Cryoprecipitate: Uses and Alternatives

Cryoprecipitate: Uses and Alternatives Man-Chiu Poon

C

RYOPRECIPITATE is the insoluble material fonned when fresh frozen plasma is thawed at 4°C. 1 The precipitate, rich in factor VIII, von Willebrand factor, and fibrinogen, can be separated by centrifugation and resuspended in a smalI amount of plasma, frozen, and stored at - 20°C for up to a year. Cryoprecipitate prepared from each single-donor unit of plasma contains about 80 to 100 U factor VIIIlvon Willebrand factor, representing 40% to 70% of the original amount in the plasma, and 100 to 250 mg fibrinogen in a volume of 10 to 20 mL. Factor VIII and von Willebrand factor represent about 5% of the total protein. 2 Other proteins in the concentrate include fibronectin (20% to 25% total protein), immunoglobulin G (lgG) (5% to 8%), IgM (1% to 2%), and albumin (5% to 8%).2 In this review, the common use of cryoprecipitate and the availability of alternative agents, with emphasis for patients with hemophilia and von Willebrand disease, will be discussed. THERAPEUTIC USE OF CRYOPRECIPITATE

Hemophilia A and von Willebrand disease. Cryoprecipitate represents one of the earlier breakthroughs in the management of patients with hemophilia A and von Willebrand disease. It corrects the factor VIII levels in hemophilia A, factor VIIII von Willebrand factor levels in patients with von Willebrand disease, and corrects the bleeding time defects in most patients with von Willebrand disease. Cryoprecipitate has been shown to contain von Willebrand factor that retains the whole spectrum of von Willebrand factor multimer sizes and structure, 3 with the ratio of von Willebrand factor ristocetin cofactor (RiCof) activity to von Willebrand factor antigen (vWF:Ag) approaching unity.4 The intact von Willebrand factor structure

From the Departments oj Medicine, Pediatrics and Laboratory Medicine, University oj Calgary and Foothills Hospital, Southern Alberta Hemophilia Clinic, Alberta Children's Hospital, and the Canadian Red Cross Centre, Calgary, Alberta, Canada. Address reprint requests to Man-Chiu Poon, MD, University oj Calgary, Foothills Hospital, 1403-29th St NW, Calgary, Alberta, Canada T2N 2T9. Copyright © 1993 by W.B. Saunders Company 0887-796319310703-0004$3.0010

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and the higher molecular weight von Willebrand factor multimers are thought to be important, although not the only detenninant, for the correction of bleeding time in patients with severe von Willebrand disease. 5 The bleeding time in a proportion of severe type III von Willebrand disease may not be corrected by cryoprecipitate,3,6,7 but may be corrected when combined with platelets 6 or 1-deamino-8-arginine vasopressin (desmopressin acetate (DDAVP]).7 Clinical experience suggested that in von Willebrand disease, whereas bleeding time nonnalization is important for stopping mucosal bleeds (eg, gastrointestinal and uterine),8,9 correction of factor VIII seems adequate for soft tissue and surgical hemostasis.IO,11 Before the era of blood product sterilization, cryoprecipitate was the favored agent for the treatment of patients with hemophilia A and von Willebrand disease, because it is the product of a single donation and therefore carried a lower risk for viral disease transmission than the other available agents. A potential for transmission of viral infection remains 12 when homologous cryoprecipitate is used, because there is no licenced viral attenuation procedure yet available for cryoprecipitate use. This risk is lower when cryoprecipitate from a single, welI-screened, and repeatedly tested donor is used for a particular patient. l3 Afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia. Cryoprecipitate is useful for the management of bleeding in patients with congenital ar acquired afibrinogenemia or hypofibrinogenemia, who have fibrinogen levels less than 0.5 to 1.0 giL, or dysfibrinogenemia. Clinical conditions resulting in acquired hypofibrinogenemia in which fibrinogen replacement is useful include disseminated intravascular coagulation and obstetrical complications such as intrauterine fetal death with prolonged retention of dead fetus, amniotic fluid embolism, and abruptio placenta. 14 Fibrin glue. Cryoprecipitate has been used for the production of fibrin glue as abiological adhesive (sealant).15-17 The effectiveness of fibin glue, fonned by the coagulation of cryoprecipitates with topical bovine thrombin, for the enhancement of local surgical hemostasis and wound healing has been reported following a variety of surgical procedures, particularly in cardiovascular and ear, Transfusion Medicine Reviews, Vol VII, No 3 (July), 1993: pp 180-192

CRYOPRECIPITATE: USES AND ALTERNATIVES

nose, and throat surgeries and neurosurgery. Although the fibrin glue is generally well tolerated, the use of topical bovine thrombin has resuIted in the development of antibodies against bovine thrombin l8-20 and contaminating bovine factor V19 in some of these patients. The bovine thrombin antibodies can cause a prolonged thrombin time, but apparently do not cause signifieant bleeding,18,20 because the antibodies often do not inactivate human thrombin. 19 ,20 Bovine factor V antibodies, on the other hand, may cross-react with human factor V, resulting in a prolongation of the prothrombin time (PT) and the partial thromboplastin time (PTT) as well as a bleeding diathesis. 19 The prolongation of the PT makes the monitoring of some of these patients who require long-terrn postoperative oral anticoagulant therapy difficult. The use of fibrin glue prepared from homologous cryoprecipitate should be discouraged because of the risk of viral infection. Fibrin glue can be prepared from a small volume of autologous plasma. 16 Moreover, commercial fibrin glue preparations that have undergone treatments for viral attenuation are available. CONTROVERSIAL USE OF CRYOPRECIPITATE

