Current concepts of hemostasis: implications for therapy

The revised model of coagulation has implications for therapy of both hemorrhagic and thrombotic disorders. Of particular interest to anesthesiologists is the management of clotting abnormalities before, during, and after surgery. Most hereditary and acquired coagulation factor deficiencies can be managed by specific replacement therapy using clotting factor concentrates. Specific guidelines have also been developed for perioperative management of patients using anticoagulant agents that inhibit platelet or coagulation factor functions. Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy.     

Intracranial hemorrhage in patients with hemophilia

Intracranial hemorrhage (ICH) is a life-threatening complication of hemophilia. Seven of the 288 hemophiliacs living in Israel suffered eight episodes of ICH during the years 1972 to 1982. All episodes occurred in hemophilia A patients, with a higher incidence among patients with factor VIII inhibitor. Diagnosis was confirmed by computed tomographic scan in seven of the eight episodes. Four of the 7 patients died despite adequate factor replacement and supportive therapy, probably due to a conservative and hesitant neurosurgical approach. The correction of factor VIII to hemostatic level alone is inadequate in the majority of cases, and there is sudden deterioration in the patient's condition and death. Operation is strongly recommended when no improvement is noted within a few hours.     

Severe postoperative hemorrhage caused by antibody-mediated coagulation factor deficiencies: report of two cases

Antibody-mediated coagulation factor deficiencies constitute a rare disorder that may develop in elderly patients without any history of a bleeding diathesis. Patients may present with severe and sometimes catastrophic bleeding. We report two cases of postoperative hemorrhage caused by a coagulation factor deficiency. In Case 1, massive intraabdominal bleeding occurred on day 3 after pancreaticoduodenectomy for bile duct cancer, and was caused by an acquired inhibitor of coagulation factor VIII. Hemostasis was achieved and the factor VIII inhibitor titer decreased to zero with activated prothrombin complex concentrates, prednisolone, and cyclophosphamide. In Case 2, intraabdominal bleeding occurred on day 7 after hepatectomy for hepatocellular carcinoma, and was caused by an acquired inhibitor against factors II (prothrombin) and V. This patient was treated with hemostatic agents containing bovine thrombin during surgery and also with prednisolone. We report these cases to highlight that antibody-mediated coagulation factor deficiencies should be considered when an elderly patient suffers sudden postoperative hemorrhage and to stress the importance of prompt diagnosis because of the risk of potentially life-threatening hemorrhage.     

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普通外科病人凝血功能障碍主要有高凝状态、血栓栓塞和低凝状态、止血障碍。可通过常规实验室检查对其进行检测,包括活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)、凝血酶时间(TT)、纤维蛋白原(FIG)以及血小板(PLT)。血栓弹力图可以连续全程监测止血功能。中、重度危险的病人推荐采取药物或器械性措施,预防静脉血栓栓塞。对于出血病人,应根据床边、即时、快速试验结果和合理指征计算输入量,有针对性地输注浓缩凝血因子和新鲜冷冻血浆等血液制品。     

The treatment of the disseminated intravascular coagulation syndrome in urosepsis patients

The hemostasis system has been assessed in 42 patients in the age range of 18 to 60 years with secondary urosepsis. All patients had been operated for upper urinary tract obstruction or suppurative destructive renal and retroperitoneal lesions. Hemostasis was examined before and after the operation using coagulation screen. Middle-molecular peptides were assayed in the patients before and after plasmapheresis. Revealed hemostatic disorders were treated with heparin, antibacterial agents and infusion of fresh frozen plasma. Plasmapheresis is indicated in patients who are unresponsive to antibacterial therapy and surgical drainage of suppurative lesions. Postoperative hemostatic disorders presented as both hypo- and hypercoagulation, with thrombinemia in most cases. The patients with urosepsis showed latent hypercoagulation phase of DIC. By removing acute phase proteins, plasmapheresis prevented fibrinolytic failure. Exfusion of small volumes of plasma did not affect antithrombin III levels and produced a coagulation-anticoagulation balance. Declining levels of middle-molecular peptides after plasmapheresis were indicative of detoxication, presenting as better clinical status and improvement of laboratory findings.     

