Timothy E. Hayes

Dysfibrinogenemia and Thrombosis

OBJECTIVES To review the state of the art relating to congenital dysfibrinogenemia as a potential risk factor for thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for the use of laboratory assays for assessing this thrombotic risk in individual patients. DATA SOURCES Review of the medical literature, primarily from the last 10 years. DATA EXTRACTION AND SYNTHESIS After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference on Diagnostic Issues in Thrombophilia. Each of the key points and associated recommendations were then presented for discussion at the conference. Recommendations were accepted if a consensus of experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS Consensus was reached on 5 conclusions and 2 recommendations concerning the use of testing for dysfibrinogens in the assessment of thrombotic risk in individual patients. Detailed discussion of the rationale for each of these recommendations is found in the text of this article. Compared with the other, more common hereditary thrombophilias, dysfibrinogenemia encompasses a diverse group of defects with varied clinical expressions. Congenital dysfibrinogenemia is a relatively rare cause of thrombophilia. Therefore, routine testing for this disorder is not recommended as part of the laboratory evaluation of a thrombophilic patient. This is an evolving area of research, and further clinical studies may change these recommendations in the future.

Effect of fondaparinux on coagulation assays: Results of College of American pathologists proficiency testing

CONTEXT Fondaparinux, a factor Xa inhibitor, is approved for thromboprophylaxis after orthopedic surgery and for treatment of venous thromboembolism. It may also be efficacious, safe, and cost-effective for other patients; thus, more widespread use of fondaparinux is likely. The effect of fondaparinux on coagulation testing needs to be thoroughly examined. OBJECTIVE To report the effects of fondaparinux on coagulation tests (prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin, factor VIII, thrombin time, anti-factor Xa) across diverse methodologies. DESIGN Samples with different concentrations of fondaparinux (0, 0.4, 0.8, and 2.0 microg/mL) were sent to laboratories participating in the College of American Pathologists Comprehensive Coagulation proficiency survey (N = 898). Laboratory-specific methods were used to assay coagulation parameters. RESULTS Prophylactic or therapeutic fondaparinux prolonged the prothrombin time by approximately 1 second and the activated partial thromboplastin time by 4 to 5 seconds, and reduced factor VIII from 119% to 107% and 102%, respectively. Supratherapeutic fondaparinux reduced factor VIII to 85%. The activated partial thromboplastin time was prolonged in 19%, 29%, and 52% of laboratories with prophylactic, therapeutic, and supratherapeutic fondaparinux levels, respectively. Fibrinogen, antithrombin, and thrombin time assays did not show clinically significant changes. When measuring fondaparinux concentration using an anti-factor Xa assay, the most accurate results were obtained when fondaparinux was used as the calibrator. CONCLUSIONS Fondaparinux, even in prophylactic doses, slightly prolongs the prothrombin time and activated partial thromboplastin time and can interfere with factor VIII assays, but it has no clinically relevant effect on fibrinogen, antithrombin, or thrombin time. A fondaparinux standard curve should be used for reporting fondaparinux levels using an anti-factor Xa assay.

Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding.

Prothrombin complex concentrates (PCCs) offer a means for the rapid reversal of warfarin, particularly in the setting of life-threatening bleeding. We evaluated the effectiveness and safety of a PCC-based protocol in patients with warfarin-associated intracerebral hemorrhage (ICH), subdural hematoma (SDH), or subarachnoid hemorrhage (SAH). This was a retrospective case-series review of patients treated with an institution-approved warfarin reversal protocol. Patients with intracranial hemorrhage and known warfarin use with an international normalized ratio (INR)>1.4 received fresh frozen plasma (FFP), vitamin K (phytonadione), and weight-based, 3-factor PCC (Profilnine(®) SD) dose based on the initial INR. Demographic and clinical information, the degree of and time to INR normalization, and adverse events were recorded. The thirty study patients included 19 with primary ICH, 7 with SDH, and 4 with SAH. The mean age was 72.8 (±11) years, including 11 (37%) patients ≥80years old. The median presenting INR was 2.3 (IQR 2-3.3) and post-treatment INR was 1.4 (IQR 1.3-1.5, Z score 6.4, p<0.001). Median time from PCC administration to the first follow up INR was 95 (IQR 50-140) min. No patients INR increased by more than 0.3 over 72h. Nine patients (30%) underwent neurosurgical procedures after PCC administration and no procedure-related bleeding complication was noted. Adverse events included 3 instances of early hematoma expansion, one ischemic stroke in a patient with endocarditis on post-PCC day 1, one pulmonary embolism 5weeks after PCC treatment, and one coronary in-stent thrombosis 60days after PCC treatment. 6 patients died prior to hospital discharge of anticipated complications of their initial event, and none from identifiable thrombotic complications of PCC. A 3-factor PCC preparation (Profilnine(®) SD), administered with FFP and vitamin K to patients with acute warfarin-associated intracranial bleeding is a reasonable approach to urgent warfarin reversal. However, randomized, prospective trials are needed to verify the safety and clinical effectiveness of PCC administration in this population.

Laboratory reporting of the international normalized ratio: Progress and problems

CONTEXT The international normalized ratio (INR) is widely used to monitor oral anticoagulation and to evaluate patients with coagulation disorders. OBJECTIVE To examine the variability of the performance and reporting of the INR and to evaluate laboratory calculation of the INR. DESIGN Between 1993 and 2003, laboratories participating in proficiency testing were surveyed. Participants provided the international sensitivity index and the mean normal prothrombin time used to calculate the INR. The INR was calculated from the data provided and compared with the INR reported to determine if the calculation was correct. RESULTS Survey data regarding the INR collected between 1993 and 2003 demonstrate an improvement in reporting, using appropriate anticoagulant, using lower international sensitivity index reagents, and matching international sensitivity index and prothrombin time method. The all-method coefficient of variation of the INR improved from 18% to 5.8%. Among 3813 laboratories studied in 2002 and 2003, 4.1% miscalculated INR. Of 29 laboratories that reported investigation of the INR miscalculation, 11 (38%) reported correcting an INR that was being reported in patient results and that this error was corrected as a result of the study. Since beginning grading of the INR calculation, miscalculation of the INR has fallen to less than 1%. CONCLUSIONS Recommendations for change in laboratory practice made by consensus conferences are implemented during the course of many years. Difficulty calculating the INR was documented, and both the calculation and the variability in the reporting of the INR showed improvement. Proficiency testing, when closely evaluated and acted on, can have a direct impact on the quality of patient care.