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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.3 Campinas May/June 2007
von Willebrand's disease and anesthesia*
Enfermedad de von Willebrand y anestesia
Fabiano Timbó Barbosa, TSAI; Rafael Martins da CunhaII; Luciano Timbó BarbosaIII
em Docência para o Ensino Superior conferido pelo Centro de Ensino Superior
de Maceió; Anestesiologista da Unidade de Emergência Dr. Armando
Lages e do Hospital Escola Doutor José Carneiro; Intensivista da Clínica
IIProfessor de Farmacologia do Centro de Ensino Superior de Maceió; Professor Convidado de Farmacologia da Escola de Ciências Médicas de Alagoas; Anestesiologista do Hospital Unimed-Maceió
IIIMédico Intensivista da Clínica Santa Juliana em Maceió; Especialista em Clínica Médica pela Sociedade Brasileira de Clínica Médica
AND OBJECTIVES: von Willebrand's disease is secondary to a mutation on chromosome
12, and is characterized by a qualitative and quantitative deficiency of the
von Willebrand's factor. The diversity of the mutations is responsible for several
different clinical manifestations, enabling the classification of several types
and subtypes. The coagulopathy is manifested basically through a platelet dysfunction
associated with a reduction in the serum levels of factor VIII. The objective
of this review was to present the perioperative care of patients with von Willebrand's
CONTENTS: The physiopathology, classification, laboratorial diagnosis, and current treatment of von Willebrand's disease, as well as the perioperative management of these patients are discussed.
CONCLUSIONS: von Willebrand's disease is the most common hereditary coagulopathy, but it is underdiagnosed due to the complexity of the disease itself. The right classification, proper use of desmopressin, and transfusion of von Willebrand's factor are fundamental for a successful anesthesia.
Key Words: DISEASES, Hematologic: von Willebrand's disease.
Y OBJETIVOS: La enfermedad de von Willebrand ocurre debido a la mutación
en el cromosoma 12 y se caracteriza por la deficiencia cualitativa o cuantitativa
del factor de von Willebrand. La diversidad de mutaciones conlleva al aparecimiento
de las más variadas manifestaciones clínicas posibilitando la
división de los pacientes en varios tipos y subtipos clínicos.
La coagulopatía se manifiesta básicamente a través de la
disfunción plaquetaria asociada con la disminución de los niveles
séricos del factor VIII coagulante. El objetivo de esa revisión
fue mostrar los cuidados relacionados con las pacientes portadoras de la enfermedad
de von Willebrand durante el período perioperatorio.
CONTENIDO: Se definieron las características de la enfermedad de von Willebrand en cuanto a las fisiopatologías, la clasificación, al diagnóstico laboratorial, al tratamiento actual y a los cuidados con el manejo del paciente en el período perioperatorio.
CONCLUSIONES: La enfermedad de von Willebrand es el disturbio hemorrágico hereditario más común, sin embargo ella está subdiagnosticada por la complejidad de la propia enfermedad. La correcta clasificación del paciente, el uso apropiado de la desmopresina y la transfusión del factor de von Willebrand son medidas fundamentales para la realización del procedimiento anestésico exitoso.
In 1926, Erich von Willebrand described a hemorrhagic disease affecting both genders 1,2. It was initially described in a Finnish girl and in 66 of her relatives 1. Contrary to hemophilia, this disease is autosomal dominant in most patients 2,3 and presents, classically, with prolonged bleeding time and normal platelets 1. It is known as von Willebrand's disease (vWD) 1,2 or angiohemophilia 5.
It is the most common hereditary hemorrhagic disease 4,6-9. It affects up to 2% of the population 1,2,4, but its real incidence is unknown since mild cases go unnoticed 3,4. Most cases are mild 2 and patients may have normal or discretely altered routine coagulation exams 3,6,8,10.
von Willebrand's disease is secondary to a mutation on the short arm of chromosome 12, being characterized by platelet dysfunction, decreased production of von Willebrand's factor (vWF), and reduced levels of factor VIII (F VIII:C) 3.
