Women and bleeding disorders: diagnostic challenges

Abstract Women with bleeding disorders suffer from multiple bleeding symptoms, including easy bruising, epistaxis, bleeding from minor wounds and the oral cavity, and bleeding after dental work or surgery. However, women with bleeding disorders especially suffer from gynecologic and obstetrical bleeding. These symptoms often are not recognized as abnormal, and many women are left undiagnosed and without access to appropriate medical care. Additional challenges to diagnosing women with bleeding disorders include lack of access to appropriate laboratory testing and issues around disease classification and nomenclature. Efforts have been undertaken to address these challenges, including the development and validation of bleeding assessment tools and strategies to clarify diagnostic thresholds and algorithms for von Willebrand disease (VWD) and platelet function disorders. Efforts to improve communication with the nomenclature used for hemophilia carriers are also underway.

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Bleeding scores: are they really useful?

Hematology ◽

10.1182/asheducation.v2012.1.152.3798226 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 152-156 ◽

Cited By ~ 30

Author(s):

Sarah H. O'Brien

Keyword(s):

Laboratory Testing ◽

Clinical Applications ◽

Von Willebrand Disease ◽

Assessment Tools ◽

Bleeding Disorders ◽

Clinical Markers ◽

Precise Quantification ◽

Bleeding Score ◽

Von Willebrand

Abstract Given the commonality of bleeding symptoms in the general population and the diagnostic limitations of available laboratory testing for mild bleeding disorders, there has been increasing interest in a more precise quantification of bleeding symptoms. The Vicenza bleeding score (and its successor, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease [MCMDM-1 VWD]) and its pediatric counterpart, the Pediatric Bleeding Questionnaire, are validated research tools that have demonstrated their ability to discriminate between healthy subjects and those with VWD. These instruments collect data regarding both the presence and severity of a variety of bleeding symptoms and generate a bleeding score by summing the severity of all symptoms reported by a subject. More recent work demonstrates the promise of these tools as a diagnostic aid in the evaluation of patients with a suspected inherited mild bleeding disorder, as well as the development of a condensed score with increased clinical applicability. This review focuses on the development of these bleeding assessment tools, recent publications applying and refining these instruments, and current limitations of bleeding scores. Needed research studies and potential clinical applications of bleeding scores are also discussed. The ultimate goal would be for bleeding scores to be integrated with the results of standardized laboratory testing to allow for a universal diagnostic approach to patients with suspected bleeding disorders.

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Risk and Management of Intracerebral Hemorrhage in Patients with Bleeding Disorders

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1740566 ◽

2022 ◽

Author(s):

Akbar Dorgalaleh ◽

Yadolah Farshi ◽

Kamand Haeri ◽

Omid Baradarian Ghanbari ◽

Abbas Ahmadi

Keyword(s):

Risk Factors ◽

Intracerebral Hemorrhage ◽

Platelet Function ◽

Hemophilia A ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Vacuum Extraction ◽

Bleeding Disorders ◽

Platelet Function Disorders ◽

Von Willebrand

AbstractIntracerebral hemorrhage (ICH) is the most dreaded complication, and the main cause of death, in patients with congenital bleeding disorders. ICH can occur in all congenital bleeding disorders, ranging from mild, like some platelet function disorders, to severe disorders such as hemophilia A, which can cause catastrophic hemorrhage. While extremely rare in mild bleeding disorders, ICH is common in severe coagulation factor (F) XIII deficiency. ICH can be spontaneous or trauma-related. Spontaneous ICH occurs more often in adults, while trauma-related ICH is more prevalent in children. Risk factors that can affect the occurrence of ICH include the type of bleeding disorder and its severity, genotype and genetic polymorphisms, type of delivery, and sports and other activities. Patients with hemophilia A; afibrinogenemia; FXIII, FX, and FVII deficiencies; and type 3 von Willebrand disease are more susceptible than those with mild platelet function disorders, FV, FXI, combined FV–FVIII deficiencies, and type 1 von Willebrand disease. Generally, the more severe the disorder, the more likely the occurrence of ICH. Contact sports and activities can provoke ICH, while safe and noncontact sports present more benefit than danger. An important risk factor is stressful delivery, whether it is prolonged or by vacuum extraction. These should be avoided in patients with congenital bleeding disorders. Familiarity with all risk factors of ICH can help prevent occurrence of this diathesis and reduce related morbidity and mortality.

