This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by James, K. M. H. Articles by Mallett, S. V. Search for Related Content PubMed PubMed Citation Articles by James, K. M. H. Articles by Mallett, S. V. Related Collections Cardiovascular Coagulation Pharmacology

---

CARDIOVASCULAR ANESTHESIOLOGY

Thromboelastography-Guided Recombinant Factor VIIa Administration in a Patient with Refractory Autoimmune Idiopathic Thrombocytopenia

Katherine M. H. James, FRCA^*, Clare N. Melikian, FRCA^*, Pratima Chowdary, MRCPath, and Susan V. Mallett, FRCA^*

From the *Department of Anesthesia, and KD Hemophilia Centre and Thrombosis Unit, Royal Free Hospital, London.

Address correspondence and reprint requests to Katherine M.H. James, FRCA, Department of Anesthesia, Royal Free Hospital, Pond Street, London NW3 2QG. Address e-mail to katherine.james{at}royalfree.nhs.uk.

Abstract

Autoimmune idiopathic thrombocytopenia poses a significant challenge for clinicians in the perioperative period. Repeat platelet transfusions may not result in satisfactory increments in the platelet count and routine coagulation screens may not reflect the degree of abnormal hemostasis. We report the use of point-of-care testing with thromboelastography and platelet counting in managing a patient with refractory autoimmune idiopathic thrombocytopenia, undergoing a splenectomy for active bleeding. These tests were successfully used to monitor the frequency of administration of recombinant factor VIIa (NovoSeven®, NovoNordisk, Copenhagen, Denmark) with platelet transfusions.

Autoimmune idiopathic thrombocytopenias (AITP) are a group of disorders characterized by antiplatelet antibodies which are targeted at platelet membrane glycoproteins. This results in opsonization of platelets and their premature removal from the circulation. Adult patients typically present with petechiae, purpura, and bruising tendency. Mucosal bleeding, including epistaxis and hematuria, tend to be more frequent when the platelet count decreases to less than 20 x 10⁹/L.1 The incidence of severe bleeding increases with platelet counts below 10 x 10⁹/L, especially intracranial hemorrhage,2 although Wang and Shen3 have shown the platelet count may not predict risk of bleeding. Platelets may be administered during bleeding episodes; however, a minority of patients with severe refractory AITP will fail to respond to platelet transfusions with no observed increase in platelet count because of continuing sequestration and destruction.

First-line therapy for AITP is based on oral corticosteroids and IV immunoglobulin (IVIG), but a minority of patients remain unresponsive and splenectomy is then one of the treatment options. The indication and timing of splenectomy is often individualized according to response to treatment, patient and physician preferences.

The perioperative management of a patient with severe refractory AITP, undergoing a splenectomy for life-threatening bleeding, is complex, especially when the effect of platelet transfusion is transient and may only increase the platelet count by a small amount.

A meta-analysis of splenectomy for ITP has shown the mortality because of laparotomy to be at 1%, and one third of these deaths were related to bleeding, with at least half of the cases having a platelet count less than 20 x 10⁹/L.4 In these circumstances, the use of recombinant factor VIIa (rVIIa) may be of benefit and there are a few case reports that describe its use to provide effective hemostasis in patients with severe refractory thrombocytopenia.5,6 Platelets promote thrombin generation and rFVIIa may help to achieve hemostasis at low platelet concentrations by increasing initial thrombin generation, thereby compensating for low platelet density.7 However, in the perioperative setting, the optimal timing and dose regime for rFVIIa is still largely unknown and the minimal levels of coagulation factors and platelets required for the optimal efficacy of rFVIIa are also uncertain.

Point-of-care (POC) monitoring of platelet count and thromboelastography (TEG®) have been used as coagulation monitors in this context. This permits rapid assessment of the coagulation status of the blood and the ability to make prompt clinical decisions about transfusion of blood and blood products. The pocH-100i (Sysmex Corporation, Japan) is one POC analyzer, which provides a full blood count within 4 min of sampling. TEG is a global test of hemostasis and provides an indirect measurement of thrombin generation. We used both POC analyzers to guide the perioperative management of a patient with severe refractory AITP undergoing a splenectomy for life-threatening bleeding.