NORMAL PRIMARY HEMOSTASIA
Primary hemostasia is the initial coagulation process triggered by vascular damage 11. Local mechanisms lead to vasoconstriction and change local permeability, shunting the blood flow to collateral vessels, causing edema 11. Local edema and extravasated blood help to compress the vessel 6,11.
Platelets participate in hemostasia by forming a platelet plug in damaged areas 12. This mechanism is extremely important for capillaries, arterioles, and venules 12.
Initially, platelets adhere to subendothelial collagen fibrils in the damaged vessels through the glycoprotein complex Ia/IIa present in surface receptors on the platelets 12. von Willebrand's factor is transported to the subendothelium and undergoes a conformational change 10. The initial platelet adherence is stabilized by the modified vWF after it binds to the glycoproteins Ib/IX 12,13. After this biological event, platelet granules are released and ADP activates and modifies the conformation of the IIb/IIIa complex 12. The subsequent binding of vWF, IIb/IIIa complex, and fibrinogen is responsible for platelet aggregation 10.
Ristocetin is an antibiotic that induces the binding of vWF and glycoprotein Ib, being used to diagnosis this disease 10.
PHYSIOPATHOLOGY AND DRUGS THAT INTERFERE WITH PLATELET FUNCTION
Normal vWF is a large multimeric glycoprotein with 22,000-dalton monomeric subunits 2. Its total molecular weight might reach 20 million daltons and its agglutinating properties are mediated mainly by the higher molecular weight multimers 2. It is synthesized by endothelial cells 4,10, megakaryocytes 4,10, and platelets 10, being the only coagulation factor that is not produced by the liver 6. The regulating mechanisms are not well understood 10. Most of it is in the plasma forming a complex with F VIII:C 3, but it is also found in the Weibel-Palade corpuscles of endothelial cells 3,14,15 and in the alpha granules of the platelets 3. Individuals with type O blood group have lower levels of vWF2,10,14.
von Willebrand factor has two main functions: to facilitate subendothelial platelet adhesion in damaged vessels 1,3,8,10,15 and to form a complex with F VIII:C, protecting it from premature activation 1,15 and blocking its proteolytic degradation 1,3,10,15. Inappropriate formation of vWF or normal formation in low amounts leads to a deficiency in platelet adhesion, hindering primary hemostasia and decreasing the half-life of F VIII:C.
Some drugs interfere with platelet function through unknown mechanisms or in ways that are not completely known, such as: acetylsalicylic acid (ASA), prostaglandin analogues, dipyridamole, clopidogrel, ticlopidine, inhibitors of the IIb/IIIa glycoprotein, heparin, b-adrenergic antagonists, betalactam antibiotics, and vitamin E 16.
Non-steroidal anti-inflammatories block platelet aggregation, but the effects of ASA are prolonged 17,18 and unreversible 18. Acetylsalicylic acid blocks cyclooxygenase 1 and the formation of thromboxane A2, which causes vasoconstriction and platelet aggregation 16. The endothelial inhibition of prostacyclin formation is not permanent because cells are capable to regenerate new enzymes promptly 16.
The analogues of prostacyclin I2 inhibit platelet aggregation and thrombus formation by stimulating receptors specific for this prostaglandin on the surface of the platelet 16. This class of drugs includes iloprost, cicaprost, and beraprost 16.
Dipyridamole is a vasodilator and has antithrombotic activity 16,18. The proposed mechanism of action is the inhibition of platelet phosphodiesterase, with an increase in cyclic AMP, and potentiation of the inhibitory effects of prostaglandin I2 16,18.
Ticlopidine and clopidogrel are thienopyridine derivatives that reduce the binding of ADP to its receptor 16. Another mechanism of action proposed for ticlopidine is the blockade of the interaction of vWF and fibrinogen with platelets 18.