Uremie bLeeding. Cryoprecipitate has been used for uremie bleeding, This use was popularized in 1980 by lanson et al,21 who reported the shortening of the bleeding time defect in six uremic patients (norrnalized in five) following the infusion of cryoprecipitate, This agent controlled bleeding in four patients and prevented excessive bleeding in five who underwent invasive procedures, Other investigators have reported variability in both effectiveness22 and ineffectiveness23 of cryoprecipitate in uremie patients. SurgieaL and massive bLeeding. Although often used to correct surgieal bleeding, the value of cryoprecipitate in the absence of specific factor VlIIlvon Willebrand factor or fibrinogen deficiency has not been shown. There is little dispute that patients with excessive bleeding, defined as a loss of 50% or more of circulating blood volume, is associated with a high incidence of a coagulopathY .24 CrystaIloid remains the replacement fluid of initial choice. Bleeding surgical patients who remain hemodynamically unstable despite the transfusion of 3 L or more of crystalloid should be given fresh frozen plasma, in addition to a trans-

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fusion of packed red blood cells. 24 Cryoprecipitate is indicated only when there is documented hypofibrinogenemia. CriticaL care. Cryoprecipitate has also been used as a source of fibronectin for the improvement of reticuloendothelial function to improve the organ function in critically ill patients, including those with sepsis. 2S The overwhelming majority of controlled clinical trials do not show evidence in support of the efficacy of fibronectin in improving organ function or survival of these patients. 26 The continued use of cryoprecipitate for these purposes in the critical care setting is therefore not warranted. RECENT DEVELOPMENT OF SAFER THERAPEUTIC MATERIAL

l-Deamino-8-D-Arginine Vasopressin, Desmopressin Acetate

DDAVP, which is capable of releasing factor VIII and von Willebrand factor from the synthetie stores, was first used in the 1970s27 ,28 and is now considered the agent of choice for the management of most bleeding episodes in patients with mild hemophilia A and mild von Willebrand disease. DDAVP is a synthetic analog of natural antidiuretic horrnone (ADH) arginine vasopressin, with a ratio of biologie antidiuretic-to-pressor activities of2,OOO to 3,000:1. 29 Following infusion at a therapeutic dose of 0..3 to 0.4 I-Lglkg body weight, DDAVP causes a twofold to fourfold (or more) increase in plasma levels of plasma factor VIII and von Willebrand factor. The factor VIII and von Willebrand factor response peaks at 30 to 60 minutes. These have half disappearance times similar to those of exogenous products (eg, cryoprecipitate). DDAVP stimulates the release of these plasma factors from the endothelial store directly or indirectly. 29,30 In addition, DDAVP possibly stimulates platelet endothelial interactions30 and has variable hemostatie effect in patients with a variety of functional platelet disorders, including those following acetylsalicylic acid (ASA) use. 31 The presence of an adequate endothelial store seems to be necessary for DDAVP to induce an increase in the plasma factor VIII and von Willebrand factor, because DDAVP usually does not provide a meaningful increase in factor VIII in severe hemophilia A patients or von Willebrand factor in severe von Willebrand disease patients.

182

Furthermore, the response of these factors decreases progressively with repeated closely spaced infusions. 27 ,28 DDAVP also stimulates a fivefold to sevenfold transient increase in plasminogen activator,28 but the use of an antifibrinolytic agent such as e-aminocaproic acid or tranexamic acid following DDAVP infusion is not routinely necessary , except in patients undergoing dental extractions or a tonsillectomy. Hemophilia A. A number of investigations have firmly established the efficacy of DDAVP in mild hemophilia A27,32-34 for both the cessation of bleeding and the prevention of minor surgical bleeding. DDAVP has been shown to be useful in patients with factor VIII level, greater than 0.05 U/mL. In patients with severe-to-moderate disease (factor VIII <0.05 U/mL) the DDAVP-stimulated increase in factor VIII is usually insufficient to produce hemostasis. DDAVP has also been used successfully to obtain hemostasis in some patients with factor VIII inhibitor. 35 ,36 Because the increase in factor VIII following DDAVP infusion may vary among patients, they should be tested for their response to DDAVP before it is used therapeutically. Because of the problem of tachyphylaxis, DDAVP may not be sufficient for patients undergoing more major surgical procedures in which a prolonged and sustained increase in factor VIII level may be required. In this situation, supplementation with blood products is usually required. von Willebrand disease. DDAVP is an effective hemostatic agent for most patients with von Willebrand disease. von Willebrand factor is found in both plasma and platelets, and is composed of a series of multimers varying in molecular weight between 0.5 (dimer) and 20 million daltons. 37 von Willebrand disease is a heterogeneous syndrorne. About 70% to 80% of von Willebrand disease patients have type I defect,38.39 with a decrease of both von Willebrand factor level and all von Willebrand factor multimers. The various type I subtypes based on the relative levels of vWF:Ag and RiCof activity in platelets will be discussed subsequently. Type II von Willebrand disease, resulting from the presence of abnormal von Willebrand factor with the loss of the high molecular weight multimers can be further subdivided into types IIa and Ub. Type Ua disease is characterized by the decrease in high and intermediate molecular weight multimers in both plasma and platelets, possibly related to abnormal cellular von Willebrand factor

