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Blood Coagulation Disorders
SECTION I Body and Organ Systems
CHAPTER 16
Blood Coagulation Disorders SallyAnne L. Ness • As the complex interactions between the cellular and vascular contributions to coagulation become increasingly recognized, the traditional coagulation cascade should be considered one of several components of coagulation, rather than the precise order by which clotting is achieved. • The perennial historical perspective of coagulation provided by Dr. Rudolf Virchow in 1845 views the general rules of coagulation as being: • A disruption of the vascular integrity • Changes in the hemodynamics or stasis of blood flow • Changes in the concentration of substances that promote and/or inhibit coagulation • Recognition of components such as antithrombin III; proteins C and S; and homeostasis between tissue and platelet activators and inhibitors is pivotal to understanding the myriad of coagulation participants that respond to the activation process, subsequent coagulation, fibrinolysis, and anticoagulation. • Coagulation disorders are represented by the following: • Hypercoagulation (thrombosis) • Hypocoagulation (bleeding diathesis) • A normal coagulation system can be present in the presence of a hemorrhagic crisis because of physical disruption of the vascular integrity, as in external trauma or spontaneous internal vascular rupture—aortic root rupture, uterine artery hemorrhage, or guttural pouch mycosis. • Initial assessment of the bleeding patient should aim to differentiate between vessel injury or vascular disease and systemic coagulopathy leading to bleeding diathesis. • Practice Tip: In horses, thrombotic disorders are more common than hemorrhagic diatheses. • Inflammation and sepsis are known initiators of systemic coagulation pathways via activation of the intrinsic coagulation cascade by circulating proinflammatory mediators such as: • Endotoxin • Tumor necrosis factor–alpha (TNF-α) • Lipoproteins • Growth factors • Activation of endothelial cells and circulating monocytes stimulates the expression of tissue factor, an important 118
initiator of thrombin formation in both health and disease. • In the septic patient, systemic hypercoagulability is potentiated by an overall reduction in endogenous anticoagulant factors including: • Antithrombin III (AT-III) • Tissue factor pathway inhibitor (TFPI) • Activated protein C (aPC)
Hypercoagulation: Thrombophilia and Thrombosis • Hypercoagulation is common in horses and is associated with: • Abnormally elevated platelet counts (thrombocytosis) • Arteritis (cranial mesenteric arteritis) • Vasculitis (purpura hemorrhagica) • Idiopathic iliac thrombosis • Spontaneous or sepsis-associated limb arterial thrombosis in foals • Laminitis • Pulmonary infarction • Deficiencies of antithrombin III and protein C or protein S cofactors • Inhibition of fibrinolysis • Consumptive coagulopathies (disseminated intravascular coagulation [DIC]). • DIC can exhibit laboratory evidence of hypocoagulation (prolonged clotting times and thrombocytopenia) while the individual has clinical evidence of hypercoagulation, thrombophilia, and no overt signs of bleeding. • Thrombophlebitis in horses frequently occurs as a sequela to systemic inflammation and loss of antithrombin III following: • Endotoxemia • Salmonella and other causes of infectious colitis • Nonsteroidal anti-inflammatory drug (NSAID) toxicity • Pleuritis • Toxic metritis • Large colon volvulus • Following intravenous administration of irritating or hypertonic solutions (phenylbutazone, enrofloxacin).
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Hypocoagulation: Bleeding Disorder and Diathesis Tendencies
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• An acute bleed is commonly accompanied by changes in vital signs—tachycardia, tachypnea, and hypothermia—and pale mucous membranes. • Peracute aortic root rupture with collapse and death usually occurs in stallions during or after breeding. • Uterine-ovarian artery rupture is most often acute and can occur before or after parturition. • A subcutaneous hematoma may follow trauma or spontaneous hemorrhage. • Ultrasound evaluation of body cavities or acute subcutaneous swellings may show the presence of extraneous “swirling smoke” fluid indicative of free blood within a space (Fig. 16-1). • Epistaxis, genitourinary hemorrhage, melena, and petechial or ecchymotic lesions may be present. • Overt epistaxis can be caused by exercise-induced pulmonary hemorrhage (EIPH), guttural pouch mycosis, ethmoidal hematoma, sinusitis, trauma, and coagulation deficiencies, including thrombocytopenia.
Clinical Signs of Hemorrhage and Thrombosis
• Obvious clinical signs of thrombosis or hemorrhage can be inapparent because of skin pigmentation and hair coat. • Clinical signs suggestive of primary hemostatic defects (platelet and von Willebrand factor disorders) include petechial or ecchymotic hemorrhage of the mucous membranes and conjunctiva. Epistaxis also may occur. • Clinical signs suggestive of secondary hemostatic defects (coagulopathies) include: • Hematoma formation • Hemarthrosis • Intracavitary hemorrhage • Vascular thrombosis may result in partial or complete ischemia of tissues supplied by the affected vessels (e.g., limb arterial thrombosis in septicemic foals). • The full extent of thrombotic lesions may be inapparent until identified at surgery or postmortem examination. • Antemortem diagnosis can be established with ultrasound identification of intravascular clot formation or with Doppler ultrasound detection of decreased blood flow. • Thrombophilia manifests clinically as: • Jugular thrombosis • Asymmetric cold limbs (saddle thrombus) • Hypothermic lameness during increased exercise • The presence of regional edema in conjunction with petechial or ecchymotic hemorrhage (purpura, vasculitis) • Thrombophilia may be associated with acute hemolytic anemias. WHAT TO DO Coagulopathy with Blood Loss
• Treatments are principally aimed at the following: • Volume replacement with crystalloids including hypertonic saline • Colloids such as whole blood, plasma, and hetastarch. Note: Hetastarch is contraindicated in patients with evidence of hypocoagulability.
Figure 16-1 Ultrasound image of a hemoabdomen in a horse with warfarin toxicity demonstrating characteristic “swirling smoke” appearance of blood within a body cavity.
