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A 77-year-old man with a prolonged activated partial thromboplastin time.

CASE DESCRIPTION

A 77-year-old man was admitted to another hospital because of increasing dyspnea and edema of the lower limbs. The patient reported a loss of appetite and a flu-like illness 4 weeks previously. He was on various medications for heart failure, including metoprolol, ramipril, spironolactone, torasemide, metformin, and digoxin. For chronic atrial fibrillation, the patient had received dabigatran (75 mg twice per day) for 12 months; dabigatran is a direct thrombin inhibitor that has recently been cleared by the US Food and Drug Administration for the prevention of stroke in patients with atrial fibrillation.

Five days before admission, the patient discontinued dabigatran on his own after recognizing a fresh hematoma on the right hip, easy bruising, and a conjunctival hemorrhage of the right eye. Routine laboratory investigations on admission revealed a prolonged activated partial thromboplastin time (aPTT) [3] of 69 s (reference interval, 25-35 s) and a slightly prolonged prothrombin time (PT). Initially, these laboratory findings and the ecchymosis were attributed to the previous anticoagulant intake.

The patient's other symptoms were felt to be due to exacerbation of congestive heart failure, and these symptoms resolved with optimization of his diuretic therapy. He developed fresh hematomas, however. Because the aPTT remained prolonged 2 days after admission (a total of 7 days after the last dabigatran intake), clotting factor activities were quantified. Clotting factor VIII activity was below the detection limit (<5 IU/dL; reference interval, 70-150 IU/dL), and the activity of factor XII was slightly reduced (53 IU/dL, reference interval, 70-150 IU/dL). Subsequently, the patient was referred to our clinic for further evaluation.

On admission, the results of a repeat aPTT test was 71.4 s (reference interval, 23-36 s), and factor VIII activity was markedly reduced in a chromogenic assay (<10 IU/dL; reference interval, 50-175 IU/dL) and a clotting assay (<1 IU/dL; reference interval, 70-150 IU/dL). The values for other coagulation parameters, including PT, fibrinogen, von Willebrand factor, platelet count, and platelet function were within their respective reference intervals.

DISCUSSION

The first step in pursuing an aPTT prolongation is to rule out an artifact. Doubtful results should be confirmed with a new sample. Such preanalytical issues as careful venipuncture technique, correct filling of sample tubes (containing adequate anticoagulant, e.g., sodium citrate), and avoidance of contamination (e.g., heparin from central catheters) are of major importance. Lipemic, icteric, or hemolyzed samples, or a high hematocrit (which increases the plasma citrate concentration) may cause interference with the clotting test (1).

Additionally, the patient's medical history is important. Unfractionated heparin, fondaparinux, or low molecular weight heparin in therapeutic doses can cause modest aPTT prolongation. After intake of excessive vitamin K antagonists like warfarin, aPTT prolongation occurs with a concomitant markedly prolonged PT. The aPTT-prolonging effect of newer anticoagulants (e.g., the direct thrombin inhibitor dabigatran) has been documented (2). In our case, dabigatran had been discontinued 5 days before admission and therefore was unlikely to have been causative because its half-life in plasma is only about 14 h (3).

[FIGURE 1 OMITTED]

If these initial considerations do not offer plausible explanations for the aPTT prolongation, further analytical workup is required. Basically, aPTT is affected by the activities of clotting factors XII, XI, X, IX, VIII, V, II, and I, as well as by high molecular weight kininogen and prekallikrein. Measuring the PT and the thrombin time (TT) can efficiently narrow the number of required analyses. When the PT and TT are normal, major deficiencies of factors X, V, II, and I are unlikely, as is heparin contamination. Increased activities of factor VIII (e.g., in an acute-phase response), however, can partially mask deficiencies of other clotting factors, giving an only slightly prolonged aPTT. Importantly, factor VIII and factor IX deficiencies or severe factor XI deficiencies are associated with an increased risk of bleeding, whereas even drastic reductions of factor XII or rarely occurring high molecular weight kininogen and prekallikrein deficiencies do not cause excessive bleeding (4). Again, the patient's clinical presentation and history taking are mandatory for target-directed laboratory analysis.