The hemostatic mechanism after open-heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation.

Blood coagulation screening profiles were performed in 512 patients who underwent open-heart surgery with extracorporeal circulation. Severe coagulation disorders were found in 29 (5.6 per cent) patients. The most common abnormalities were low one-stage prothrombin time (PT) activities and impaired whole blood clot retractions. In the majority of patients the discrepancy between low PT's and normal or only slightly depressed factor II, V, VII, and X activities was explained by the presence of an inhibitor of the extrinsic system. Eight patients demonstrated the heparin rebound phenomenon but only 1 bled excessively. The pattern of severe hepatic dysfunction was found in 4 and severe depression of vitamin K-dependent factors due to oral anticoagulants in 2. Two had disseminated intravascular coagulation. Seventeen patients with normal coagulation screening profiles bled excessively postoperatively. Of these, 2 had moderate thrombocytopenia associated with a marked platelet functional abnormality. Revision of the wound in 13 revealed a surgical hemostatic defect and in 2 the cause of bleeding could not be determined.     

The effect of tranexamic acid in traumatic brain injury: A randomized controlled trial

Purpose: Traumatic brain injury (TBI) is a leading cause of death and disability. Intracranial hemorrhage (ICH) secondary to TBI is associated with a high risk of coagulopathy which leads to increasing risk of hemorrhage growth and higher mortality rate. Therefore, antifibrinolytic agents such as tranexamic acid (TA) might reduce traumatic ICH. The aim of the present study was to investigate the extent of ICH growth after TA administration in TBI patients. Methods: This single-blind randomized controlled trial was conducted on patients with traumatic ICH (with less than 30 ml) referring to the emergency department of Vali-Asr Hospital, Arak, Iran in 2014. Patients, based on the inclusion and exclusion criteria, were divided into intervention and control groups (40 patients each). All patients received a conservative treatment for ICH, as well as either intravenous TA or placebo. The extent of ICH growth as the primary outcome was measured by brain CT scan after 48 h. Results: Although brain CT scan showed a significant increase in hemorrhage volume in both groups after 48 h, it was significantly less in the TA group than in the control group (p ¼ 0.04). The mean total hemorrhage expansion was (1.7 ± 9.7) ml and (4.3 ± 12.9) ml in TA and placebo groups, respectively (p < 0.001). Conclusion: It has been established that TA, as an effective hospital-based treatment for acute TBI, could reduce ICH growth. Larger studies are needed to compare the effectiveness of different doses.     

Preoperative hemostatic assessment of the adenotonsillectomy patient

Intraoperative or postoperative hemorrhage in the patient who has undergone an adenotonsillectomy because of an unrecognized hemostatic defect may increase morbidity and can be potentially life-threatening to the patient in what should be a "routine" procedure. Preoperative identification of occult hemostatic abnormalities, coupled with perioperative management directed at correcting the effects of the defects, should serve to reduce the incidence of this distressful complication. Routine use of preoperative laboratory screening tests for this purpose has been discouraged recently as a result of concerns over cost-effectiveness and the low predictiveness of the tests for bleeding. Our experience with the routine use of a comprehensive hemostatic laboratory screening panel--which includes a bleeding time test--in the adenotonsillectomy patient population demonstrated that 11.5% of our patients had abnormal initial screening laboratory tests; these results were ultimately attributable to occult hemostatic defects. Clinical history, the universally recommended method of preoperative hemostatic assessment, failed to detect any previously unrecognized coagulation disorder. Laboratory screening improved preoperative detection of occult hemostatic defects and allowed for appropriate alterations in perioperative care. Our results with this approach are presented, along with illustrative case histories and a discussion of the current recommendations for preoperative laboratory screening of the hemostatic system, as found in a review of the literature.     

