Thrombosis in Veterinary Medicine PDF

1/28/25 Thrombosis in veterinary medicine Benjamin Brainard VMD dipl ACVAA, ACVECC VETM 5291 Thrombosis and thromboembolism Obstructive shock Impaired regional oxygen delivery Impaired blood flow Organ dysfunction/fa...

1/28/25 Thrombosis in veterinary medicine Benjamin Brainard VMD dipl ACVAA, ACVECC VETM 5291 Thrombosis and thromboembolism Obstructive shock Impaired regional oxygen delivery Impaired blood flow Organ dysfunction/failure Primarily microthrombosis Complicates therapy E.g. catheter associated thrombosis 1  1/28/25 Diagnosis of thrombosis Physical exam: Extremity is colder than other extremities Ischemic muscles are painful and hard (ischemic myopathy) Thrombophlebitis characterized by warmth and swelling over vein, usually at site of prior venipuncture or catheter Thrombosis of gastrointestinal tract identifiable as an acutely painful abdomen Signs of organ failure Pulmonary thromboembolism characterized by acute onset dyspnea Acute kidney injury Hepatic injury Stroke or other acute neurologic deterioration Sudden death may occur from massive thrombosis Ultrasound or other imaging (e.g. CT) may identify thrombi in situ Pouzot-Nevoret C, et al. J Feline Med Surg. 2017 Hypercoagulability: theory Virchow (c. 1845) Endothelial damage Hypercoagulable state Blood stasis/ alterations in blood flow 2  1/28/25 Endothelial dysfunction Alterations of glycocalyx exposing procoagulant triggers Inflammation Fluid therapy Direct injury Release of vWF Activated endothelial cell Iba T. J Thromb Haemost. 2019;17(2):283-294. Hypercoagulable state Increased procoagulant proteins Sepsis Inflammation Surgery (fibrinogen) 10 Hyperadrenocorticism 9 Heritability 8 Fibrinogen (g/L) 7 Decreased anticoagulant 6 proteins 5 4 Sepsis 3 Inflammation 2 Loss 1 0 GI -24 pre in tra end sx 2h 24 h 48 h 72 h 120 h Renal lap ch ole thyroid ab d pro c THR con trol 3  1/28/25 Blood stasis Activation of intrinsic pathway Decreased blood flow Abnormal blood flow Intravascular foreign material Negative charge Biofilm production Jaffer IH, Weitz JI. Acta Biomater. 2019;94:2-10. Fluckiger JU et al. J Magn Reson Imaging. 2013;38(3):580. Arterial vs venous thrombosis Arterial clots “white clots” Predominantly platelets Activated with high shear blood flow Antiplatelet agents as primary therapy Venous clots “red clots” Low pressure/venous stasis Rich in fibrin, erythrocytes Anticoagulant agents as primary therapy 4  1/28/25 Cardiac Disease Feline cardiac disease Left atrial dilation, spontaneous echocontrast, reduced left atrial appendage flow velocity are risk factors. Thromboembolic sequelae primarily: arterial thromboembolism = ATE Heartworm (pulmonary artery thrombosis) Worm thrombus vs clot Transvenous pacemakers Uncommon clot formation on lead Immune mediated hemolytic anemia (IMHA) Strongly associated with thrombosis in dogs Anticoagulation is standard component of therapy Risk factors include: Severe inflammatory response High fibrinogen, decreased antithrombin RBC membranes in circulation Corticosteroid therapy IV access, sometimes multiple Multiple blood transfusions 5  1/28/25 Protein Losing conditions Protein losing nephropathy (PLN) Associated with thrombosis Presumably due to loss of antithrombin Protein losing enteropathy (PLE) Loss of proteins including antithrombin Small and large animal Glucocorticoids, hyperadrenocorticism Treatment with corticosteroids is associated with a hypercoagulable state Is there a clear risk of thrombosis? Hyperadrenocorticism (dogs) May favor hypercoagulable state Considered to be a risk factor Elevated Factors II, V, VII, IX, X, XII Fibrinogen Thrombin-antithrombin complexes Antithrombin Rose LJ, et al. Vet Clin Pathol. 2011;40(4):426-434. 