Inhibitors of the IIb/IIIa glycoprotein complex have been successfully used in acute coronary syndromes, and are being tested in patients with ischemic strokes 19. Tirofiban is an antagonist of platelet aggregation that belongs to this class of drugs 16.
Heparin can bind to a protein in the membrane of platelets, form an antigenic complex, and induce the formation of IgG 20. This immunoglobulin aggregates the platelets, leading to venous and arterial thrombosis 20.
The mechanism of action of b-adrenergic antagonists is not well understood 16. Propranolol has antiplatelet effects in patients with coronary insufficiency but not in healthy individuals, while timolol causes platelet aggregation 16.
There is also reference in the literature to coagulation deficit after using some colloidal solutions 21. Dextran decreases platelet adhesion and reduces the activity of F VIII:C 21. Hydroxiethylamide decreases serum levels of vWF and F VIII:C, besides increasing fibrinolysis 22. Human albumin causes minimal changes in the plasma levels of vWF and F VIII:C 22.
Cephalosporins may cause transient coagulation abnormalities, increasing prothrombin time by inhibiting the carboxylation of vitamin K on coagulation factors dependent on that vitamin 23. Cefotaxime may lead to the immune-mediated inhibition of vWF or accelerate the proteolysis of larger multimers, causing acquired vWD 23.
DIAGNOSIS, CLASSIFICATION, AND CLINICAL MANIFESTATIONS
The disease can be diagnosed by the bleeding time and activated partial thromboplastin time (PTT), but they may be normal and, for that reason, they alone cannot confirm the diagnosis 10. The activated partial thromboplastin time reflects the level of F VIII:C 8 and usually, in baseline conditions, there is enough factor to normalize the test 10. If the PTT is too prolonged, it is probably a case of severe disease 10. Cohen et al. 24 reported that bleeding time helps define the risk and that a level of F VIII above 60% results in normal bleeding time and absence of bleeding.
Platelet count is usually normal, but in subtype 2B it can be decreased 8.
The diagnosis can only be confirmed after determination of: the levels of F VIII:C, quantification of the vWF antigen, and the activity of the ristocetin cofactor 2,3,8. The activity of the ristocetin cofactor is the most specific exam for platelet function, and can be decreased even in mild disease 2.
von Willebrand's disease is an autosomal disease with altered platelet function 1, while hemophilia is related with chromosome X and has change only on F VIII:C 6. Mutations on the von Willebrand's gene cause qualitative and quantitative deficiencies 3. In 1994, several phenotypes of the disease were classified by a subcommittee of the International Society of Homeostasis and Thrombosis, as follows 3,10:
- Type 1 Affects 70 to 80% of patients. It is an autosomal dominant disease with variable expression. There is partial quantitative deficiency with reduction of the serum level without structural changes in the vWF.
- Type 2 Affects approximately 20% of the patients. The pattern of genetic transmission is autosomal dominant. There is qualitative deficiency of the vWF. In subtype 2A, high molecular weight multimers are absent. Von Willebrand's factor is structural and functionally abnormal. In subtype 2B, the affinity of the vWF for glycoprotein Ib is increased, leading to thrombocytopenia, which is worsened by the use of desmopressin. In subtype 2N, the affinity of the vWF for F VIII:C is decreased and platelet function is normal.
- Type 3 Affects 0.5% of the patients. It is an autosomal recessive disease. Plasma levels of vWF are undetectable.
- Pseudo-von Willebrand disease (p-vW) Its frequency is unknown 25. It is an autosomal dominant disease secondary to a mutation in the gene of the 1b glycoprotein complex on chromosome 17 25. It is phenotypically similar to subtype 2B 25.
The most common clinical manifestations include: epistaxis 3,4,10, menorrhagia 2-4,10, gingival bleeding 2-10, ecchymosis 2,4,10, hematoma 10, gastrointestinal bleeding 3, hemarthrosis 2,3, and prolonged bleeding after surgeries 4.
Trauma and other emergency situations sometimes do not allow complete blood testing, making it difficult to diagnose this condition. But some aspects can be observed in the anamnesis that will indicate the differential diagnosis between coagulation factors disturbances and platelet diseases 11.