泌尿系结核合并严重出血11例分析

目的提高泌尿系结核合并严重出血的诊治水平。方法回顾性分析11例泌尿系结核合并严重出血病例的临床资料。结果本组11例,其中8例经补液、止血、输血、导尿等处理1周内出血停止。2例行膀胱镜下清除血块及膀胱造瘘,1例予膀胱切开探查并造瘘,术后7—10天出血停止。结论非典型临床表现的泌尿系结核需结合病史、尿检、影像学检查以及病原学检查等多种方法以明确诊断。以严重出血为主要症状的泌尿系结核予保守治疗多能止血,可避免手术探查。     

From normal to pathological hemostasis

Purpose

To review the evolution of knowledge on physiological hemostasis and the main abnormalities that may interfere with hemostasis in the perioperative period.

Methods

Narrative review of the literature, including relevant papers published in English. Principal findings: Physiological hemostasis controls blood fluidity and rapidly induces hemostatic plug formation in order to stop or limit bleeding. The three distinct phases of the hemostatic process, primary hemostasis, coagulation and fibrinolysis are closely linked to each other and precisely regulated in order to efficiently close vessel wounds, promote vascular healing and maintain vessel patency. Primary hemostasis is the result of complex interactions between the vascular wall, platelets and adhesive proteins. Initiation of the coagulation pathway in vivo is secondary to the exposure of tissue factor (TF) and the formation of TF/VIIa complex which can activate both FIX and FX. This initiation phase is followed by a propagation phase with amplification of thrombin generation. Several control mechanisms exist for localizing fibrin formation to the site of injury including tissue factor pathway inhibitor, protein C system, antithrombin, and glycosaminoglycans on the vessel wall. Fibrinolysis is also a highly regulated system that controls fibrin dissolution. Both constitutive and acquired hemostasic defects exist. The consequences of these abnormalities are highly variable according to the type of defect, and to the genetic and environmental background.

Conclusion

Hemostasis is one of the most complex physiological self-defence systems, not only involved in control of blood fluidity but also interfering in major physiopathological processes. The evolution of our knowledge of the physiology of hemostasis has numerous implications for therapy.

     

Intracerebral hemorrhage in patients with chronic liver disease

The characteristics of intracerebral hemorrhage (ICH) accompanying chronic liver disease (CLD) were investigated in ICH patients hospitalized between 1998 and 2008 divided into the CLD group (55 ICHs in 49 patients) and the idiopathic group without CLD (668 ICHs in 648 patients). The CLD group included a subgroup with liver cirrhosis (LC). Age, sex, history of hypertension, Glasgow Coma Scale (GCS) score on admission, and hematoma locations were reviewed. Outcomes on discharge and causes of in-hospital death were also studied. Factors associated with life prognosis in CLD patients were investigated using uni- and multivariate analyses. History of hypertension and deep cerebral hemorrhage were less frequent in the LC subgroup compared to the idiopathic group. Distributions of GCS scores on admission were not significantly different, but incidence of in-hospital death was significantly higher in the CLD group than in the idiopathic group. LC was an independent prognostic factor for CLD patients, but hematoma enlargement was not. Death primarily due to ICH was less frequent in the CLD group than in the idiopathic group. In conclusion, hemostatic disorders seemed to be related to site of hemorrhage, but not to life prognosis in the CLD group. Prognosis was mainly worsened by non-neurological complications.     

Hepatic artery pseudoaneurysm,bronchobiliary fistula in a patient with liver trauma

Background

A wide variety of hemostats are available as adjunctive measures to improve hemostasis during surgical procedures if residual bleeding persists despite correct application of conventional methods for hemorrhage control. Some are considered active agents, since they contain fibrinogen and thrombin and actively participate at the end of the coagulation cascade to form a fibrin clot, whereas others to be effective require an intact coagulation system. The aim of this study is to provide an evidence-based approach to correctly select the available agents to help physicians to use the most appropriate hemostat according to the clinical setting, surgical problem and patient’s coagulation status.