MAN-CHIU POON

multimer assembly or the increased susceptibility of von Willebrand factor to proteolysis. 40 In type IIb disease the higher von Willebrand factor multimers are decreased in plasma but preserved in the platelets. 41 It has been shown that in type IIb disease, the higher molecular weight multimers of the abnormal von Willebrand factor have higher affinity to platelet receptors, resulting in the higher tumover of high molecular weight multimers in the plasma. 41 An entity called pseudo-von Willebrand disease (platelet-type von Willebrand disease) has plasma and platelet von Willebrand factor multimer pattems similar to those found in type Ub patients. In these patients the platelet receptors have a higher affinity to von Willebrand factor, resulting in the removal of the higher molecular weight multimers from the plasma. 42 ,43 Both type IIb and platelet-type von Willebrand disease have enhanced platelet aggregation response to low-dose ristocetin (0.5 mg/mL), but platelet-type von Willebrand disease is distinguished by the ability of an exogenous source of von Willebrand factor, such as cryoprecipitate, to induce platelet agglutination in vitro. About l % to 2% of von Willebrand disease patients have type III disease, with markedly reduced levels of von Willebrand factor in both the plasma and the platelets. Additional rarer type I, type II, and other variants can be recognized by the abnormal pattem of the individual multimer units, and a further description of these subtypes is beyond the scope of this review. von Willebrand factor is important for platelet interaction with damaged subendothelium,44 and patients with von Willebrand disease have a prolonged bleeding time in addition to a decrease in the plasma concentrations of factor VIII and von Willebrand factor. In patients with type I von Willebrand disease, the degree to which the bleeding time is prolonged seems to relate to the quantity and quality of von Willebrand factor in the platelets. 45 Thus, type I patients can be classified further according to the characteristics of von Willebrand factor in platelets. The platelet RiCof and vWF:Ag can be normal (platelet normal) ar equally low (platelet low). Finally, the platelet vWF:Ag may be normal with discordant1y low RiCof (platelet discordant).46 The differences between plasma and platelet von Willebrand factor may explain the wide variation from grossly prolonged to normal bleeding times observed in patients with the type I defect. DDAVP is effective in about 80% to 85% of

CRYOPRECIPITATE: USES AND AlTERNATIVES

patients with von Willebrand disease. Infusion of DDAVP results in an increase in both factor VIII and von Willebrand factor levels, with correction of the skin bleeding time and effective hemostasis in most patients with type I disease. Patients who are platelet-Iow or platelet-discordant subtypes represent the small proportion of type I patients who respond poorly to DDAVP. 47 The variation of the hemostatic defect in this group of patients requires that patients be given a DDAVP test dose before it is used for therapy. Infusion of DDAVP into patients with type II disease results in the release of abnormal von Willebrand factor and can be expected to be less effective in correcting the bleeding time and hemostatic defect. Some patients with type IIa disease do respond to DDAVP ,48 and prior testing in this group for evidence of response is therefore important. DDAVP increases the plasma factor VIII and von Willebrand factor in patients with type IIb disease and, in some of these patients, also shortens the bleeding time. 49 However, the abnormally polymerized von Willebrand factor released has been reported to cause platelet agglutination and transient thrombocytopenia. 50 Most experts recommend that DDAVP not be used in this group of patients. This reluctance to use DDAVP in type IIb von Willebrand disease patients may need to be reeonsidered in light of the reeent finding that the thrombocytopenia observed following DDAVP infusion in these patients may be completely or partially spurious, relating to the presenee of a ealcium chelating agent used during blood collection. 49 Platelet agglutination and thrombocytopenia are also observed in patients with the platelettype von Willebrand disease following DDAVP infusion. 51 Low-dose (0.5 mg/ mL) ristocetin-induced platelet aggregation enhancement can be used to identify these two subgroup of patients before DDAVP testing. DDAVP by itself has not been shown to be useful for patients with type III disease, but it has been shown to shorten the bleeding time of type III patients 1 hour following eryoprecipitate administration, which by itself had produeed a poor response. 6 The effectiveness of DDAVP for hemostasis in patients with aequired von Willebrand disease secondary to lymphoproliferative disorders or monoclonal gammopathy has also been reported. 52 ,53 In these patients the half disappearance time for factor VIII, von Willebrand factor, and bleeding time correction seem shorter than expected.

