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Disorders of haemostasis
/content/chapter/10.22233/9781910443255.chap6
Disorders of haemostasis
- Author: Tracy Stokol
- From: BSAVA Manual of Canine and Feline Clinical Pathology
- Item: Chapter 6, pp 94 - 122
- DOI: 10.22233/9781910443255.6
- Copyright: © 2016 British Small Animal Veterinary Association
- Publication Date: March 2016
Abstract
Haemostasis is a simple word that means ‘stop bleeding’. Yet the simplicity of the word belies the incredible complexity of a process whereby an array of cells and proteins intimately interact in a finely tuned and balanced system, first to form a fibrin clot then to dissolve the clot to restore vessel patency. This chapter considers an overview of haemostasis, diagnostic assays for haemostasis and disorders of haemostasis. Case examples are included.
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Figures
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6.3
The haemostatic pendulum. (a) Haemostasis is activated upon blood vessel injury. (b) This swings the pendulum in favour of procoagulant forces. Exposure of procoagulant extracellular matrix proteins and tissue factor initiates platelet plug formation and thrombin generation, respectively. Thrombin forms the fibrin clot, which is enmeshed with the platelet plug. At the same time, thrombin inhibits fibrinolysis, preventing clot breakdown. (c) Once the clot has formed and the vessel heals, the stimulus for thrombin generation decreases, thrombin begins to inhibit its own production and no longer inhibits fibrinolysis, swinging the pendulum in favour of fibrinolysis. (d) Lysis of the clot restores vessel patency and the original status quo. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.3
The haemostatic pendulum. (a) Haemostasis is activated upon blood vessel injury. (b) This swings the pendulum in favour of procoagulant forces. Exposure of procoagulant extracellular matrix proteins and tissue factor initiates platelet plug formation and thrombin generation, respectively. Thrombin forms the fibrin clot, which is enmeshed with the platelet plug. At the same time, thrombin inhibits fibrinolysis, preventing clot breakdown. (c) Once the clot has formed and the vessel heals, the stimulus for thrombin generation decreases, thrombin begins to inhibit its own production and no longer inhibits fibrinolysis, swinging the pendulum in favour of fibrinolysis. (d) Lysis of the clot restores vessel patency and the original status quo. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.4
Sequence of events in primary haemostasis that culminate in formation of a platelet plug. ADP = adenosine diphosphate; GP = glycoprotein; PS = phosphatidylserine; vWF = Willebrand factor. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.4
Sequence of events in primary haemostasis that culminate in formation of a platelet plug. ADP = adenosine diphosphate; GP = glycoprotein; PS = phosphatidylserine; vWF = Willebrand factor. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.5
Epistaxis in a young Bassett Hound with inherited thrombopathia, which is due to a mutation in calcium diacylglycerol guanine nucleotide exchange factor-1 (CalDAG–GEF1) in platelets. This is a signalling protein that is important for activation of the fibrinogen receptor on platelets, and the mutation results in an absence of platelet aggregation in response to ADP and collagen. Epistaxis can be seen in any disorder of primary haemostasis but is not typical of disorders of secondary haemostasis. (Courtesy of Dr M Brooks, Comparative Coagulation Laboratory, Cornell University) © 2016 British Small Animal Veterinary Association
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6.5
Epistaxis in a young Bassett Hound with inherited thrombopathia, which is due to a mutation in calcium diacylglycerol guanine nucleotide exchange factor-1 (CalDAG–GEF1) in platelets. This is a signalling protein that is important for activation of the fibrinogen receptor on platelets, and the mutation results in an absence of platelet aggregation in response to ADP and collagen. Epistaxis can be seen in any disorder of primary haemostasis but is not typical of disorders of secondary haemostasis. (Courtesy of Dr M Brooks, Comparative Coagulation Laboratory, Cornell University)
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6.6
Severe preputial and abdominal ecchymoses after castration of a German Shepherd Dog with Scott syndrome. Scott syndrome is caused by an inherited defect in platelet membrane flipping, i.e. activated platelets do not exteriorize phosphatidylserine and do not support fibrin formation. Note that such ecchymoses are not specific for disorders of primary haemostasis but can be seen with defects of secondary haemostasis and fibrinolysis. (Courtesy of Dr M Brooks, Comparative Coagulation Laboratory, Cornell University) © 2016 British Small Animal Veterinary Association
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6.6
