In this question they also do not stop dropping clues to throw us headlong into the correct diagnosis. Let's review: a small child who suffers a hemarthrosis without clear trauma. An uncle of his had similar problems, so we suspect hereditary disease. The APTT, which evaluates the intrinsic coagulation pathway (involving factors V, VIII, IX, X, XI and XII) is elongated. Hereditary coagulation problem. We thus discard answers 1, 2 and 5. We are left with von Willebrand's disease and hemophilia A. I consider that the correct answer is 4, hemophilia A, since the inheritance pattern is X-linked and its main clinical manifestation is soft tissue bruising and spontaneous hemarthrosis, without apparent trauma, while von Willebrand disease is characterized by bleeding after surgery or trauma and a prolonged bleeding time with a normal platelet count is characteristic (data not mentioned in the statement).

In this question they also do not stop dropping clues to throw us headlong into [HIDDEN]. Let's review: a small child who suffers a hemarthrosis without clear trauma. An uncle of his had similar problems, so we suspect hereditary disease. The APTT, which evaluates the intrinsic coagulation pathway (involving factors V, VIII, IX, X, XI and XII) is elongated. Hereditary coagulation problem. We [HIDDEN]. We are left with von Willebrand's disease and hemophilia A. I consider that [HIDDEN], since the inheritance pattern is X-linked and its main clinical manifestation is soft tissue bruising and spontaneous hemarthrosis, without apparent trauma, while von Willebrand disease is characterized by bleeding after surgery or trauma and a prolonged bleeding time with a normal platelet count is characteristic (data not mentioned in the statement).

18-month-old boy, with complete vaccination schedule to date, who consults the Emergency Department for swelling of the right knee after playing in the park, without obvious trauma. In the directed anamnesis, the mother refers that an uncle of hers had similar problems. The ultrasound examination is compatible with hemarthrosis and in the analysis performed only an APTT lengthening of 52″ (normal 25-35″) stands out. What is the most likely diagnostic hypothesis?

Further evidence for recessive inheritance of von Willebrand disease with abnormal binding of von Willebrand factor to factor VIII.

A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling.

The dental patient with a congenital bleeding disorder.

Congenital bleeding disorders account for approximately one in 10,000 births. Dentists are often anxious about delivering treatment to this special group of patients. In the Irish Republic, patients with inherited bleeding disorders have their dental care co-ordinated centrally at the National Centre for Hereditary Coagulation Disorders (NCHCD), St James's Hospital, Dublin. Dental care is normally integrated with routine outpatient haematological appointments. This ensures regular monitoring of oral health and the early treatment of any hard/soft tissue pathology. This article describes, in simple diagrammatic form, the normal coagulation mechanism (Figures 1 and 2), explains common coagulation terms (Appendix 1), and examines the three most common congenital bleeding disorders: haemophilia A, haemophilia B, and von Willebrand disease. General recommendations based on the current literature are provided with respect to procedures that are appropriate to perform in a general dental practice setting. Although not discussed in this article, it is important to note that non-coagulation bleeding disorders also exist. These include: hereditary haemorrhagic telangiectasia; blood vessel wall defects resulting from connective tissue disorders such as Marfan syndrome and Ehlers-Danlos syndrome; and, platelet disorders such as Bernard-Soulier syndrome, resulting in defective platelet adhesion.

Erik Adolf von Willebrand

He published a Swedish-language article in 1926 about the disease, titled Hereditär pseudohemofili ("Hereditary pseudohemophilia"). He referenced six previous publications from the years of 1876 to 1922, totalling 19 cases on families with bleeding diatheses. The earlier authors attributed the condition to hemophilia (even in the cases of females) or to thrombopathy, which was discovered shortly before as the cause of what had previously been known as purpura hemorrhagica or Werlhof's disease. Von Willebrand also conducted hematological examinations on Hjördis and some of her family members. He recorded a normal or slightly reduced number of platelets and an undisturbed clot retraction, unlike Glanzmann's thrombasthenia. The bleeding time (Duke) was greatly prolonged, extending to more than 2 hours in some cases, while the clotting time was within the normal range. He concluded that the disease was either a new form of thrombopathy or a condition of the capillary endothelium.

Ehlers-Danlos syndrome, clotting disorders and muscular dystrophy.

