Platelet Function Tests in Bleeding Disorders.

Functional disorders of platelets can involve any aspect of platelet physiology, with many different effects or outcomes. These include platelet numbers (thrombocytosis or thrombocytopenia); changes in platelet production or destruction, or capture to the liver (Ashwell receptor); altered adhesion to vascular injury sites and/or influence on hemostasis and wound healing; and altered activation or receptor functions, shape change, spreading and release reactions, procoagulant and antifibrinolytic activity. Procoagulant membrane alterations, and generation of thrombin and fibrin, also affect platelet aggregation. The above parameters can all be studied, but standardization and quality control of assay methods have been limited despite several efforts. Only after a comprehensive clinical bleeding assessment, including family history, information on drug use affecting platelets, and exclusion of coagulation factor, and tissue deficits, should platelet function testing be undertaken to confirm an abnormality. Current diagnostic tools include blood cell counts, platelet characteristics according to the cell counter parameters, peripheral blood smear, exclusion of pseudothrombocytopenia, whole blood aggregometry (WBA) or light transmission aggregometry (LTA) in platelet-rich plasma, luminescence, platelet function analysis (PFA-100) for platelet adhesion and deposition to collagen cartridges under blood flow, and finally transmission electron microscopy to exclude rare structural defects leading to functional deficits. The most validated test panels are included in WBA, LTA, and PFA. Because platelets are isolated from their natural environment, many simplifications occur, as circulating blood and interaction with vascular wall are omitted in these assays. The target to reach a highly specific platelet disorder diagnosis in routine clinical management can be exhaustive, unless needed for genetic counseling. The elective overall assessment of platelet function disorder primarily aims at better management of hemostasis in case of emergency surgery or other interventions and acute bleeding events.

The obstetric, gynaecological and fertility implications of homozygous PAI-1 deficiency: single-centre experience.

Complete plasminogen activator inhibitor type 1 (PAI-1) deficiency is an exceedingly rare autosomal recessive bleeding disorder previously identified and reported in a large Old Order Amish (OOA) kindred in Indiana [Fay et al. Blood 1997; 90: 204]. Mouse models suggest that proteolysis via the plasminogen activator/plasmin system plays a crucial role in reproduction including degradation of the follicular wall during ovulation, fertilization, embryo implantation and embryogenesis [Leonardsson et al., Proc Natl Acad Sci USA 1995; 92: 12446]. We report the obstetric, gynaecological and fertility histories of OOA individuals with homozygous PAI-1 deficiency. In this family, there are 10 affected members identified to date ranging in age between 10 and 32 years, including seven female patients and three male patients. To date, two women have achieved pregnancies without difficulty; however, they experienced antenatal bleeding and preterm labour. The early initiation and continuation of antifibrinolytic agents, Epsilon-aminocaproic acid or tranexamic acid, during the pregnancy and in the postpartum period, was believed to be successful in preventing major bleeding complications in our patients with complete PAI-1 deficiency.

Value and risk of laparoscopic surgery in hemophiliacs-experiences from a tertiary referral center for hemorrhagic diatheses.

PURPOSE: Laparoscopic surgery (LS) is gaining popularity worldwide because of benefits like faster recovery, earlier hospital discharge, and better cosmetic results. In hemophiliacs, surgery in general harbors an increased risk for severe complications. Whether LS or conventional surgery (CS) should be recommended in these patients is controversial and therefore the issue of our present study. METHODS: We performed a retrospective matched-pair analysis including laparoscopically operated non-hemophiliacs (LONH), laparoscopically operated hemophiliacs (LOH), and conventionally operated hemophiliacs (COH) concerning duration of surgery, drainages, hospital stay, complications, factor use (VIII, IX, and X), and blood values. Mann-Whitney U test was used (significance level P = 0.05). RESULTS: No significant differences were found in duration of surgery and drains in laparoscopically or conventionally operated hemophiliacs versus matched pairs. Complication rate did not differ among the different groups. Concerning the total duration of hospital stay (t-DHOS) and the postoperative duration of hospital stay (p-DHOS), there was no statistical difference between LOH versus matched LONH. However, in COH versus matched LOH, a longer time was required for preparation and recovery (t-DHOS, P = 0.04; p-DHOS, P < 0.001). Also, the median factor supply perioperatively including the day of surgery did not differ between laparoscopically versus conventionally operated hemophiliacs. CONCLUSIONS: Our study underscores the safety and benefits of laparoscopic procedures in hemophiliacs by showing a significantly shorter hospital stay for these patients resulting in reduced therapeutic costs and a faster mobilization. Still, the surgical and perioperative management of hemophiliacs continues to be a challenge requiring an experienced interdisciplinary team.