Laboratory Assessment of Coagulation • The following laboratory tests are available for evaluation of hemostasis in the equine patient. Screening tests are categorized into: • Tests of primary hemostasis (platelet plug formation) • Tests of secondary hemostasis ○ Tests of fibrin clot formation and breakdown (fibrinolysis) • The following specialized tests may necessitate referral of samples to a research laboratory following consultation: • Coagulation factors • von Willebrand disease • Antibody-coated platelet • Protein assays • Note: If known laboratory values are not available, a normal control sample is recommended to aid in the interpretation of individual results. • Platelet counts: • False platelet aggregation can occur in ethylenediaminetetraacetic acid (EDTA) and therefore may necessitate sample collection in sodium citrate for quantitative counts.
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• Hypocoagulation in the horse can be associated with: • Thrombocytopenia (immune mediated or acquired) • Thrombasthenia (abnormal platelet function) • Toxicosis (warfarin/anticoagulant rodenticides toxicity, moxalactam and related antibiotics) • Inherited disorders (hemophilia A, von Willebrand disease) • Primary fibrinolysis (hyperplasminemia) • It also occurs in advanced DIC as a consumptive coagulopathy with secondary fibrinolysis. • Rapid volume replacement with hetastarch and/or crystalloid fluids following severe blood loss can result in dilution of coagulation factors and loss of normal hemostatic ability. • Bleeding disorders can be acute or chronic.
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SECTION I Body and Organ Systems
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Figure 16-2 Typical thromboelastogram with measured parameters: R = time to the initiation of clot formation, K = time for the tracing to achieve a set clot strength, Ang = Angle, the rate of clot formation, MA = maximum amplitude, the greatest clot strength, χ = clot strength at 60 minutes after MA, CL60 = 100× (χ/MA). (From Epstein, KL et al: Thromboelastography in 26 healthy horses with and without activation by recombinant human tissue factor, J Vet Emerg Crit Care 19(1): 96-101, 2009.)
•
•
•
•
1
mm
• A scan of a hematologic slide for adequate platelet numbers by a laboratory technician is accurate in detecting inadequate numbers. Practice Tip: At least 10 platelets per high-powered field (magnification: ×1000) is considered adequate if clumping of platelets is not observed. Template bleeding time: • In vivo evaluation of primary hemostasis and platelet plug formation following vascular injury. • The hair distolateral to the accessory carpal bone is clipped and a template bleeding device is used to produce a small incision. • Filter paper is used to absorb blood 1 to 2 mm below the incision site. • Timing starts when the incision is made and ends when bleeding stops; reported normal bleeding time for healthy horses ranges from 2 to 6 minutes, and may be prolonged with both quantitative— thrombocytopenia—and qualitative—von Willebrand disease, Glanzmann thrombasthenia—disorders. Platelet function analysis (PFA-1001): • A point-of-care assay validated in horses for evaluation of primary hemostasis. Cartridges coated in collagen and ADP activate platelets and simulate platelet adhesion and aggregation after vascular injury. • The PFA-100 is able to identify inherited, acquired, and drug-induced thrombocytopathies, including functional disorders in which platelet counts may be normal—von Willebrand disease, Glanzmann thrombasthenia—and can be used to monitor response to aspirin therapy. Activated clotting time (ACT): • Point-of-care evaluation of secondary hemostasis, specifically the intrinsic and common pathways • Deficiencies in factors V, VIII, IX, X, XI, XII, prothrombin (factor II), or fibrinogen result in prolonged ACT. Activated partial thromboplastin time (aPTT): • Point-of-care evaluation of secondary hemostasis, specifically the intrinsic and common pathways • Similar to evaluation by ACT but with higher sensitivity • Deficiencies in factors V, VIII, IX, X, XI, XII, prothrombin (factor II) or fibrinogen result in prolonged aPTT.
PFA-100 (Dade-Behring, Newark, Delaware).
Ang MA
x Time (min)
R
•
•
•
•
•
2
K
60 min
• Can be used to monitor heparin therapy with the goal to prolong the aPTT to 1.5 times pretreatment baseline levels. Prothrombin time (PT): • Aids in the evaluation of the extrinsic coagulation system, specifically the extrinsic and common pathways and their ability to convert fibrinogen to fibrin • Deficiencies in tissue factor (factor III), factors V, VII, X, prothrombin, or fibrinogen result in prolonged PT. • Often used to detect or monitor vitamin K antagonist anticoagulants (e.g., warfarin, [Coumadin]) Fibrinogen: • Quantification of fibrinogen can be performed by means of heat precipitation, fibrometer, or point-ofcare automated analyzer (VetScan VSpro2). • Decreased fibrinogen levels may be observed with DIC, but this is a less sensitive test in horses compared with other species. Fibrin degradation products (FDPs): • Evaluation of primary (fibrinogenolysis without clot formation) or secondary (clot dissolution) fibrinolysis. • Elevated FDP concentrations suggest increased fibrinogenolysis or fibrinolysis activity, and may be observed with DIC, severe inflammatory processes, and hemorrhagic disorders. D-dimers: • End product of fibrinolysis • D-dimers are released following cleavage of fibrin bonds by plasmin. • Differs from FDPs in that it is specific for fibrinolysis (i.e., dissolution of fibrin generated from active thrombin production). • Elevated D-dimers are common in foals <1 week of age, presumably due to resolution of umbilical vessel clots. Thromboelastography (TEG): • A point-of-care hemostatic assay that records changes in the viscoelastic properties of whole blood from initiation of clot formation through fibrinolysis (Fig. 16-2). • It can detect both hypocoagulopathies and hypercoagulopathies and may be a more accurate representation of
VetScan VSpro (Abaxis, Union City, California).
