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C H A P T E R 40 Acquired coagulation disorders Peter W Collins1 , Jecko Thachil2 and Cheng-Hock Toh3 1 Schoolof Medicine, Cardiff University, University Hospital of Wales, Cardiff, UK...

C H A P T E R 40 Acquired coagulation disorders Peter W Collins1 , Jecko Thachil2 and Cheng-Hock Toh3 1 Schoolof Medicine, Cardiff University, University Hospital of Wales, Cardiff, UK 40 2 Department of Haematology, Manchester Royal Infirmary, Manchester, UK 3 Roald Dahl Centre, Royal Liverpool University Hospital, Liverpool, UK Introduction Tests of coagulation and point-of-care Acquired disorders of haemostasis are a heterogeneous group of testing conditions with varied and often complex aetiologies. Patients may have multiple and overlapping causes for bleeding and dis- Routine tests of haemostasis tinct conditions often have similar pathophysiologies. In order To investigate a patient suspected of an acquired haemostatic to manage acquired haemostatic failure it is important to under- defect, a platelet count is required and examination of the stand the mechanisms by which haemostatic disturbance occurs blood film is often useful. Routine coagulation tests include and how these apply in different ways to a variety of conditions. the prothrombin time (PT), activated partial thromboplastin Systemic disease may present to haematologists with symp- time (APTT), thrombin time (TT) and Clauss fibrinogen level. toms of bleeding or bruising or abnormalities of coagulation Derived fibrinogen assays should not be used because results are tests. Alternatively, patients with known disorders may need likely to be misleading. haematological input to manage symptoms or at the time of inva- If screening tests are abnormal, correction studies help to dis- sive procedures. Assessment of patients with symptoms of bleed- tinguish factor deficiencies from inhibitors. Comparison of TT ing or bruising requires clinical review and laboratory investi- with the reptilase time will establish whether abnormal results gation. Serial laboratory testing is often required because the are due to heparin. Measurement of fibrin breakdown products, haemostatic disturbance may evolve rapidly. The possibility of such as D-dimers, is required for investigation of possible dis- a congenital disorder should be considered. seminated intravascular coagulation (DIC). Further measure- Haematologists are also often involved in the management of ment of individual coagulation factor and von Willebrand factor acutely bleeding patients who may have complex medical condi- (VWF) levels may be required. Assessment of platelet function tions and in whom bleeding is usually multifactorial. Critical to may be useful in some circumstances, through platelet aggre- optimizing the management of these patients is a well-organized gation studies, platelet nucleotides or a bleeding time, although multidisciplinary team approach. Hospitals should have systems these results may be difficult to interpret in the context of an in place to respond rapidly to massive haemorrhage and hospi- acquired haemostatic defect. The role of global platelet function tal transfusion committees should establish protocols for these analysers remains to be defined, but these are available in many medical emergencies. Laboratories should be geared to produc- hospitals. ing accelerated full blood count (FBC) and coagulation results. The rapid supply of blood products and efficient transfer of these Thromboelastometry to the patient is vital to success and ‘Fire drills’ to test responses Tests based on thromboelastometry are point-of-care tests that to emergencies are good practice. assess the viscoelastic properties of whole blood under low-shear Postgraduate Haematology, Seventh Edition. Edited by A Victor Hoffbrand, Douglas R Higgs, David M Keeling and Atul B Mehta. © 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd. 743 Postgraduate Haematology α-angle MA A60 2 mm 20 mm 60 min r time k time Coagulation Fibrinolysis Time Figure 40.1 Representative thromboelastographic trace. conditions (Figure 40.1). Their main advantage is the assessment APTT biphasic waveform of the different components of clot formation, including platelets The multichannel discrete analyser generates an optical and coagulation factors, and rapid availability of results. They are profile charting changes in light transmittance during clot used to guide blood product administration in patients under- formation