CASE DESCRIPTION

A 25-yr-old man was referred to the Royal Free Hospital for specialist multidisciplinary treatment of continuing epistaxis. He had a history of Hodgkins Lymphoma which had been treated with chemotherapy and autologous blood stem cell transplant over a year earlier. Apart from mild asthma, there was no other medical history of note. He was found to have a platelet count of 7 x 10⁹/L and a diagnosis of immune-mediated thrombocytopenia purpura was made, having excluded recurrence of lymphoma and other possible causes of low platelet count.

Despite standard treatment with high dose corticosteroids, intermittent IVIG, danazol and rituximab and multiple platelet transfusions his platelet count remained below 10 x 10⁹/L. Further investigations revealed the presence of high titer anti-IIb/IIIa receptor antibodies, which were potentially affecting the transfused platelets. He continued to have intermittent severe epistaxis managed by packing the nasal cavity, and also developed gross hematuria which was managed by continual bladder irrigation. Because of failed medical management and severe bleeding phenotype, splenectomy was considered the best available option. A decision was made to combine a splenectomy with removal of nasal packs in the operating room. Because the previous use of 120 µg/kg rFVIIa (NovoSeven®, NovoNordisk, Copenhagen, Denmark) with platelet transfusions had successfully terminated an episode of severe epistaxis in this patient, it was decided to follow a similar regimen. As part of the management plan, he received 2 g/kg of IVIG 48 h before surgery, 2 U of pooled platelets along with 120 µg/kg rFVIIa immediately preprocedure. A provisional plan was made to repeat rFVIIa administration in 2 h time and transfuse platelets as necessary.

POC testing (POCT) was performed throughout the perioperative period with pocH-100i and TEG, using unactivated native blood. Baseline blood tests before start of surgery revealed a platelet count of 23 x 10⁹/L, hemoglobin of 8.2 g/dL, International normalized ratio of 1.2, activated partial thromboplastin time of 44.8 s, fibrinogen of 390 mg/dL, and normal coagulation factor assays. The prolongation of the activated partial thromboplastin time was ascribed to the presence of lupus anticoagulant and explains the flat line on the initial TEG trace (Table 1).

Sequential TEG and POCT (Table 1) were performed throughout the operation. Tests were not based on an algorithm, but were run after all treatment interventions to assess efficacy, and also if the clinical picture suggested that the hemostatic status had deteriorated further. Red blood cells were administered to maintain the Hb at or >8 g/dL and platelet transfusions administered to maintain the count around 30 x 10⁹/L and/or a maximum amplitude (MA) >35 mm. The patient was stable throughout, and by the end of the surgery hemostasis had been achieved with a total operative transfusion requirement of 3 U of red cells and six pools of platelets. Postoperatively, the patient continued to receive platelets and blood products in the intensive care unit, as guided by TEG and laboratory tests and there was no further evidence of bleeding.

DISCUSSION

Undertaking any surgical procedure in a patient with refractory thrombocytopenia is a challenging problem. Platelet transfusions may not increase platelet count (because of continuing sequestration and destruction), and the platelet count alone may not accurately reflect the severity of the bleeding disorder. Consequently, the optimal management of these patients in the perioperative setting requires access to POC technology that readily provides rapid and repeated platelet counts. In this patient, platelet counts were performed intraoperatively as part of our standard practice by POCT (pocH-100i) which provides a more useful indicator of trends in the acute setting when there is a rapidly changing clinical scenario than slower laboratory studies. (The platelet count as measured by POCT (pocH-100i), uses an impedance method of measurement that has been shown to give slightly lower readings than the newer laboratory methods, such as the Advia 120,8 which uses an optical measurement technique. However, in most consensus guidelines, transfusion thresholds have been set based on impedance platelet counting).