Chapter 16
• • •
Blood Clotting Disorders Thrombocytopenia
• Thrombocytopenia is not an uncommon clinical finding in equine practice and is usually associated with a severe systemic inflammatory response or as a result of immunemediated platelet removal by the spleen. • Infectious diseases such as infection with Anaplasma (formerly Ehrlichia equi) and equine infectious anemia (EIA) are commonly associated with thrombocytopenia. • The autoimmune phenomena can result from: • Viral infection • Abscessation • Neoplasia (especially hemangiosarcoma) • Colostral antibodies • Drug-associated causes ○ Trimethoprim-sulfa products are the most common offender • Idiopathic causes • If thrombocytopenia occurs in conjunction with autoimmune hemolytic anemia (a positive result on Coombs test), the disorder is known as Evans syndrome and is more commonly associated with a primary neoplasia or abscess. • An unusual thrombocytopenia (often severe) with oral vesicles and skin lesions has been reported in foals and appears to be an immune reaction to colostral antibodies. • A low platelet count can be evident on a blood smear or by absolute count. • Practice Tip: Petechiation typically is observable with platelet counts in the 40,000 to 60,000 per microliter range. A more serious bleed (epistaxis) can occur in the 10,000 to 20,000 per microliter range, and life-threatening hemorrhage can develop at less than 10,000 per microliter. • Blood samples can be tested at specialized laboratories such as Kansas State University (www.vet.ksu.edu/depts/ dmp/service/immunology/index.htm) for antibodycoated platelets and/or a regenerative platelet response, reticulated (messenger RNA) platelets.
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Increased mean platelet volume (MPV) reported on some hematology analyzers is another indication of regenerative platelet response • The platelet count can be normal during clinical evidence of bleeding if the underlying disorder is related to platelet function rather than quantity (e.g., Glanzmann thrombasthenia, von Willebrand disease, drug-induced thrombocytopathy [aspirin-induced bleeding has not been reported among horses]). ○
WHAT TO DO Thrombocytopenia
• Most foals with colostral-associated thrombocytopenia recover with or without steroid therapy. Stall confinement until platelet counts are above 40,000 per microliter is recommended. • Management of platelet autoimmune deficiencies consists primarily of administration of corticosteroids. Dexamethasone is considered the most effective drug as long as caution is practiced regarding an associated laminitis. Doses may vary from a low of 10 mg to a high of 80 mg per adult, preferably administered intravenously with a 20-gauge needle or per os (PO) every 12 or 24 hours as divided doses. • Azathioprine, 3 mg/kg PO q24h, can be used for refractory cases or when steroids are contraindicated. Alternatively, azathioprine can be used in addition to dexamethasone when platelet counts are extremely low (<10,000 per microliter). • Practice Tip: For severe thrombocytopenia believed to be immune mediated, both drugs can be used simultaneously! • Platelet counts should be measured every 3 to 6 days until numbers reach levels consistent with near-normal values, and then steroid administration can be tapered. In suspected cases of immunemediated platelet destruction (e.g., those with splenomegaly), the use of vincristine, 0.004 mg/kg (2 mg/450 kg horse) IV weekly, can be combined with the steroid, q24h for 3 to 5 days, twice a week for 1 to 2 weeks, and finally once a week until the platelet counts are stable, to increase platelet release from the bone marrow. • A plasma transfusion has been beneficial in some horses, allegedly as a source of blocking antibody. Plasma or whole blood collected in plastic bags provides a source of platelets that may inhibit bleeding. If the thrombocytopenia is a result of increased consumption, there is little benefit from the transfusion. • Fresh frozen plasma may have hemostatically functional platelet microparticles.
Clinical Presentation • Horses and foals with severe sepsis or systemic inflammatory syndrome frequently have moderately low platelet counts (50,000 to 80,000). • Although an unfavorable prognostic finding, abnormal bleeding rarely occurs unless other coagulation parameters—PT, PTT, DIC—are abnormal.
Clotting Factor Deficiencies
• Clotting factor deficiencies are relatively uncommon among horses. • Hemophilia A is the most common inherited disorder. • Foals with hemophilia A are usually colts (X-linked trait) that present with hemarthrosis of many joints or bleed excessively from minor wounds.
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•
global in vivo hemostasis than traditional coagulation assays, which only evaluate isolated components of the coagulation cascade and do not incorporate contributing cellular elements. Specific activators such as tissue factor or kaolin may be added to expedite coagulation. Hemoscopic TEG PlateletMapping is a modified TEG assay designed specifically to assess platelet function. Polycythemia has been shown to induce hypocoagulabilty on TEG without concurrent changes in other coagulation parameters, and dilution of plasma coagulation factors by increased red cell mass may be an important confounder when interpreting TEG in horses with elevated hematocrits. TEG reference intervals vary significantly among different laboratories and personnel.
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SECTION I Body and Organ Systems
• The aPTT (intrinsic system) is prolonged, and factor VIII is deficient. • Factor VIII–associated deficiency occurs with von Willebrand disease and is linked with qualitative deficiencies in platelet function that cause an increase in the in vivo bleeding time test results. • Warfarin or warfarin-derivative anticoagulant toxicity in horses overdosed with Coumadin or with inadvertent access to rodenticide compounds produces clinical signs of bleeding related to antagonism of vitamin K–dependent factors (II, VII, IX, X). Prolonged therapy with exogenous vitamin K may be required, depending on the inciting compound. Generally both PT and PTT are prolonged with warfarin toxicity; however, only PT may be prolonged in the early stages of toxicity. • Protein C is also vitamin K dependent. Some lactam and beta-lactam antibiotics, most notably moxalactam and carbenicillin, are capable of causing hypoprothrombinemia. Advanced liver disease often results in intrinsic and extrinsic factor deficiencies (see liver disease, Chapter 20, p. 268). WHAT TO DO Coagulopathy
• Fresh frozen plasma is the preferred treatment. • Vitamin K1, 500 mg subcutaneously (SQ) q12-24h for an adult horse, is the required treatment for warfarin toxicity. Do not administer intravenously.