Patients with disturbances of coagulation factors 11 usually have a positive family history, predominance of male gender, visceral bleeding, ineffective response to compression of an open vessel, and delayed bleeding after trauma followed by persistent bleeding.
Patients with platelet disorders 11 usually have a negative family history, more common in women, with the presence of petechiae, purpura, hematuria, mucosal and central nervous system bleeding, and vessel compression is usually effective; bleeding is concomitant with the trauma and it is short-lived.
The objective of the treatment is to correct the deficiency of the activity of the vWF to a level above 50% of normal and the activity of F VIII to levels appropriate for the clinical situation 2. This objective is achieved using desmopressin or by the transfusion of the specific factor 2,3.
Desmopressin (DDAVP) is the drug of choice for patients with types 1 and 2A 1-3,10. It is a synthetic analogue of vasopressin 1,26 and stimulates the release of vWF by endothelial cells 26. It can be administered intravenously at a dose of 0.3 µg.kg-1 in 50 mL of normal saline over 15 to 20 minutes 2,3,26 or 150 µg in each nostril 2. The increase in vWF has a maximal effect in 30 minutes and lasts from 6 to 8 hours 10.
The side effects of DDAVP reported so far include headache 1, rubor 1,27, hypotension 1,27, tachycardia, hyponatremia 1,2,4, and water intoxication 2,4. In order to decrease water intoxication, hyponatremia, and consequent seizures, the administration of water, orally or intravenously, should be restricted for 4 to 6 hours after the use of the drug 2.
Desmopressin also increases the level of F VIII; however, in hemophilia A, this effect is temporary while in vWD this elevation persists for 48 hours 10.
Cryoprecipitate originates from the bag of fresh frozen plasma after slow thawing and centrifugation 26,28. In the common preparation, the cryoprecipitate is not submitted to viral attenuation 26 and, therefore, poses an increased risk of infection 1,2,10,28. It has F VIII:C, vWF, factor XIII and fibrinogen 11. It can be used for the differential diagnosis between p-vW and subtype 2B, since only patients with p-vW show platelet aggregation 25.
Factor VIII concentrate is prepared from the pool of plasma from a large number of donors or through the technology of recombinant DNA 26. It undergoes viral attenuation 26, and contains F VIII:C and vWF 11.
Antifibrinolytic treatment can be used for the prevention and treatment of bleeding during oral surgeries, because it inhibits the fibrinolytic action of the enzymes in the saliva 26. It can also be used as adjuvant to DDAVP 2. It is contra-indicated in cases of hematuria 2,26 an menorrhagia 2. Epsilon-aminocaproic acid may be orally or intravenously administered, at a dose of 200 mg.kg-1 followed by 100 mg.kg-1 every 6 hours (maximum of 5 g/dose), and tranexamic acid can be administered in the oral dose of 25 mg.kg-1 (maximum of 1.5 g) or 10 mg.kg-1 (maximum 1 g) intravenously 26.
Plasma can be used in cases in which the specific concentrate is not available 26. It has all coagulation factors 11.
In the case of unsatisfactory response to DDAVP or resistance to factor transfusion, one can transfuse platelets in an attempt to correct the platelet defect 10. Platelets are the first choice of treatment only in patients with p-vW because cryoprecipitate, factor F VIII concentrate, and DDAVP can cause thrombocytopenia in these patients 25.