183

Uremie bleeding. DDAVP has aIso been used in patients with uremic bleeding. In a randomized, double-blind, cross-over trial, Mannucei et al. 54 studied 12 uremie patients with prolonged bleeding times. Following DDAVP infusion, eorreetion of bleeding time, lasting for at least 4 hours, was eomplete in six patients and partial in the remaining six. DDAVP was suceessfully used for invasive proeedures in an additional nine patients. As anticipated, infusion of DDAVP inereased the plasma faetor VIII and von Willebrand factor leveIs in uremic patients, with transient increase in the higher molecular weight multimers. As in the case of cryoprecipitate, the effectiveness of DDAVP in uremic patients in correeting the bleeding time has also been disputed. 55 Other modalities that may be useful in long-term eorrection of bleeding time in uremia include the use of estrogen,23 the eorrection of anemia with red blood cell transfusion,56 or the administration of recombinant human erythropoietin,57 Nonintravenous desmopressin acetate administration. The intravenous preparation of DDAVP (4f.Lg/mL) can be used at a similar dosage subcutaneously.58,59 A more concentrated preparation (1.5 mg/mL) suitable for intranasal use at a dosage of 150 to 300 f.Lg, and hence eonvenient for home self-therapy, is under investigation. 58 ,60 Side effects oj desmopressin acetate. Side effects of DDAVP are minor, and consist of facial flushing, headache, nausea, abdominal cramps, vulvar pain, tachycardia, and uncommonly hypertension and hypotension. Rarely, water intoxication with extreme hyponatremia may occur, especially in ehildren following repeated infusions at short intervals.61,63 Monitoring blood pressure, sodium level, and urine output, and avoiding hyponatremic fluids following DDAVP infusion is therefore important, especially for the very young, the elderly, and patients with hypertension. Recently, in elderly patients with arteriosclerosis, episodes of thrombosis, including myocardial infarction, have been reported following DDAVP infusions. Whether the use of an antifibrinolytie agent in combination with DDAVP has anyeontributing role in the development of a thrombotic event is not known. A recent survey suggests that thrombotic complications are rare, with about 10 occurrances per 433,000 treated individuals during 1985 to 1988, the period of the survey. 64 Caution should nonetheless be exereised when treating elderly persons with DDAVP.

MAN-CHIU POON

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Factor VIII Concentrate jor Hemophilia A and the Virallnactivation oj Blood Products Since the early 1970s a number of plasmaderived concentrates rich in factor VIII have been available for the effective treatment of hemophilia A. 65 Successive technological evolution has resulted in the availability of concentrates of increasing purity. Some of the concentrates produced by monoclonal antibody affinity chromatography approach a specific activity of 3,000 Ulmg, and require formulation in albumin for stability. However, the use of the earlier concentrates has been associated with the transmission of hepatitis B, non-A non-B/C hepatitis, and since the late 1970s, human immunodeficiency virus (HIV). In an attempt to inactivate hepatitis viruses, the heat treatment of factor VIII concentrates was attempted. Although present methods are effective, earlier methods are questionable. Since the discovery in the early 1980s that patients with hemophilia may develop the acquired immune deficiency syndrome (AIDS) as a result of replacement therapy, intense research has talcen place to develop methods for screening blood donations and virucidal methods for plasma-derived blood product concentrates. At present in Canada, in addition to blood donor screening and self-deferral programs, aU blood units are screened for the hepatitis B surface antigen, the hepatitis C antibody, and antibodies to

HIV-1 and HIV-2 as well as human T-Iymphotrophic virus-1 (HTLV-1). Antibodies to HTLV-2 and surrogate markers for non-A, non-B hepatitis such as the hepatitis B core antibody (anti-HBc) and serum alanine aminotransferase (ALT) also are performed on donors in the United States and several other countries. Recent estimates suggest that in the Vnited States, the risk of infection per unit of blood product, including cryoprecipitate, is about 1140,000 to 225,000 for HIV, 1150,000 for HTLV-1 and 2, 11200,000 for hepatitis B, and 113,300 for hepatitis C. 12 The precise risk of each nonsterilized blood product will obviously depend as well on the location where the blood donations are obtained. Solvent detergent treatment of plasma for inactivation of viruses has recently been reported,66 and fresh frozen plasma treated in this way is now undergoing clinical trial. 12 Virally attenuated cryoprecipitate is not yet available. Other plasma-derived coagulation factor concentrates available for the management of hemophilia now undergo virucidal treatment, and the effectiveness of the various procedures to inactivate HIV, hepatitis B, and non-A non-B/C hepatitis has been summarized recently by Bloom65 (Table 1). It seems that all the procedures presently in use are effective against HIV. Combined with appropriate donor screening, the enhanced viral inactivation procedures involving vapor treatment, wet

Table 1. Efficacy ot Virallnactivation Procedures for Plasma·Derived Coagulation Factor Concentrates No. 01 Patients Reported (Infected/Studied) Viral Inactivation Procedure Dry heat 60' to 68'C, 24 to 72 hr

NANB

HBV

HIV

2/?

0/24 (other

7/37

0/18

0/27

0/51

4/28 0/14

0/28

0/15 ono

2/55

19/24

reports positive) Heptane suspension 60°C, 20 hr Vapor treated One step (60'C, 10 hr, 1,190 mbar) Two step (60°C, 10 hr, 1,190 mbar + 80°C, 1 hr, 1,375 mbar) Wet pasteurized Solventldetergent Dry heat 80°C, 72 hr Monoelonal Dry heat:f Solventldetergent

0/>32

0/12 ono 0/>53

0/77

0/>16t

On7

1/20

* *

0/17

0/17

NOTE: Data not exhaustive. Viral inaetivation and removal is also dependent on the type of eoncentrate. Abbreviations: NANB, non A, non B hepatitis virus; HBV, hepatitis B virus. * Vaeeinated. t More treated but vaeeinated. :I: More reeent wet pasteurized produet available. Data from referenee no. 65.

