Osteogenesis Imperfecta, Perioperative Bleeding, and Desmopressin
Keegan, Mark T. M.B., M.R.C.P.I.*; Whatcott, Brett D. M.D.†; Harrison, Barry A. M.B.B.S., F.A.N.Z.C.A., F.R.A.C.P.‡
OSTEOGENESIS imperfecta (OI), also known as “brittle-bone disease,” is a genetic disorder of connective tissue that causes susceptibility to fractures. In OI, there is a 10–30% incidence of bleeding diathesis, and these individuals have an increased risk of bleeding when undergoing surgery. 1,2
The coagulation defect is related to the effect of abnormal collagen on platelet-endothelial cell interactions and capillary strength. By its action on capillary endothelial cells, desmopressin, 3
a synthetic analog of antidiuretic hormone, may improve the coagulation abnormality seen in patients with OI. We describe the use of desmopressin in a patient with OI who experienced excessive bleeding in the setting of a major surgical procedure.
A 72-yr-old man with adenocarcinoma of the prostate and transitional cell carcinoma of the bladder presented for cystoprostatectomy. The patient had a history of OI tarda that had manifested as multiple fractures in childhood and reduced hearing on the right side. His past medical history was also significant for hypertension and bleeding hemorrhoids. There was no history of spontaneous bleeding, easy bruising, or excessive surgical bleeding. The patient was not taking aspirin or nonsteroidal antiinflammatory drugs. Physical examination revealed the presence of blue sclera, a dorsal kyphosis, and bilateral reduction in hip mobility. His prostate gland was slightly enlarged and had areas of induration at the bases and right apex. His prostate-specific antigen level was 6.9 ng/ml (reference, < 5.6). Preoperative cystoscopic examination with biopsy revealed an invasive grade 3 transitional cell carcinoma of the bladder, and prostate biopsy results were positive for adenocarcinoma of the prostate. The cardiorespiratory examination was unremarkable. The patient's preoperative platelet count was 220 × 109/l.
Standard American Society of Anesthesiologists monitors were placed. General anesthesia was induced with propofol and fentanyl and maintained with isoflurane in air and oxygen. An inline fluid warmer and Bair Hugger (Augustine Medical, Eden Prairie, MN) were used. Muscle relaxation was achieved using cisatracurium, and intermittent doses of morphine were used for analgesia. Marked vascularity and friability of the vessels complicated the dissection, leading to excessive, diffuse bleeding. Within 40 min of the incision, an estimated 1500 ml of blood had been lost, causing the patient's hemoglobin concentration to decrease from 13 g/dl (as measured preoperatively) to 8.7 g/dl. In light of the patient's hemodynamic instability and excessive, ongoing blood loss, 4 units of packed erythrocytes and 6 units of platelets were transfused. Despite this, the diffuse surgical bleeding continued, but no other bleeding sites were identified. Twenty minutes after administration of the platelets, 0.3 μg/kg (total dose, 22 μg) desmopressin acetate was administered in an effort to improve platelet function and to decrease blood loss. The drug was infused over 20 min to avoid severe hypotension. Within minutes of the infusion, the excessive, diffuse bleeding stopped. No further abnormal bleeding occurred, and the patient remained hemodynamically stable for the remainder of the procedure. In total, the patient received 6 units of packed erythrocytes, 6 units of platelets, 500 ml of 5% albumin, 500 ml hetastarch, and 5,600 ml lactated Ringer's solution. At the end of the case, the patient's hemoglobin concentration was 11.8 g/dl, and 4 h later his hemoglobin concentration was 11.2 g/dl, his platelet count was 199 × 109/l, his prothrombin time was 11.9 s (reference range, 8.4–12.0 s), and his activated partial thromboplastin time was 25 s (reference range, 21–33 s). Prior to the onset of bleeding, the patient's temperature was 35.9°C, and it increased to 36.6°C after the bleeding episode. The patient's recovery and postoperative course were uneventful.
Osteogenesis imperfecta is a heterogenous group of inherited disorders of collagen type I caused by mutations of the COL1A1
Although the classic clinical description of OI is of a patient with brittle bones, blue sclera, and premature deafness, other organ systems are affected. The disease may cause cardiac valvular lesions, kidney stones, neurologic abnormalities, and metabolic derangements. In addition, the defect in collagen synthesis can cause excessive bruising and generalized oozing from wound sites. Surgical procedures performed in patients with OI carry a higher risk of bleeding complications. Laboratory investigations of patients with OI have demonstrated increased capillary fragility, decreased platelet retention, decreased levels of factor VIII, and deficient collagen-induced platelet aggregation. 5,6
It is believed that the collagen defect results in friable tissues, small blood vessels that are unable to constrict adequately, and a defect in the platelet aggregation response around exposed subendothelium. The bleeding may occur despite normal results of coagulation studies and bleeding times, making predictions about intraoperative bleeding difficult. 7
Coagulopathy with sudden development of widespread petechiae has been reported, 8
as has fatal hemorrhage secondary to accidental rib fractures during spinal fusion surgery. 9
The evaluation of platelet function and the role of platelet transfusion in OI are difficult to assess. Because OI is due to an impairment of the platelet-endothelial cell interaction, the thromboelastogram may not be useful. Indeed, we could not find a published case report regarding the use of the thromboelastogram in OI. The American Society of Anesthesiologists transfusion guidelines state, “platelet transfusion may be indicated despite an apparently adequate platelet count if there is known platelet dysfunction and microvascular bleeding.”10
Bleeding time and platelet aggregation tests are not useful in the operating room, 10
and “there is an urgent need for the development of clinically relevant measures of in vivo
platelet function and bleeding risk to guide the rational use of platelet transfusion.”11
Desmopressin is a synthetic analog of antidiuretic hormone. It has a significant antidiuretic effect mediated via
V2 receptors and little or no vasoconstrictive effect (V1). 3,12
The drug, mediated via
V2 effects, causes endothelial cells to release von Willebrand factor, tissue type plasminogen activator, and factor VIII:C. Desmopressin may be used in patients with uremia, chronic liver disease, and certain types of hemophilia, in which increased release of von Willebrand factor promotes platelet adhesiveness to the vascular endothelium and, hence, increases hemostatic activity. There are conflicting reports as to the utility of desmopressin in the reduction of blood loss during operations that involve substantial bleeding. Studies involving patients undergoing coronary artery bypass grafting, spinal fusion, and hip surgery have varied in their methodology and outcome. 13–16
The adverse effects associated with the use of desmopressin are few. 3
They include facial flushing, headache, hypotension, tachycardia, and the possibility of thrombosis. In addition, the antidiuretic effect may increase the difficulty of assessing the intravascular volume status. There have been a few reports of hyponatremia and seizures, mostly in children.