on the routine APTT. In contrast to the sig- going liver transplantation and cardiopulmonary bypass. Other moidal appearance of a normal APTT waveform, a ‘biphasic’ reported uses include the assessment of coagulation in liver dis- appearance correlates with acquired haemostatic dysfunction ease, neonates, obstetrics and trauma, although more studies (Figure 40.2). The reliability of this method has been validated are required to validate their role. The two main instruments in several reports and correlates with the diagnosis of overt are TEG and ROTEM, which measure the viscoelastic proper- DIC according to the International Society for Thrombosis ties of an evolving clot in similar, but distinct ways. Results are and Haemostasis (ISTH) criteria. This biphasic response is due displayed graphically and show the developing and dissolving to calcium-dependent complex formation between C-reactive clot. Different activators are available and heparinase cups can be protein and very low-density lipoprotein, which has been shown used to investigate heparinized samples. Tests that correlate with to increase thrombin generation. fibrinogen levels are available. If thromboelastometry is used, hospitals should have agreed algorithms for interpretation and Activated clotting time infusion of blood products. This test is used to monitor anticoagulation with heparin dur- ing cardiopulmonary bypass (CPB) surgery. It uses whole blood and has a linear response at the high concentrations of heparin Thrombin generation assays used during CPB. The APTT cannot be used because plasma is These tests measure the amount of thrombin generated over unclottable using this method at these heparin concentrations. time and may reflect an individual’s coagulation potential. They Measured using a specialized analyser, the activated clotting are not available in routine practice. Assays are initiated by the time (ACT) reference range varies according to the method and addition of a trigger, usually tissue factor (TF), to recalcified usually falls within 70–180 s. During heparinization for CPB, the plasma in the presence of phospholipids. Thrombin is detected goal is to exceed 400–500 s. Off-pump cardiac surgery has been through cleavage of a chromogenic or fluorogenic substrate. described using less anticoagulation and lower ACT reference When low concentrations of TF are used, contact activation ranges of 200–300 s. must be inhibited by corn trypsin inhibitor. Several variations of these assays have been developed by varying the concentra- tions of TF, corn trypsin inhibitor, phospholipid and protein-C- Disseminated intravascular coagulation sensitizing reagents such as soluble thrombomodulin. Thrombin generation tests have been studied in the context of haemophilia, DIC is characterized by the loss of localization or compensated including monitoring of inhibitor bypass agent therapy. Other control of intravascular activation of coagulation. Arising from studies have examined thrombophilia and liver disease and diverse causes (Table 40.1), its pathology can manifest systemi- monitoring of anticoagulant therapy and warfarin reversal. The cally and contribute to a worse prognosis for the patient. Uncou- clinical utility of many of these potential applications remains to pling of the highly regulated balance between procoagulant, be demonstrated. anticoagulant, profibrinolytic and antifibrinolytic processes can 744  Chapter 40 Acquired coagulation disorders (a) (b) 100 100 80 80 Transmittance (%) Transmittance (%) 60 60 40 40 20 20 Figure 40.2 Representative normal and biphasic waveforms. Activated partial thromboplastin time waveform patterns: (a) normal; (b) biphasic. Dashed 0 0 lines denote transmittance level at 18 s (TL18) as the 12 18 24 30 36 42 48 12 18 24 30 36 42 48 quantitative index: (a) TL18 = 100; (b) TL18 = 63. Time (seconds) Time (seconds) Table 40.1 Clinical conditions associated with disseminated intravascular coagulation. result in simultaneous bleeding and microvascular thrombosis at different vascular sites (Figure 40.3). Removal of the inciting Sepsis/severe infection cause is the best means of restoring haemostatic control, but may Potentially any microorganism, including Gram-positive and not be possible. Sepsis and trauma cause more than half the cases Gram-negative bacteria, viruses, fungi and rickettsial of DIC. infections Malaria and other protozoal infections Pathophysiology Trauma There are several important themes in the pathophysiology of