Severe preputial and abdominal ecchymoses after castration of a German Shepherd Dog with Scott syndrome. Scott syndrome is caused by an inherited defect in platelet membrane flipping, i.e. activated platelets do not exteriorize phosphatidylserine and do not support fibrin formation. Note that such ecchymoses are not specific for disorders of primary haemostasis but can be seen with defects of secondary haemostasis and fibrinolysis. (Courtesy of Dr M Brooks, Comparative Coagulation Laboratory, Cornell University)
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6.8
Screening tests of secondary haemostasis created the classic model of the coagulation cascade, whereby fibrin formation can be initiated by surface contact activation of FXII in the intrinsic pathway or with exogenous tissue factor (TF, in the form of brain thromboplastin) in the extrinsic pathway. However, contact or FXIIa does not activate secondary haemostasis and FXII has no role in fibrin formation under physiological conditions in vivo. This is exemplified by cats with FXII deficiency, which do not show clinical signs of abnormal haemorrhage. ACT = activated coagulation time; aPTT = activated partial thromboplastin time; Ca2+ = calcium ions; PS = phosphatidylserine; PT = prothrombin time; TCT = thrombin clot time. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.8
Screening tests of secondary haemostasis created the classic model of the coagulation cascade, whereby fibrin formation can be initiated by surface contact activation of FXII in the intrinsic pathway or with exogenous tissue factor (TF, in the form of brain thromboplastin) in the extrinsic pathway. However, contact or FXIIa does not activate secondary haemostasis and FXII has no role in fibrin formation under physiological conditions in vivo. This is exemplified by cats with FXII deficiency, which do not show clinical signs of abnormal haemorrhage. ACT = activated coagulation time; aPTT = activated partial thromboplastin time; Ca2+ = calcium ions; PS = phosphatidylserine; PT = prothrombin time; TCT = thrombin clot time. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.9
Sequence of events in secondary haemostasis. Initiation: on endothelial injury, plasma FVII binds to tissue factor (TF) on subendothelial fibroblasts. Once bound to TF, FVII autoactivates and the TF–FVII complex forms the ‘extrinsic tenase’, which activates FX on fibroblast membranes. The extrinsic pathway is rapidly inhibited by tissue factor pathway inhibitor and produces only a small amount of thrombin. Amplification: the small amount of thrombin generated by the extrinsic pathway amplifies its own production by activating FXI of the intrinsic pathway and FVIII and FV, the intrinsic and common pathway cofactors. FXIa then activates FIX, which forms a potent ‘intrinsic tenase’ complex with FVIIIa on the platelet surface. FIX produced by the TF–FVIIa complex (alternative pathway) supplements the ‘intrinsic’ tenase (not shown). Propagation: the phosphatidylserine (PS)-enriched surfaces of activated platelets help amplify and propagate thrombin generation, producing a ‘thrombin burst’. Fibrin formation: the thrombin burst is essential for forming crosslinked fibrin from fibrinogen (and also for concurrently inhibiting fibrinolysis). The formed fibrin closely intercalates and binds to the platelet plug, forming a stable fibrin clot. Note that calcium and PS-expressing surfaces are crucial for fibrin formation. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.9
Sequence of events in secondary haemostasis. Initiation: on endothelial injury, plasma FVII binds to tissue factor (TF) on subendothelial fibroblasts. Once bound to TF, FVII autoactivates and the TF–FVII complex forms the ‘extrinsic tenase’, which activates FX on fibroblast membranes. The extrinsic pathway is rapidly inhibited by tissue factor pathway inhibitor and produces only a small amount of thrombin. Amplification: the small amount of thrombin generated by the extrinsic pathway amplifies its own production by activating FXI of the intrinsic pathway and FVIII and FV, the intrinsic and common pathway cofactors. FXIa then activates FIX, which forms a potent ‘intrinsic tenase’ complex with FVIIIa on the platelet surface. FIX produced by the TF–FVIIa complex (alternative pathway) supplements the ‘intrinsic’ tenase (not shown). Propagation: the phosphatidylserine (PS)-enriched surfaces of activated platelets help amplify and propagate thrombin generation, producing a ‘thrombin burst’. Fibrin formation: the thrombin burst is essential for forming crosslinked fibrin from fibrinogen (and also for concurrently inhibiting fibrinolysis). The formed fibrin closely intercalates and binds to the platelet plug, forming a stable fibrin clot. Note that calcium and PS-expressing surfaces are crucial for fibrin formation. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.10