Ehlers-Danlos syndrome includes 11 distinct entities. The diversity of this collagen dysplasia and its combination with other abnormalities make it difficult to understand physiopathologically. A case of Ehlers-Danlos syndrome is reported, which is novel owing to its combination with clotting abnormalities and especially with muscular dystrophy. To our knowledge this has not previously been reported. The patient was a young man aged 16 years who presented with Ehlers-Danlos syndrome satisfying Perelman's diagnostic criteria. His father and two brothers had comparable clinical symptoms, but his mother and sister were healthy. The four male subjects had an increased cephalin-kaolin time, reduced levels of factor VIII and Willebrand's factor (but without haemophilia A or Willebrand's disease), and, especially, an abnormal platelet ATP secretion. The proband alone had muscular disease with bilateral quadriceps fatigability and amyotrophy. The muscle enzyme levels were greatly increased, the electromyographic trace was myogenic, and the biopsy showed severe muscular dystrophy. This new observation poses the problem of the relation between clotting abnormalities and collagen abnormalities in the Ehlers-Danlos syndrome. It is difficult to classify this case within any of the 11 known types because of its muscular manifestations. It may perhaps be a fortuitous combination or an extension of the nosological framework of this syndrome.

List of MeSH codes (C15)

– hemorrhagic disorders – afibrinogenemia – bernard-soulier syndrome – disseminated intravascular coagulation – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – platelet storage pool deficiency – hermanski-pudlak syndrome – purpura, thrombocytopenic, idiopathic – thrombasthenia – thrombocythemia, hemorrhagic – vascular hemostatic disorders – cryoglobulinemia – ehlers-danlos syndrome – hemangioma, cavernous – hemangioma, cavernous, central nervous system – multiple myeloma – pseudoxanthoma elasticum – purpura, hyperglobulinemic – purpura, schoenlein-henoch – scurvy – shwartzman phenomenon – telangiectasia, hereditary hemorrhagic – waldenstrom macroglobulinemia – vitamin k deficiency – hemorrhagic disease of newborn – von willebrand disease – waterhouse-friderichsen syndrome

Diagnostic Challenges in Children With Congenital Bleeding Disorders: A Developing Country Perspective.

To assess the frequency and characteristics of children with inherited bleeding disorders that were initially misdiagnosed, leading to inappropriate disease management. This study was conducted at the Haematology/Pathology Department of Fauji Foundation Hospital, Rawalpindi, Pakistan, from August 2014 to August 2018. Children who were diagnosed with an inherited bleeding disorder but did not respond to initial therapy were reevaluated. In total, 62 children were diagnosed with a bleeding disorder. Of these, 27 were diagnosed with an inherited bleeding disorder and 35 with an acquired bleeding disorder. Of the 27 children with inherited bleeding disorders, 18% (n = 5) were misdiagnosed and treated inappropriately. The median age of the misdiagnosed patients was 9 years (range, 5-13 years). Three patients with Bernard-Soulier syndrome had been misdiagnosed as having immune thrombocytopenic purpura, 1 patient with von Willebrand disease had been misdiagnosed as having hemophilia A, and 1 patient with haemophilia B had been misdiagnosed as having hemophilia A. There are chances of misdiagnosis and improper or invasive management if comprehensive laboratory evaluation and a thorough clinical evaluation are not performed in children with congenital bleeding disorders.

InternalMed_Harrison

Hemophilia is a sex-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (hemophilia A, orclassic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 141). Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is a common problem with both types of hemophilia and can lead to a deforming arthritis. The frequency and severity of hemarthrosis are related to the degree of clotting factor deficiency. Hemarthrosis is not common in other disorders of coagulation such as von Willebrand disease, factor V deficiency, warfarin therapy, or thrombocytopenia. Hemarthrosis occurs after 1 year of age, when a child begins to walk 2241 and run. In order of frequency, the joints most commonly affected are theknees,ankles,elbows,shoulders,andhips.Smalljointsofthehands and feet are occasionally involved.

Von Willebrand disease

Diagnosis Basic tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Patients with abnormal tests typically undergo further testing for hemophilias. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