Genetic aberrations with impaired synthesis or functional defects are responsible for hereditary forms of reduced clotting factor activity, as seen in hemophilias A (factor VIII), B (factor IX), and C (factor XI). Acquired factor deficiencies may be attributable to underlying diseases (e.g., cirrhosis) or bleeding with high turnover. In these cases, the PT is also regularly affected. Because factor VIII reductions can be associated with impaired protection by its carrier protein, von Willebrand factor, it is advisable to quantitatively measure the von Willebrand factor antigen and test for the functional von Willebrand factor ristocetin cofactor. von Willebrand disease can occur in congenital or acquired variants. The latter potentially can occur as a paraneoplastic syndrome or be due to degradation of high molecular weight multimers (detectable in a multimer analysis) in cases of mechanical destruction, e.g., shear stress at prosthetic heart valves (5). In younger individuals with a bleeding history, slightly prolonged or borderline aPTTs can be associated with mild forms of hemophilia or von Willebrand disease.

aPTT prolongations may also arise in the presence of unspecific antiphospholipid antibodies interfering with clotting assays. Additionally, the presence of specific inhibitors, commonly targeting factor VIII, can cause clotting factor degradation.

An algorithm for the workup for a prolonged aPTT is shown in Fig. 1.

CASE FOLLOW-UP

In our patient, a normal TT excluded heparin contamination. Lupus anticoagulant was ruled out by the results of 2 different assays (lupus-sensitive aPTT and diluted Russell viper venom time), as suggested by current guidelines (6). Because of the normal PT, only the activities of factors VIII, IX, XI, and XII were measured. The factor VIII activity was <1 IU/dL, and this low activity was most likely responsible for the patient's bleeding. The slight reduction in clotting factor XII activity (53 IU/dL; reference interval 70-150 IU/dL) was considered secondary.

The patient's history did not point to a congenital disorder such as severe hemophilia A. Tests for von Willebrand factor antigen and von Willebrand factor ristocetin cofactor showed normal values, thereby excluding von Willebrand disease. Therefore, the strikingly impaired factor VIII activity was most likely caused by an acquired factor VIII inhibitor. This supposition was confirmed by aPTT-based plasma-mixing studies. The addition of small amounts of the patient's plasma to normal plasma (containing clotting factor activities of about 100 IU/dL, thereby balancing potential clotting factor deficiencies) produced severe and nonlinear aPTT prolongation (see Fig. 2). This phenomenon became apparent only after a 2-h incubation at 37 [degrees]C, a finding characteristic of a so-called progressive inhibitor (7).

[FIGURE 2 OMITTED]

Factor VIII inhibitors can be quantified with the Bethesda assay or its Nijmegen modification, and the results of such quantification are essential for treatment decisions. In this procedure, factor VIII activity is measured in mixtures of serially diluted patient plasma with factor VIII-containing plasma (8). This test yielded a titer of 223 Bethesda units (BU)/mL in our patient.

Commonly, in the case of serious bleeding events, factor VIII concentrates can be used if inhibitor titers are very low. For patients with higher inhibitor titers (>5 BU/mL), bypassing agents or recombinant activated factor VII is preferable (9).

Acquired factor VIII inhibitors have a reported prevalence of approximately 1.5 cases per million per year, with a major peak in elderly patients of either sex (9). Pathophysiologically, the binding of auto- or alloantibodies to factor VIII impedes its clotting activity, with potentially life-threatening complications. Of note is that quantification of acquired autoantibodies with the Bethesda assay tends to underestimate the potency of the inhibitor, because the assay is based on linear type I kinetics, whereas coagulation factor inhibitors often follow the nonlinear, nonsaturable complex pattern of type II kinetics (8).

About 50% of affected patients were previously healthy (9). In the other half, associations with autoimmune diseases, malignant disorders, or pregnancy have been reported. Rarely, medications such as antibiotics (penicillins, sulfonamides, and chloramphenicol) and anticonvulsants can be causative. Drug-induced factor VIII autoantibodies frequently arise after preceding hypersensitivity reactions and mostly remit after discontinuation of the drug (10).

Our patient received treatment with prednisolone (initial dose, 1.5 mg/kg body weight) and a single cyclophosphamide dose (500 mg/m2 body surface area). Under this regimen, the inhibitor titer dropped gradually. Meanwhile, the patient achieved complete remission, and prednisolone was gradually tapered to a current dose of 5 mg/day. Investigations for associated diseases yielded unremarkable results.