rFVIIa is a prohemostatic drug that was first developed for use in bleeding hemophilia A patients with high-titer inhibitors against factor VIII or IX9 and reported for "off-license" treatment for uncontrolled bleeding for different causes. Several case reports have shown successful use of rFVIIa in patients with severe thrombocytopenia and active bleeding.6,10,11 The optimal method to monitor the efficacy of rFVIIa treatment is not clearly defined.12 Research on TEG-guided use of rFVIIa has focused mainly around hemophilia patients.13 However, TEG tracings have been presented in other situations in which unactivated samples have been used such as liver transplantation14 and Glazmann's thrombasthenia.15

In severe thrombocytopenia, the hemostatic properties of rFVIIa are due to accelerating thrombin generation, enhanced platelet activation, and rapid clot formation, with improvements in clot strength and stability.7,14 In vitro analysis of rFVIIa using TEG shows a rFVIIa concentration-dependent reduction in reaction (R) time and increase in MA with normal whole blood and a reduction in R and increase in MA as platelet counts increased.16 This demonstrates there is a shortening of the initial stage of coagulation and amplification of the rate and extent of clot formation in the presence of rVIIa.

rFVIIa enhances thrombin generation on platelets.6 Cell-based models of thrombocytopenia have shown that thrombin generation is dependent on platelets and that in profound thrombocytopenia (platelet count 10 x 10⁹/L), rFVIIa is not able to promote peak thrombin generation.17 However, other in vitro studies have demonstrated that platelet counts as low as 20–30 x 10⁹/L may be adequate to initiate hemostasis and generate sufficient thrombin to produce a normal clot MA.16 This case suggests that levels of platelet counts more than 25–30 x 10⁹/L may be required for successful use of rFVIIa and supports the efficacy of combination therapy with rFVIIa and platelets for severe refractory autoimmune thrombocytopenia.18

After the transfusion of 2 U of pooled platelets and rFVIIa administration there was evidence of clot formation on TEG. A reduction in the severity of hematuria paralleled this initial improvement in coagulation status. A further unit of pooled platelets was given 50 min later as the platelet count was again 22 x 10⁹/L. This resulted in an increase in the MA on the TEG and complete cessation of hematuria. Two hours after the first dose of rFVIIa was given, the reappearance of frank hematuria and grossly abnormal clot formation on the TEG occurred. Transfusion of 2 U of pooled platelets increased the platelet count from 26 x 10⁹/L to 44 x 10⁹/L, with a corresponding increase in the MA from 33.8 to 45.9 mm. However, the R time became more prolonged and recurrent active bleeding occurred. A second dose of 120 µg/kg rFVIIa was given with improvement in coagulation as assessed by TEG with resolution of hematuria. These observations correlate with the documented half-life of rFVIIa of 2.3 h (NovoSeven® Prescribing Information, 2006).

In summary, POCT and TEG were used to monitor the coagulation status of a patient with refractory thrombocytopenia undergoing surgery for life-threatening hemorrhage. We were able to assess the need for blood products on a "real-time" basis. The recent introduction of "Rapid-TEG," which uses tissue factor activation to provide accelerated information on clot formation and tensile strength ( angle and MA) may be potentially useful in cases in which the primary area of interest is overall clot strength, although the R time in inactivated samples provides useful information about the initial stages of coagulation. Despite the potential hazards of major surgery in a bleeding patient with severe refractory thrombocytopenia, our patient received just 3 U of packed cells and had a Hb of 8.9 g/dL immediately postoperatively. To our knowledge, this is first report of TEG traces used to guide the administration of rVIIa in severe refractory thrombocytopenia during the perioperative period.

Footnotes

Accepted for publication March 20, 2008.