Special care dentistry: part 3. Dental management of patients with medical conditions causing acquired bleeding disorders.

UNLABELLED: The second paper in this three part series discussed the dental management of patients with drug-related acquired bleeding disorders. This paper will discuss and outline the dental management of patients with acquired bleeding disorders that can result from medical conditions. Again, these may be associated with vascular defects, platelet defects or coagulation defects. In an age when people are living longer, and medical interventions are continually becoming more advanced, clinicians will need to be aware of systemic disorders and treatments that may cause complications in the dental setting. CLINICAL RELEVANCE: Being able to recognize which medical conditions, including their management, may cause bleeding problems at an early stage will lead to good patient management, particularly in planning and delivering treatment involving any invasive dental procedures that can cause bleeding. Whilst most patients can be successfully treated in general dental practice, the clinician may need to make a decision on whether or not to refer a patient to specialist services for all dental treatment, or to share care between primary care and specialist services.

Special Care Dentistry: Part 2. dental management of patients with drug-related acquired bleeding disorders.

UNLABELLED: The first of this series of three articles discussed the dental management of patients with inherited bleeding disorders. This paper will discuss and outline the dental management of patients with acquired bleeding disorders that can result from drug therapy. These may be associated with vascular defects, platelet defects or coagulation defects. In an age when people are living longer, and medical interventions are continually becoming more advanced, clinicians will need to be aware of systemic disorders and treatments that may cause complications in the dental setting. According to National Statistics, the UK population is projected to increase by 0.7% by 2016. This trend is shared with other European countries which also have ageing populations. The proportion of people aged over 65 is predicted to increase from 16% in 2006 to 22% in 2031. CLINICAL RELEVANCE: Being able to recognize which drugs may cause bleeding problems at an early stage will lead to good patient management, particularly in planning and delivering treatment following invasive procedures such as dental extractions. Whilst most patients can be successfully treated in general dental practice, the clinician may need to make a decision on whether or not to refer a patient to specialist services for all dental treatment, or to share care between primary care and specialist services for selected procedures.

Puerperal loss (lochia) in women with or without inherited bleeding disorders.

OBJECTIVE: To assess the quantity and duration of lochia in women with or without inherited bleeding disorders and to identify factors that influence lochial loss. STUDY DESIGN: Pictorial blood assessment chart was completed by 115 pregnant women (21 with or carriers of inherited bleeding disorder and 94 without bleeding disorder) using standardized sanitary products. RESULTS: The median duration of lochia was significantly longer in women with (or carriers of) inherited bleeding disorder (39 days; range 21-58) compared with women without bleeding disorder (31 days; range, 10-62; P = .03); however, the median lochial loss were similar (441 mL; range, 135-1290 vs 429 mL; range, 112-1295; P = .59). Long labor and instrumental delivery were associated with heavier lochia. CONCLUSION: Pictorial blood assessment chart is potentially a useful tool in the assessment of lochia. Women with inherited bleeding disorders experience longer period of lochia compared with women without bleeding disorder. Labor duration and mode of delivery influence lochial loss.

Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance.