In summary, this case illustrates the laborious laboratory workup for aPTT prolongations. In addition to the clinical implications, a thorough evaluation of aPTT prolongations can have an important influence on the interpretation of other aPTT-based coagulation assays (e.g., protein C and S activities, activated protein C resistance, lupus inhibitors).

QUESTIONS TO CONSIDER

1. Which differential diagnoses should be considered when aPTT prolongation is detected?

2. To what extent do new anticoagulants, such as direct thrombin inhibitors, affect standard coagulation tests?

3. What techniques should be used to evaluate the cause of a prolonged aPTT?

POINTS TO REMEMBER

* After ruling out an artifact, the evaluation of aPTT prolongations comprises measurements of clotting factors and exclusion of interfering lupus anticoagulant or contaminations with heparin.

* In patients with aPTT prolongations and hemorrhagic diathesis, acquired clotting factor inhibitors have to be considered.

* aPTT-based plasma-mixing studies give the first evidence of inhibitors.

* Acquired factor VIII inhibitors can cause serious, life-threatening bleeding despite relatively low inhibitor concentrations as quantified with the Bethesda assay or its Nijmegen modification.

* Direct thrombin inhibitors such as dabigatran and other emerging new anticoagulants must be considered as potential causes of aPTT prolongations.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: U. Steigerwald, Bayer Healthcare.

Stock Ownership: None declared.

Honoraria: U. Steigerwald, Bayer Healthcare, Roche Diagnostics, and Siemens Diagnostics.

Research Funding: None declared.

Expert Testimony: None declared.

Other Remuneration: U. Steigerwald, CSL Behring, Bayer Healthcare, Biotest AG, and Roche Diagnostics.

Acknowledgments: We thank Karin Sauer, Mareike Hueller, and Gudrun Balling for critically reading the manuscript. We are also indebted to Ulrich Walter for generous support and discussion.

Commentary

This is a classic case of a patient with a hemorrhagic presentation and an isolated prolonged activated partial thromboplastin time (aPTT).

Lessons to be learned:

1. Don't blame the dabigatran. Although the patient had discontinued anticoagulation therapy 5 days prior, his prolonged aPTT value was erroneously attributed to dabigatran. If there is concern about dabigatran presence, a thrombin time (TT), which is very sensitive to the presence of direct thrombin inhibitors, can be performed to avoid the delay in appropriate evaluation.

2. Do a mixing study. That will determine whether the prolongation is due to a factor deficiency (in which case the normal plasma will complement the patient's plasma and the aPTT will normalize) or to an inhibitor (the patient's plasma will "anticoagulate" the normal plasma, and the aPTT will be prolonged).

3. Do an incubated mixing study. Acquired factor VIII inhibitors exhibit time- and temperature-dependent binding to factor VIII. Thus, a mixing study done immediately may show substantial correction of the clotting time, but after a 2-h incubation at 37[degrees]C, the aPTT will become reprolonged. This reprolongation after incubation is highly suggestive of acquired hemophilia.

4. Check a factor VIII activity level and a Bethesda titer. A bleeding patient with an isolated prolonged aPTT should have his or her activity levels for factors VIII, IX, and XI measured, but factor VIII inhibitors are the most common acquired (nonpharmacologic) bleeding disorder. This individual had an expectedly low factor VIII activity level, and a Bethesda assay to quantify the strength of the inhibitor is required.

5. Ignore factor XII. Low factor XII levels can be found in samples that have been frozen and thawed, and factor XII deficiency is not a hemorrhagic disorder.

This patient had an acquired autoantibody to factor VIII. These are function-blocking antibodies rather than clearing antibodies. Treatment requires treating bleeding with bypassing agents and inhibitor eradication by immunosuppression.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: A.D. Ma, Novo Nordisk, Bayer, and CSL Behring.

Stock Ownership: None declared.

Honoraria: A.D. Ma, Novo Nordisk.

Research Funding: None declared.

Expert Testimony: None declared.

Alice D. Ma *

Division of Hematology-Oncology, University of North Carolina, Chapel Hill, NC.

* Address correspondence to the author at: University of North Carolina, Division of Hematology-Oncology, 101 Manning Dr., CB 7305 3rd Floor POB, Chapel Hill, NC 27599. Fax 919-490-1567; e-mail alice_ma@med.unc.edu.

Received September 8, 2011; accepted September 13, 2011.