Hemophilia -- Differential Diagnosis

Other conditions can also present similarly with bleeding after minor trauma or spontaneous bleeds and require exclusion before confirming the diagnosis of hemophilia. Some of these conditions include von Willebrand disease, scurvy, diseases of platelet dysfunction, deficiency of other coagulation factors like V, VII, X, or fibrinogen, Ehlers-Danlos syndrome, Fabry disease, disseminated intravascular coagulation, and child abuse. In von Willebrand disease, bleeding symptoms can be similar to mild hemophilia, but patients with von Willebrand disease have more mucosal bleeding compared to musculoskeletal bleeding seen in hemophilia. Von Willebrand disease is diagnosed by checking for von Willebrand factor antigen or von Willebrand factor multimers. [40] Similarly, in scurvy, Ehlers-Danlos syndrome, and Fabry disease; also, the bleeding is usually mucosal, unlike hemophilia, where it is musculoskeletal. In scurvy, there is a deficiency of vitamin C. [41] In Ehlers-Danlos syndrome, the skin is hyperextensible, and joints are hypermobile. The diagnosis is usually through clinical features, genetic testing, and tissue biopsy. [42] Similarly, in Fabry disease, patients may also have other organs being affected, including kidneys and heart, and have skin lesions called angiokeratomas. They also have pain in the extremities. Fabry disease is usually diagnosed with clinical findings and genetic testing. [43] In cases of platelet dysfunction disorders, bleeding is usually mucocutaneous, unlike hemophilia. Usually, these disorders are diagnosed by platelet aggregation studies or platelet electron microscopy. [44] In the deficiency of other coagulation factors, musculoskeletal bleeding is uncommon. In fact, sometimes thrombosis can occur, especially in patients with factor VII or fibrinogen deficiency or in patients with combined factor V and VIII deficiency. Specific coagulation factor assays usually confirm the diagnosis. Disseminated intravascular coagulation (DIC) that mimics hemophilia is hard to differentiate, but usually, there is an underlying condition in DIC, for example, acute promyelocytic leukemia. Diagnosis is usually carried out by blood tests that show decreased platelet count and the absence of factor VIII autoantibodies. Child abuse can sometimes be misidentified and confused with hemophilia, and it is essential to find inconsistencies in the history of how trauma has occurred. Other signs of malnourishment require vigilance, and x-rays may reveal evidence of fractures of different ages. [45] [46]

Von Willebrand Disease -- Differential Diagnosis

Factor X deficiency Factor XI deficiency Hemophilia A Hemophilia B Bernard-Soulier syndrome Platelet function defects Antiplatelet drug ingestion Fibrinolytic defects

Hemophilia A -- Differential Diagnosis

Acquired hemophilia Ehlers-Danlos syndrome Factor XI deficiency Glanzmann thrombasthenia Haemophilia C Haemophilia type B Physical child abuse Platelet disorders Von Willebrand disease

Spontaneous iliopsoas muscle hematoma in a patient with von Willebrand disease: a case report.

Iliopsoas hemorrhage is a serious complication of bleeding disorders that occurs most commonly in patients with hemophilia and less commonly in patients with von Willebrand disease. It causes severe pain, muscle dysfunction and occasionally femoral nerve palsy. We describe the case of a patient with von Willebrand disease type 3 with a large iliopsoas hematoma who was treated with a von Willebrand factor concentrate (Humate-P). A 20-year-old Iranian man was referred to our emergency ward because of the gradual onset of right flank pain. He was known to have been diagnosed with von Willebrand disease type 3 at age two years old. Magnetic resonance imaging showed a mass in the right iliopsoas muscle. The diagnosis of iliopsoas hemorrhage and partial femoral nerve palsy was established, and he responded to medical treatment. We report a case of von Willebrand disease type 3 with spontaneous iliopsoas hematoma associated with femoral nerve palsy that was well managed with Humate-P treatment.

List of MeSH codes (C15)

– blood coagulation disorders – coagulation protein disorders – activated protein c resistance – afibrinogenemia – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – von willebrand disease – disseminated intravascular coagulation – blood coagulation disorders, inherited – activated protein c resistance – afibrinogenemia – antithrombin iii deficiency – bernard-soulier syndrome – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hermanski-pudlak syndrome – hypoprothrombinemias – protein c deficiency – thrombasthenia – von willebrand disease – wiskott-aldrich syndrome – platelet storage pool deficiency – hermanski-pudlak syndrome – protein s deficiency

Congenital bleeding disorders in Karachi, Pakistan.

