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Acquired Bleeding Disorders This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0. CME Acquired bleeding disorders N Alli,1 MB BCh, FCPathHaem (SA); J Vaughan,1 MB BCh, FCPathHaem (SA), MMed Haem; S Louw,1 MB BCh, FCPathHaem (SA), MMed Haem; S Moodly,1 NDip MedTech, NHD MedTech, MSc Medicine; M Patel,2 MB ChB, FCP (SA), MMed, FRCP (Lond), PhD 1 Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and National Health Laboratory Service, Johannesburg, South Africa 2 Department of Clinical Haematology, Division of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, and School of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: N Alli ([email protected]) Bleeding disorders are divided into two broad categories, i.e. inherited, discussed in part 1 of this CME series, and acquired, which is the subject of discussion in the current issue. In contrast to inherited haemorrhagic disorders, where generally a single haemostatic abnormality is found, multiple haemostatic defects are commonly present in acquired haemorrhagic diseases. Bleeding is often a presenting manifestation of systemic disease and requires a multidisciplinary team approach. Iatrogenic causes of abnormal haemostasis are of particular importance to the emergency physician. This CME article aims to provide an approach to the diagnosis and management of acquired bleeding disorders encountered in general practice. S Afr Med J 2018;108(3):159­165. DOI:10.7196/SAMJ.2018.v108i3.13158 Suspected acquired bleeding disorder Acquired bleeding disorders encompass a heterogeneous group of conditions with varied and often complex aetiologies. Baseline screening: Clinical evaluation of patients presenting INR, PTT, FBC and blood smear with a bleeding disorder often provides clues as to whether the abnormality resides in coagulation factors, platelets or blood vessels. INR ↑ INR ↑ PTT ↑ INR ↑ INR N INR N A detailed history and complete physical PTT ↑ PTT N INR N PTT ↑ PTT N PTT N Platelets N Platelets N Platelets N Platelets ↓ Platelets N Platelets ↓ examination are therefore imperative for meaningful interpretation of laboratory Warfarin DIC Blood smear tests, as complex haemostatic derangements Early liver disease Liver disease Early DIC may accompany specific clinical scenarios. Vit K deficiency Interpretation based solely on laboratory Red cell fragments tests may be misleading. Warfarin/super-warfarin Does not Corrects on Functional platelet Blasts or No evidence of For discussion purposes, acquired Vit K deciency correct on mixing studies abnormalities (renal LER inltrate Liver disease mixing studies failure, antiplatelet ‡ bleeding disorders are divided into Dys/hypobrinogenaemia agents, hypothermia, MAHA Acquired factor X hypocalcaemia, acidosis) the following groups: (i) clotting factor deciency* Vascular defects Leukaemia ITP deficiencies; (ii) abnormalities of platelet Heparin Consider Bone marrow Bone marrow number or function; (iii) vascular defects; . Acquired factor inherited causes inltration aplasia inhibitor of factor Megakaryocytic or (iv) various combinations of the three Antiphospholipid deciencies suppression antibody† Hypersplenism, abovementioned disorders. The last group etc. includes liver disease, disseminated intra­ vascular coagulation (DIC) and chronic Fig. 1. Laboratory approach to a suspected acquired bleeding disorder. (LER = leuko-erythroblastic kidney disease. blood reaction (signifying possible bone marrow infiltration); INR = international normalised Basic laboratory tests (partial thrombo­ ratio; PTT = partial prothrombin time; N = normal; FBC = full blood count; DIC = disseminated plastin time (PTT), international normalised intravascular coagulation; vit = vitamin; MAHA = microangiopathic haemolytic anaemia; ITP = ratio (INR), full blood count (with peripheral immune thrombocytopenia.) (*Associated with amyloidosis; †Antiphospholipid antibodies usually blood smear assessment)) and accurate cause thrombosis, not bleeding; however, rare instances of prothrombin deficiency can be associated clinical information form a basis for further with bleeding; ‡Except for DIC.) investigations. To this end, an algorithmic approach is incorporated to serve as a guide that neutralise specific coagulation factors. spontaneously as auto­antibodies, resulting (Fig. 1). These antibodies can develop against any in the bleeding condition termed acquired factor in the coagulation cascade, but haemophilia. The presence of inhibitors Clotting factor factor VIII (FVIII) is most frequently is suspected in a patient with abnormal deficiencies involved, and may develop in patients bleeding without any prior bleeding Coagulation factor inhibitors with inherited