Desmopressin works in congenital and acquired platelet disorders by increasing plasma concentrations of factor VIII, von Willebrand factor, and tissue plasminogen activator and by increasing platelet adhesiveness. 3,12
The hemostatic effect is almost immediate after administering an intravenous dose of 0.3 μg/kg. 3
Desmopressin may be useful for improving hemostasis and ultimately decreasing transfusion requirements in the surgical patient with OI. By increasing platelet deposition onto vascular subendothelium, desmopressin would seem to be an excellent adjunct to the perioperative management of patients with OI.
We cannot say definitively that desmopressin stopped the bleeding in this case, but circumstantial evidence supports this hypothesis. A review of the literature failed to reveal any previous reports of the use of desmopressin to treat the coagulopathy associated with OI. Although further investigation is warranted, due to the low incidence of OI and the difficulty in documenting the coagulopathy associated with OI, randomized, controlled trials will be difficult to perform. Qualitative tests of platelet function, performed before and after the administration of desmopressin, may help to elucidate the drug's role in this setting. However, given the relatively benign side effect profile of desmopressin and the theoretical basis for its effectiveness, consideration should be given to the use of desmopressin in patients with OI undergoing major surgery when complicated by significant microvascular bleeding.
1. Morton ME: Excessive bleeding after surgery in osteogenesis imperfecta. Br J Oral Maxillofac Surg 1987; 25: 507–11
2. Siegel BM, Friedman A, Schwartz SO: Hemorrhagic disease in osteogenesis imperfecta. Am J Med 1957; 22: 315–21
3. Lethagen S: Desmopressin (DDAVP) and hemostasis. Ann Hematol 1994; 69: 173–80
4. Marini JC: Osteogenesis imperfecta—managing brittle bones. N Engl J Med 1998; 339: 986–7
5. Evensen SA, Myhre L, Stormorken H: Haemostatic studies in osteogenesis imperfecta. Scand J Haematol 1984; 33: 177–9
6. Hathaway WE, Solomons CC, Ott JE: Platelet function and pyrophosphates in osteogenesis imperfecta. Blood 1972; 39: 500–9
7. Wong RS, Follis FM, Shively BK, Wernly JA: Osteogenesis imperfecta and cardiovascular diseases. Ann Thorac Surg 1995; 60: 1439–43
8. Edge G, Okafor B, Fennelly ME, Ransford AO: An unusual manifestation of bleeding diathesis in a patient with osteogenesis imperfecta. Eur J Anaesthesiol 1997; 14: 215–9
9. Sperry K: Fatal intraoperative hemorrhage during spinal fusion surgery for osteogenesis imperfecta. Am Forensic Med Pathol 1989; 10: 54–9
10. Practice Guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. A nesthesiology 1996; 84: 732–47
11. Norfolk DR, Ancliffe PJ, Contreras M, Hunt BJ, Machin SJ, Murphy WG, Williamson LM: Consensus Conference on Platelet Transfusion, Royal College of Physicians of Edinburgh, 27–28 November 1997. Br J Haematol 1998; 101: 609–14
12. Stoelting RK: Pharmacology and Physiology in Anesthetic Practice, 3rd edition. Philadelphia, Lippincott-Raven, 1999, p 424
13. Theroux MC, Corddry DH, Tietz AE, Miller F, Peoples JD, Kettrick RG: A study of desmopressin and blood loss during spinal fusion for neuromuscular scoliosis. A nesthesiology 1997; 87: 260–7
14. Frankville DD, Harper GB, Lake CL, Johns RA: Hemodynamic consequences of desmopressin administration after cardiopulmonary bypass. A nesthesiology 1991; 74: 988–96
15. Mongan PD, Hosking MP: The role of desmopressin acetate in patients undergoing coronary artery bypass surgery. A nesthesiology 1992; 77: 38–46
16. Guay J, Reinberg C, Poitras B, David M, Mathews S, Lortie L, Rivard GE: A trial of desmopressin to reduce blood loss in patients undergoing spinal fusion for idiopathic scoliosis. Anesth Analg 1992; 75: 405–10
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