Methods

The literature from 2000 to 2016 was systematically screened according to PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses] protocol. Sixty-six articles were reviewed by a panel of experts to assign grade of recommendation (GoR) and level of evidence (LoE) using the GRADE [Grading of Recommendations Assessment, Development and Evaluation] system, and a national meeting was held.

Results

Fibrin adhesives, in liquid form (fibrin glues) or with stiff collagen fleece (fibrin patch) are effective in the presence of spontaneous or drug-induced coagulation disorders. Mechanical hemostats should be preferred in patients who have an intact coagulation system. Sealants are effective, irrespective of patient’s coagulation status, to improve control of residual oozing. Hemostatic dressings represent a valuable option in case of external hemorrhage at junctional sites or when tourniquets are impractical or ineffective.

Conclusions

Local hemostatic agents are dissimilar products with different indications. A knowledge of the properties of each single agent should be in the armamentarium of acute care surgeons in order to select the appropriate product in different clinical conditions.

     

A mathematical model for fresh frozen plasma transfusion strategies during major trauma resuscitation with ongoing hemorrhage.

BACKGROUND: Randomized controlled trials of how best to administer fresh frozen plasma (FFP) in the presence of ongoing severe traumatic hemorrhage are difficult to execute and have not been published. Meanwhile, coagulopathy remains a common occurrence during major trauma resuscitation and hemorrhage remains a major cause of traumatic deaths, suggesting that current coagulation factor replacement practices may be inadequate. METHODS: We used a pharmacokinetic model to simulate the dilutional component of coagulopathy during hemorrhage and compared different FFP transfusion strategies for the prevention or correction, or both, of dilutional coagulopathy. Assuming the rates of volume replacement and loss are roughly equal, we derived the hematocrit and plasma coagulation factor concentration over time based on the rate of blood loss and replacement, the hematocrit and coagulation factor concentration of the transfusate, and the hematocrit and plasma factor concentration at the time when FFP transfusion begins. RESULTS: Once excessive deficiency of factors has developed and bleeding is unabated, 1-1.5 units of FFP must be given for every unit of packed red blood cells (PRBC) transfused. If FFP transfusion should start before plasma factor concentration drops below 50% of normal, an FFP:PRBC transfusion ratio of 1:1 would prevent further dilution. CONCLUSION: During resuscitation of a patient who has undergone major trauma, the equivalent of whole-blood transfusion is required to correct or prevent dilutional coagulopathy.     

Topical Hemostatic Agents: A Review

Topical hemostatic agents play an important role in both common and specialized dermatologic procedures. These agents can be classified based on their mechanism of action and include physical or mechanical agents, caustic agents, biologic physical agents, and physiologic agents. Some agents induce protein coagulation and precipitation resulting in occlusion of small cutaneous vessels, while others take advantage of latter stages in the coagulation cascade, activating biologic responses to bleeding. Traditional and newer topical hemostatic agents are discussed in this review, and the benefits and costs of each agent will be provided.     

Surgery in patients with congenital disorders of blood coagulation.

Surgical procedures on patients with congenital disorders of blood coagulation can be performed with a high degree of confidence and an acceptable incidence of complications. During the period 1960-1975, 42 patients with congenital disorders of blood coagulation underwent 94 operative procedures at the New York Hopital-Cornell Medical Center. The coagulation defect was diagnosed preoperatively, in nearly all patients. Careful hematologic management, including specific factor replacement, is essential. The importance of meticulous hemostasis at surgery and careful monitoring of blood coagulation in the postoperative period is strongly emphasized.     