Serious tissue injury DIC (Figure 40.3): first is the central role played by the gener- Head injury ation of thrombin; second, mechanisms that perpetuate throm- Fat embolism bin generation become pathogenic in its dissemination; third, Burns parallel and concomitant activation of inflammation and fourth, Malignancy the importance of the endothelial microvasculature in this Solid tumours process. Haematological malignancies (e.g. acute promyelocytic Excess bleeding in DIC is partly attributable to the depletion leukaemia) of coagulation factors and platelets. However, other factors may Obstetric complications contribute, including abnormal platelet function and hyperfib- Placental abruption rinolysis. Conversely, microvascular thrombosis can be precip- Amniotic fluid embolism itated by reduced levels of circulating anticoagulant proteins as Pre-eclampsia well as loss of receptors, such as thrombomodulin. Endothelial Intrauterine fetal demise dysfunction can also lead to the depletion of nitric oxide and Vascular abnormalities result in uninhibited platelet activation. Giant haemangiomas (Kasabach–Merritt syndrome) Large vessel aneurysms (e.g. aortic) Thrombin generation in vivo Severe toxic or immunological reactions The TF pathway plays the major role in initiating thrombin gen- Snake bites eration. In sepsis, infecting micro-organisms induce TF expres- Recreational drugs sion on monocytes and other inflammatory cells, while in Severe transfusion reactions trauma thromboplastin-like substances can be released from Transplant rejection injured tissues such as the brain. During obstetric complica- Miscellaneous tions, the placenta and amniotic fluid act as rich sources of Severe pancreatitis TF, while malignant cells release products with TF-like activ- Heat stroke ity. Although the TF pathway is considered more important in ABO mismatch transfusion thrombin generation, the contact pathway through factor (F)XII activation contributes to the pathological state by activation of 745 Postgraduate Haematology Normal coagulation Procoagulant (factors VIII, V, XI) Profibrinolytic Thrombin Antifibrinolytic (tPA) (TAFI) Anticoagulant (APC) Disseminated intravascular coagulation Prolongation of PT and APTT FFP, platelets, cryoprecipitate Bleeding Thrombocytopenia and or fibrinogen concentrate hypofibrinogenaemia Clotting factor and platelet consumption Antifibrinolytics Excess Hyperfibrinolysis Excess antifibrinolysis thrombin Increased D-dimers Thrombosis Increase in TAFI Bleeding Increased thrombin– and PAI levels antithrombin complexes Anticoagulant consumption Activated protein C Increased thrombin– Antithrombin Thrombosis antithrombin complexes Heparin Decreased protein C and AT Figure 40.3 The changes in disseminated intravascular has occurred. The therapeutic intervention in each setting is given coagulation are compared with the normal coagulation. The excess by the arrow towards each double box. TAFI, thrombin activatable thrombin generation in DIC leads to either bleeding or thrombosis fibrinolysis inhibitor; PAI, plasminogen activator; AT, (left) based on the predominant coagulation change (right) which antithrombin. the kallikrein–kinin system, causing vasodilatation, hypotension Links between inflammation and coagulation and activation of fibrinolysis. Once activated, the inflammatory and coagulation pathways interact to amplify the response. Cytokines and proinflamma- tory mediators such as tumour necrosis factor (TNF), inter- Mechanisms for disseminating and sustaining leukin (IL)-1 and high mobility group box protein (HMGB)- thrombin generation 1 induce activators of coagulation. Thrombin and other When the inciting insult is persistent or severe, the amount of serine proteases interact with protease-activated receptors thrombin generated becomes continuous and excessive. This can (PARs) on cell surfaces to promote inflammation. When this lead to consumption and depletion of coagulation and antico- process escapes the well-developed local checks, it results in agulant factors. Increased exposure of negatively charged phos- a dysregulated response that fuels a vicious cycle. An impor- pholipid surfaces facilitates the assembly and enhances the rate tant role for the complement system has also been increasingly of coagulation reactions. Such surfaces, mainly rich in phos- identified in DIC. Thrombin can convert C5 to C5a, while the phatidylserine, are provided by externalization of the inner mannan-binding lectin pathway triggers coagulation