Characterization and treatment of congenital thrombotic thrombocytopenic purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n = 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P = .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P = .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P = .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality.

Hepatitis C infection and outcomes in the Scottish haemophilia population.

Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow-up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty-four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV-infected cohorts. Liver transplantation has been used successfully for the treatment of end-stage liver failure and hepatocellular carcinoma.

Assessment of von Willebrand disease as a risk factor for primary postpartum haemorrhage.

It is not clear whether von Willebrand disease (VWD) is associated with an increased risk of postpartum haemorrhage (PPH). We assessed the effect of VWD on PPH in a case-control study. Logistic regression was used to test for differences in the odds of PPH in deliveries to women with and without VWD, before and after adjustment for known risk factors. A total of 62 deliveries in 33 women with VWD were compared with controls matched for age, year of delivery and parity. Primary PPH was observed in 12/62 (19.4%) deliveries in women with VWD and 16/124 (12.9%) controls. The unadjusted odds ratio (OR) for VWD as a risk factor for PPH was 1.62 (95% CI 0.75-3.49, P = 0.22). After adjustment for other risk factors for PPH, the OR for VWD as a risk factor for PPH was 1.31 (95% CI 0.48-3.60, P = 0.60). PPH was observed in 7/24 (29%) deliveries in women known prepregnancy to have VWD. The unadjusted odds for VWD as a risk factor for PPH in this group was significantly greater than the control group (OR 2.78 (95% CI 1.03-7.49) P = 0.043) and remained significant after adjusting for other significant risk factors (OR 3.41 (95% CI 1.07-10.9) P = 0.038). VWD in itself may not be a significant risk factor for PPH, however, women known to have VWD predelivery may represent an at risk sub-group.

Perceived hazards of transfusion: can a clinician tool help patients' understanding?

OBJECTIVE: To evaluate the use of a tool prompting counselling behaviour for blood transfusion by assessing clinicians' self-reported counselling behaviours, and changes in patients' beliefs about transfusion. METHODS AND MATERIALS: Mixed quantitative and qualitative methodology undertaken in two phases. In phase 1, clinicians' responses (n = 12) to a semi-structured questionnaire were analysed to identify the content of discussions with patients about different aspects of receiving a blood transfusion. The content of discussions was coded using illness representation concepts from the Common Sense Self-Regulation Model. Phase 2 included patients (n = 14) scheduled for elective surgery who completed a questionnaire on their beliefs about transfusion before and after counselling. RESULTS: The most frequently coded illness representations targeted by clinicians using the tool were 'consequence of treatment' (32%) and 'cure/control' (30.5%). Two patient beliefs showed significant change following counselling using the checklist. After counselling, patients were more likely to disagree/strongly disagree with the statement that doctors relied too much on transfusion (P = 0.034) and more likely to agree/strongly agree that blood transfusion can result in new health problems (P = 0.041). CONCLUSION: This pilot study provides insight into how clinicians use a tool for blood transfusion counselling and shows the potential to influence patients' beliefs about transfusion. Whilst the checklist has a role in standardising practice, this pilot study highlights the need for optimising its use before undertaking a fully randomised evaluation of the tool.

UKHCDO guidelines on the management of HCV in patients with hereditary bleeding disorders 2011.

Chronic HCV infection continues to be of significant clinical importance in patients with hereditary bleeding disorders. This guideline provides information on the recent advances in the investigation and treatment of HCV infection and gives GRADE system based recommendations on the management of the infection in this patient group.

Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology.

The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 x 10(9)/l transfusion of platelets should be considered. In non-bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1 g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co-existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half-life and reversibility. Weight adjusted doses (e.g. 10 mu/kg/h) may be used without the intention of prolonging the APTT ratio to 1.5-2.5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24 microg/kg/h for 4 d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30 x 10(9)/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half-life approximately 20 min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1 g every 8 h).

Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures. British Committee for Standards in Haematology.