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Obstetric analgesia and anaesthesia in women with inherited bleeding disorders

Thrombosis and Haemostasis ◽

10.1160/th08-10-0694 ◽

2009 ◽

Vol 101 (06) ◽

pp. 1104-1111 ◽

Cited By ~ 52

Author(s):

Claudia Chi ◽

Christine Lee ◽

Adrian England ◽

Jaishree Hingorani ◽

James Paintsil ◽

...

Keyword(s):

Von Willebrand Disease ◽

Factor Vii ◽

Bleeding Disorders ◽

Factor X ◽

Factor Xi Deficiency ◽

Obstetric Analgesia ◽

Regional Block ◽

Platelet Function Disorders ◽

Coagulation Defects ◽

Von Willebrand

SummaryA retrospective review was carried out on the methods of obstetric analgesia/anesthesia used in 80 pregnancies amongst 63 women with inherited bleeding disorders (19 factor XI deficiency, 16 carriers of haemophilia, 15 von Willebrand disease, seven platelet function disorders, four factor VII deficiency, one factor VII and XI deficiency and one factor X deficiency). In 72 pregnancies, the woman was seen antenatally in a multidisciplinary clinic to discuss and plan pain relief options. Regional block was performed for 41 pregnancies. The mothers were known to have a bleeding disorder in 35 of these pregnancies. Prophylactic cover was given in 10 pregnancies prior to the insertion of regional block but not required in the remaining 25 pregnancies because the coagulation defects had spontaneously normalised at term. There were six reported adverse effects from regional block similar to that found in the general population: inadequate anesthesia/analgesia (2), bloody tap (2), hypotension and a possible dural puncture which was treated conservatively. There were no reports of long-term complications. The findings show that it is possible to offer women with inherited bleeding disorders the option of regional block provided their coagulation defects have normalised, either spontaneously during pregnancy or following adequate haemostatic cover.

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Cryptogenic oozers and bruisers

Hematology ◽

10.1182/hematology.2021000236 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 85-91

Author(s):

Kristi J. Smock ◽

Karen A. Moser

Keyword(s):

Platelet Function ◽

Coagulation Factor ◽

Fibrin Clot ◽

Von Willebrand Disease ◽

Bleeding Disorders ◽

Diagnostic Challenge ◽

Primary Hemostasis ◽

Platelet Function Disorders ◽

Number Of Patients ◽

Von Willebrand

Abstract Bleeding disorders with normal, borderline, or nondiagnostic coagulation tests represent a diagnostic challenge. Disorders of primary hemostasis can be further evaluated by additional platelet function testing modalities, platelet electron microscopy, repeat von Willebrand disease testing, and specialized von Willebrand factor testing beyond the usual initial panel. Secondary hemostasis is further evaluated by coagulation factor assays, and factor XIII assays are used to diagnose disorders of fibrin clot stabilization. Fibrinolytic disorders are particularly difficult to diagnose with current testing options. A significant number of patients remain unclassified after thorough testing; most unclassified patients have a clinically mild bleeding phenotype, and many may have undiagnosed platelet function disorders. High-throughput genetic testing using large gene panels for bleeding disorders may allow diagnosis of a larger number of these patients in the future, but more study is needed. A logical laboratory workup in the context of the clinical setting and with a high level of expertise regarding test interpretation and limitations facilitates a diagnosis for as many patients as possible.