Spontaneous severe ecchymoses on the inner leg of a German Shepherd Dog with haemophilia A (<1% factor VIII coagulant activity). This extensive spontaneous haemorrhage is more typical of disorders of secondary haemostasis than primary haemostasis. (Courtesy of Dr M Brooks, Comparative Coagulation Laboratory, Cornell University) © 2016 British Small Animal Veterinary Association
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6.10
Spontaneous severe ecchymoses on the inner leg of a German Shepherd Dog with haemophilia A (<1% factor VIII coagulant activity). This extensive spontaneous haemorrhage is more typical of disorders of secondary haemostasis than primary haemostasis. (Courtesy of Dr M Brooks, Comparative Coagulation Laboratory, Cornell University)
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6.11
Fibrinolysis is triggered when injured endothelial cells release tissue plasminogen activator (tPA), which then cleaves plasminogen (which is tightly bound to fibrin) to plasmin. Plasmin lyses fibrin into degradation products (FDPs, d-dimer). The FXIIa/kallikrein complex converts high molecular weight kininogen into bradykinin, which is a potent stimulus of tPA release. Kallikrein and FXIIa can also act as weak plasminogen activators (not shown). Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.11
Fibrinolysis is triggered when injured endothelial cells release tissue plasminogen activator (tPA), which then cleaves plasminogen (which is tightly bound to fibrin) to plasmin. Plasmin lyses fibrin into degradation products (FDPs, d-dimer). The FXIIa/kallikrein complex converts high molecular weight kininogen into bradykinin, which is a potent stimulus of tPA release. Kallikrein and FXIIa can also act as weak plasminogen activators (not shown). Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.12
Degradation products (FDPs) released from plasmin-mediated cleavage of fibrinogen or fibrin. Classic FDPs (measured in serum or plasma) are released when plasmin cleaves fibrinogen or soluble fibrin. In contrast, crosslinked degradation products are released when plasmin cleaves crosslinked fibrin; the smallest crosslinked product is d-dimer. Since crosslinking requires thrombin to activate FXIII and create the d-dimer neo-epitope, d-dimer is specific for crosslinked fibrinolysis. In contrast, FDPs can be yielded by plasmin-mediated cleavage of fibrinogen without thrombin being present. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.12
Degradation products (FDPs) released from plasmin-mediated cleavage of fibrinogen or fibrin. Classic FDPs (measured in serum or plasma) are released when plasmin cleaves fibrinogen or soluble fibrin. In contrast, crosslinked degradation products are released when plasmin cleaves crosslinked fibrin; the smallest crosslinked product is d-dimer. Since crosslinking requires thrombin to activate FXIII and create the d-dimer neo-epitope, d-dimer is specific for crosslinked fibrinolysis. In contrast, FDPs can be yielded by plasmin-mediated cleavage of fibrinogen without thrombin being present. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.13
Suggested diagnostic test algorithm for a bleeding animal. a Genetic test results do not necessarily correlate with clinical signs. b Thrombopathia (decreased platelet function) is an uncommon cause of haemorrhage, but can be inherited or secondary to drugs (e.g. aspirin) or disease (e.g. uraemia). A complete medical history, including drug administration or exposure to toxins, is imperative for bleeding animals. c Disseminated intravascular coagulation (DIC) panels vary, but usually include FDP/d-dimer, fibrinogen and antithrombin activity along with screening assays. NB If there is a high clinical suspicion of DIC (sick animal with underlying predisposing disease, e.g. bacterial sepsis), consider concurrent DIC panel and platelet count (versus sequential testing as illustrated). d If a specific diagnosis has not been obtained, consider referral of the patient. e If diagnostic tests are not helpful, still consider empirical treatment for Angiostrongylus vasorum in endemic areas. f See section on thrombocytopenia. aPTT = activated partial thromboplastin time; BMBT = buccal mucosal bleeding time; CBC = complete blood count; PT = prothrombin time; TCT = thrombin clot time; vWD = von Willebrand’s disease; vWf:Ag = von Willebrand factor antigen. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.13
