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Clinical Case Study |
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
aAddress correspondence to this author at: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. E-mail eby{at}wustl.edu.
CASE DESCRIPTION
A 47-year-old African American woman was evaluated for a prolonged prothrombin time (PT) result obtained before she underwent right total hip arthroplasty. The patient had no history of gastrointestinal or intracranial bleeding, epistaxis, or hemarthrosis. However, she reported a tendency toward easy limb bruising and menorrhagia, which required iron supplementation. She had a negative family history of abnormal bleeding. Initial laboratory studies included findings within reference intervals for complete blood cell count and activated partial thromboplastin time (aPTT) (30.8 s, reference interval 23–36 s), prolonged PT (20.3 s, reference interval 11.0–15.0 s), and International Normalized Ratio (INR) (1.78, reference interval 0.9–1.2). No preanalytical artifacts were identified, and the result of a repeat PT was also prolonged.
DISCUSSION
laboratory evaluation of prolonged results for screening coagulation tests
PT and aPTT are commonly requested screening tests. In vivo, the initiation of coagulation depends on tissue factor–mediated factor VII (FVII) activation, and sustained thrombin generation requires activation of factors XI, IX, VIII, X, and V. For the interpretation of PT and aPTT results, however, coagulation factor activation culminating in a fibrin clot can be organized into intrinsic, extrinsic, and common pathways (Fig. 1
). An isolated result showing aPTT prolongation suggests a deficiency or inhibitor of one or more of the intrinsic pathway clotting factors (prekallikrein, high molecular weight kininogen, factors XII, XI, IX, and VIII). An isolated PT prolongation suggests a deficiency or inhibition of the extrinsic pathway (FVII), but mild factor X, V, and II deficiencies are also possible causes. Prolongation of both aPTT and PT suggests a deficiency or inhibition of the common pathway coagulation factors (factor X, V, and II), or a qualitative or quantitative fibrinogen defect.
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When evaluating an unexpected prolonged aPTT and/or PT result, the first step is to rule out preanalytical causes of inaccuracy(1). Anticoagulant contamination due to blood collection from a venous or arterial line flushed with heparin is a common artifact, and although most commercial PT reagents contain a substance capable of neutralizing approximately 2 U/mL of heparin, this capacity can be overwhelmed if blood is collected from heparin-containing catheters. Other preanalytical variables include the use of collection tubes containing a higher sodium citrate anticoagulant concentration (3.8% instead of 3.2%), hemolyzed samples interfering with photo-optical clot detection methods, and a prolonged time lapse between specimen collection and performance of aPTT (>4 hours) and PT (>24 hours) assays. An increase of the citrate:plasma ratio, which decreases the ionized calcium concentration [e.g., in samples from patients with high hematocrit (>55%) or samples collected in underfilled collection tubes] may produce erroneously prolonged PT and aPTT results.
The second step in evaluating an unexpected prolonged aPTT and/or PT result should be to repeat the aPTT or PT assay, taking care to eliminate potential sources of preanalytical artifact. If the screening coagulation test continues to show prolonged times, the third step is to perform a mixing study on a 50:50 mixture of patient plasma and normal pooled plasma. Correction to within the reference interval is consistent with a deficiency of one or more factors, and no or partial correction is consistent with inhibitor activity due to an anticoagulant, a factor-specific neutralizing antibody, or a nonspecific lupus anticoagulant.
additional patient data
We performed a mixing study, and the PT was corrected to 14.5 s, a result suggestive of an FVII deficiency because lupus anticoagulant, common pathway, and fibrinogen defects usually prolong the aPTT as well. FVII activity measurement performed on a mechanical clot detection instrument with rabbit thromboplastin activator was 5% (reference interval 60%–150%). Additional investigations ruled out a coexisting common pathway defect (factor V 144%, factor X 86%, factor II not done), fibrinogen deficiency (fibrinogen, 3700 mg/L, reference interval 1800–4000 mg/L), a direct thrombin inhibitor (thrombin time, 18.4 s, reference interval 16–22 s), and a nonspecific inhibitor (negative lupus anticoagulant screen).