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Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing

Life ◽

10.3390/life11030202 ◽

2021 ◽

Vol 11 (3) ◽

pp. 202

Author(s):

Réka Gindele ◽

Adrienne Kerényi ◽

Judit Kállai ◽

György Pfliegler ◽

Ágota Schlammadinger ◽

...

Keyword(s):

Next Generation Sequencing ◽

Hereditary Hemorrhagic Telangiectasia ◽

Von Willebrand Disease ◽

Differential Diagnostics ◽

Bleeding Disorders ◽

Next Generation ◽

Illumina Platform ◽

Clinical Patient ◽

Von Willebrand ◽

Generation Sequencing

Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, n = 63), hypo-or dysfibrinogenemia (n = 27), hereditary hemorrhagic telangiectasia (HHT, n = 10) and unexplained activated partial thromboplastin time (APTT) prolongation (n = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (ACVRL1, ENG, MADH4, GDF2, RASA1, F5, F8, FGA, FGB, FGG, KLKB1, ADAMTS13, GP1BA and VWF) selected on the basis of laboratory results. We identified forty-seven mutations, n = 29 (6 novel) in vWD, n = 4 mutations leading to hemophilia A, n = 10 (2 novel) in fibrinogen disorders, n = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing “bleeding disorders databases”, which are excellent supports for clinical patient management.

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Platelet Disorders

10.2310/im.1410 ◽

2015 ◽

Author(s):

Lawrence L K Leung ◽

James L. Zehnder

Keyword(s):

Platelet Function ◽

Clinical Manifestations ◽

Von Willebrand Disease ◽

Drug Induced ◽

Excessive Bleeding ◽

Vascular Integrity ◽

Patient Reports ◽

Platelet Function Disorders ◽

Hemorrhagic Disorders ◽

Von Willebrand

A bleeding disorder may be suspected when a patient reports spontaneous or excessive bleeding or bruising, often secondary to trauma. Possible causes can vary between abnormal platelet number or function, abnormal vascular integrity, coagulation defects, fibrinolysis, or a combination thereof. This review addresses hemorrhagic disorders associated with quantitative or qualitative platelet abnormalities, such as thrombocytopenia, platelet function disorders, thrombocytosis and thrombocythemia, and vascular purpuras. Hemorrhagic disorders associated with abnormalities in coagulation (e.g., von Willebrand disease and hemophilia) are not covered. An algorithm shows evidence-based practice guidelines for the management of immune thrombocytopenic purpura. Tables list questions regarding bleeding and bruising to ask patients, clinical manifestations of hemorrhagic disorders, typical results of tests for hemostatic function in bleeding disorders, causes of thrombocytopenia, other forms of drug-induced thrombocytopenia, classification of platelet function disorders, and selected platelet-modifying agents. This review contains 1 highly rendered figure, 7 tables, and 82 references.

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Coagulopathies

10.2310/em.4124 ◽

2020 ◽

Author(s):

Michael Levine

Keyword(s):

Key Words ◽

Bleeding Disorder ◽

Von Willebrand Disease ◽

Coagulation Cascade ◽

Bleeding Disorders ◽

Platelet Disorders ◽

Von Willebrand

Coagulopathy can be caused by numerous hereditary or acquired etiologies. Although some of these conditions are known and the patient is aware of the bleeding disorder, other bleeding disorders are diagnosed only after the onset of excessive hemorrhage. This review discusses both hereditary and acquired disorders of coagulopathy. Platelet disorders are discussed elsewhere. This review contains 2 figures, 7 tables, and 72 references. Key words: Coagulopathies; Coagulopathy; Bleeding disorder; Hereditary bleeding disorder; Acquired bleeding disorder; von Willebrand disease; Hemophilia; Coagulation cascade; Hemorrhage; Anticoagulant-associated hemorrhage

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THE ROLE OF BLEEDING HISTORY AND CLINICAL MARKERS FOR THE CORRECT DIAGNOSIS OF VWD