Unselected coagulation testing is widely practiced in the process of assessing bleeding risk prior to surgery. This may delay surgery inappropriately and cause unnecessary concern in patients who are found to have 'abnormal' tests. In addition it is associated with a significant cost. This systematic review was performed to determine whether patient bleeding history and unselected coagulation testing predict abnormal perioperative bleeding. A literature search of Medline between 1966 and 2005 was performed to identify appropriate studies. Studies that contained enough data to allow the calculation of the predictive value and likelihood ratios of tests for perioperative bleeding were included. Nine observational studies (three prospective) were identified. The positive predictive value (0.03-0.22) and likelihood ratio (0.94-5.1) for coagulation tests indicate that they are poor predictors of bleeding. Patients undergoing surgery should have a bleeding history taken. This should include detail of previous surgery and trauma, a family history, and detail of anti-thrombotic medication. Patients with a negative bleeding history do not require routine coagulation screening prior to surgery.

Measurement of rivaroxaban concentrations demonstrates lack of clinical utility of a PT, dPT and APTT test in estimating levels.

INTRODUCTION: Rivaroxaban concentrations were measured in 127 inpatient samples using an HPLC-MS/MS assay. METHODS: We compared this measurement with a calibrated anti-Xa assay and performed PT, aPTT and dilute PT tests to assess the value of clot-based assays in clinical decision-making. RESULTS: The correlation between the anti-Xa assay and the HPLC-MS/MS at therapeutic concentrations was strong (R2  = 0.98). The PT, RecombiPlasTin 2G, and aPTT, Actin FS, showed a linear dose-response but poor correlation (R2  = 0.32 and 0.44, respectively) and at dilutions of 1 in 150 to 1 in 750 the dilute PT assay also showed poor correlation with rivaroxaban concentrations measured by specific assays. A normal PT or aPTT alone did not identify a likely safe rivaroxaban concentration to allow surgery or invasive procedures, but the combination of normal PT and aPTT identified a group of patients with rivaroxaban levels less than 90 ng/mL. Combined normal PT and aPTT had specificity and sensitivity of 0.97 (95% CI 0.92-0.99) and 0.37 (95% CI 0.1-0.74) for a rivaroxaban concentration < 32 ng/mL. CONCLUSIONS: The PT and aPTT show poor correlation with rivaroxaban levels measured by calibrated anti-Xa and HPLC-MS/MS assays. A normal combined PT and APTT identified low rivaroxaban levels with high specificity but lacked sensitivity. The dPT assay at several dilutions could not be used to quantify rivaroxaban in clinical samples. The utility of these PT, aPTT and dilute PT assays in a clinical setting is very limited, and results generated must be interpreted with caution.

Approach to the diagnosis and management of mild bleeding disorders.

Symptoms suggestive of the presence of a mild bleeding tendency are commonplace. Whilst the majority with such symptoms are healthy, it is important to identify those with bleeding disorders in order to manage symptoms, to minimize risk from invasive procedures and to avoid unnecessary exposure to blood products. Thorough clinical assessment remains the cornerstone of the diagnostic strategy for mild bleeding disorders, although the sensitivity and specificity of the clinical history and examination are limited. When clinical suspicion is aroused the use of a staged protocol of laboratory investigations is appropriate, but the limitations of currently available tests of primary hemostasis and blood coagulation must be recognized if diagnostic errors are to be avoided. Whilst there is considerable current interest in global assays of hemostasis and coagulation, none has yet been demonstrated conclusively to be more effective than the more standard approach. Iatrogenic bleeding has increasing prominence in clinical practise. The expanding use of anticoagulants and platelet inhibitor drugs has resulted in an increased proportion of the population being at risk of abnormal bleeding. Knowledge of the levels of risk associated with particular drugs and combinations, and the advantages and hazards of interruption of drug use for planned interventional procedures, are essential in order to reduce the incidence of iatrogenic bleeding. Prevention and treatment of hemorrhage in subjects with mild bleeding disorders includes the application of general measures, including attention to surgical technique, measures specific to the precise diagnosis, and less specific treatments that enhance hemostasis and coagulation or inhibit fibrinolysis. The last of these includes the widely prescribed drugs desmopressin, aprotinin, epsilon aminocaproic acid and tranexamic acid. Data are now available on their efficacy and safety in a range of clinical situations.

Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies.

BACKGROUND AND OBJECTIVES: Patients with myeloproliferative disease (MPD) have an increased risk of thrombosis. We studied markers of platelet and coagulation activation in a large cohort of patients with MPD (n = 118) and related this to Janus Kinase 2 (JAK2) V617 F mutation status, a marker of clonality, and the presence of antiphospholipid antibodies (APA), all of which have been associated with thrombosis in MPD. METHODS: D-dimer, thrombin-antithrombin complexes (TAT), prothrombin fragments 1 + 2 (F(1+2)), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin) levels were compared between patients and hypertensive controls (n = 127). Assays for lupus anticoagulant (LA), anticardiolipin antibodies (ACA), antibeta2 glycoprotein 1 antibodies (anti-beta(2)GP1), and antiprothrombin antibodies (alpha-Pro) were also performed. The JAK2 V617F mutation status was determined in the cohort using amplification refractory mutation system (ARMS) polymerase chain reaction. Disease clonality was determined in 54 patients using the HUMARA assay. RESULTS: sP-selectin was significantly increased in patients with MPD (P

An observational study of direct oral anticoagulant awareness indicating inadequate recognition with potential for patient harm.

UNLABELLED: Essentials Ignorance of direct oral anticoagulants' effects on coagulation tests may be a safety issue. An electronic questionnaire was sent to prescribers in NHS Grampian with 143 respondents. We found widespread evidence of inappropriate interpretation of the clinical scenarios given. The study suggests potential for patient harm due to lack of knowledge and education is required. SUMMARY: Background Lack of awareness of the nature of the direct oral anticoagulants (DOACs) combined with the poor correlation between routine coagulation test prolongation and the activity of these drugs represents a potential for patient harm. Objectives To establish the level of awareness of the different DOACs, and to assess whether prescribers were able to recognize the state of anticoagulation in a hypothetical patient. Methods and results An electronic questionnaire was sent by email to prescribers in our health board. Among 143 respondents, we found significant differences in awareness of the currently licensed drugs. Of the respondents, 88%, 80% and 50%, respectively, recognized rivaroxaban, dabigatran, and apixaban. When provided with a routine clinical situation, only 13.5%, 17.5% and 16.8%, respectively, recognized that the hypothetical patient was anticoagulated, and only 55-58% recognized that it was unsafe to proceed with an invasive procedure. Conclusion These results indicate a significant risk for patient harm related to lack of knowledge about this new group of frequently used drugs, and indicate that additional education and training on this subject are required.

Immunological abnormalities in haemophiliacs.

10 years ago, it became apparent that haemophiliacs were developing diseases which were indicative of underlying immunodeficiency. The results of investigation confirmed that many had abnormal immune systems, particularly with regard to cell-mediated immunity. These abnormalities were thought to be a consequence of the use of clotting factor concentrates, and indeed the discovery of HIV and its mode of transmission, confirmed these suspicions. However, it subsequently became clear that HIV infection did not explain all the abnormalities observed. Many in vivo studies have shown that the immune systems of HIV-negative haemophiliacs are not entirely normal, and in vitro studies have shown that clotting factor concentrates per se have a modulating effect on immune function. We have reviewed particularly the abnormalities seen in HIV-negative haemophiliacs and their possible causes, as well as the specific features of HIV infection in haemophiliacs.

An HIV positive haemophiliac with acute lymphoblastic leukaemia successfully treated with intensive chemotherapy and syngeneic bone marrow transplantation.