To determine the frequency of inherited bleeding disorders, its complications, and treatment modalities available for its treatment. Cross-sectional study. Patients with a history of bleeding tendency were tested for confirmation of the diagnosis. History and clinical findings were recorded. Laboratory analysis included prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time (BT), and fibrinogen assay. Patients with prolonged APTT were tested for factors VIII (FVIII) and IX (FIX). If FVIII was low, von Willebrand factor: antigen (vWF:Ag) and von Willebrand factor:ristocetin cofactor (vWF:RCo) were performed. When PT and APTT both were prolonged, FV, FX, and FII were tested. Platelet aggregation studies were done when there was isolated prolonged BT. Urea clot solubility test was done when all coagulation tests were normal. All patients with hemophilia A and B were evaluated for inhibitors. Of the 376 patients, inherited bleeding disorder was diagnosed in 318 (85%) cases. Median age of patients was 16.4 years. Hemophilia A was the commonest inherited bleeding disorder that was observed in 140 (37.2%) followed by vWD 68 (18.0%), platelet function disorders 48 (12.8%), and hemophilia B in 33 (8.8%) cases. We also found rare congenital factor deficiencies in 13 (3.4%), low VWF in 11 (3.0%) participants and 5 (1.3%) in female hemophilia carriers. Hemarthrosis was the most frequent symptom in hemophilia A and B (79.7%) involving knee joint. Inhibitor was detected in 21 (15%) cases. Fresh frozen plasma/cryoprecipitate were the most common modality of treatment. In 58 patients, no abnormality was detected in coagulation profile. Hemophilia A and vWD are the most common congenital bleeding disorders in this study. Hemarthrosis involving knee joint was the most common complication. Inhibitor was detected in a significant number of patients. Plasma is still the most common modality of treatment.

Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome.

The authors report a case of hemarthrosis complicated by severe anemia related to a congenital connective tissue disease: Ehlers-Danlos syndrome. A boy fell down and suffered tumefaction of both knees with bilateral rupture of the rotula tendon. He underwent surgical reinsertion of each tendon on the rotula. He later showed an unexpected ongoing hematic effusion, with severe anemia. He was screened for coagulation disorders with no results. On taking a more detailed history and investigating the patient's phenotypical features, the authors diagnosed Ehlers-Danlos syndrome, hypermobile variant. The hemarthrosis and anemia were thus concluded to be consequences of excessive tissue fragility due to a congenital connective tissue disease.

Clinical profile of hemophilia patients in Jodhpur Region.

Hemophilia is widely distributed all over the world, but little is known about its clinical profile in resource-limited regions. An insight into its clinical spectrum will help in the formulation of policies to improve the situation in these areas. To study the clinical profile of hemophiliacs (age <18 years) in Jodhpur region and screen them for transfusion-transmitted infections. A cross-sectional study conducted in the Department of Pediatrics, Umaid Hospital, Dr. S. N. Medical College, Jodhpur, over a period of 12 months. Out of a total of 56 cases enrolled, 51 (91%) cases were diagnosed as hemophilia A while 5 (9%) were diagnosed as hemophilia B. Positive family history was found in 26 (46%) cases. According to their factor levels, 25 (44%) cases had severe disease, 20 (36%) had moderate disease, and 11 (20%) had mild disease. The mean age of onset of symptoms and diagnosis was 1.73 ± 1.43 and 3.87 ± 3.84 years, respectively. First clinical presentation was posttraumatic bleed in 20 (36%), gum bleeds in 17 (30%), epistaxis in 4 (7%), joint bleeds in 4 (7%), skin bleeds in 4 (7%), and circumcision bleed in 3 (5%) cases. Knee joint was the predominant joint affected by hemarthrosis in 38 (68%), followed by ankle in 29 (52%), elbow in 20 (36%), and hip joint in 7 (13%) cases. All patients had a negative screening test for transfusion-transmitted infections. Occurrence of posttraumatic bleeds and gum bleeds in an otherwise normal child should warn the clinician for evaluation of hemophilia.

Bernard–Soulier syndrome

Differential diagnosis The differential diagnosis for Bernard–Soulier syndrome includes both Glanzmann thrombasthenia and pediatric Von Willebrand disease. BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease. Following is a table comparing its result with other platelet aggregation disorders: Treatment Bleeding events can be controlled by platelet transfusion. Most heterozygotes, with few exceptions, do not have a bleeding diathesis. BSS presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury. In the event of an individual with mucosal bleeding tranexamic acid can be given. The affected individual may need to avoid contact sports and medications such as aspirin, which can increase the possibility of bleeding. A potential complication is the possibility of the individual producing anti-platelet antibodies.

Von Willebrand Disease -- History and Physical

In the case of a qualitative defect, von Willebrand disease may mimic hemophilia and predominantly present with bleeding into soft tissues, joints, and hematuria rather than mucocutaneous bleeding. Sometimes, type 2N von Willebrand disease is misdiagnosed as hemophilia.

The role of ultrasonography in the diagnosis of the musculo-skeletal problems of haemophilia.