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2013.051 ◽

2013 ◽

Vol 5 (1) ◽

pp. e2013051 ◽

Cited By ~ 4

Author(s):

Alberto Tosetto

Keyword(s):

Correct Diagnosis ◽

Von Willebrand Disease ◽

Assessment Tools ◽

Bleeding Tendency ◽

Clinical Markers ◽

Web Based ◽

Bleeding Score ◽

Bleeding History ◽

Von Willebrand ◽

Willebrand Factor

Quantification of the bleeding severity by use of bleeding assessment tools (BAT) and bleeding score (BS) has been consistently shown to improve the clinical diagnosis of von Willebrand disease (VWD) while helping researchers establish phenotype/genotype correlations. Subjects with a BS equal or higher than 3 may be consider having a bleeding tendency, and should be referred for a laboratory investigation, particularly for VWD. In the diagnosis of type 1 VWD, the use of the BS has been shown to be highly specific (>95%) with reported sensitivities ranging from 40 to 100%. The BS is related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. Therefore, in clinical practice the use of BAT should always be the first step to standardize the assessment of patients with suspected VWD. The use of the recent ISTH consensus BAT is suggested to harmonize the collection of bleeding symptoms in patients with a suspected or confirmed hemostatic disorder, particularly VWD. The ISTH BAT is also coupled with a Web-based repository of bleeding symptoms, therefore providing an integrated framework for collaboration in the field of clinical evaluation of VWD and mild bleeding disorders.

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Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders [see comments]

Blood ◽

10.1182/blood.v72.5.1449.1449 ◽

1988 ◽

Vol 72 (5) ◽

pp. 1449-1455 ◽

Cited By ~ 233

Author(s):

PM Mannucci

Keyword(s):

Arginine Vasopressin ◽

Von Willebrand Disease ◽

Synthetic Analogue ◽

Bleeding Disorders ◽

Spinal Fusion Surgery ◽

Prolonged Bleeding Time ◽

Normal Individuals ◽

Transfusion Requirements ◽

Coagulant Activity ◽

Von Willebrand

Abstract Desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) is a synthetic analogue of the antidiuretic hormone L-arginine vasopressin. Because it can raise circulating levels of factor VIII coagulant activity (FVIII) and von Willebrand factor and shorten the prolonged bleeding time, DDAVP is established as a nontransfusional form of treatment for mild and moderate hemophilia and von Willebrand disease. Recently, DDAVP has also been purported to be useful for shortening the prolonged skin bleeding times that occur with uremia, cirrhosis, and platelet dysfunctions of various etiologies. Finally, there is evidence from controlled clinical trials that DDAVP can reduce blood loss and transfusion requirements for hemostatically normal individuals undergoing spinal fusion surgery and for patients undergoing cardiopulmonary bypass surgery. The purpose of this report is to review the therapeutic applications of DDAVP in congenital and acquired bleeding disorders and to discuss areas in which further basic and clinical research is needed.

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Management Strategies of Stroke and Acute Coronary Syndrome In Von Willebrand Disease and Hemophilia: Experience From a Case Series and a Swiss Survey of Frequencies.

Blood ◽

10.1182/blood.v116.21.1406.1406 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1406-1406 ◽

Cited By ~ 1

Author(s):