by con- leaflet of cell membranes upon activation and apoptosis. Cell verting prothrombin to thrombin. damage also leads to the generation of microparticles from platelets, monocytes and endothelial cells that increase the circu- Endothelial cell activation and dysfunction lating surface area for coagulation reactions. Phospholipid sur- Dysfunction and failure of the endothelium beyond the host faces are also provided by very low-density lipoprotein, which adaptive response can lead to the development of DIC. The can increase several-fold in severe sepsis to further enhance degree to which this occurs and the dominance of throm- and sustain thrombin generation. Together, these mechanisms botic or bleeding sequelae depend on genetic and other host- promote a spatially and temporally expanded response that is related factors. Damage to and activation of the endothelium the hallmark of DIC. downregulates and depletes its anticoagulant receptors, such as 746  Chapter 40 Acquired coagulation disorders thrombomodulin and endothelial protein C receptor, exposes bleeding to thrombosis. Although bleeding, ranging from subendothelial collagen that binds activated platelets, and oozing at venepuncture sites to major gastrointestinal or releases plasminogen activator inhibitor (PAI)-1, which inhibits intracranial haemorrhage, is the archetypal and most obvious fibrinolysis and ultra-large VWF multimers, which increase manifestation of DIC, organ failure due to microvascular throm- platelet aggregation. bosis is more common and often unrecognized. For example, in meningococcal septicaemia and rarely pneumococcal infec- Neutrophil extracellular traps and histones tion, thrombosis of the adrenal vessels can lead to adrenal insuf- In contrast to the well-known modes of cell death like apop- ficiency and Waterhouse–Friderichsen syndrome. tosis or necrosis, a unique type of neutrophil death has been recently described known as NETosis. This process, where neu- Diagnosis trophils release extracellular traps (NETs), can aid in the removal of pathogens. At the same time, NETs can activate coagulation by DIC is a clinicopathological syndrome and, as such, there is no assisting in the extracellular delivery of tissue factor, degrade tis- single laboratory test that can confirm or refute the diagnosis. sue factor pathway inhibitor, stimulate platelets and cause aggre- In clinical practice, the diagnosis is usually made by a combina- gation, and also cause endothelial damage. In other words, a tion of routinely available coagulation tests in a clinical situation beneficial antimicrobicidal function in septic states can turn to where DIC is suspected. DIC must be differentiated from other become deleterious, causing disseminated coagulation. Another acquired disorders of haemostasis (Table 40.2). The typical find- pathogenic player in DIC is the most abundant protein in the ings are a prolonged PT and APTT, elevated products of fibrin nucleus, histones. High levels of histones have been detected in breakdown (e.g. D-dimer), thrombocytopenia and reduced fib- the plasma of experimental animals, and human patients with rinogen. However, results within the normal range for these tests sepsis and trauma, common causes of DIC. Extracellular his- do not exclude a significant consumptive coagulopathy, because tones released after cell damage can cause massive thromboem- the acute-phase response shortens the APTT and increases fib- bolism associated with consumptive coagulopathy and are major rinogen. A fall in platelet number within the normal range may mediators of death in sepsis. It can also cause acute lung injury be significant. in trauma models and may be a useful therapeutic target. It is important to recognize that DIC is a dynamic process and thus interpreting a series of laboratory tests over time is more relevant than looking at a single set of results. The ISTH Sub- Clinical features Committee of the Scientific and Standardization Committee on The perturbed coagulation associated with DIC can man- DIC has recommended the use of a scoring system for overt DIC ifest clinically at any point in a spectrum varying from (Table 40.3). This has been prospectively validated, indicating Table 40.2 Differential diagnosis of disseminated intravascular coagulation (DIC). Condition Similarities Differences Liver disease Bleeding common D-dimer usually normal∗ PT, APTT abnormal FVIII levels not affected Platelet count low Fibrinogen low Microangiopathic haemolytic anaemia Microthrombi common Bleeding uncommon (e.g. HELLP, TTP) Platelet count low Coagulation tests normal† Hyperfibrinolysis PT, APTT abnormal Platelet count normal Fibrinogen low Catastrophic antiphospholipid antibody PT, APTT abnormal Fibrinogen not low syndrome Platelet count low D-dimer normal‡ Massive transfusion PT, APTT abnormal D-dimer normal Fibrinogen low Platelet count low ∗ Unlessadditional disorders which increase the D-dimer coexist. † Unlesscoexisting DIC. ‡ Some antibodies can affect the D-dimer results. HELLP, haemolysis, elevated liver enzymes, low platelet count (syndrome); TTP, thrombotic thrombocytopenic purpura. 