REFERENCES

1. Chong BH. Diagnosis, treatment and pathophysiology of autoimmune thrombocytopenias. Crit Rev Oncol Hematol 1995; 20:271–96[Web of Science][Medline]
2. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005;106:2244–51[Free Full Text]
3. Wang ZY, Shen ZX. Megakaryocytes and platelets in immune thrombocytopenic purpura. Baillieres Clin Haematol 1997; 10:89–107[Web of Science][Medline]
4. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004;104:2623–34[Abstract/Free Full Text]
5. Wrobel G, Dobaczewski G, Patkowski D, Sokol A, Grotthus E. Experiences with recombinant activated factor VII in the treatment of severe refractory thrombocytopenia. Pediatric Blood Cancer 2002;47:729–30
6. Gerotziafas GT, Zervas C, Gavrielidis G, Tokmaktsis A, Hatjiharissi E, Papaioannou M, Lazaridou A, Constantinou N, Samama MM, Cristakis J. Effective hemostasis with rFVIIa treatment in two patients with severe thrombocytopenia and life-threatening hemorrhage. Am J Hematol 2002;69:219–22[Web of Science][Medline]
7. Gerotziafas GT, Chakroun T, Depasse F, Arzoglou P, Samama MM, Elalamy I. The role of platelets and recombinant factor VIIa on thrombin generation, platelet activation and clot formation. Thromb Haemost 2004;91:977–85[Web of Science][Medline]
8. Segal HC, Briggs C, Kunka S, Casbard A, Harrison P, Machin SJ, Murphy MF. Accuracy of platelet counting haematology analysers in severe thrombocytopenia and potential impact on platelet transfusion. Br J Haematol 2005;128:520–5[Web of Science][Medline]
9. Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest 1983;71:1836–41[Web of Science][Medline]
10. Vidarsson B, Onundarson PT. Recombinant factor VIIa for bleeding in refractory thrombocytopenia. Thromb Haemost 2000;83:634–5[Web of Science][Medline]
11. Busani S, Marietta M, Pasetto A, Girardis M. Use of recombinant factor VIIa in a thrombocytopenic patient with spontaneous intracerebral haemorrhage. Thromb Haemost 2005;93:381–2[Web of Science][Medline]
12. Coppola A, Simone CD, Palmieri NM, Coppola D, Lanza F, Ruosi C, Amoriello A, Di Minno G. Recombinant activated factor VII for hemostatic cover of orthopedic interventions in a girl with thrombocytopenia with absent radii syndrome. Blood Coagul Fibrinolysis 2007;18:199–201[Web of Science][Medline]
13. Sorensen B, Ingerslev J. Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa. J Thromb Haemost 2004;2:102–10[Web of Science][Medline]
14. Hendricks H. Effects of recombinant activated VII on coagulation measured by thromboelastography in liver transplantation. Blood Coagul Fibrinolysis 2002;13:309–13[Web of Science][Medline]
15. Dargaud Y, Bordet JC, Trzeciak MC, Vinciguerra C, Negrier C. A case of Glanzmann's thrombasthenia successfully treated with recombinant factor viia during a surgical procedure: observations on the monitoring and the mechanism of action of this drug. Haematologica 2006;91:ECR20[Abstract/Free Full Text]
16. Kawaguchi C, Takahashi Y, Hanesaka Y, Yoshioka A. The in vitro analysis of the coagulation mechanism of activated factor VII using thrombelastogram. Thromb Haemost 2002;88:768–72[Web of Science][Medline]
17. Kjalke M, Ezban M, Monroe DM, Hoffman M, Roberts HR, Hedner U. High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system. Br J Haematol 2001;114:114–20[Web of Science][Medline]
18. Savani BN, Dunbar CE, Rick ME. Combination therapy with rFVIIa and platelets for hemorrhage in patients with severe thrombocytopenia and alloimmunization. Am J Hematol 2006;81:218–19[Web of Science][Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by James, K. M. H. Articles by Mallett, S. V. Search for Related Content PubMed PubMed Citation Articles by James, K. M. H. Articles by Mallett, S. V. Related Collections Cardiovascular Coagulation Pharmacology