Sara C. Meyer ◽

Elina Armstrong ◽

Christine Perdrizat ◽

Hans-Rudolf Schmid ◽

Riitta Lassila ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Ct Scan ◽

Treatment Strategies ◽

Case Series ◽

Von Willebrand Disease ◽

Bleeding Disorders ◽

Coronary Syndrome ◽

Federal Statistical ◽

Swiss Population ◽

Von Willebrand

Abstract Abstract 1406 Introduction: Thrombolysis and combined antiplatelet therapy is considered contraindicated in patients (pts) with bleeding disorders such as von Willebrand disease (VWD) and hemophilia (HP) presenting with stroke or acute coronary syndrome (ACS). Conservative treatment e.g. of stroke is often unsatisfactory in pts within the time window for thrombolysis. As stroke and ACS are common disorders, they may coincide with prevalent bleeding disorders such as VWD and HP and increase in frequency due to growing life expectancy in VWD and HP. An emergency protocol for safe management is desirable. Methods: We report on the management of 5 Caucasians with known VWD or HP suffering from stroke or ACS. In addition we screened the Swiss population of VWD and HP patients over 10y for the occurrence of stroke or ACS based on the data of the Swiss Federal Statistical Office. Case Series. Pt 1 is a 54-y-old Swiss female suffering from mild VWD 1 with a relevant bleeding history and characteristic VWF multimers (Tab 1). She presented with acute stroke with right hemiparesis (NIHSS 9) 2h after onset. CT scan excluded intracranial bleeding. Substitution of VWF/FVIII concentrate aiming at 80% of VWF activity resulted in 55% VWF ristocetin cofactor activity (RCo) and 76% VWF antigen (Ag). Concomitant thrombolysis with full-dose rtPA was performed. After 24h NIHSS improved to 6, RCo was 45%, Ag 63% and no signs of bleeding occurred. Secondary prophylaxis with aspirin was started. She fully recovered after 3 months. Pt 2, a 68-y-old Finnish female with VWD 2A presented with a minor stroke with mild left hemiparesis and a fall (NIHSS 2) 2h after onset. CT scan was normal and she was treated with dipyridamole. Symptoms regressed to NIHSS 0 after 6h. Pt 3 to 5 had ACS. Pt 3, a 73-y-old Swiss male with hemophilia B was successfully treated for unstable angina by percutaneous coronary intervention (PCI) with stenting at a subtotal stenosis of the RCA after substitution of FIX to 65%. Postinterventionally he was on clopidogrel for 2y and then switched to aspirin. Concomitant weekly substitution of FIX led to FIX peaks of ≂f55% and nadir of ≂f15%, was then reduced in frequency and stopped after 15 months. No bleeding complications occurred. Pt 4, a 67-y-old Finnish female with symptomatic VWD 3 presented with a NSTEMI and was successfully treated without PCI or platelet inhibition. Pt 5, a 70-y-old Finnish male with symptomatic VWD 2A suffered from ACS and had angiography with substitution of VWF/FVIII concentrate to 40–134% RCo and 134–252% Ag. Aortocoronary bypass surgery was planned due to 3-vessel disease. No antiplatelet therapy was started. Survey. The analysis of the Swiss Federal Statistical Office revealed 39 cases of VWD or HP with stroke or ACS over 10y (1998-2008) in the Swiss population of 7.70 millions (2008). A lower mean age at death in pts with VWD and HP (63 y) as compared to the normal population (77y), underreporting in the early years and a potential protective effect may contribute to reduced numbers. 19 pts with VWD showed 13 events of stroke and 6 of ACS while 20 hemophiliacs had 8 events of stroke and 12 of ACS. Conclusion: Our survey confirms the occurrence of stroke and ACS in pts with VWD and HP. Observed treatment strategies are very heterogeneous. Intravascular mechanical intervention such as PCI appears advantageous in pts with VWD and HP. If intravascular therapy is not timely available or not possible, we suggest substitution to ≂f80% VWF immediately followed by full-dose thrombolysis as described in pt 1. Repetitive substitution of VWF on a 12–24h basis or infusion over 48h may be adequate in severe deficiencies (Blood 2009;114:5256). A FIX level of 25% may suffice for safe PCI in hemophilia B given the clinical experience with oral anticoagulation. Generally, treatment strategies for stroke and ACS in pts with VWD and HP should be individually tailored and balanced between thrombotic and bleeding risk. Disclosures: No relevant conflicts of interest to declare.

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