Disseminated Intravascular Coagulation (DIC)
• DIC is an acquired hypercoagulable syndrome characterized by the deposition of fibrin throughout the microvascular. • DIC always occurs secondary to a primary disease process capable of inducing systemic activation of coagulation; including but not limited to: • Sepsis • Systemic inflammatory response syndrome • Endotoxemia • Trauma • Immune reaction • Multiple organ dysfunction (MODS) or failure • DIC is a true consumptive coagulopathy and is associated with a poor prognosis. • DIC can be acute or chronic and can be local or systemic. • The full gamut of coagulation (activation, coagulation, fibrinolysis, and anticoagulation) may be present but is rarely proportional in horses, with multisystemic thrombosis being the most prevalent clinical sign. • The diagnosis of DIC can be made by clinical evidence of hypercoagulation or hypocoagulation (or both) and some or all of the following laboratory abnormalities: • Prolonged activated coagulation time, PT, aPTT • Decreased platelet count and fibrinogen levels • Elevated levels of fibrin degradation products and/or D-dimers
• The level of antithrombin III (heparin cofactor) often is less than 60% to 70% of normal. • Deficiency of anticoagulant proteins C and S may also occur • Microscopic examination of blood smears may show increased sheared red cells (schistocytes) consistent with a microangiopathic hemolytic anemia (MAHA). • Occasionally in end-stage DIC, platelet and coagulation factor depletion produces clinical signs of bleeding; however, most cases of equine DIC are characterized by hypercoagulability and thrombophilia, and observed morbidity and mortality are generally the result of microvascular thrombosis and subsequent organ failure. WHAT TO DO Disseminated Intravascular Coagulation
• Treat for the primary disorder, if known, and direct treatments that slow the consumptive process. • Crystalloids and colloids are the mainstay of treatment. If there is evidence of bleeding (less common than thrombosis in the horse), high doses of hetastarch should not be used. • Heparin in conjunction with normalizing plasma antithrombin III levels has traditionally been recommended at dosages of 40 to 80 IU/kg SQ or IV q6-8h. Subcutaneous dosing can result in local swelling, and unfractionated heparin has been associated with secondary anemia and thrombocytopenia. Adverse heparin reactions are not known to occur with the use of low-molecular-weight heparins (dalteparin, 50 to 100 IU/kg SQ q24h; enoxaparin, 0.5 to 1 mg/kg [40 to 80 IU/kg] SQ q24h). • Blood and plasma transfusions are controversial in regard to adding “fuel to the fire” by providing additional components for the continuation of the consumptive process and infarctive thrombosis. However, absolute contraindications also are rare. If supported based on clinical or laboratory results, plasma transfusion is indicated whenever low antithrombin III levels are present or suspected. • Treatment of DIC often is difficult and must be individualized to include the primary disorder. The prognosis is usually poor with systemic DIC. • Note: The key word is individualized treatment.
Therapeutic Intervention of Hemostasis and Anticoagulation
• Medical therapies that affect the coagulation system are becoming increasingly available to practitioners. The choice of therapy will depend on the clinical diagnosis and the nature of the presenting coagulopathy. The following are potential therapies for various coagulation abnormalities in the equine patient: • Administer plasma products at 10 to 15 mL/kg IV. • Administer vitamin K1 at 500 mg SQ q12-24h for warfarin toxicity. Do not administer intravenously. • Administer heparin at 40 to 80 IU/kg SQ or IV q6-8h. Subcutaneous dosing can result in local swelling, and unfractionated heparin has been associated with secondary anemia and thrombocytopenia. Adverse heparin reactions are not known to occur with the use of lowmolecular-weight heparins (dalteparin, 50 to 100 IU/kg
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hours and persist for 2 or more days. Administer fibrinolysins—thrombolytics such as streptokinase, urokinase, and tissue plasminogen activator (TPA). • Administer antifibrinolytic agents—plasminogen inhibitors such as epsilon-aminocaproic acid (Amicar), 5 to 20 g diluted IV q6-8h. • Administer conjugated estrogen (Premarin), 25 to 50 mg slowly IV in saline/adult horse for uterine bleeding. Conjugated estrogens have occasionally been reported to be of value in decreasing chronic bleeding from sites other than the uterus. Mechanism of activity is unproven and is believed to increase factor VIII activity. • Administer Yunnan Baiyao, 2 bottles (8 g) PO q12h. This is a traditional Chinese herbal medicine that has been used as a hemostatic drug for over 100 years. It has recently been shown in human patients to reduce postoperative hemorrhage; however, its efficacy in horses is unknown.
References References can be found on the companion website at www.equine-emergencies.com.
Drs. Ness, Orsini, and Divers would like to acknowledge and thank Dr. Doug Byars for his contributions to this chapter in all previous editions of this book and to his generous sharing of knowledge in this and many other areas of equine medicine.