747 Postgraduate Haematology Table 40.3 ISTH Sub-Committee of the Scientific and issue, prothrombin complex concentrates (PCCs) could be con- Standardization Committee on DIC recommended scoring system sidered, but these will only correct vitamin-K-dependent com- for overt disseminated intravascular coagulation (DIC). ponents. Activated PCCs may precipitate or worsen DIC. Severe hypofibrinogenaemia (100, score 0; tibia or fibula >neck of femur), isolated or mul- thalidamide and bevacizumab to inhibit VEGF. tiple fractures, age (10–40 years) and gender (occurs more in males). Although more common after lower limb fractures, fat Kasabach–Merritt syndrome embolism syndrome can also occur after liposuction, bone mar- Kasabach–Merritt syndrome is a rare condition in which a vas- row harvesting, total parenteral nutrition, sickle cell crisis and cular tumour (Kaposiform haemangioendothelioma) is associ- pancreatitis. Classically, it presents with the triad of respiratory ated with thrombocytopenia, hypofibrinogenaemia and bleed- distress, mental status changes and petechial rash 24–48 hours ing, which can be life-threatening. The thrombocytopenia in after pelvic or long-bone fracture. The rash is pathognomonic Kasabach–Merritt syndrome is presumed to be due to platelet and is seen usually on the conjunctiva, oral mucous membranes adhesion to the abnormally proliferating endothelium. This and upper body, possibly due to embolization of fat droplets leads to activation of platelets with secondary consumption of accumulating in the aortic arch. The diagnosis is made clinically clotting factors, including VWF, resulting in systemic haemo- because laboratory and radiographic diagnosis is non-specific static failure. Excessive flow and shear rates secondary to and inconsistent. Thrombocytopenia is common, due to platelet arteriovenous shunting also contribute and microangiopathic activation and consumption into the thrombi. Management is haemolysis may be seen. The platelet count is often less than supportive to ensure haemodynamic stability. Aspirin and cor- 20 × 109 /L and the platelet half-life dramatically reduced. ticosteroids have also been shown to be helpful, although the use Intralesional bleeding can cause rapid enlargement of the of heparin is controversial. haemangioma and can worsen the consumptive coagulopathy. Intralesional thrombosis may rarely occur, causing spontaneous Warfarin-induced skin necrosis resolution of some lesions. Management involves supportive care and, if possible, removal of the lesion. Steroids, interferon, Warfarin-induced skin necrosis is a rare condition that is due chemotherapy with vincristine, radiotherapy and antiangiogenic to microvascular thrombi provoked by a transient imbalance agents have been tried. between procoagulant and anticoagulant factors. It most com- monly affects the breasts, buttocks and thighs. It may occur on initiation of warfarin, especially in patients with heterozygous Microthromboembolic disease protein C or protein S deficiency because of the relatively short half-life proteins compared with prothrombin. It is also seen in Cholesterol embolism association with heparin-induced thrombocytopenia. It is pre- vented by bridging the initiation of warfarin with heparin and Cholesterol embolism is a complication of widespread avoiding high loading doses. Treatment requires discontinua- atherosclerotic disease. Rupture of an atherosclerotic plaque tion of warfarin and starting therapeutic heparin. Intravenous can occur spontaneously or, more commonly, at the time of infusions of protein C concentrate may also be used in the vascular surgery or invasive procedures. Anticoagulant or short term. fibrinolytic therapy can weaken thrombi that usually prevent the release of cholesterol crystals. The characteristic presen- tation is with small limb-vessel occlusion with well-preserved