Recurrent haemarthrosis is the final cause of haemophilic arthrosic disease in haemophilia patients. Therefore, it is essential to diagnose it early, both clinically and by imaging. In addition, haemophilia patients experience chronic synovitis, joint degeneration, muscle haematoma and pseudotumours. The objective of this article is to highlight the value of ultrasounds in the diagnosis and control of the evolution of musculo-skeletal problems in haemophilia patients. To this end, we have performed a literature search in the PubMed, Web of Science(®) (WOS) and SciVerse bases, using the following keywords: hemophilia or haemophilia and ultrasonography (US), ultrasound, echography and sonography. The search was limited to studies published in English between the years 1991 and 2011, finding a total of 221 references. After reviewing the title or abstract for evidence of the use of US for the diagnosis of musculo-skeletal lesions in haemophilia, we selected 24 of these references. We added data collected from our experience to the most important data found in the references. Our main conclusion is that US is highly valuable for the diagnosis of musculo-skeletal diseases in haemophilia. It is a fast, effective, safe, available, comparative, real-time technique that can help us confirm the clinical examination. It is particularly important in acute haemarthrosis, as it can be used to objectively identify the presence of blood in the joints, measure its size, pinpoint its location, assess its evolution and confirm its complete disappearance.

Nonsurgical synovectomy in the treatment of arthropathy in Von Willebrand's Disease.

Von Willebrand's disease is the most common inherited bleeding disorder, with an overall prevalence in the general population of 0.8% to 1.3%. Hemarthrosis occurs mainly in the severest forms of the disease (type III), with a frequency of 3.5% to 11%, and can cause severe arthropathy similar to that seen in hemophilia. We retrospectively reviewed our experience with nonsurgical synovectomy in the treatment of recurrent hemarthrosis with arthropathy in patients with von Willebrand's disease. Four of our six patients had type III disease and the remaining two had type II disease. The age range was 13 to 63 years. The frequency of hemarthrosis prior to synovectomy was one to four per month. One (n = 2) or both (n = 1) knees were treated in 4 cases, one (n = 1) or both (n = 1) ankles in 3 cases and an elbow in one case. We used yttrium 90 in a dose of 5 mCi for one knee, rhenium 186 in a dose of 2 mCi for two ankles and the elbow and osmic acid for two knees and one ankle. Clinical and radiological results were evaluated six months after synovectomy using the World Federation of Hemophilia score. Radiologic lesions remained stable and clinical manifestations improved in every case (p < 0.05). Five patients achieved a complete remission. Safety was satisfactory. The clinical efficacy of synovectomy done, using radiocolloids or osmic acid in arthropathy due to von Willebrand's disease, seems similar to that in hemophilia.

The value of ultrasonography in detecting early arthropathic changes and contribution to the clinical approach in patients of hemophilia.

PURPOSE\AIM: Hemophilia affects the blood clotting process, is a genetic disease characterized by recurrent bleeding. The hemophilia early arthropathy detection with ultrasound (HEAD-US) procedure and scoring method were designed for the detection of early changes in affected joints of patients. In this article, it was aimed to detect early arthropathic changes in the joints of hemophilia patients with the HEAD US scoring system and to investigate its clinical contribution. It was aimed to investigate the effectiveness of HEAD-US scoring in showing early joint damage in subclinical hemophilia cases and its contribution to treatment. The present study included 50 hemophilia patients who were admitted to Departments of Pediatric and Adult Hematology for routine follow-up. During routine follow-up controls, patients were scored by physical examination and HJHS 2.1 and by ultrasonography and HEAD US. Statistical tests were used to analyze joint health status and the results of US examination in the patient group. A total of 294 joints (elbow n = 100, knee n = 94, ankle n = 100) were evaluated by ultrasonography. The mean HJHS and HEAD-US scores of the patients were 14.94 ± 15.18 and 15.6 ± 12.6, respectively. HEAD-US is accepted to be more sensitive than HJHS in detecting early signs of arthropathy. Detection of early abnormalities by ultrasonography will enable the development of individualized treatment protocols and to the prevention of arthropathy development.

Joint assessment in von Willebrand disease. Validation of the Haemophilia Joint Health score and Haemophilia Activities List.