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SQ q24h; enoxaparin, 0.5 to 1 mg/kg [40 to 80 IU/kg] SQ q24h). • Administer aspirin at 10 to 20 mg/kg PO or per rectum every other day (EOD). Aspirin is still one of the most common platelet inhibitors used in both human and equine medicine. Its effect is through inhibition of platelet arachidonic acid and thromboxane, which may stimulate platelet activation/aggregation. Although aspirin inhibits thromboxane in healthy horses, it may have an inconsistent effect on platelet aggregation in normal horses and a minimal effect in horses with inflammatory diseases. • Administer platelet aggregation antagonist clopidogrel (Plavix), 2 mg/kg PO q24h, following a 4-mg/kg loading dose. Clopidogrel effectively decreases ADP-induced platelet aggregation in horses, and its therapeutic application for equine diseases associated with platelet activation (laminitis, thrombosis) is currently being evaluated. • Practice Tip: There are many activators of platelets in horses with inflammatory disease, and aspirin may inhibit collagen activation but not ADP and vice versa for clopidogrel. Therefore, both drugs could be used concurrently. When given orally, antiplatelet effects can be seen in less than 6
Chapter 16
CHAPTER 16
Blood Coagulation Disorders SallyAnne L. Ness • As the complex interactions between the cellular and vascular contributions to coagulation become increasingly recognized, the traditional coagulation cascade should be considered one of several components of coagulation, rather than the precise order by which clotting is achieved. • The perennial historical perspective of coagulation provided by Dr. Rudolf Virchow in 1845 views the general rules of coagulation as being: • A disruption of the vascular integrity • Changes in the hemodynamics or stasis of blood flow • Changes in the concentration of substances that promote and/or inhibit coagulation • Recognition of components such as antithrombin III; proteins C and S; and homeostasis between tissue and platelet activators and inhibitors is pivotal to understanding the myriad of coagulation participants that respond to the activation process, subsequent coagulation, fibrinolysis, and anticoagulation. • Coagulation disorders are represented by the following: • Hypercoagulation (thrombosis) • Hypocoagulation (bleeding diathesis) • A normal coagulation system can be present in the presence of a hemorrhagic crisis because of physical disruption of the vascular integrity, as in external trauma or spontaneous internal vascular rupture—aortic root rupture, uterine artery hemorrhage, or guttural pouch mycosis. • Initial assessment of the bleeding patient should aim to differentiate between vessel injury or vascular disease and systemic coagulopathy leading to bleeding diathesis. • Practice Tip: In horses, thrombotic disorders are more common than hemorrhagic diatheses. • Inflammation and sepsis are known initiators of systemic coagulation pathways via activation of the intrinsic coagulation cascade by circulating proinflammatory mediators such as: • Endotoxin • Tumor necrosis factor–alpha (TNF-α) • Lipoproteins • Growth factors • Activation of endothelial cells and circulating monocytes stimulates the expression of tissue factor, an important 118
initiator of thrombin formation in both health and disease. • In the septic patient, systemic hypercoagulability is potentiated by an overall reduction in endogenous anticoagulant factors including: • Antithrombin III (AT-III) • Tissue factor pathway inhibitor (TFPI) • Activated protein C (aPC)
Hypercoagulation: Thrombophilia and Thrombosis • Hypercoagulation is common in horses and is associated with: • Abnormally elevated platelet counts (thrombocytosis) • Arteritis (cranial mesenteric arteritis) • Vasculitis (purpura hemorrhagica) • Idiopathic iliac thrombosis • Spontaneous or sepsis-associated limb arterial thrombosis in foals • Laminitis • Pulmonary infarction • Deficiencies of antithrombin III and protein C or protein S cofactors • Inhibition of fibrinolysis • Consumptive coagulopathies (disseminated intravascular coagulation [DIC]). • DIC can exhibit laboratory evidence of hypocoagulation (prolonged clotting times and thrombocytopenia) while the individual has clinical evidence of hypercoagulation, thrombophilia, and no overt signs of bleeding. • Thrombophlebitis in horses frequently occurs as a sequela to systemic inflammation and loss of antithrombin III following: • Endotoxemia • Salmonella and other causes of infectious colitis • Nonsteroidal anti-inflammatory drug (NSAID) toxicity • Pleuritis • Toxic metritis • Large colon volvulus • Following intravenous administration of irritating or hypertonic solutions (phenylbutazone, enrofloxacin).
Chapter 16
Hypocoagulation: Bleeding Disorder and Diathesis Tendencies
119
• An acute bleed is commonly accompanied by changes in vital signs—tachycardia, tachypnea, and hypothermia—and pale mucous membranes. • Peracute aortic root rupture with collapse and death usually occurs in stallions during or after breeding. • Uterine-ovarian artery rupture is most often acute and can occur before or after parturition. • A subcutaneous hematoma may follow trauma or spontaneous hemorrhage. • Ultrasound evaluation of body cavities or acute subcutaneous swellings may show the presence of extraneous “swirling smoke” fluid indicative of free blood within a space (Fig. 16-1). • Epistaxis, genitourinary hemorrhage, melena, and petechial or ecchymotic lesions may be present. • Overt epistaxis can be caused by exercise-induced pulmonary hemorrhage (EIPH), guttural pouch mycosis, ethmoidal hematoma, sinusitis, trauma, and coagulation deficiencies, including thrombocytopenia.
Clinical Signs of Hemorrhage and Thrombosis
• Obvious clinical signs of thrombosis or hemorrhage can be inapparent because of skin pigmentation and hair coat. • Clinical signs suggestive of primary hemostatic defects (platelet and von Willebrand factor disorders) include petechial or ecchymotic hemorrhage of the mucous membranes and conjunctiva. Epistaxis also may occur. • Clinical signs suggestive of secondary hemostatic defects (coagulopathies) include: • Hematoma formation • Hemarthrosis • Intracavitary hemorrhage • Vascular thrombosis may result in partial or complete ischemia of tissues supplied by the affected vessels (e.g., limb arterial thrombosis in septicemic foals). • The full extent of thrombotic lesions may be inapparent until identified at surgery or postmortem examination. • Antemortem diagnosis can be established with ultrasound identification of intravascular clot formation or with Doppler ultrasound detection of decreased blood flow. • Thrombophilia manifests clinically as: • Jugular thrombosis • Asymmetric cold limbs (saddle thrombus) • Hypothermic lameness during increased exercise • The presence of regional edema in conjunction with petechial or ecchymotic hemorrhage (purpura, vasculitis) • Thrombophilia may be associated with acute hemolytic anemias. WHAT TO DO Coagulopathy with Blood Loss
• Treatments are principally aimed at the following: • Volume replacement with crystalloids including hypertonic saline • Colloids such as whole blood, plasma, and hetastarch. Note: Hetastarch is contraindicated in patients with evidence of hypocoagulability.
Figure 16-1 Ultrasound image of a hemoabdomen in a horse with warfarin toxicity demonstrating characteristic “swirling smoke” appearance of blood within a body cavity.