peripheral pulses, which may occasionally lead to gangrene. Haemostatic dysfunction associated with Another common skin finding is livedo reticularis, where the paraproteinaemia and amyloidosis cutaneous venous plexus becomes visible because of increased Paraproteinaemia amounts of desaturated venous blood. Organ involvement from cholesterol emboli is dependent on the vascular supply, with Bleeding and thrombotic complications both occur in associ- renal ischaemia being the commonest. The diagnosis is often ation with paraproteinaemias, although abnormalities in lab- missed unless the occurrence of the clinical features is related to oratory tests are found much more frequently than clinical the triggering procedure. Fundoscopy can reveal the presence of effects. Bleeding is more common in Waldenström macroglob- retinal cholesterol crystals (Hollenhorst plaques) in about 25% ulinaemia and amyloidosis than multiple myeloma. Among of cases. Biopsy of the cutaneous lesion or the affected organ myeloma patients, bleeding is most common in those with IgA is required for definitive diagnosis. The prostacyclin analogue paraproteinaemia. The circulating paraprotein in these condi- iloprost has been used successfully in painful cutaneous necrotic tions can: (i) cause hyperviscosity and lead to arterial and retinal lesions and renal insufficiency in a single report. bleeds due to abnormal wall shear stress; (ii) inhibit or increase 757 Postgraduate Haematology clearance of FVIII and VWF leading to acquired von Willebrand Table 40.8 Bleeding symptoms in patients with acquired disease; (iii) impair platelet aggregation; (iv) inhibit fibrin poly- haemophilia A∗. merization and (v) have heparin-like anticoagulant function that can be reversed by protamine. Management of these conditions All bleeds at is directed towards the underlying cause. Plasma exchange is of presentation Bleeds requiring help as a temporary measure. Site of bleeding (%) treatment (%) N = 172 N = 65 Amyloidosis Subcutaneous/skin 81 23 Muscle 45 32 The pathophysiology of bleeding associated with systemic amy- Subcutaneous only 24 Not applicable loidosis is multifactorial. The type of amyloidosis and the pattern Gastrointestinal/ 23 14 of organ involvement are important determinants of the haem- intra-abdominal orrhagic tendency (Chapter 30). AL amyloidosis, where liver and Genitourinary 9 18 spleen involvement is frequent, is the commonest type associ- Retroperitoneal/ 9 5 ated with bleeding. FX deficiency is seen most commonly; how- thoracic ever, decreased levels of all factors, including VWF, have been Other 9 23 reported. The coagulation factor deficiencies are thought to be Postoperative 0 11 due to adsorption onto amyloid fibrils. Abnormal fibrin poly- Joint 7 2 merization and hyperfibrinolysis can also contribute to bleed- None 4 Not applicable ing. Prolongation of the TT is the most common abnormality, Intracranial 3 0 seen in up to 90% of patients. A prolonged PT and APTT sug- haemorrhage gest FX deficiency. Abnormal coagulation screening tests correct Fatal 9 No data with normal plasma. ∗ Patients had often had multiple bleeds. Platelet dysfunction may be seen, due to the binding of the Source: Data from Collins et al. (2007) and [Morrison et al., Blood amyloid light chains to the platelet membrane. Deposition of 81,1513–20, 1993]. amyloid fibrils in the blood vessel wall and perivascular tis- sue may lead to impaired vasoconstriction and vessel fragility. This is exemplified by cerebral amyloid angiopathy, which can in younger patients where there is a female preponderance asso- lead to intracerebral haemorrhage, especially in elderly non- ciated with pregnancy. Acquired haemophilia A presents with a hypertensive individuals. The microvascular involvement also typical bleeding pattern that is distinct from that seen in congen- explains the ‘raccoon eyes’ (bilateral periorbital purpura from ital haemophilia. Widespread subcutaneous bleeding is com- coughing or prolonged inverted positioning for lower gastroin- mon, as are muscle bleeds and gastrointestinal and genitourinary testinal procedures) and the ‘pinch purpura’ (skin pinching lead- bleeding. Neurovascular compression may be limb-threatening. ing to purpura). Several treatments have been described, includ- Haemarthroses are relatively uncommon. Fatal bleeding, such ing factor replacement with FFP or PCCs, platelet transfusion, as intracranial, pulmonary, gastrointestinal and retroperitoneal, desmopressin and rFVIIa. Severe