Fibrinolysis serves an important role in the process of coagulation, ensuring that clots that are formed in response to injury resolve after the injured tissue is repaired. Fibrinolysis occurs because the protein plasminogen is converted to the active serine protease plasmin by its activating molecules (primarily tissue plasminogen activator). One of the inhibitors of fibrinolysis is alpha(2)-antiplasmin, which acts as the primary inhibitor of plasmin(ogen). Congenital deficiency of alpha(2)-antiplasmin causes a rare bleeding disorder because of increased fibrinolysis. Despite the rare nature of this disorder, understanding of the actions of alpha(2)-antiplasmin and the results of its deficiency has provided the opportunity for better understanding of the fibrinolytic system in both how it affects the risk of bleeding and its impact on other bodily systems. Here, we review the history of the discovery of alpha(2)-antiplasmin, our understanding of its genetics and function, and our current knowledge of its congenital deficiency. We also discuss some of the current avenues of investigation into its impact on other diseases and physiological states.

Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation.

OBJECTIVE: A study was conducted to develop a short, easy to administer screening tool useful for stratifying women with unexplained menorrhagia for hemostatic testing for underlying bleeding disorders. STUDY DESIGN: One hundred forty-six women with a physician diagnosis of menorrhagia underwent comprehensive hemostatic testing for the diagnosis of bleeding disorders, including von Willebrand disease, platelet dysfunction, and coagulation factor deficiencies. A 12 page questionnaire of bleeding symptoms was administered. Bleeding symptoms with high predictive values for laboratory hemostatic abnormalities were combined and used as single variables to calculate sensitivity, specificity, and positive and negative predictive values in order to develop a short screening tool to identify females for testing and evaluation. RESULTS: A combination of 8 questions in 4 categories resulted in a sensitivity of 82% (95%CI 75-90) for bleeding disorders. Adding a pictorial blood assessment chart score > 100 increased the sensitivity of the screening tool to 95% (95%CI 91-99). CONCLUSION: These results demonstrate the feasibility of a simple questionnaire based screening tool to identify females for testing and evaluation for bleeding disorders.

Impact of genetic variation on perioperative bleeding.

Variation in bleeding in the perioperative period is a complex and multifactorial event associated with immediate and delayed consequences for the patient and health care resources. Little is known about the complex genetic influences on perioperative bleeding. With the discovery of multiple variations in the human genome and ever-growing databases of well-phenotyped surgical patients, better identification of patients at risk of bleeding is becoming a reality. In this review, polymorphisms in the platelet receptor genes, plasminogen activator inhibitor, and angiotensin genes among others will be discussed. We will explore the nature, effects, and implications of the genetics that influence perioperative bleeding above and beyond surgical bleeding, particularly in cardiac surgery.

[Coagulation disorders in cirrhosis]. / Trastornos de coagulación en el cirrótico.

The liver plays a central role in the clotting process. In this organ are sintetizated the major part of the coagulation factors. Historically, was considered that alteration in liver function causes important bleeding disorders. However, actual evidence is not in agreement with this asseveration. Decreased synthesis of clotting and inhibitor factors, decrease clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis and intravascular coagulation are some of the defects observed in liver diseases. Thrombotic events, even if rare in cirrhotic patients, occur manly in the portal and mesenteric veins. The aim of the present work is to review the present evidence in coagulation disorders and liver disease.

Haemostatic problems in acute promyelocytic leukaemia.

Despite the development of highly effective treatment strategies for acute promyelocytic leukaemia around 10% of patients die in the presentation period as a consequence of the associated bleeding diathesis. The cause of the coagulopathy is complex resulting from a combination of tissue factor (TF) and cancer procoagulant (CP) induced disseminated intravascular coagulation, exaggerated fibrinolysis due predominantly to enhanced expression of annexin II on APL blast cell membranes and blast cell production of cytokines. All-trans retinoic acid (ATRA) has revolutionised the treatment of APL. When combined with chemotherapy long term survival rates of up to 80% can be achieved. Commencement of ATRA induces APL blast cell differentiation and is associated with a rapid resolution of the bleeding tendency through a combination of effects which include up regulation of thrombomodulin and down regulation of TF and CP production and cell surface expression of annexin II.