Assessment of clinical outcome after joint bleeding is essential to identify joint damage and optimise treatment, to prevent disability. However, disease-specific tools to assess the musculoskeletal status in patients with von Willebrand disease (VWD) are lacking. We aimed to determine validity and reliability of the Haemophilia Joint Health Score (HJHS) and Haemophilia Activities List (HAL) in patients with Von Willebrand disease (VWD). Ninety-six patients with VWD were included (mean age 46 years) of whom 27 had more than five documented joint bleeds. The HJHS was performed in all patients and all patients completed the HAL and Impact on Participation and Autonomy (IPA) questionnaires. Health-related quality of life (SF36) results were obtained from the prior 'Willebrand in the Netherlands' study. Joint X-rays of knees, elbows and ankles were scored according to Pettersson (PS). Internal consistency of the HJHS (Cronbach's α (α)=0.75) and HAL (α=0.89) were good. Inter-observer agreement of the HJHS was good (ICC 0.84; Limits of Agreement ± 10.3). The HJHS showed acceptable correlation with the X-ray PS (Spearman's r (r<subs</sub)>0.60 all joints) and HAL (r<subs</sub=0.71). The HAL also showed acceptable correlation with the SF36 physical functioning (r<subs</sub=0.65) and IPA (r<subs</sub=0.69). Hypothesis testing showed adequate discriminative power of both instruments: in patients with a history of >5 versus ≤ 5 joint bleeds (median HJHS 10 vs 2 (p<0.01); median HAL 77 vs 98 (p<0.01)), independent from age. In conclusion, both the HJHS and HAL are feasible to assess clinical outcome after joint bleeds in VWD.

Vascular-type Ehlers-Danlos syndrome caused by a hitherto unknown genetic mutation: a case report.

Vascular-type Ehlers-Danlos syndrome is an autosomal dominant disease that causes arterial spurting, intestinal perforation, uterine rupture and hemopneumothorax due to decreased production of type III collagen. The average age at death is 48 years old, and it is considered to be the most severe form of Ehlers-Danlos syndrome. We report the case of a 64-year-old Japanese woman and her 38-year-old daughter who were diagnosed with this disease. A 64-year-old Japanese woman was referred to our hospital because of right anterior chest pain following cough and pharyngeal discomfort. Pleurisy was suspected due to the presence of right pleural effusion, so the next day she was referred to our department, where a detailed examination led to the diagnosis of hemothorax. The bleeding that caused the right hemothorax was difficult to control, so our patient was transferred to the Department of Thoracic Surgery for hemostasis control. Our patient's personal history of uterine hemorrhage and skin ulcers, as well as the finding of skin fragility during surgery, were indicative of a weak connective tissue disease; therefore, after improvement of the hemothorax, a genetic analysis was performed. This revealed a heterozygous missense mutation in COL3A1, c.2411 G>T p.Gly804Val (exon 36). A detailed investigation conducted at a later date revealed that her daughter also had the same genetic mutation. This led to the diagnosis of vascular-type Ehlers-Danlos syndrome characterized by a new gene mutation. We report a new genetic mutation associated with vascular-type Ehlers-Danlos syndrome. We present the clinical and imaging findings, and the disease and treatment course in this patient. We believe this information will be important in treating future cases of vascular-type Ehlers-Danlos syndrome in patients with this mutation.

Gastric perforation leading to the diagnosis of classic Ehlers-Danlos syndrome: a case report.

Ehlers-Danlos syndrome is a clinically and genetically heterogeneous group of heritable connective tissue disorders caused by a defect in collagen synthesis and structure. The vascular subtype (Ehlers-Danlos syndrome IV) is reported to be associated with a higher incidence of gastrointestinal perforations. The most reported site of perforation is the colon, followed by the small bowel. Perforation of the stomach is very rare, and there are no reported cases to date of classic types I and II. We present the case of a 14-year-old Saudi girl who visited our emergency department with abdominal pain and vomiting. Initially, she was diagnosed with gastroenteritis and discharged once her condition stabilized. After 48 hours, she developed severe abdominal pain with recurrent vomiting and peritonitis evident on clinical examination. Initial abdominal x-ray failed to show any free air; however, enhanced computed tomography revealed free air and contrast extravasation in the proximal gut. During exploratory laparotomy, a large perforation was found on the anterior wall of the stomach due to the underlying ischemia. The posterior wall had ischemic mucosa with an intact healthy serosa. A free-hand partial gastrectomy was performed to resect all ischemic parts of the stomach. Detailed examinations and laboratory workup were carried out after the surgery to figure out the possible underlying cause. The clinical findings during the physical examination supported marfanoid features. Marfan's syndrome and related disorders sequencing panel was requested, and Deoxyribonucleic acid (DNA) samples were sent. Given results were supporting the diagnosis of classical Ehlers-Danlos syndrome, the patient was labeled as a case of Ehlers-Danlos syndrome. During the postoperative period, she developed a wound infection that was managed successfully with vacuum-assisted closure dressing. She recovered well without gastrointestinal sequelae in the 4 years of follow-up. Heritable systemic connective tissue diseases must be given serious consideration in young patients with unusual spontaneous perforation. Such patients might develop life-threatening conditions that require immediate intervention. Hence, correct and timely diagnosis is important to prepare for the anticipated complications.