haemophilia A as an immune diathesis, or when a patient with known Coagulation factor inhibitors are antibodies response to factor­replacement therapy, or haemophilia has more extreme bleeding 159 March 2018, Vol. 108, No. 3 CME than usual or fails to achieve haemostasis after factor replacement. Management Prolongation of the screening clotting assays, i.e. INR and/or PTT, Management of patients with acquired inhibitors entails: (i) control with failure to correct on mixing with normal plasma, should alert of bleeding with haemostatic agents, as for inherited haemophilia the attending clinician to the presence of an inhibitor. patients with inhibitors (part 1);[1] (ii) eradication of the inhibitor with immune modulating agents (e.g. corticosteroids and rituximab); Factor inhibitors in inherited haemophilia A and B and (iii) treatment of the underlying pathogenic disease process. This has been discussed in part 1 of this series.[1] Thrombotic complications, including myocardial infarctions and cerebrovascular accidents, can occur in relation to haemostatic agent Acquired haemophilia A administration.[2­6] Acquired haemophilia A (AHA) is a rare (~1 per million of the population per year), potentially life­threatening auto­immune Vitamin K deficiency bleeding disorder due to inhibiting auto­antibodies (inhibitors) Vitamin K is responsible for gammacarboxylation of FII, FVII, FIX against endogenous FVIII. Although documented as a rare condition, and FX, as well as for proteins C, S and Z. Gammacarboxylation AHA is probably under­diagnosed. Mortality in cases of AHA enables binding to phospholipid membranes via Ca++ bridges. Vita­ exceeds 20% in patients >65 years of age and those with comorbid min K deficiency is encountered in various clinical scenarios and causes disease, such as underlying malignancies. Although death directly include: haemorrhagic disease of the newborn (currently termed vitamin due to excessive bleeding is not common, it does contribute to K deficiency bleeding), reduced dietary intake, prolonged antibiotic use, morbidity, thereby increasing the duration and cost of hospitalisation cholestatic liver disease, malabsorption, and drugs, e.g. anticonvulsants (e.g. delayed wound healing and increased transfusion requirements). and warfarin. The mode of therapy is oral or intravenous vitamin K, and Immune modulation therapy to eradicate the inhibitor also patients with severe bleeding are treated with fresh­frozen plasma (FFP) contributes significantly to cost and mortality. In contrast to inherited or prothrombin complex concentrate (PCC). haemophilia, AHA affects both males and females and is most common in the elderly (median age 64 ­ 78 years). AHA can, Anticoagulation and antiplatelet agents however, occur in younger patients in relation to pregnancy and Warfarin auto­immune diseases. Most cases are idiopathic, but underlying Warfarin, a coumarin derivative, inhibits the enzyme vitamin K precipitating causes include pregnancy, auto­immune diseases (most epoxide reductase and thereby impairs production of vitamin commonly rheumatoid arthritis), infection, malignancy and drugs K­dependent coagulation factors, i.e. FII, FVII, FIX and FX, as well (e.g. interferon alpha). Research suggests that the breakdown of as proteins C, S and Z. Patients treated with coumarin derivatives immune tolerance to FVIII is due to both genetic and environmental have reduced concentrations of these coagulation factors, with factors. The majority (94.6%) of patients present with bleeding, consequent increased risk of bleeding that is amplified when the which can either be spontaneous or provoked, e.g. after surgery. INR is supratherapeutic (particularly >5). Other factors that increase The site of bleeding is most commonly subcutaneous, followed by the bleeding risk include advanced age, a prior history of bleeding, the gastrointestinal tract, intramuscular sites and genito­urinary previous stroke, hypertension, other drugs associated with a bleeding tract. Bleeding in other sites (intracranial and retroperitoneal) can risk (such as non­steroidal anti­inflammatory drugs (NSAIDs)), and occur, but in contrast to congenital haemophilia, joint bleeding is abnormal liver or renal function. infrequent. Because of the second­order (non­linear) kinetics of Management of warfarin­associated bleeding depends on the the anti­FVIII antibodies in AHA, FVIII levels are not predictive of severity of bleeding, the level of the INR and the indication for bleeding risk and patients can have serious bleeding despite having anticoagulation. For over­warfarinisation without bleeding, stoppage only modestly reduced laboratory­determined FVIII activity
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