Molecular mechanisms of Ebola pathogenesis.

Ebola viruses (EBOVs) and Marburg viruses (MARVs) are among the deadliest human viruses, as highlighted by the recent and widespread Ebola virus outbreak in West Africa, which was the largest and longest epidemic of Ebola virus disease (EVD) in history, resulting in significant loss of life and disruptions across multiple continents. Although the number of cases has nearly reached its nadir, a recent cluster of 5 cases in Guinea on March 17, 2016, has extended the enhanced surveillance period to June 15, 2016. New, enhanced 90-d surveillance windows replaced the 42-d surveillance window to ensure the rapid detection of new cases that may arise from a missed transmission chain, reintroduction from an animal reservoir, or more important, reemergence of the virus that has persisted in an EVD survivor. In this review, we summarize our current understanding of EBOV pathogenesis, describe vaccine and therapeutic candidates in clinical trials, and discuss mechanisms of viral persistence and long-term health sequelae for EVD survivors.

Hermansky-Pudlak Syndrome.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diatheses, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes, including HPS-1, HPS-2, and HPS-4. HPS pulmonary fibrosis shows many of the clinical, radiologic, and histologic features found in idiopathic pulmonary fibrosis, but occurs at a younger age. Despite knowledge of the underlying genetic defects, there are currently no definitive therapeutic or preventive approaches for HPS pulmonary fibrosis other than lung transplant.

Causes of isolated prolonged activated partial thromboplastin time in an acute care general hospital.

INTRODUCTION: To determine the causes of isolated prolonged activated partial thromboplastin time (APTT) in an acute care general hospital setting so as to rationalise fresh frozen plasma usage. METHODS: A prospective study of consecutive patients with isolated prolonged APTT presenting to our hospital between February 2002 and January 2004 was performed. All patients had normal prothrombin time and thrombin time. For all patients, an initial 50:50 correction with plasma was done and a standard panel of tests was performed. These included detection of lupus anticoagulant using two different sensitive tests; measurement of coagulant factors VIII (FVIII), IX, XI and XII, which are involved in the intrinsic arm of haemostasis; von Willebrand factor antigen (vWF:Ag) levels and for those with FVIII levels less than 10 percent, an inhibitor assay using the Nijmegen modification of the Bethesda method. RESULTS: 177 patients were included in the study. The cohort was typical of an acute care general hospital patient population in Singapore in terms of age, sex and racial distribution. The most common cause of an isolated prolonged APTT in our study was the presence of lupus anticoagulant (53.1 percent of cases). In 31.6 percent of cases, obvious cause could be detected after our panel of tests. These patients mostly had mildly prolonged APTT that could be both correctable and non-correctable by normal plasma. Prolonged APTT due to factor deficiency was relatively rare with those that may potentially cause haemorrhagic problems only accounting for 4.5 percent of cases. CONCLUSION: Our study suggests that most of the causes of isolated prolonged APTT do not lead to haemorrhagic complications. In fact, in a majority, it may signify an underlying thrombophilic condition. As a result, prolongation of APTT should be fully investigated and correction with fresh frozen plasma should be used only when appropriate.

Haemostatic problems in acute leukaemia.

Disseminated intravascular coagulation (DIC) is a frequent complication of acute leukaemia, in particular acute promyelocytic leukaemia. Although procoagulant substances released from leukaemic blast cells may induce DIC by activating conventional coagulation pathways, there is increasing evidence to suggest that direct activation of fibrinogen by proteases released from blast cells may be the predominant mechanism by which DIC is initiated. Primary fibrinolysis has also been proposed as the cause of the haemorrhagic diathesis in some cases of acute leukaemia. Although plasminogen activators have been demonstrated in leukaemic blast cells supporting this view, cases of primary fibrinolysis would appear to be rare. A bleeding tendency attributed to primary fibrinolysis may more often be the result of an exaggerated fibrinolytic response secondary to DIC. The main strategies of treatment for leukaemia associated DIC are rapid initiation of chemotherapy and vigorous blood product support until the DIC resolves once the blast cells have been eradicated. The role of heparin in the management of leukaemia associated DIC remains controversial. There is recent evidence to suggest that heparin therapy does reduce the incidence of haemorrhagic death although it has been recommended that relatively low intravenous doses should be administered initially to reduce the risk of heparin induced haemorrhage.