FX deficiency can be difficult occurs in about 3–8% of cases (Table 40.8). Patients remain at to manage and first-line therapy is with PCCs or FFP. risk of severe bleeding until the inhibitor has been eradicated, even if they present with mild bleeding. Acquired haemophilia A is associated with an underlying autoimmune (systemic lupus erythematosus or rheumatoid arthritis), malignant, lymphopro- Acquired inhibitors of coagulation factors liferative or dermatological (pemphigoid) disease or pregnancy in about half of cases (Table 40.9). If acquired haemophilia Inhibitory autoantibodies to all coagulation factors have been A presents in association with pregnancy, it may recur in described, although those against FVIII and VWF are most subsequent pregnancies and, if antenatal, the fetus may be common. affected. Early diagnosis and urgent treatment of bleeding are key to successful management. The diagnosis is suggested by the Acquired haemophilia A clinical presentation and an isolated prolonged APTT. FVIII Acquired haemophilia A has an annual incidence of about inhibitors are time and temperature dependent and in mixing 1.5 per million and usually affects older patients with a median studies normal plasma must be incubated for 1–2 hours other- age of about 75 years. It affects males and females equally, except wise the diagnosis may be missed. The diagnosis is confirmed 758  Chapter 40 Acquired coagulation disorders Table 40.9 Diseases associated with acquired haemophilia A. by a low FVIII and positive Bethesda titre (Figure 40.6). In some cases diagnosis is complicated because all the intrinsic factors Green and may be low due to inhibition of FVIII in the factor-deficient Lechner Morrison Collins et al. plasma used to assay other intrinsic factors. Dilution will result (1981) et al. (1993) (2007) in increased levels of the non-specifically reduced factors while FVIII remains low. It is important to exclude a lupus anticoagu- Number of patients 215 65 150 lant because this can also be associated with an apparently low Idiopathic (%) 46 55 63 FVIII and an APTT that does not correct with normal plasma. Collagen, vascular 18 17 17 Acquired FVIII inhibitors have complex kinetics, so that not and other all FVIII is inhibited in a Bethesda assay. It is therefore often autoimmune not possible to measure the inhibitor titre accurately. The FVIII diseases (%) level and inhibitor titre are not predictive of the severity of the Malignancy (%) 7 12 15 bleeding. Skin diseases (%) 5 2 3 Treatment involves minimizing invasive procedures, pro- Possible drug 6 3 0 tecting the patient from trauma, treatment of bleeds and reaction (%) eradication of the inhibitor. At present, the available therapies Pregnancy (%) 7 11 2 to treat bleeds are with bypassing agents, namely rFVIIa or the activated PCC FEIBA (factor eight inhibitor bypassing activity) Source: Data from [Green and Lechner, Thrombosis and Haemostasis 45: 200–203, 1981], [Morrison et al., Blood 81,1513–20, 1993] and and are equally efficacious. Multiple doses may be required Collins et al. (2007). to control bleeds and prevent recurrence. There is a risk of thrombosis associated with bypassing agents, particularly in Assess personal and family Isolated prolonged aPTT history of bleeding Confirm prolonged aPTT Exclude heparin contamination Suspect coagulation factor deficiency or lupus anticoagulant (LA) Mixing tests with pooled normal plasma (immediate and incubated) aPTT correction Weak/no aPTT correction Suspect clotting factor deficiency Suspect acquired haemophilia or LA Time and temperature dependent Not time and temperature dependent Measure FVIII, IX, XI, XII Measure FVIII, IX, XI, XII and inhibitor Tests for LA Negative Positive Single factor deficiency Acquired haemophilia Lupus anticoagulant Figure 40.6 Diagnostic algorithm for an isolated prolonged APTT and possible acquired haemophilia A. 759 Postgraduate Haematology elderly patients. FVIII is unlikely to be efficacious in acquired Acquired protein S deficiency haemophilia A, although mild bleeds in patients with low-titre Autoantibodies to protein S have been reported in association inhibitors and measurable FVIII may respond to desmopressin. with infection, particularly chickenpox. Patients present with Initial trials with recombinant B-domain-deleted porcine factor skin necrosis and DIC. have been encouraging and this agent is likely to be available soon. If standard haemostatic treatment with bypassing agents fails, FVIII and