A 26-year-old HIV positive severe haemophiliac developed Burkitt-type acute lymphoblastic leukaemia with intracranial involvement. He underwent standard combination therapy, and entered complete remission. Syngeneic bone marrow transplantation (BMT) was undertaken; the donor was also HIV positive. The patient died 18 months from transplant of isolated intracranial relapse, with no evidence of systemic relapse. Unlike other types of non-Hodgkin's lymphoma, Burkitt's type occurs in HIV positive patients with relatively normal CD4 cell counts. Remission can be achieved using intensive chemotherapy, and since these patients may otherwise have a reasonable life expectancy, BMT may be appropriate.

Transfusion associated graft versus host disease in an immunocompetent individual following coronary artery bypass grafting.

Transfusion associated graft versus host disease (TA-GVHD) is a rare but commonly fatal complication of transfusion of cellular blood products, which usually occurs in immunosuppressed individuals following transfusion and subsequent engraftment of viable T lymphocytes. Very rarely it may arise in apparently immuno-competent individuals. A case is reported of TA-GVHD in a non-immunocompromised 60 year old white man, resulting from red cell transfusion after coronary artery bypass grafting. HLA typing confirmed homozygosity of the donor for an HLA type shared by the recipient--the classic scenario for the development of TA-GVHD in immunocompetent individuals. The patient died 21 days after transfusion. There is a perceived increased risk of TA-GVHD following bypass grafting and other surgical procedures where cardiopulmonary bypass is required. TA-GVHD is probably underreported and the incidence in the UK is felt to be too low to warrant routine irradiation of cellular products for this group of patients. Clinicians, pathologists, and transfusion centres should be aware of this rare but devastating complication of blood transfusion after cardiac surgery.

Rare acquired bleeding disorders.

Accurate diagnosis of the cause of bleeding is a prerequisite for determination of the optimal therapeutic response. Clinicians are generally aware of the more prevalent hemorrhagic syndromes but some rare acquired conditions are also of importance. In many of these, inhibitors of coagulation factors or of platelet adhesion/aggregation cause bleeding. These inhibitors are generally, but not always, immunoglobulins. In this review, the less common inhibitors of coagulation and hemostasis, as well as some important but rare nutritional, iatrogenic and disease associated hemorrhagic disorders, are described.

Warfarin and epistaxis--a case controlled study.

Patients anticoagulated with warfarin form a small proportion of those admitted with epistaxis annually to ENT units. The authors formed the impression that such patients spend longer in hospital and have more complicated management than controls. A prospective age and sex matched controlled study of 20 consecutive patients admitted with epistaxis whilst anticoagulated was performed. This showed that these patients spent significantly longer in hospital than controls, with an additional expense in the study period of 10,500 pounds for inpatient bed nights alone. The management of these patients is more complicated and there is a subgroup of poorly controlled patients who present most of the problems. A potential solution is to improve community warfarin control and to involve general practitioners and haematologists in the re-establishment of warfarin following admission for epistaxis.

Combined risk factors contributing to cerebral venous thrombosis in a young woman.

Cerebral venous thrombosis is a rare condition affecting predominantly adolescents or young adults. The presentation is often non-specific, and delay in diagnosis is common. The otolaryngologist may be consulted about the radiological findings of lateral sinus thrombosis and mastoid changes. The association of congenital thrombophilia with unusual presentations of venous thrombosis, especially in young individuals is now well documented. We present a case of lateral and sagittal sinus thrombosis complicated by cerebral venous infarction in a girl with protein C deficiency and masked mastoiditis. Unusual forms of venous thrombosis, including cerebral venous thrombosis may develop in association with a single risk factor for thrombosis, but additional risk factors should be sought especially when thrombosis presents in very young individuals. This case draws attention to the multi-causal nature of cerebral venous thrombosis in young adults, and highlights the issue of masked mastoiditis. A coordinated approach by otolaryngological and haematological teams is recommended in such cases.

Oral direct inhibitors of coagulation.

For the first time in 50 years new oral anticoagulants of proven efficacy and with acceptable safety profiles are available for patients with atrial fibrillation and venous thromboembolism. Here is a brief overview of the benefits and possible disadvantages of using these drugs.