6  1/28/25 Infectious disease Dogs with sepsis (esp. endocarditis, septic peritonitis, aspiration pneumonia) without coagulopathy are at risk of thrombosis Does not support routine anticoagulation of septic dogs Small subset of cats with sepsis Neonatal sepsis (foals) Presence of coagulopathy worsens prognosis EHV-1 infection (adult horses) Vasculitis, thrombosis à myeloencephalopathy Equine gastrointestinal disease Jugular thrombophlebitis or other thrombosis Ischemic/strangulating GI lesions Colitis Duodenitis/proximal jejunitis Right dorsal colitis Jugular thrombophlebitis more likely in horses with surgically treated colic that develop fever or diarrhea Salmonellosis also risk factor Thrombosis may initiate at venipuncture site or on catheter 7  1/28/25 Other conditions Neoplasia Carcinomas in dogs associated with a risk of thrombosis. Overall prevalence of thrombosis associated with cancer is unknown Cerebrovascular disease May result from a thrombotic event rather than be the cause of one Pancreatitis (dogs) Extracorporeal circuits (eg. dialysis) Activates coagulation during treatment Vascular access/devices Transvenous pacemaker leads IV catheters Central lines Catheter-associated thrombi generally in patients with severe inflammation Consideration to number and type of venous catheter Catheter alone not usually a risk factor. 8  1/28/25 When are anticoagulant drugs indicated? In animals with existing thrombi/thromboembolism In animals with a single strong risk factor Animals with multiple moderate risk factors Always indicated for dogs with IMHA, cats with heart disease Disease risk factor summary: CURATIVE guidelines Antithrombotics recommended…? Condition Thrombosis risk Yes, Insufficient Yes Consider No Strongly evidence IMHA Strong ✓ PLN (dog) Yes ✓ Pancreatitis Yes ✓ Steroids Yes ✓ hyperadrenocorti Weak ✓ cism Neoplasia Yes ✓ Sepsis individual var ✓ Feline Heart Strong ✓ Disease deLaforcade A, et al. JVECC 2019;29(1):37-48. 9  1/28/25 Disease risk factor summary 2.0 Antithrombotics recommended…? Condition Thrombosis Yes, risk Insufficient Strongl Yes Consider No evidence y Heartworm yes ✓ IMHA (cats) Weak ✓ PLN (cats) Weak ✓ Hepatic individual ✓ (dogs) var PSS (d/c) no ✓ Arrhythmia Yes ✓ Moderate(d) PLE ✓ ✓ Weak (c) TV Weak (d) ✓ ✓ pacemaker None (c) deLaforcade A, et al. JVECC 2022;32(3):289-314. Anticoagulant drugs Clear evidence on superiority of one drug or drug class over another is missing in veterinary medicine. Specific mechanism for disease (eg. platelet vs factor) Ease of administration and cost may trump focused selection Antiplatelet agents Antithrombotic agents Fibrinolytic agents 10  1/28/25 Xiang YZ et al. Thromb Res. 2008;123:35. ADP collagen thrombin 11  1/28/25 Clopidogrel (Plavix) P2Y12 ADP receptor inhibitor Decreases degree of platelet aggregation Decreases platelet activation state Prodrug Requires hepatic conversion P450, interindividual variability Irreversible block of receptor Effective in dogs, cats, horses Gachet C. Thromb Haemost. 2001;86:222. Clopidogrel Dog Rapid onset 1 mg/kg PO q 24h Cat 18.75 mg PO q 24h Horses Variable onset and termination àLoading 4 mg/kg then 2mg/kg SID Brainard BM, et al. JVIM. 2011;25(1):116-22. Brainard BM, et al. AJVR. 2010;71(7):822-30. Hogan DF et al. JAVMA, 2004;225(9):1406-11. 12  1/28/25 Acetylsalicylic acid (ASA; Aspirin) Inhibits cyclooxygenase (COX) Prevents production of AA metabolite Thromboxane (TXA2) Thromboxane is potent platelet agonist, vasoconstrictor Irreversible inhibition of COX ASA Decreases platelet aggregation in dogs Does reliably impact platelet aggregation in cats or horses NSAID-associated toxicities Gastric ulceration/bleeding Renal impairment depending on dose Brainard BM, et al. AJVR. 2007;68(3):251-7 Brainard BM, et al. JVIM. 2011;25(1):116-22 Cathcart CJ, et al. JVECC. 2012;22(1):99-106. 