0118

185

CRYOPRECIPITATE: USES AND ALTERNATIVES

pasteurization, solvent/detergent treatment, and dry heating at 80°C for 72 hours are effective against the non-A, non-B/C hepatitis virus. Thus, the available plasma-derived blood product concentrates for hemophilia A are effective for increasing factor VIII levels for hemostasis in such patients, and the units treated with enhanced viral inactivation methods relatively safe as far as HIV and non-A, non-B/C hepatitis virus transmission is concerned. However, these methods may not necessarily be totally effective for the hepatitis B virus, and all patients with bleeding disorders should, whenever possible, receive prophylactic hepatitis B vaccination before exposure to blood products. Furthermore, high-purity concentrates treated by heat or solvent!detergent methods seem to continue to transmit parvovirus B19,67 which is pathogenetic to humans, especially the immunocompromised, and has been associated with sporadic cases of erythema infectiosum68 and transient hypoplastic anemia69 in hemophilia patients. Recently, an unusual outbreak of hepatitis A was reported in a group of Italian hemophilia A patients receiving a solvent!detergent treated, high-purity factor VIII concentrate. 70 Thus, viruses of unknown pathogenetic significance resistant to the presently available virucidal and removal methods may still be present in clotting factor concentrates treated as outlined herein. Recently, two recombinant factor VIII concentrates have been developed for clinical trial and are licensed in North America. These recombinant products are expressed in either hamster kidney cells (Kogenate; Cutter, Berkeley, CA)71 or Chinese hamster ovary cells, which coexpress human von Willebrand factor (Recombinate; Baxter, Glendale, CA),72 should be free of transmissible human viruses. Each product is purified using a number of procedures, including affinity chromatography with mouse monoclonal antibodies. The final product is formulated and stabilized in human serum albumin. The structure, in vitro activation kinetics, and in vivo pharmacokinetics of each are similar to those of the plasma-derived factor VIII. 65,71,73 In separate clinical triais , 198 patients had been treated with Kogenate74 and 135 patients with Recombinate. 75 The materials were effective in treating over 7,300 bleeding episodes, for prophylactic treatment, and for the management of at least 84 surgical procedures. Adverse reactions have been uncommon and mild, and none of the clinical participants have developed antibodies to

either hamster proteins or mouse immunoglobulins. One observation that merits further investigation is the seemingly higher incidence of inhibitor development in previously untransfused patients (PUPs) receiving recombinant factor VIII. Antibodies to factor VIII have developed in 16 of 79 (20.3%) PUPs of all disease severity, in 14 of 49 (28.6%) with severe disease within the first year of exposure in the Kogenate trial (74), and in 12 of66 (18.2%) with severe disease in the Recombinate trial. 75 Seventeen of the 28 inhibitors were of low titer so that recombinant factor VIII continued to be therapeutically effective. Seven of these lowtiter inhibitors were transient and disappeared despite continued treatments with recombinant factor VIII. The remaining 11 PUPs had inhibitor titer higher than 10 Bethesda units, with 3 successfully abrogated by continuous high-dose factor VIII immunotolerance therapy. Whether the incidence of inhibitor development caused by recombinant factor VIII therapy is really higher than that caused by intermediate-purity plasma-derived factor VIII is uncertain, because patients receiving recombinant factor VIII were more closely monitored at 3-month intervals. A recently reported prospective study suggests that the prevalence of inhibitor in patients receiving plasma-derived factor VIII may be much higher than the 3.6% to 25% previously suggested by retrospective studies. 76 In this series, inhibitors developed in 15 of 46 (33%) treated moderate and severe hemophilia A patients, in 14 of 27 (52%) treated severe patients, and in 14 of 42 (33%) moderate and severe patients who had received onIy crude and/or intermediate-purity factor VIII concentrates. Further studies will be required to assess the true incidence of inhibitor development. The obvious benefit of the use of recombinant factor VIII is the complete elimination of the possibility of human virus transmission. Blood Products for Patients With von Willebrand Disease

Earlier factor VIII concentrates failed to correct the bleeding time or to effect hemostasis in patients with von Willebrand disease. Although such concentrates provided a source of factor VIII, they were not recommended for the management of von Willebrand disease. 8.9 With the increasing safety of blood product concentrates and the inability to sterilize cryoprecipitate, there have been efforts to obtain concentrates suitable for use in the management of von Willebrand disease patients. Indeed,