DOI: 10.1373/clinchem.2011.174177

Commentary

Acquired hemophilia A (AHA)2 is a rare but life-threatening bleeding disorder caused by an autoantibody directed against factor VIII, known as a factor VIII-specific inhibitor. Approximately 50% of AHA cases are idiopathic, whereas the remaining cases are often associated with an autoimmune disorder, malignancy, pregnancy, or drugs. The diagnosis must be made promptly to minimize the time that patients are at risk of severe bleeding and to avoid nonessential invasive procedures and delay in the initiation of appropriate treatment.

In this Clinical Case Study by Ehrenschwender et al., the authors described the step-by-step laboratory investigations of the isolated prolongation of the activated partial thromboplastin time (aPTT) in an elderly individual with unprovoked bleeding. This case stresses the importance of automatic laboratory investigation of isolated aPTT prolongation in identifying and treating patients with AHA. Prompt and thorough laboratory investigation is essential, considering that up to 6% of patients with AHA have been reported to have no bleeding at presentation.

One aspect not discussed in the Clinical Case Study is that AHA may occur in patients with lupus anticoagulant (LAC), with or without thrombosis. These patients often are receiving anticoagulation therapy. Because LAC also causes aPTT prolongation, it is important not to simply attribute aPTT prolongation to LAC or therapy and then stop further laboratory workup, especially if patients have bleeding episodes. Furthermore, given that LAC interferes with in vitro clotting-based assays, esoteric chromogenic assays should be used in this setting to measure factor VIII activity and the strength of the factor VIII inhibitor, which can provide essential guidance regarding patient management.

Also of note is that although coagulation factor assays are designed to quantify factor activity levels, the assays can also detect interfering inhibitors, including LAC and inhibitors of individual factors (in which "nonparallelism" indicates the presence of an inhibitor), and therefore are an integral part of laboratory investigations of isolated aPTT prolongation, as was demonstrated in this case.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Chuanyi M. Lu [1] *

[1] Department of Laboratory Medicine, University of California and Veterans Affairs Medical Center, San Francisco, CA.

[2] Nonstandard abbreviations: AHA, acquired hemophilia A; LAC, lupus anticoagulant.

* Address correspondence to the author at: Department of Laboratory Medicine (113A), VAMC, 4150 Clement St., San Francisco, CA 94121. Fax 415-750-6948; e-mail mark.lu@va.gov.

Received March 7, 2012; accepted March 9, 2012.

DOI: 10.1373/clinchem.2012.182196

References

(1.) Adcock D, Hoefner D, Kottke-Marchant K, Marlar A, Szamosi D, Warunek D. Collection, transport, and processing of blood specimens for testing plasma-based coagulation assay and molecular hemostasis assays; approved guideline. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.

(2.) van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-27.

(3.) Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009;15(Suppl 1):9S-16S.

(4.) Stavrou E, Schmaier AH. Factor XII: What does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res 2010;125:210-5.

(5.) Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006;4: 2103-14.

(6.) Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, De Groot PG. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009;7:1737-40.

(7.) Sahud MA. Laboratory diagnosis of inhibitors. Semin Thromb Hemost 2000;26:195-203.

(8.) Verbruggen B. Diagnosis and quantification of factor VIII inhibitors. Haemophilia 2010;16:20-4.

(9.) Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 2008;112:250-5.

(10.) Franchini M. Acquired hemophilia A. Hematology 2006;11:119-25.

Martin Ehrenschwender, [1,2] ** Juergen Koessler, [1] ([dagger]) Kirsten Brunner, [1] and Udo Steigerwald [1]

[1] Institut fur Klinische Biochemie und Pathobiochemie mit Zentrallabor, Universitatsklinikum Wurzburg, Wurzburg, Germany; [2] current affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.

[3] Nonstandard abbreviations: aPTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time; BU, Bethesda units.

* Address correspondence to this author at: Institute for Medical Microbiology and Hygiene, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Fax 941-9446402; e-mail martin.ehrenschwender@ klinik.uni-regensburg.de.

([dagger]) M. Ehrenschwender and J. Koessler contributed equally to the work, and both should be considered as first authors.

Received May 10, 2011; accepted August 8, 2011.

DOI: 10.1373/clinchem.2011.168393
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Title Annotation:Clinical Case Study
Author:Ehrenschwender, Martin; Koessler, Juergen; Brunner, Kirsten; Steigerwald, Udo
Publication:Clinical Chemistry
Article Type:Clinical report
Geographic Code:1USA
Date:Oct 1, 2012
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