis is the major postoperative complication associated with splenectomies in ITP patients [144]. To protect against postoperative bacterial sepsis, the ITP patient must be immunized with pneumococcal, H

Box 1. Idiopathic thrombocytopenic purpura therapy guidelines Platelet count >20–30,000  109/L: no treatment Platelet count <20,000  109/L:  Prednisone 1 mg/kg/day, orally  Intravenous (IV) immune anti-D antibody (±IV anti-D), 50–75 mg/kg  IV immune globulin (±IVIG) (1 g/kg/day  2–3) as needed, or dexamethasone 40 mg/day orally  4 days/month

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influenzae, and meningococcal vaccines 2 weeks before the first elective surgery [145]. It is also recommended that the ITP patient be revaccinated every 5 to 10 years [146]. Lifelong use of prophylactic penicillin or erythromycin is not needed, nor is it recommended, except for patients who are immunocompromised or children under 5 years of age [146]. Careful attention should be paid to all febrile illnesses. In addition, all ITP patients are advised to wear a medical alert bracelet; this is particularly true for the ITP patient who has undergone a splenectomy. Patients who have proven to be refractory to multiple courses of antibiotic therapy as well as the elderly who have secondary forms of ITP have less favorable outcomes after splenectomy [136].

Regional anesthesia and anticoagulation Neuraxial anesthesia techniques are well-established methods for providing perioperative analgesia. In addition, early mobilization, improved pulmonary function, and early restoration of bowel function are some of the recognized advantages of employing regional techniques; however, one of the most devastating complications associated with neuraxial regional anesthesia techniques is the development of spinal/epidural hematoma formation with concomitant neurological complications. Care must be taken and the proper guidelines must be followed when administering neuraxial anesthesia to patients who have received or will be receiving anticoagulation therapy in the perioperative period. A discussion of the use of anticoagulation agents and platelet-altering medications before or following the placement of spinal axis blocks is beyond the scope of this article. For more detailed information on this and related regional anesthesia matters, readers are invited to view the American Society of Region Anesthesia Web site at www.ASRA.com. At the Web site are brief but concise sets of guidelines for the placement of spinal/epidural blocks or catheter removals in patients who have received or will receive anticoagulation therapy. For a more in-depth discussion of each of the anticoagulation/antiplatelet medications and how they should be managed before placement of a neural axis block, readers are invited to read the recently published review articles by Broadman and colleagues [147–150].

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