Hemophilic arthropathy in patients with von Willebrand disease.

von Willebrand disease (VWD) affects approximately 1% of the population. Joint bleeds are not a predominant symptom of VWD, however they do occur. Especially in patients with severe VWD, joint bleeds have been described in up to 45% of the patients. Recurrent hemarthroses can lead to joint destruction which is the main cause of morbidity, as is observed in hemophilia patients. In VWD however, the occurrence, severity, onset, treatment and impact of arthropathy have not been well described. This literature review summarizes all publications on arthropathy in patients with hereditary VWD, published until 1-5-2012. Joint bleeds in VWD are associated with low FVIII levels and seem to occur at young age. Depending on the severity of VWD, arthropathy occurs in 2-30% of the patients. Radiological joint damage can be seen but has not systematically been studied. Arthropathy can affect daily functioning and interfere with the quality of life. For acute management of joint bleeds FVIII/VWF concentrates can be used in VWD patients unresponsive to desmopressin or desmopressin in responsive VWD patients. When severe joint bleeds have caused synovitis and arthropathy, chemical or radioactive synovectomy and surgical joint procedures seem feasible to prevent further joint damage. Additional research is needed to learn more about the severity, onset and impact of arthropathy in VWD. Ongoing studies will hopefully answer the question whether prophylactic treatment with coagulation factor concentrates should be considered standard of care in severe VWD to prevent arthropathy.

Cervical artery dissection

Spontaneous Spontaneous cervical artery dissections are dissections that occur without any trauma to the neck. More specifically, this can include potential causes such as hereditary connective tissue diseases, family history of strokes, infections and other miscellaneous causes such as smoking, hypertension, migraines and contraceptive use. Hereditary connective tissue diseases include autosomal polycystic kidney disease, Ehlers-Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, and osteogenesis imperfecta type 1 although studies have shown that the link between hereditary connective tissue diseases and cervical artery dissection is low, ranging from 0-0.6% in one study and 5-18% in another study.

Study of clinical characteristics, presentation, and complications among patients with congenital coagulation disorders.

To study the clinical characteristic, presentation, complications in patients with congenital coagulation disorders who attended the Congenital Coagulation Disorders Center, Baghdad, Iraq. This cross-sectional study was conducted in the Center of Congenital Coagulation Disorders, Al-Mansour Pediatric Teaching Hospital, Baghdad, Iraq between March 2008 and August 2008. The sample comprised 243 patients with different congenital coagulation disorders. We collected the data through structured questionnaire form and carried out the physical examination of the patient under the supervision of the physician-in-charge at the center. Hemophilia and Von Willebrand Disease (VWD) constituted 90.1% of the sample, while rare bleeding disorders constituted 9.9%. Most patients (82.7%) have had onset of symptoms during the first year of life. Clinically, 52.7% of patients presented with hemarthroses were hemophiliacs and factors X deficiency. This distribution was also true for joint limitations. Most patients were hemophiliacs and the highest prevalent of symptom was 6-12 months old, and the diagnosis of the disease was highest within one month after the onset of symptoms. Most patients with joint limitation was hemophiliacs and approximately 50% had limitation of 3 or more joints.

[A case of type 2N von Willebrand disease with homozygous R816W mutation of the VWF gene in a Nepalese woman].

