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The Laboratory Approach to Inherited and Acquired Coagulation Factor Deficiencies 1078 Requires Active Use of Clinical Information

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The Laboratory Approach to Inherited and Acquired Coagulation Factor Deficiencies 1078 Requires Active Use of Clinical Information View metadata, citation and similar papersARTICLE at core.ac.uk IN PRESS brought to you by CORE provided by ZENODO 1 2 The Laboratory 3 4 Approach to Inherited 5 6 and Acquired 7 8 Coagulation Factor 9 10 Deficiencies 11 12 a,c a b 13 Ben L.Wagenman , Kelly T.Townsend ,PrasadMathew , Kendall P. Crookstona,c,* 14 KEYWORDS 15 Hemophilia Coagulation factor deficiency 16 Hypoprothrombinemia Hemostasis Prothrombin time 17 Activated partial thromboplastin time Pre-analytical variables 18 Bleeding Coagulation factor inhibitors 19 20 21 Coagulation factors are usually either enzymes (eg, F9, F2) or cofactors (eg, F5, F8) 22 that circulate at varying concentrations in the blood. Rather than reporting the abso- 23 lute concentration of the circulating factors (as is done with most chemistry analytes), 24 the clinical laboratory reports activities for most coagulation factors (ie, the functional 25 activity of the factor in the patient’s plasma compared with that of calibrator or a stan- 26 dard plasma, the latter with a defined assayed activity of 100%). 27 Factor deficiencies traditionally are classified as type 1 or type 2. In type 1 defi- 28 ciency, the protein structure of the factor is normal, but there is a decreased concen- 29 tration in the circulation, so the activity level is decreased. This can be caused by 30 increased clearance or decreased production of the factor. Essentially all acquired 31 and many inherited disorders fall into this category. In type 2 deficiencies, there is 32 a normal or nearly normal concentration of a circulating protein that is intrinsically 33 defective and therefore also demonstrates a lower overall activity level. Either type 34 35 36 This work was supported in part by a grant from Blood Systems Inc. 37 Note: Although Roman numerals traditionally are used to identify coagulation factors (eg, FIX, FVII), Arabic numerals will be used in this discussion (eg, F9, F7) as the latter are less confusing for the learner and also for an international audience. 38 a 39 Department of Pathology, University of New Mexico, TriCore Reference Laboratories, 915 Camino de Salud NE, Albuquerque, NM 87102, USA b Department of Pediatrics, and the Ted R. Montoya Hemophilia Program, University of New 40 Mexico, 2211 Lomas Boulevard NE, Albuquerque, NM 87106, USA 41 c United Blood Service of New Mexico, 1515 University Avenue, NE, Albuquerque, NM 87102, USA 42 * Corresponding author. 43 E-mail address: [email protected] (K.P. Crookston). Clin Lab Med - (2009) -–- doi:10.1016/j.cll.2009.04.002 labmed.theclinics.com 0272-2712/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved. CLL469_proof 13 June 2009 2:22 pm ARTICLE IN PRESS 2 Wagenman et al 44 of deficiency will show decreased activity when measured by laboratory assays. When 45 measuring the protein itself using an antigen assay, type 2 deficiencies show a relative 46 preservation of the antigen level in relation to the activity level, while type 1 deficiency 47 also shows decreased antigen. This situation is illustrated best in von Willebrand 48 disease (vWD) (see article by Torres in this issue). 49 A brief survey of the clinical aspects of the inherited and acquired factor deficiencies 50 is presented first, followed by a discussion of the laboratory considerations in evalu- 51 ating patients who have possible factor deficiencies. Table 1 and Box 1 illustrate 52 the etiologies, relative incidence, and other characteristics of the various factor defi- 53 ciencies discussed. Some deficiencies of proteins involved in hemostatic regulation 54 also will lead to bleeding diatheses (eg, alpha-2-antiplasmin); however, these abnor- 55 malities are not within the scope of this article. 56 57 INHERITED FACTOR DEFICIENCIES 58 59 Inherited bleeding disorders have been recognized since ancient times, often caused 60 by severe bleeding with circumcision or minor trauma. Severe hemophilia A and B, 61 and severe F11 deficiency typically prolong the patient’s activated partial thrombo- 62 plastin time (aPTT), but this abnormality is not always overwhelming. Many patients 63 present with an aPTT between the upper end of the normal reference range and the 64 middle of the typical aPTT heparin reference range. Deficiencies of the contact 65 factors—most commonly F12—can prolong the aPTT more significantly, similar to 66 what is seen with a high level of therapeutic heparin or heparin contamination after 67 blood is drawn through a heparinized line. Hemophilia A (F8 deficiency) and B (F9 defi- 68 ciency) are the only factor deficiencies typically inherited in a sex-linked pattern. 