Hemostasis in renal disease: pathophysiology and management.

The hemostatic abnormalities commonly encountered in patients with renal disease can significantly threaten the well-being of the patient and pose difficult management issues for the clinician. In this review, we explore the pathophysiology underlying the bleeding diathesis and hypercoagulability that can occur. Current therapeutic interventions are also discussed.

Capillary microscopic and rheological dimensions for the diagnosis of von Willebrand disease in comparison to other haemorrhagic diatheses.

It is known that angiodysplasia influence macrocirculation as well as microcirculation in patients with vWD. In the present study it was examined if intravital capillary microscopic dimensions (morphologic and dynamic) in skin (nailfold) in combination with rheologic parameters could give indications for the presence of vWD in patients with haemorrhagic diathesis. Patients with vWD (n = 100; 92 type 1: definite type 1:78 and possible type 1:14: 8 type 2A) have in comparison to patients with other haemorrhagic diathesis [thrombocytopathy (n = 122), thrombocytopenia (n = 101). severe haemophilia A (n = 50) and severe haemophilia B (n = 20). congenital dysfibrinogenaemia (n = 22), oral anticoagulation with phenprocoumone (n = 112)] and to apparently healthy subjects (n = 100) a significantly increased capillary torquation (median index: 3.5), a venolar and an arteriolar capillary dilatation (median: 16.5 microm; median: 15.1 microm) and the highest part of microscopic bleedings (extravasates) with 40% in the video capillary microscopy as morphological changes. Only the congenital dysfibrinogenaemia appears with a larger dilatation in venolar capillaries (median: 14.5 microm). Microscopic bleedings are much less common in other haemorrhagic diatheses with a frequency between 4% and 13%. In the vWD a significantly reduced duration of reactive hyperaemia (median: 150 sec). This is the only dynamic change that can be taken as a possible hint for a loss of flexibility within the precapillary vessels. A significantly reduced plasma viscosity (< 1.25 mPas) is typical for the vWD due to the increase of the shear stress in blood plasma because of the reduction of vWF-activities. Changes of the capillary morphology (dilatation, extravasates, capillary torquation) and the hypoplasmaviscosity are most sensitive for the vWD (75%, 65%, 40%, 80%) with a fairly high specifity (up to 93%) and a positive predictive value of 99%. As a conclusion it seems reasonable to discuss the introduction of video capillary microscopy as a screening test for haemostasiological and angiological centers.

Disorders of hemostatic function in patients with systemic lupus erythematosus.

A wide spectrum of hemostatic abnormalities is found in patients with SLE. Thrombocytopenia and qualitative platelet disorder (impaired aggregation to collagen) are probably both due to antiplatelet antibodies, which can be found in most patients with the disease. About 10% of patients with SLE have a circulating anticoagulant. These circulating anticoagulants are broadly heterogeneous. Although most reported cases act at the level of the prothrombin converting complex, 15 of the 74 cases here reviewed had other points of action. The anticoagulants are probably all antibodies; they differ (with rare exceptions) from other naturally occurring circulating anticoagulants in having an immediate rather than a progressive effect, and in acting, not against pre-existing procoagulants, but against unstable complexes. An anticoagulant of the type found in SLE is only rarely observed in the absence of SLE; its presence in a patient is thus of some diagnostic importance. Hypoprothrombinemia is a common second lesion in patients with circulating anticoagulants. Its pathogenesis is obscure. Two patients with acquired von Willebrand's disease have been observed. All the hemostatic abnormalities found in SLE probably have immunologic bases; all respond to glucocorticoid treatment.