Type 2N von Willebrand disease (vWD) can be confused with hemophilia A due to decreased factor VIII levels and a bleeding tendency, and differential diagnosis is of importance for providing the optimal treatment and genetic counseling. For the accurate diagnosis of type 2N vWD, von Willebrand Factor (vWF) function tests, multimer assay and gene mutation analysis are needed. The patient was a 38-yr-old Nepalese woman with a history of bleeding manifestations from childhood, such as hemarthrosis, intramuscular hematoma, and menorrhagia. Family history revealed that her mother and elder brothers also had bleeding manifestations from childhood. When she had a laparotomy in 1991, she was diagnosed as hemophilia A with factor VIII level of 3.6% and was transfused with whole blood, factor VIII and cryoprecipitates. In June 2007, she was admitted to our hospital for further evaluation of bleeding tendency. Blood tests revealed normal CBC; bleeding time, 2 min; PT, 14.9 sec (11-14 sec); aPTT, 51.2 sec (24-38 sec); and factor VIII, 4.9% (50-150%). The prolonged aPTT was corrected by 1:1 mixing test to the levels of 106% and 84%, respectively, before and after 2 hr-incubation at 37degrees C. No abnormalities were found in the vWF antigen level (71.3%), ristocetin cofactor assay (130.4%), and multimer assay. Direct DNA sequencing of the VWF gene revealed homozygous missense mutation located in exon 19, c.2446C>T (p.Arg816Trp), confirming the diagnosis of type 2N vWD.

Clinical features of children, adolescents, and adults with coexisting hypermobility syndromes and von Willebrand disease.

We present five patients with coexistent von Willebrand disease (VWD) and Ehlers-Danlos syndrome and 21 with VWD and joint hypermobility. Females outnumbered males ten to three, Beighton scores were documented in 58% (15 of 26 patients), and several patients experienced moderately severe bleeding. We believe coexistent hypermobility disorder with VWD potentially affects bleeding severity and want to raise awareness among hematologists. Evaluation by geneticists is recommended because of the varying complexities observed across the disease spectrum, and the availability of new genetic tests should lead to more accurate diagnoses for the various hypermobility disorders.

Bleeding time

Normal values fall between 3 – 10 minutes depending on the method used. A disadvantage of Ivy's method is closure of puncture wound before stoppage of bleeding. Duke's method With the Duke;s method, the patient is pricked with a special needle or lancet, preferably on the earlobe or fingertip, after having been swabbed with alcohol. The prick is about 3–4 mm deep. The patient then wipes the blood every 30 seconds with a filter paper. The test ceases when bleeding ceases. The usual time is about 2–5 minutes. This method is not recommended and cannot be standardized because it can cause a large local hematoma. Interpretation Bleeding time is affected by platelet function, certain vascular disorders and von Willebrand Disease—not by other coagulation factors such as haemophilia. Diseases that cause prolonged bleeding time include thrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier disease, and Glanzmann's thrombasthenia.

Aortic aneurysm

Risk factors Coronary artery disease Hypertension Loeys-Dietz Syndrome Hypercholesterolemia Hyperhomocysteinemia Elevated C-reactive protein Tobacco use Alcohol use Peripheral vascular disease Marfan syndrome Ehlers-Danlos type IVO Bicuspid Aortic Valve Syphilis IgG4-related disease Pregnancy Chronic obstructive sleep apnea Pathophysiology An aortic aneurysm can occur as a result of trauma, infection, or, most commonly, from an intrinsic abnormality in the elastin and collagen components of the aortic wall. While definite genetic abnormalities were identified in true genetic syndromes (Marfan, Elher-Danlos and others) associated with aortic aneurysms, both thoracic and abdominal aortic aneurysms demonstrate a strong genetic component in their aetiology.

Early orthopaedic challenges in haemophilia patients and therapeutic approach.

There is growing evidence that subclinical joint bleeding early in life may lead to subtle changes in joint function, gait, and muscle development in young children with haemophilia. The early identification of such changes provides an opportunity for clinicians to intervene before irreversible structural changes occur. We have undertaken motion analysis of the knee in 273 children (mean age 9.8 years) with haemophilia A, haemophilia B, or von Willebrand disease and compared the results with those from 200 healthy age- and sex-matched controls (mean age 10.3 years). We have also completed detailed orthopaedic assessments and evaluated overall fitness in most of these children. There was a clear correlation between total motion score and age: r(2)=0.47 for the healthy children and r(2)=0.69 for the haemophilic children. The differences were most striking in children aged 3-4 years. Significant between-group differences were also observed in the comparison of knee bends, gait scores, and rhythmicity. Orthopaedic examinations revealed previously clinically silent pressure pains in the ligaments of the knee joints of 38% of children and in the ligaments and capsule of the ankle joints of 60% of children. The five-item fitness check showed significant deficits relative to controls in overall fitness, endurance, coordination, and flexibility. Children and adolescents with haemophilia show significant functional impairments relative to normal controls. Early comprehensive assessments of the musculoskeletal system should be made so that individualized physical, physiotherapy, and sports therapy programmes can be developed.