原位肝移植术后腹腔内出血的原因和处理

目的 探讨肝移植术后腹腔内出血的原因和处理方法.方法 回顾性分析中山大学附属第一医院2004年1月至2008年12月施行的638例同种原位肝移植(orthotopic liver transplantation,OLT)患者的临床资料.总结原位肝移植术后腹腔内出血的诊治经过.结果 638例肝移植患者共发生术后腹腔内出血53例,发生率为8.3%(53/638).53例患者分别根据出血的原因、部位和严重程度采取相应的止血措施,其中对31例考虑为凝血功能障碍所致创面或肝周渗血而仅行非手术治疗,另22例为外科因素所致的术后活动性腹腔内出血,在应用止血药物、输血和积极扩充血容量等抗休克治疗无效后则中转二次探查止血手术.53例腹腔内出血患者死亡12例,死亡原因主要是严重感染和多器官功能衰竭;其余41例治愈且无并发症发生.与腹腔内出血相关的病死率为22.6%(12/53).结论 OLT术后可能出现不同部位的腹腔内出血,死亡率较高;临床上须掌握术后腹腔内出血的常见原因,一旦发生则应及时做出正确的治疗选择以改善预后.     

Repeated intracerebral hemorrhage associated with impaired platelet aggregation--report of two cases.

The authors report two cases of hypertensive intracerebral hemorrhage (ICH) repeated at the same site within 1 or 2 days causing death in a 53-year-old male and a 48-year-old female. In both cases, platelet aggregation was significantly impaired. Acquired platelet dysfunction may be important in the expansion of hemorrhage in patients with repeated hypertensive ICH. In such cases administration of normal platelets may be required to prevent devastating hemorrhage.     

Current use of factor concentrates in pediatric cardiac anesthesia

Excessive bleeding following pediatric cardiopulmonary bypass is associated with increased morbidity and mortality, both from the effects of hemorrhage and the therapies employed to achieve hemostasis. Neonates and infants are especially at risk because their coagulation systems are immature, surgeries are often complex, and cardiopulmonary bypass technologies are inappropriately matched to patient size and physiology. Consequently, these young children receive substantial amounts of adult‐derived blood products to restore adequate hemostasis. Adult and pediatric data demonstrate associations between blood product transfusions and adverse patient outcomes. Thus, efforts to limit bleeding after pediatric cardiopulmonary bypass and minimize allogeneic blood product exposure are warranted. The off‐label use of factor concentrates, such as fibrinogen concentrate, recombinant activated factor VII, and prothrombin complex concentrates, is increasing as these hemostatic agents appear to offer several advantages over conventional blood products. However, recognizing that these agents have the potential for both benefit and harm, well‐designed studies are needed to enhance our knowledge and to determine the optimal use of these agents. In this review, our primary objective was to examine the evidence regarding the use of factor concentrates to treat bleeding after pediatric CPB and identify where further research is required. PubMed, MEDLINE/OVID, The Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched to identify existing studies.     

Cryoprecipitate-topical thrombin glue. Initial experience in patients undergoing cardiac operations

The use of fibrin glues as topical hemostatic agents is reported in the European literature. We have composed an analogous compound in our operating rooms using cryoprecipitate and topical thrombin (1000 units/ml) in equal volumes applied directly to the bleeding site. We have used cryoprecipitate-topical thrombin glue in 26 patients undergoing cardiac operations. Severe bleeding not responding to usual methods of control was encountered during or after coronary artery bypass (n = 17), valve replacement (n = 3), bypass plus valve replacement (n = 5), or repair of postinfarction ventricular septal defect (n = 1). Five patients were operated on emergently and four were undergoing their second cardiac operation. The glue was used in four patients while on bypass and fully heparinized and in 17 patients who continued to bleed after separation from bypass and administration of protamine. Hemostasis was achieved in all patients and none required reexploration for bleeding. In five patients undergoing reexploration for postoperative hemorrhage (none having received cryoprecipitate-topical thrombin glue during the initial operation), the glue provided hemostasis when other measures failed, and no additional reexplorations were needed. No patient exhibited hypersensitivity, fibrinolysis, or coagulopathy following the use of this glue. In 16 patients followed for 9 to 12 months postoperatively, no hepatitis has occurred. The highly concentrated fibrinogen in cryoprecipitate is activated by thrombin to form fibrin and bring about rapid hemostasis. Cryoprecipitate-topical thrombin glue is a readily available, reliable, and inexpensive topical hemostatic agent in the patient undergoing a cardiac operation.