Laboratory Assessment of Coagulation • The following laboratory tests are available for evaluation of hemostasis in the equine patient. Screening tests are categorized into: • Tests of primary hemostasis (platelet plug formation) • Tests of secondary hemostasis ○ Tests of fibrin clot formation and breakdown (fibrinolysis) • The following specialized tests may necessitate referral of samples to a research laboratory following consultation: • Coagulation factors • von Willebrand disease • Antibody-coated platelet • Protein assays • Note: If known laboratory values are not available, a normal control sample is recommended to aid in the interpretation of individual results. • Platelet counts: • False platelet aggregation can occur in ethylenediaminetetraacetic acid (EDTA) and therefore may necessitate sample collection in sodium citrate for quantitative counts.
COAG
• Hypocoagulation in the horse can be associated with: • Thrombocytopenia (immune mediated or acquired) • Thrombasthenia (abnormal platelet function) • Toxicosis (warfarin/anticoagulant rodenticides toxicity, moxalactam and related antibiotics) • Inherited disorders (hemophilia A, von Willebrand disease) • Primary fibrinolysis (hyperplasminemia) • It also occurs in advanced DIC as a consumptive coagulopathy with secondary fibrinolysis. • Rapid volume replacement with hetastarch and/or crystalloid fluids following severe blood loss can result in dilution of coagulation factors and loss of normal hemostatic ability. • Bleeding disorders can be acute or chronic.
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Figure 16-2 Typical thromboelastogram with measured parameters: R = time to the initiation of clot formation, K = time for the tracing to achieve a set clot strength, Ang = Angle, the rate of clot formation, MA = maximum amplitude, the greatest clot strength, χ = clot strength at 60 minutes after MA, CL60 = 100× (χ/MA). (From Epstein, KL et al: Thromboelastography in 26 healthy horses with and without activation by recombinant human tissue factor, J Vet Emerg Crit Care 19(1): 96-101, 2009.)
•
•
•
•
1
mm
• A scan of a hematologic slide for adequate platelet numbers by a laboratory technician is accurate in detecting inadequate numbers. Practice Tip: At least 10 platelets per high-powered field (magnification: ×1000) is considered adequate if clumping of platelets is not observed. Template bleeding time: • In vivo evaluation of primary hemostasis and platelet plug formation following vascular injury. • The hair distolateral to the accessory carpal bone is clipped and a template bleeding device is used to produce a small incision. • Filter paper is used to absorb blood 1 to 2 mm below the incision site. • Timing starts when the incision is made and ends when bleeding stops; reported normal bleeding time for healthy horses ranges from 2 to 6 minutes, and may be prolonged with both quantitative— thrombocytopenia—and qualitative—von Willebrand disease, Glanzmann thrombasthenia—disorders. Platelet function analysis (PFA-1001): • A point-of-care assay validated in horses for evaluation of primary hemostasis. Cartridges coated in collagen and ADP activate platelets and simulate platelet adhesion and aggregation after vascular injury. • The PFA-100 is able to identify inherited, acquired, and drug-induced thrombocytopathies, including functional disorders in which platelet counts may be normal—von Willebrand disease, Glanzmann thrombasthenia—and can be used to monitor response to aspirin therapy. Activated clotting time (ACT): • Point-of-care evaluation of secondary hemostasis, specifically the intrinsic and common pathways • Deficiencies in factors V, VIII, IX, X, XI, XII, prothrombin (factor II), or fibrinogen result in prolonged ACT. Activated partial thromboplastin time (aPTT): • Point-of-care evaluation of secondary hemostasis, specifically the intrinsic and common pathways • Similar to evaluation by ACT but with higher sensitivity • Deficiencies in factors V, VIII, IX, X, XI, XII, prothrombin (factor II) or fibrinogen result in prolonged aPTT.
PFA-100 (Dade-Behring, Newark, Delaware).
Ang MA
x Time (min)
R
•
•
•
•
•
2
K
60 min
• Can be used to monitor heparin therapy with the goal to prolong the aPTT to 1.5 times pretreatment baseline levels. Prothrombin time (PT): • Aids in the evaluation of the extrinsic coagulation system, specifically the extrinsic and common pathways and their ability to convert fibrinogen to fibrin • Deficiencies in tissue factor (factor III), factors V, VII, X, prothrombin, or fibrinogen result in prolonged PT. • Often used to detect or monitor vitamin K antagonist anticoagulants (e.g., warfarin, [Coumadin]) Fibrinogen: • Quantification of fibrinogen can be performed by means of heat precipitation, fibrometer, or point-ofcare automated analyzer (VetScan VSpro2). • Decreased fibrinogen levels may be observed with DIC, but this is a less sensitive test in horses compared with other species. Fibrin degradation products (FDPs): • Evaluation of primary (fibrinogenolysis without clot formation) or secondary (clot dissolution) fibrinolysis. • Elevated FDP concentrations suggest increased fibrinogenolysis or fibrinolysis activity, and may be observed with DIC, severe inflammatory processes, and hemorrhagic disorders. D-dimers: • End product of fibrinolysis • D-dimers are released following cleavage of fibrin bonds by plasmin. • Differs from FDPs in that it is specific for fibrinolysis (i.e., dissolution of fibrin generated from active thrombin production). • Elevated D-dimers are common in foals <1 week of age, presumably due to resolution of umbilical vessel clots. Thromboelastography (TEG): • A point-of-care hemostatic assay that records changes in the viscoelastic properties of whole blood from initiation of clot formation through fibrinolysis (Fig. 16-2). • It can detect both hypocoagulopathies and hypercoagulopathies and may be a more accurate representation of
VetScan VSpro (Abaxis, Union City, California).