186

the efficacy of several concentrates that have undergone viral inactivation has been demonstrated recently. In initial nonrandomized studies, several intermediate- and high-purity factor VIlI concentrates and a very high-purity von Willebrand factor concentrate containing negligible concentration of factor VIII have been shown to be efficacious. Efficacy was reported in patients with soft tissue and mucosal bleeding episodes, and for the surgical hemostasis of 39 von Willebrand disease patients of whom 8 had type m, 16 type II, and 15 type I disease (Table 2).77-87 These investigators also reported the variable shortening of bleeding times in most ofthese patients. The factor VIII concentrate, Hemate P (Beringwerke, Marburg, Germany), was reported to normalize the bleeding time (mostly by the less sensitive Duke method) in all 9 patients with type m von Willebrand disease, 9 type II, 10 type I, and 1 platelet-type diseases. 77 -82 Factor VIII concentrate 8Y (Bio Products Laboratory, EIstree, United Kingdom) was reported to normalize the bleeding time (by the more sensitive Ivy method) in three of four type III and three of four type II patients,83,84 with that of the remaining two partially corrected. The Centre Regional de Transfusion Sanguine (CRTS) high-purity factor VIII concentrate (Biotransfusion, Lille, France) normalized the Duke bleeding time of one patient with type III disease, four type II, and partially corrected that of one type I patient. 85 The CRTS factor VIII concentrate was less effective when the Ivy bleeding time method was used85 (Table 2). Koate-HP (Cutter, Berkley, CA) normalized the bleeding time of two type III patients. 86 The very high-purity von Willebrand factor concentrate normalized both the Ivy and template bleeding times of two type III patients and partially corrected those of two type II patients. 87 Recently, a randomized, cross-over studyon two intermediate-purity (Hemate P, 8Y) and one high-purity (Alpha vm; Profilate HP, Alpha Therapeutics, Los Angeles, CA) factor VIII concentrates and one very high-purity von Willebrand factor concentrate has been reported by Mannucci et al47 (Table 3). Each of the 10 type III patients with bleeding time greater than 30 minutes received each agent (with a wash-out period of ;::: 15 days) at a dose of 60 RiCof U/kg to attain l-hour postinfusion RiCof levels of more than 1 UlmL. As indicated in Table 3, at 1 hour after infusion,

MAN-CHIU POON

normalization of Simplate bleeding time occurred. in only three patients with Hemate P, one with 8Y, none with very high-purity von Willebrand factor concentrate, and one with Alpha VIII. Partial correction of bleeding time (shortening by 30% or more) occurred in five patients with Hemate P, four with 8Y, three with Alpha vm, and two with von Willebrand factor. The finding that factor VIII concentrate did not consistently correct the Simplate bleeding time in type III patients was not surprising, because the correction of bleeding time in these severe patients has not been consistently observed with cryoprecipitate3,6,7 (Table 3). The factors responsible for the correction of bleeding time and hemostatic defect in severe von Willebrand disease patients by these concentrates is not precisely known. The efficacy of Hemate P could be attributed to the presence of relatively normal von Willebrand factor multimer pattem in the concentrates and in the plasma of patients immediately following the infusion of these concentrates;79,81,82,88 the ratio of RiCof to vWF:Ag in Hemate P was hight at >0.9. 79 ,88 On the other hand, 8Y and Alpha vm, lacking the high molecular weight multimers, also corrected the bleeding time of some severe patients,47,83,84 with 8Y clinically efficacious in nonrandomized studies. 83 ,84 Interestingly, the very high-purity von Willebrand factor concentrate, with its more intact von Willebrand factor structure87 ,89 and high RiCof to von Willebrand factor antigen ratio (average 0.79),89 was no more effective than 8Y and Alpha vm in the correction of bleeding time in the randomized, cross-over study of Mannucci et al47 (Table 2). These observations together with the failure of cryoprecipitate with normal multimer sizes and structure to correct the bleeding time defect in all severe type III von Willebrand disease patients3,6,7 (Table 3) suggests that, whereas normal von Willebrand factor multimers of appropriate size and structure are important determinants, it is not the only factor affecting the bleeding time or involved in the hemostatic correction of von Willebrand disease patients. von Willebrand factor is normally present in both plasma and platelets, and is markedIy decreased or absent in severe type III von Willebrand disease. Infused von Willebrand factor corrects the plasma von Willebrand factor but not necessarily that of the platelets. 90 Thus, complete correction of bleeding time in all patients with severe von Willebrand disease may not be achievable if platelet von

CRYOPRECIPITATE: USES AND ALTERNATIVES

187

Table 2. Hemostatic Efficacy ot Various Clotting Faetor Concentrates in Patients With Different Types Disease: Non-Randomized Studies Clinical Hemostalic Effects Effective/No. (Types Reference No.

Bleeding Ttme Normafization

ot Palients

Effective/No. of Patients

ot Bleeding/Surgery) Type II

Type I

ot von Willebrand

Type III

Oosage

Type I Type II

Type III

PlaleletType

BT Method

Oosage

Hemate (wet pasteurizedl

77

1/1 (Cardiac surgery)

212 (Gaslrointestinal

20-30 FVill U/kg

111

20-80

414

111

Mielke

33-40 FVIII Ulkg

surgery; traumatic bleed) 78

4/4

nol slated

FVIII U/kg

(Denlal e>
20-80 FVIII Ulkg

soft tissue bleed) 79

1/1

Ouke

14.4

nol stated

4,000 FVIII Uldose

Ouke

14-28

vWF:Ag Ulkg 80

111 (Denlal e>
81

212 (Epistaxis)

111 (Gl bleed)

1,200 FVIII Uldose

111

111

313 (Epislaxts; genital bleed;

14-28 FVIII Ulkg

313

414

2/2

FVIII Ulkg

(42-76 RiCof

hemorrhoid

(42-76 RiCof Ulkg)

Ulkg)

bleedl 82

8Y {dry heated 80°C x 72 hrl 111 83 (Elbaw bleed and surgeryl

84

2/2 (Hemia surgery; denlal)