13  1/28/25 FAT-CAT: aspirin vs clopidogrel Prevention of recurrent ATE 85 cats 42 clopidogrel 18.75 mg PO q 24h 43 ASA 81 mg PO q 72h Recurrent TE in 19/39 clopidogrel (49%) 27/36 ASA (75%) Median time to recurrence 443 days (7 – 990 d) clopidogrel 192 days (6 - 883 days) ASA Hogan DF, et al J Vet Cardiol. 2015;17 Suppl 1:S306-17. Heparin Potentiates AT inhibition Unfractionated heparin (UFH) Binds AT and FIIa, FXa Low-Molecular weight heparin (LMWH) Binds Xa Dalteparin Enoxaparin Can measure anti-Xa activity to dose either Directly correlated to [drug] Weitz JI. NEJM1997;337:688-698 14  1/28/25 Types of heparins Unfractionated Heparin (UFH) In dogs, cats, horses at risk of thrombosis, IV or SQ Individual variation in optimal UFH dose likely Interaction with plasma proteins, endothelial cells, macrophages Bleeding—UFH less specific binding clotting factors (esp IIa) Erythrocyte agglutination and thrombocytopenia (horses) Low molecular weight heparin Used in dogs, cats, horses, variable dosing intervals Frequent dosing may be necessary to achieve the human effective range More predictable PK/PD Not associated with RBC agglutination in horses Other uses for heparin in horses Hyperlipemia Increase release of lipoprotein lipase Increase release of hepatic lipase LMWH may prevent platelet activation from EHV-1 Adhesion prevention: effective? Stokol et al, PlosOne, 2015 Watson TD, et al. Vet Rec. 1992;131(3):48-51 Stokol et al. Front Vet Sci. 2018;5:106. Alonso Jde M,et al. Vet Med Int. 2014;2014:279730. 15  1/28/25 Direct Xa inhibitors Rivaroxaban (Xarelto), Apixaban (Elliquis) Inhibit factor Xa directly No need for antithrombin Inhibits free Xa and Xa in prothrombinase complex Predictable pharmacokinetics Not impacted by food Irreversible inhibition of Factor Xa Problematic for rapid reversal of drug effect Well-tolerated in dogs and cats Galgani A, et al.Front Neurol. 2018;9:1067. Jiang X et al. Thromb Haemost. 2009;101(4):780-2. Antiplatelet agents vs Anticoagulants for ATE Dogs Antiplatelet agents may be more effective vs anticoagulants for prevention of ATE Anticoagulants may also be effective for prevention of ATE Cats Recommend clopidogrel for prevention of ATE. FATCAT: median time to ATE recurrence Clopidogrel 443 days (7 – 990 d) Aspirin 192 days (6 - 883 days) No recommendations re: anticoagulants SUPERCAT: median time to ATE recurrence Clopidogrel: 663 days Rivaroxaban: 513 days Combination therapy? Case report, 3 cats ATE, dual therapy (RVX, Clopid) 502 days (IQR = 171-663) Brainard BM et al. JAVMA. 2024 doi: 10.2460/javma.24.09.0584. Hogan DF, et al J Vet Cardiol. 2015;17 Suppl 1:S306-17 Lo ST, et al. J Feline Med Surg. 2022;24(4):277-283 16  1/28/25 Combination therapy? In humans: Combination associated with higher incidence of bleeding complications Especially gastrointestinal (PPI are recommended) Clopidogrel preferred > ASA, ASA and clopidogrel together higher risk Deescalate therapy (usually anti-platelet drug) after acute need, based on risk Coadministration of rivaroxaban/clopidogrel Bleeding in one dog (0.8 mg/kg RVX, 4 mg/kg Clopid) 0.5 mg/kg RVX, 2 mg/kg clopidogrel successful Coadministration of apixaban/clopidogrel Apixaban up to 1 mg/kg PO q12h, clopidogrel 1.875 mg/kg PO q24h Appears safe in healthy dogs. Barnes GD. Hematology. 2020 Dec 4;2020(1):642-648. Uchida M et al. J Vet Med Sci. 2020;82(9):1271-1276. Sakamoto Y, et al. BMC Vet Res. 2020;16(1):418. Gagnon AL et la. ACVIM forum abstract 2019 Fibrinolytic drugs Tissue plasminogen activator (tPA) Injectable activator of plasmin Rapid effect: may cause reperfusion injury Breaks down all clots Catheter delivered May be superior Must use early Pan Y, et al. Front Neurol. 2021;12:593887. 17  1/28/25 [email protected] Instagram: ollieoopz 18  1/28/25 Feline aortic thromboembolism 19 1/28/25 20