Some precautions are recommended in vWD for a safer anesthesia, with reduced incidence of complications. Among them we should mention:
Prior evaluation by a hematologist 14. This helps the prophylactic treatment both in odontological surgeries and major surgeries. When indicated, in types 1 and 2A, DDAVP should be infused 60 minutes before the surgery 29. Since types 1 and 2A represent 95% of all patients 1, this approach is fundamental both for minor and major surgeries. Odontological and minor surgeries can be performed with the administration of DDAVP alone 6,15, although hospitalization of the patient is recommended for postoperative observation 3. Resistant patients, with subtype 2B and type 3, need factor transfusion before any surgery 2;
After using DDAVP, normalization of the bleeding time and improved levels of F VIII should be confirmed before the surgery in patients in whom they were abnormal 29. Up to 10% of type 1-patients are non-responsive 22, while individuals with subtype 2A present a variable response 1;
Give preference to general anesthesia. Patients with coagulopathies undergoing neuroaxis block have an increased risk of developing a hematoma and compression of neurological structures. The diagnosis is confirmed by CT scan or MRI 30. Radiography of the spine are non-diagnostic; therefore, it is extremely difficult to make the diagnosis in small centers, and this delay may affect the resolution of the case, which is treated surgically. Laminectomy should be performed up to eight hours after puncturing the vessels, and approximately 38% of the patients show partial or complete resolution of the symptoms 30. The speed in which compression develops is more important than the compression itself 30;
|4)||Avoid traumas during the anesthesia 31. Arterial puncture for determination of arterial blood gases is not recommended 31. Laryngeal trauma during tracheal intubation may cause hematoma, with the possibility of postoperative obstruction of the airways 31. The intramuscular administration of medications should also be avoided;|
|5)||Avoid drugs that interfere with platelet function. Acetaminophen can be used for analgesia since it has a clinically insignificant influence on platelet function 6. Crystalloid solutions should be used for intraoperative volume replacement 22. Albumin should be used whenever the administration of a colloid is necessary 22;|
|6)||Monitor sodium serum levels after using DDAVP. This drug is a synthetic analogue of the anti-diuretic hormone and increases renal reabsorption of water 1. Hyponatremia can cause seizures 1. Normal saline with glucose should be used instead of 5% glucose in water.|
|7)||Bleeding time and serum levels of F VIII should be checked at least once a day postoperatively 29. It might be necessary to use DDAVP once a day after the surgery until the proper healing of the surgical wound 29. Patients with types 2B and 3 should be transfused every 12 hours until complete cicatrisation 29.|
VON WILLEBRAND'S DISEASE AND PREGNANCY
von Willebrand's disease is the most frequent hereditary hemorrhagic coagulopathy in women in childbearing age 15. During pregnancy, the levels of vWF and F VIII are increased 375% and 200%, respectively 7,32, associated with decreased fibrinolysis 32. Hemorrhagic complications during pregnancy are rare 14. After uterine emptying, the levels of F VIII and vWF decrease rapidly 7,15 and the incidence of post-partum hemorrhage in type 1 reaches 18.5% and in type 2, 20% 15.
Some authors have reported successful neuroaxis anesthesia 7,15 and others consider this procedure a viable alternative to general anesthesia in parturients 9,32. These authors recommend a few precautions before performing the block, such as: 1) One should know the natural history of the disease, its treatment, and request the evaluation by a hematologist 32; 2) Prior administration of DDAVP or factor transfusion 9; 3) The puncture should be performed in the midline by an experienced anesthesiologist 15; 4) If a catheter is used for administration of the anesthetic drug, the space should be dilated before it is introducted 15; 5) Use a round tip catheter 15; and 6) Use DDAVP for 7 to 10 days after delivery 9.
Even with these recommendations, there is a risk of a hematoma of the neuroaxis, and it should be considered before any puncture. General anesthesia should be used if tracheal intubation is not difficult to perform 33. The patient should be aware of the risks and benefits of any technique that might be chosen.
von Willebrand's disease is the most common hereditary hemorrhagic disorder, but it is underdiagnosed due to its complexity. The proper classification of the patient, adequate use of desmopressin, and transfusion of von Willebrand's factor are fundamental for a successful anesthetic procedure.
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Fabiano Timbó Barbosa
Rua Comendador Palmeira, 113/202. Ed. Erich Fromm Farol
57051-150 Maceió, AL
em 26 de abril de 2006
Accepted para publicação em 21 de janeiro de 2007
* Received from Unidade de Emergência Doutor Armando Lages