The differential diagnosis for a patient with an isolated FVII deficiency is limited, because conditions that substantially reduce coagulation factor synthesis additionally prolong the aPTT. It is unlikely that subtle changes in hepatic function or vitamin K metabolism would produce such a profound, isolated decrease of FVII as was seen in this case. The patient described a varied diet with no alcohol consumption, and her medical records from 2 years earlier documented normal hepatic function, normal aPTT, and prolonged PT results. These findings support a diagnosis of FVII deficiency.
diagnosis
FVII Deficiency.
overview of fvii deficiency
Isolated FVII deficiency may be acquired or inherited. Reports of acquired FVII deficiency are rare, and the majority of cases are associated with malignancy, sepsis, and/or bone marrow transplantation(2). In some cases, in vitro evidence supports production of autoantibodies that either neutralize FVII activity or accelerate its clearance. A case of transient acquired FVII deficiency associated with surgery has been successfully treated with recombinant activated FVII (rFVIIa, NovoSeven)(2).
Congenital FVII deficiency has an estimated prevalence of 1:500 000(3) and is often discovered incidentally. Patients may be asymptomatic or have spontaneous joint and cerebral hemorrhages. Bleeding complications usually occur in homozygotes and compound heterozygotes, and unlike factor VIII and IX deficiencies (found in males with hemophilia A and B, respectively), the degree of FVII deficiency is poorly correlated with bleeding tendency.
A public database (europium.csc.mrc.ac.uk) lists 136 unique mutations in the coagulation FVII (F7) gene, along with associated FVII activity, antigen concentration, and bleeding severity. Most F7 mutations are missense and occur in the catalytic domain, but various types of mutations have been identified at sites scattered throughout the F7 gene. Uncommon F7 mutations may cause life-threatening hemorrhages in neonates. Such mutations typically prevent protein expression and produce FVII activities <2%. F7 mutations associated with mild-to-moderate bleeding histories are usually missense mutations affecting circulating FVII, with activities ranging from 1% to 50%. Asymptomatic FVII-deficient patients have FVII activities of 4%–61%, and in these cases all F7 mutations are missense.
In the presence of rabbit tissue factor, used in some commercial PT reagents, some F7 mutations show only negligible FVII activity but may show approximately 30% activity in the presence of human tissue factor(4). The first variant to display different FVII activities depending on the source of tissue factor was named FVII Padua(5). This variant is due to glutamine substitution for arginine at position 304 (R304Q), which impairs formation of the FVIIa–tissue factor–FX complex(6), resulting in phenotypes’ ranging from asymptomatic to moderate bleeding. To avoid reporting an inaccurately low activity, laboratories should always use recombinant human thromboplastin when evaluating patients with FVII deficiency.
patient management
Our patient presented with a prolonged PT and 5% FVII activity, findings that were not entirely consistent with her mild bleeding history. Therefore, we repeated the FVII activity assay with recombinant human thromboplastin and obtained an activity of 31%. In consultation with the patient’s orthopedic surgeon, who estimated intraoperative blood requirements of approximately 4–6 units due to the anticipated duration and complexity of the surgery, we recommended transfusion with 5 units of fresh frozen plasma during the operation, equivalent to approximately 20% of the patient’s plasma volume. Recombinant FVIIa was available if severe hemorrhage developed. The patient received 2 units of red cells intraoperatively, and the surgeon described normal hemostasis. Postoperatively, the surgery team suspected formation of a deep hematoma due to persistent anemia despite transfusion of 5 additional units of red cells over 6 days. However, the patient’s hemoglobin stabilized, wound drainage stopped, she received no additional blood components, and she was discharged 12 days postsurgery. At an outpatient visit 1 month later, the patient’s incision was healed without evidence of bleeding and her physical activity level was improving.
POINTS TO REMEMBER
summary and recommendations
In the absence of a severe bleeding history, most FVII-deficient patients are at risk for hemorrhagic complications only following major surgery or trauma(8). Each case requires individual management because of the poor correlation between F7 mutations, FVII activity, and phenotype(7). The patient’s bleeding history, current clinical situation, and an FVII activity assay performed with recombinant human thromboplastin must guide initial management of FVII deficiency(8)(9) (Fig. 2
). FVII can be temporarily supplemented by infusing fresh frozen plasma, prothrombin complex concentrates containing factors X, IX, VII, and II derived from plasma, and recombinant FVIIa (NovoSeven®). Fresh frozen plasma infusion may produce volume overload in susceptible patients, and thrombotic complications are a potential risk with prothrombin complex concentrates and NovoSeven® therapy.
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Acknowledgments
Grant/Funding Support: None declared.
Financial Disclosures: None declared.
References
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Severe bleeding includes life-threatening mucosal or gastrointestinal bleeding, spontaneous soft tissue and joint bleeds, and/or central nervous system and ocular bleeding.