immunoadsorption may be used, although Prothrombin deficiency associated with lupus this treatment modality is only available in a few specialized anticoagulant centres. Although lupus anticoagulants are typically associated with Immunosuppression should be started as soon as the diagno- thrombosis, occasionally cross-reactivity with prothrombin can sis is made and is usually with steroids alone or steroids plus lead to a bleeding disorder. Acquired deficiencies of other a cytotoxic agent such as cyclophosphamide or azathioprine. A procoagulant and antifibrinolytic proteins have occasionally response is usually seen after 2–3 weeks, but full remission takes been described. Bleeding manifestations are variable and some a median of about 5 weeks. If first-line therapy fails, rituximab, patients with markedly abnormal laboratory tests do not bleed. ciclosporin or combinations of cytotoxic agents may be used. Intravenous immunoglobulin does not increase the response rate to other immunosuppressive agents. Selected bibliography Acquired von Willebrand syndrome Collins PW, Hirsch S, Baglin TP et al. (2007) Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the Acquired von Willebrand syndrome may be associated with an United Kingdom Haemophilia Centre Doctors’ Organisation. Blood autoantibody, typically in the context of monoclonal gammopa- 109: 1870–7. thy of undetermined significance, Waldenström macroglobuli- De Paepe A, Malfait F (2004) Bleeding and bruising in patients with naemia and other lymphoproliferative diseases, myeloprolifer- Ehlers–Danlos syndrome and other collagen vascular disorders. ative disease and systemic lupus erythematosus. The antibody British Journal of Haematology 127: 491–500. leads to either rapid clearance or functional inhibition of VWF. Eby C (2009) Pathogenesis and management of bleeding and thrombo- sis in plasma cell dyscrasias. British Journal of Haematology 145: Low VWF:Ag, VWF:RCo and VWF:CB are found, and mea- 151–63. surement of the VWF propeptide may be useful in demonstrat- Falanga A, Rickles FR (2003) Pathogenesis and management of the ing rapid clearance. Mixing studies may not demonstrate an bleeding diathesis in acute promyelocytic leukaemia. Best Practice inhibitor. and Research in Clinical Haematology 16: 463–82. Low VWF levels are also seen in hypothyroidism and Huth-Kuhne A, Baudo F, Collins P et al. (2009) International recom- increased VWF is associated with hyperthyroidism. Increased mendations on the diagnosis and treatment of patients with acquired proteolysis of VWF in high-shear environments such as leak- haemophilia A. Haematologica 94: 566–75. ing cardiac values leads to a syndrome of acquired type 2A Levi M, Toh CH, Thachil J, Watson HG (2009) Diagnosis and manage- VWS. VWF has also been reported in association with malig- ment of disseminated intravascular coagulation. British Journal of nancy and it is suggested that it may be adsorbed onto malignant Haematology 145: 24–33. cells. Hydroxyethyl starches used as plasma expanders have been Levy JH, Dutton RP, Hemphill JC 3rd, Shander A et al. (2010) Multi- disciplinary approach to the challenge of hemostasis. Anesthesia and associated with bleeding secondary to VWF deficiency. Treat- Analgesia 110: 354–64. ment options include desmopressin, VWF concentrates and, Lisman T, Leebeek FW, de Groot PG (2002) Haemostatic abnormalities in patients with an inhibitory antibody, high-dose intravenous in patients with liver disease. Journal of Hepatology 37: 280–7. immunoglobulin. Roberts I, Shakur H, Coats T et al. (2013) The CRASH-2 trial: a ran- domised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion Acquired factor V deficiency requirement in bleeding trauma patients. Health Technology Assess 17(10): 1–79. Acquired inhibitors to FV may arise spontaneously but are usu- Wada H, Thachil J, Di Nisio M et al. (2013) Guidance for diagnosis and ally associated with exposure to topical thrombin preparations treatment of DIC from harmonization of the recommendations from that have trace amount of bovine FV. Laboratory findings are three guidelines. Journal of Thrombosis and Haemostsis 11(10): of prolonged PT and APTT that do not correct with normal 761–7. plasma. Patients may respond to FFP and, in resistant cases, Zangari M, Elice F, Fink L, Tricot G (2007) Hemostatic dysfunction platelets may be useful because surface-associated FV appears in paraproteinemias and amyloidosis. Seminars in Thrombosis and to bypass the inhibitor. Hemostasis 33: 339–49. 760