313 (Epistaxis; dental e>
111 (Laparotomy)

not stated

212 (Epislaxis;

Oosage lo

knee surgery) 313 Elbow bleed and surgery;

gaslrointestinal

epistaxis,

bleed)

excision;

111

313

m

Ouke

30-70 FVIII Ulkg

1/1

raisa plasma FVIII by 0.5-1.0 U/mL 18-55 FVIII Ulkg

111

Ivy

Oosage to raise plasma FVIII by 0.5-1.0 U/mL

213-

213-

Ivy

18-55 FVIII U/kg

bunion

ankle bleed CRTS Faclor VIII Concentrate (soventldetergent-treated) 85

3/3 (Dental; salpingectomy; cardiac surgery)

20-64

4/4 (Currettage;

FVIJI Ulkg

0/1-

4/4 2/41

1/1

Ouke Ivy

21-43

0/1*

212

not stated

40 FVIII U/kg

2/2

Ivy/

not given

genitourinary bleed; hystereetomy;

FVIII U/kg (37 -76 RiCof Ulkg)

epistaxis Koate-HP (solventldetergent-treated) 1/1 (hematochezia)

86

40 FVIII U/kg

Very high-purity vWF concentrate (solventldetergent-treated) 87

1/1 (peridurai anesthesia)

1/1 (Abdominal surgery)

not given

0/2*

Template

NOTE: Patients with a normai bleeding lime before concentrate infusions are excluded from analysis of bleeding time normafization. - Remaining patients had their bleeding time partially corrected. l One patient had their bleeding time partially corrected, and 1 not corrected. Bleeding time not corrected.

*

188

MAN-CHIU POON

labie 3. Bleeding lima Correction Following Cryoprecipitate or Clotting Factor Concentrates in Severe von Willebrand Disease No. of Patients With Bleeding Times Blood Products and Time After Infusion (hr) Cryoprecipitate (wet)* 1 6

24 Hemate Pt 1 6

24 8 Yt 1 6

24 Very high-purity vWF concentratet 1 6

24 Alpha Vlllt 1 6

24

Normalized

Partially Corrected

2

1

1

O O

O

Not Corrected

2 4 5

3 O

5

2

2

.0

O

8 10

1

4

O O

1

O

5 9 10

O O O

6

4

2 O

8 10

2

3 2 O

5 7 10

1

O

NOlE: Partial bleeding time correction means shortening by ;;;'30% (ie, from ;;;.30 min to "'21 min;;;. normai range). * From data of Mannucci et al. 3 Five patients each were given wet cryoprecipitate, Iyophilized cryoprecipitate, and fraction I-O at random order with wash-out period of ;;;.15 days, at dosage sufficient to raise plasma RiCof to ;;;'0.5 U/mL for 3 hr after infusion. Only data on wet cryoprecipitate is tabulated. t From data of Mannucciet al. 47 Ten patients (5 had participated previously in the cryoprecipitate study) were each given these four concentrates in a cross-over, randomized study with wash-out period of ;;;.15 days, at dosage of 60 RiCof U/kg (to raise plasma RiCof to 1.0 U/mi 1 hr after infusionl.

Willebrand factor is required for plateletsubendothelial interaction44 and securing anormai bleeding time. 45 ,46 It has been suggested that in von Willebrand disease, whatever the bleeding time, correction of factor VIII is sufficient for hemostasis in soft tissue bleeds and postoperative bleeds,1O,1l,47 whereas correction of bleeding time is required for hemostasis in mucosal bleeding involving the gastrointestinal tract and from uterine sources. 8,9,47 This assertion implies that each of the intermediatepurity factor VIII concentrates will be useful for soft tissue bleeding and surgical hemostasis, because the factor VIII level following infusion of

the concentrate increases to an expected level and persists for more than 24 hours. 47 ,79-86 Paradoxically, von Willebrand factor concentrate may not be practical for this purpose, because the factor VIII increase tends to be delayed for as long as 6 to 8 hours. 47 ,87 If this concentrate is used, extra infusions several hours before an operation may be required to obtain adequate surgical hemostasis. 47 The same assertion also implies that neither the concentrates nor, for that matter, cryoprecipitate will always be useful in patients with severe and prolonged mucosal bleeds or for surgical procedures involving mucosal surfaces, because none consistant1y correct the bleeding time of these patients. In severe patients in whom cryoprecipitate failed to correct the bleeding time, follow-up infusion l hour later with DDAVP 6 or platelets 7 has been shown to be efficacious, possibly through improved platelet-subendothelial interaction. An additional infusion of platelets containing normal von Willebrand factor can be expected to correct the bleeding time in patients in whom factor VIII or von Willebrand factor concentrates alone is ineffective. Whether DDAVP can be used in place of platelets in these patients for the correction of the bleeding time defect not achieved with factor VIII ar von Willebrand factor concentrate infusion is unknown, because data is lacking. A combination af DDAVP and a sterilized concentrate may be a safer combination than the use of unsterilized blood products such as cryoprecipitate and/or platelet concentrates. Fibrin Glues