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• • •
Blood Clotting Disorders Thrombocytopenia
• Thrombocytopenia is not an uncommon clinical finding in equine practice and is usually associated with a severe systemic inflammatory response or as a result of immunemediated platelet removal by the spleen. • Infectious diseases such as infection with Anaplasma (formerly Ehrlichia equi) and equine infectious anemia (EIA) are commonly associated with thrombocytopenia. • The autoimmune phenomena can result from: • Viral infection • Abscessation • Neoplasia (especially hemangiosarcoma) • Colostral antibodies • Drug-associated causes ○ Trimethoprim-sulfa products are the most common offender • Idiopathic causes • If thrombocytopenia occurs in conjunction with autoimmune hemolytic anemia (a positive result on Coombs test), the disorder is known as Evans syndrome and is more commonly associated with a primary neoplasia or abscess. • An unusual thrombocytopenia (often severe) with oral vesicles and skin lesions has been reported in foals and appears to be an immune reaction to colostral antibodies. • A low platelet count can be evident on a blood smear or by absolute count. • Practice Tip: Petechiation typically is observable with platelet counts in the 40,000 to 60,000 per microliter range. A more serious bleed (epistaxis) can occur in the 10,000 to 20,000 per microliter range, and life-threatening hemorrhage can develop at less than 10,000 per microliter. • Blood samples can be tested at specialized laboratories such as Kansas State University (www.vet.ksu.edu/depts/ dmp/service/immunology/index.htm) for antibodycoated platelets and/or a regenerative platelet response, reticulated (messenger RNA) platelets.
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Increased mean platelet volume (MPV) reported on some hematology analyzers is another indication of regenerative platelet response • The platelet count can be normal during clinical evidence of bleeding if the underlying disorder is related to platelet function rather than quantity (e.g., Glanzmann thrombasthenia, von Willebrand disease, drug-induced thrombocytopathy [aspirin-induced bleeding has not been reported among horses]). ○
WHAT TO DO Thrombocytopenia
• Most foals with colostral-associated thrombocytopenia recover with or without steroid therapy. Stall confinement until platelet counts are above 40,000 per microliter is recommended. • Management of platelet autoimmune deficiencies consists primarily of administration of corticosteroids. Dexamethasone is considered the most effective drug as long as caution is practiced regarding an associated laminitis. Doses may vary from a low of 10 mg to a high of 80 mg per adult, preferably administered intravenously with a 20-gauge needle or per os (PO) every 12 or 24 hours as divided doses. • Azathioprine, 3 mg/kg PO q24h, can be used for refractory cases or when steroids are contraindicated. Alternatively, azathioprine can be used in addition to dexamethasone when platelet counts are extremely low (<10,000 per microliter). • Practice Tip: For severe thrombocytopenia believed to be immune mediated, both drugs can be used simultaneously! • Platelet counts should be measured every 3 to 6 days until numbers reach levels consistent with near-normal values, and then steroid administration can be tapered. In suspected cases of immunemediated platelet destruction (e.g., those with splenomegaly), the use of vincristine, 0.004 mg/kg (2 mg/450 kg horse) IV weekly, can be combined with the steroid, q24h for 3 to 5 days, twice a week for 1 to 2 weeks, and finally once a week until the platelet counts are stable, to increase platelet release from the bone marrow. • A plasma transfusion has been beneficial in some horses, allegedly as a source of blocking antibody. Plasma or whole blood collected in plastic bags provides a source of platelets that may inhibit bleeding. If the thrombocytopenia is a result of increased consumption, there is little benefit from the transfusion. • Fresh frozen plasma may have hemostatically functional platelet microparticles.
Clinical Presentation • Horses and foals with severe sepsis or systemic inflammatory syndrome frequently have moderately low platelet counts (50,000 to 80,000). • Although an unfavorable prognostic finding, abnormal bleeding rarely occurs unless other coagulation parameters—PT, PTT, DIC—are abnormal.
Clotting Factor Deficiencies
• Clotting factor deficiencies are relatively uncommon among horses. • Hemophilia A is the most common inherited disorder. • Foals with hemophilia A are usually colts (X-linked trait) that present with hemarthrosis of many joints or bleed excessively from minor wounds.
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•
global in vivo hemostasis than traditional coagulation assays, which only evaluate isolated components of the coagulation cascade and do not incorporate contributing cellular elements. Specific activators such as tissue factor or kaolin may be added to expedite coagulation. Hemoscopic TEG PlateletMapping is a modified TEG assay designed specifically to assess platelet function. Polycythemia has been shown to induce hypocoagulabilty on TEG without concurrent changes in other coagulation parameters, and dilution of plasma coagulation factors by increased red cell mass may be an important confounder when interpreting TEG in horses with elevated hematocrits. TEG reference intervals vary significantly among different laboratories and personnel.
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SECTION I Body and Organ Systems
• The aPTT (intrinsic system) is prolonged, and factor VIII is deficient. • Factor VIII–associated deficiency occurs with von Willebrand disease and is linked with qualitative deficiencies in platelet function that cause an increase in the in vivo bleeding time test results. • Warfarin or warfarin-derivative anticoagulant toxicity in horses overdosed with Coumadin or with inadvertent access to rodenticide compounds produces clinical signs of bleeding related to antagonism of vitamin K–dependent factors (II, VII, IX, X). Prolonged therapy with exogenous vitamin K may be required, depending on the inciting compound. Generally both PT and PTT are prolonged with warfarin toxicity; however, only PT may be prolonged in the early stages of toxicity. • Protein C is also vitamin K dependent. Some lactam and beta-lactam antibiotics, most notably moxalactam and carbenicillin, are capable of causing hypoprothrombinemia. Advanced liver disease often results in intrinsic and extrinsic factor deficiencies (see liver disease, Chapter 20, p. 268). WHAT TO DO Coagulopathy
• Fresh frozen plasma is the preferred treatment. • Vitamin K1, 500 mg subcutaneously (SQ) q12-24h for an adult horse, is the required treatment for warfarin toxicity. Do not administer intravenously.