69 Sufficient hemostasis often can be achieved despite having coagulation factor 70 levels below the normal laboratory reference ranges. Similarly, a modest increase in 71 the endogenous circulating factor activity level (eg, from 0.5% to 5%) in hemophilia 72 can have major clinical implications, essentially converting a severe to a mild pheno- 73 type. This provides hope to researchers working to use gene therapy as a possible 74 treatment of inherited hemophilia.1 75 76 Factor 8 Deficiency (Hemophilia A) 77 Hemophilia A2 is the most common inherited factor deficiency. This X-linked disorder 78 is caused by a deficiency of F8. F8 is the cofactor that works with F9 to activate F10, 79 increasing the reaction rate by several orders of magnitude. Older nomenclature calls 80 the F8 coagulant activity ‘‘VIII:C’’ and the measurement of the antigen ‘‘VIII:Ag.’’ The 81 F8 molecule usually circulates in the bloodstream, protected from degradation by 82 forming a stable complex with von Willebrand factor (vWF). Deficiency of vWF leads 83 to increased clearance of F8 from the circulation; therefore, F8 activity typically is 84 included in screening panels for vWD. 85 Many different genetic mutations have been classified in various hemophilia A pedi- 86 grees.3,4 Mild and moderate hemophilias typically are caused by one of many 87 missense mutations induced by single base pair substitutions. Severe hemophilia A, 88 by contrast, is caused more often by larger gene defects, including inversions (intron 89 22), large deletions, and insertions. Thus, both activity and antigenic protein measures 90 are typically very low. Intrachromosomal intron–exon recombinations of the X chromo- 91 some account for about half of the severe forms. For the prenatal genetic diagnosis of 92 known males to be effective, family studies must identify the mutation particular to that 93 pedigree. There is a high sporadic occurrence (high spontaneous mutation rate), 94 however, of hemophilia also; thus, about 30% of newly diagnosed severe hemophilia CLL469_proof 13 June 2009 2:22 pm ARTICLE IN PRESS Coagulation Factor Deficiencies 3 95 96 97 98 99 100 101 102 103 104 105 Moderate (1% to 5%) Severe (<1%) No bleeding Moderate to severe; postoperative Variable Variable—may be asymptomatic Variable 106 Variable 107 108 109 110 111 112 113 114 115 116 117 118 genes) mutations at 4q31) mutations at 4q31) 119 mutations at 4q31) Autosomal recessive (various A subunit: 6p24-p25 B subunit: 1q31-q32 Autosomal dominant (various Autosomal dominant (various Autosomal dominant (various Autosomal recessive (18q21, 2p21) Variable 120 — 121 122 123 124 125 126 127 128 129 130 131 Rare, unknown <1:1 million Rare Rare Rare Rare 132 Rare 133 134 135 136 137 138 139 140 141 142 143 144 prekallikrein, high molecular weight kininogen) F9 (hemophilia B)F11F2 (prothrombin)F5F7F10F12Other contact 1:30,000 factors (including RareF13 Rare, 5% in Ashkenazi Jews 1:1 million 1:500,000 Autosomal X-linked recessive recessive (4q32q3) (Xq27) 1:500,000 Rare Autosomal recessive (11p11–q12) Mild to severe Mild to severe Mild to Autosomal moderate recessive (1q21–q25) Autosomal recessive (13q34) Autosomal recessive (13q34) Mild to moderate Autosomal recessive 5q33 Mild to severe Mild to severe No bleeding Table 1 Congenital factor deficiencies Factor DeficiencyF8 (hemophilia A) Estimated Incidence 1:10,000 Inheritance Pattern/Genes Involved Bleeding Severity X-linked recessive (Xq28) Mild >5% Afibrinogenemia Dysfibrinogenemia Hypofibrinogenemia Combined F5 and F8 145 Combined F2, F7, F9, & F10 CLL469_proof 13 June 2009 2:22 pm ARTICLE IN PRESS 4 Wagenman et al 146 Box 1 147 Acquired factor deficiencies 148 149 Immune-mediated factor deficiencies 150 Alloantibody factor inhibitors in hereditary hemophilia patients 151 F8 inhibitors in hemophilia A patients on factor replacement therapy (incidence 5 24% of 152 hemophilia A patients) 153 F9 inhibitors in hemophilia B patients on factor replacement therapy (incidence 5 1.5–3% 154 of hemophilia B patients) 155 156 Autoantibodies causing acquired hemophilia 157 Acquired hemophilia A (most common, may cause severe bleeding) 158 Prothrombin deficiency complicating the antiphospholipid syndrome (rare) 159 160 Acquired F5 deficiency (from antibodies to bovine thrombin preparation used in certain 161 fibrin glues, uncommon) 162 Nonimmune-mediated 163 Increased destruction 164 165 Disseminated intravascular coagulation (DIC) 166 Extracorporeal membrane oxygenation (ECMO) 167 Fibrinolytic drugs in thrombolytic therapy (eg, tissue plasminogen activator) 168 169 Decreased production 170 Liver disease 171 172 Abnormal production 173 Warfarin use 174 Other causes of vitamin K deficiency 175 176 Loss and sequestration 177 Nephrotic syndrome 178 179 Acquired F10 deficiency associated with light chain amyloidosis (accelerated removal of F10 caused by adsorption of the factor to the amyloid fibrils); 8.7% of amyloidosis patients 180 had F10 levels less than 50% of normal; 56% of these had bleeding complications if F10 181 less 25% of normal; can be fatal 182 Plasma exchange apheresis (particularly decreased fibrinogen) 183 184 Inactivation 185 Direct thrombin inhibitor use (eg, hirudin, argatroban) 186 187 188 patients may not have a family history. Activity assays sometimes are performed on 189 cord blood from male newborns delivered to a known carrier in a family with severe 190 hemophilia.
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