Commercial preparations of fibrin glues are now readily available. The preparation most familiar to clinicians in North America is Tisseel (IMMUNO, Vienna, Austria). This is a two-component fibrin sealant. The first component consists of fibrinogen, factor XIII, and a fibrinolytic inhibitor bovine aprotinin, which are applied topically as a solution to the wound site. The second component consists af bovine thrombin and calcium chloride solution in the presence of a fibrinolytic inhibitor bovine aprotinin, which is applied subsequent to the first component. The human plasma-derived components have been vapor heat treated at 60°C for 10 hours at a pressure of 1,190 mbar. The spectrum of surgery and trauma with which this preparation has been used for wound healing and local hemostasis seem to be similar to that for cryoprecipitates. 91 ,92

CRYOPRECIPITATE: USES AND ALTERNATIVES

The safety of this virally attenuated product for the transmission of HIV and hepatitis viruses has been documented. 91 ,93 Another similar preparation, Beripiast P (Behringwerke AG, Marburg, Germany), with the human proteins wet pasteurized at 60°C for 10 hours, has been marketed in Europe. Blood Products Jor the Management oj Patients With Fibrinogen Disorders

At least two virally attenuated fibrinogen concentrates are being investigated in Europe for the management of congenital and acquired fibrinogen disorders. One concentrate, Haemocomplettan P (Behringwerke AG, Marburg, Germany), is wet pasteurized (60°C for 20 hours), and the other Fibrinogen IMMUNO (IMMUNO AG, Vienna, Austria), is virally attenuated by a two-step steam treatment (60°C for 10 hours, and 80°C for 3 hours). The length of heating for these fibrinogen preparations seems to be longer than that for other c10tting factors. Clinical data concerning their use is at present limited, although the products have been shown to be efficacious and safe in patients with congenital fibrinogen disorders. 94 ,95 There are no published data addressing their c1inical efficacy and safety in patients with acquired fibrinogen disorders. Unlike patients with congenital coagulation problems, patients with acquired coagulation disorders are seldom immunized against hepatitis B. Fibrinogen concentrates must have demonstrated safety for this hardy virus before instead of cryoprecipitate is recommended for use in such patients. CONCLUSIONS

Cryoprecipitate has been proven to be an efficacious blood product, especially for the management of hemophilia A, von Willebrand disease, fibrinogen disorders, and as a source of fibrinogen and factor XIII for the- preparation of fibrin glue. With the introduction of effective donor screening procedures and tests for various transmissible viruses, cryoprecipitate is nowamuch safer product than it was in the past. However, a smalI but definite risk of viral transmission remains, especially for non-A/non-B/C hepatitis. Alternate pharmacological agents or blood products treated by enhanced virucidal methods should be used where possible. In addition, all patients with congenital bleeding disorders should be protected against hepatitis B through vaccination.

189

The pharmacological agent DDAVP should be the frrst-line treatment for patients with mild hemophilia (factor VIII level >0.05 U/mL) and in 80% to 90% of the von Willebrand disease patients with type I but also with other variants that respond to this agent. DDAVP is especially useful in situations in which a single dose is all that is required. In hemophilia A patients in whom DDAVP is not effective, a number of factor VIII concentrates treated with enhanced viral inactivation methods should be used. Recombinant factor VIII concentrates are now available, and their use should eliminate the transmission of human viruses. In DDAVP-nonresponsive von Willebrand disease patients, or when the use of DDAVP is insufficient to controI bleeding or contraindicated, virally attenuated factor VIII concentrates containing von Willebrand factor with documented efficacy should be the blood product of choice. Several factor VIII concentrates have been shown to be c1inically efficacious in nonrandomized trials (Table 2), with the reported experience more extensive with Hemate P and 8Y. Hemate P is becoming the product against which the efficacy of other products is being compared, because it contains most of the higher molecular weight von Willebrand factor multimers, and has been shown to correct the bleeding times of type III von Willebrand disease patients at a frequency similar to that obtained with cryoprecipitate47 (Table 3). In the absence of randomized c1inical trial data, concentrates that more consistent1y correct the bleeding time defect should be preferred for bleeding episodes (especially of mucosal nature) that are not responsive to DDAVP. It is possible that most factor VIII concentrates available are effective for soft tissue and nonmucosal surgical hemostasis. With recent interest in the identification of virally attenuated blood products for von Willebrand disease, it is anticipated that additional effective products will be identified by careful dinical trials. At thistime, very high-purity factor VIII concentrates that lack von Willebrand factor are not recommendated for von Willebrand disease, especially for patients with mucosal bleeding. Fibrin glue is becoming increasingly popular as a local hemostatic agent for surgical procedures. Homologous cryoprecipitate should not be used for this purpose because commercial preparations that have been treated with enhanced virucidal procedures are available. Fibrin glue prepared

MAN-CHIU POON

190

from autologous plasma is another altemative, although not aH hospitals will find this approach practical. Fibrinogen concentrates treated with enhanced virucidal procedures should soon be available for the treatment of congenital hypofibrinogenemia,

afibrinogenemia, and dysfibrinogenemia. Until then, cryoprecipitate should continue to be used for congenital and acquired hypofibrinogenemia, particularly until the clinical efficacy and hepatitis B safety of fibrinogen concentrates have been cleady demonstrated in these patients.

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CRYOPRECIPITATE: USES AND ALTERNATIVES

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191

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192

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MAN-CHIU POON

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