Disseminated Intravascular Coagulation (DIC)
• DIC is an acquired hypercoagulable syndrome characterized by the deposition of fibrin throughout the microvascular. • DIC always occurs secondary to a primary disease process capable of inducing systemic activation of coagulation; including but not limited to: • Sepsis • Systemic inflammatory response syndrome • Endotoxemia • Trauma • Immune reaction • Multiple organ dysfunction (MODS) or failure • DIC is a true consumptive coagulopathy and is associated with a poor prognosis. • DIC can be acute or chronic and can be local or systemic. • The full gamut of coagulation (activation, coagulation, fibrinolysis, and anticoagulation) may be present but is rarely proportional in horses, with multisystemic thrombosis being the most prevalent clinical sign. • The diagnosis of DIC can be made by clinical evidence of hypercoagulation or hypocoagulation (or both) and some or all of the following laboratory abnormalities: • Prolonged activated coagulation time, PT, aPTT • Decreased platelet count and fibrinogen levels • Elevated levels of fibrin degradation products and/or D-dimers
• The level of antithrombin III (heparin cofactor) often is less than 60% to 70% of normal. • Deficiency of anticoagulant proteins C and S may also occur • Microscopic examination of blood smears may show increased sheared red cells (schistocytes) consistent with a microangiopathic hemolytic anemia (MAHA). • Occasionally in end-stage DIC, platelet and coagulation factor depletion produces clinical signs of bleeding; however, most cases of equine DIC are characterized by hypercoagulability and thrombophilia, and observed morbidity and mortality are generally the result of microvascular thrombosis and subsequent organ failure. WHAT TO DO Disseminated Intravascular Coagulation
• Treat for the primary disorder, if known, and direct treatments that slow the consumptive process. • Crystalloids and colloids are the mainstay of treatment. If there is evidence of bleeding (less common than thrombosis in the horse), high doses of hetastarch should not be used. • Heparin in conjunction with normalizing plasma antithrombin III levels has traditionally been recommended at dosages of 40 to 80 IU/kg SQ or IV q6-8h. Subcutaneous dosing can result in local swelling, and unfractionated heparin has been associated with secondary anemia and thrombocytopenia. Adverse heparin reactions are not known to occur with the use of low-molecular-weight heparins (dalteparin, 50 to 100 IU/kg SQ q24h; enoxaparin, 0.5 to 1 mg/kg [40 to 80 IU/kg] SQ q24h). • Blood and plasma transfusions are controversial in regard to adding “fuel to the fire” by providing additional components for the continuation of the consumptive process and infarctive thrombosis. However, absolute contraindications also are rare. If supported based on clinical or laboratory results, plasma transfusion is indicated whenever low antithrombin III levels are present or suspected. • Treatment of DIC often is difficult and must be individualized to include the primary disorder. The prognosis is usually poor with systemic DIC. • Note: The key word is individualized treatment.
Therapeutic Intervention of Hemostasis and Anticoagulation
• Medical therapies that affect the coagulation system are becoming increasingly available to practitioners. The choice of therapy will depend on the clinical diagnosis and the nature of the presenting coagulopathy. The following are potential therapies for various coagulation abnormalities in the equine patient: • Administer plasma products at 10 to 15 mL/kg IV. • Administer vitamin K1 at 500 mg SQ q12-24h for warfarin toxicity. Do not administer intravenously. • Administer heparin at 40 to 80 IU/kg SQ or IV q6-8h. Subcutaneous dosing can result in local swelling, and unfractionated heparin has been associated with secondary anemia and thrombocytopenia. Adverse heparin reactions are not known to occur with the use of lowmolecular-weight heparins (dalteparin, 50 to 100 IU/kg
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hours and persist for 2 or more days. Administer fibrinolysins—thrombolytics such as streptokinase, urokinase, and tissue plasminogen activator (TPA). • Administer antifibrinolytic agents—plasminogen inhibitors such as epsilon-aminocaproic acid (Amicar), 5 to 20 g diluted IV q6-8h. • Administer conjugated estrogen (Premarin), 25 to 50 mg slowly IV in saline/adult horse for uterine bleeding. Conjugated estrogens have occasionally been reported to be of value in decreasing chronic bleeding from sites other than the uterus. Mechanism of activity is unproven and is believed to increase factor VIII activity. • Administer Yunnan Baiyao, 2 bottles (8 g) PO q12h. This is a traditional Chinese herbal medicine that has been used as a hemostatic drug for over 100 years. It has recently been shown in human patients to reduce postoperative hemorrhage; however, its efficacy in horses is unknown.
References References can be found on the companion website at www.equine-emergencies.com.
Drs. Ness, Orsini, and Divers would like to acknowledge and thank Dr. Doug Byars for his contributions to this chapter in all previous editions of this book and to his generous sharing of knowledge in this and many other areas of equine medicine.
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SQ q24h; enoxaparin, 0.5 to 1 mg/kg [40 to 80 IU/kg] SQ q24h). • Administer aspirin at 10 to 20 mg/kg PO or per rectum every other day (EOD). Aspirin is still one of the most common platelet inhibitors used in both human and equine medicine. Its effect is through inhibition of platelet arachidonic acid and thromboxane, which may stimulate platelet activation/aggregation. Although aspirin inhibits thromboxane in healthy horses, it may have an inconsistent effect on platelet aggregation in normal horses and a minimal effect in horses with inflammatory diseases. • Administer platelet aggregation antagonist clopidogrel (Plavix), 2 mg/kg PO q24h, following a 4-mg/kg loading dose. Clopidogrel effectively decreases ADP-induced platelet aggregation in horses, and its therapeutic application for equine diseases associated with platelet activation (laminitis, thrombosis) is currently being evaluated. • Practice Tip: There are many activators of platelets in horses with inflammatory disease, and aspirin may inhibit collagen activation but not ADP and vice versa for clopidogrel. Therefore, both drugs could be used concurrently. When given orally, antiplatelet effects can be seen in less than 6
Chapter 16