Suggested diagnostic test algorithm for a bleeding animal. a Genetic test results do not necessarily correlate with clinical signs. b Thrombopathia (decreased platelet function) is an uncommon cause of haemorrhage, but can be inherited or secondary to drugs (e.g. aspirin) or disease (e.g. uraemia). A complete medical history, including drug administration or exposure to toxins, is imperative for bleeding animals. c Disseminated intravascular coagulation (DIC) panels vary, but usually include FDP/d-dimer, fibrinogen and antithrombin activity along with screening assays. NB If there is a high clinical suspicion of DIC (sick animal with underlying predisposing disease, e.g. bacterial sepsis), consider concurrent DIC panel and platelet count (versus sequential testing as illustrated). d If a specific diagnosis has not been obtained, consider referral of the patient. e If diagnostic tests are not helpful, still consider empirical treatment for Angiostrongylus vasorum in endemic areas. f See section on thrombocytopenia. aPTT = activated partial thromboplastin time; BMBT = buccal mucosal bleeding time; CBC = complete blood count; PT = prothrombin time; TCT = thrombin clot time; vWD = von Willebrand’s disease; vWf:Ag = von Willebrand factor antigen. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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6.16
(a) Platelet numbers can be estimated from the monolayer of a good quality blood smear (usually a distance of one X10 objective field from the feathered edge of the blood smear, moving towards the body of the smear). Approximately 1 platelet/X100 oil immersion field (OIF) = 15 × 109/l in dogs and 15–20 × 109/l in cats. Healthy dogs and cats typically have >10 platelets/OIF (>150 × 109/l). A monolayer may not be present in very anaemic animals. In this case, a platelet estimate should be performed at the distance indicated above. (b) Platelet clumps decrease the platelet counts obtained by most methods. These are usually a consequence of poor venepuncture technique in dogs, but are often unavoidable in cats. Clumps are typically seen at the feathered edge; the number and size vary between samples and between blood smears made from the same sample. Small clumps can also be seen throughout the body of the smear (arrowed) and also affect the platelet count. It should not be assumed that the platelet count is within reference intervals if clumps are present. (c) Blood smear from a dog with severe immune-mediated thrombocytopenia; no platelets are seen in the monolayer (and no clumps were detected). © 2016 British Small Animal Veterinary Association
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6.16
(a) Platelet numbers can be estimated from the monolayer of a good quality blood smear (usually a distance of one X10 objective field from the feathered edge of the blood smear, moving towards the body of the smear). Approximately 1 platelet/X100 oil immersion field (OIF) = 15 × 109/l in dogs and 15–20 × 109/l in cats. Healthy dogs and cats typically have >10 platelets/OIF (>150 × 109/l). A monolayer may not be present in very anaemic animals. In this case, a platelet estimate should be performed at the distance indicated above. (b) Platelet clumps decrease the platelet counts obtained by most methods. These are usually a consequence of poor venepuncture technique in dogs, but are often unavoidable in cats. Clumps are typically seen at the feathered edge; the number and size vary between samples and between blood smears made from the same sample. Small clumps can also be seen throughout the body of the smear (arrowed) and also affect the platelet count. It should not be assumed that the platelet count is within reference intervals if clumps are present. (c) Blood smear from a dog with severe immune-mediated thrombocytopenia; no platelets are seen in the monolayer (and no clumps were detected).
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6.18
Representative thromboelastographic tracings and data generated with the analyser (TEG®) in a normal (upper image), hypercoagulable (middle image) and hypocoagulable sample. For the hyper- and hypocoagulable tracings, the dotted line is a superimposed normal tracing. The most frequently used data from the analyser include the time for fibrin to start forming or reaction time (R), rate of fibrin formation (K and alpha) and the strength of the fibrin clot or maximum amplitude (MA). (NB Coagulability index and fibrinolytic results are not shown.) Similar tracings are obtained using thrombelastometry, although different terminology is used (clot versus reaction time, clot formation time versus K and maximal clot firmness versus amplitude). Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2016 British Small Animal Veterinary Association
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6.18
Representative thromboelastographic tracings and data generated with the analyser (TEG®) in a normal (upper image), hypercoagulable (middle image) and hypocoagulable sample. For the hyper- and hypocoagulable tracings, the dotted line is a superimposed normal tracing. The most frequently used data from the analyser include the time for fibrin to start forming or reaction time (R), rate of fibrin formation (K and alpha) and the strength of the fibrin clot or maximum amplitude (MA). (NB Coagulability index and fibrinolytic results are not shown.) Similar tracings are obtained using thrombelastometry, although different terminology is used (clot versus reaction time, clot formation time versus K and maximal clot firmness versus amplitude). Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.