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TRANSFUSIONS IN PRACTICE PART 2: DIAGNOSIS AND MANAGEMENT OF COAGULOPATHY
Kristin Welch, DVM, DACVECC
DVM STAT 24/7
2019

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Is it a Coagulopathy?
-ANY patient that presents has the potential to have a coagulopathy
-Melena
-Hyphema
-Epistaxis
-Hemoptysis
-Hematemesis
-Gingival hemorrhage
-Cavitary effusion
-Pericardial effusion
-Postop hemorrhage
-Anemic patients

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Categorization Based on PE
Primary Coagulopathy
-Petechiae, ecchymosis
-Gingival hemorrhage
-Hyphema
-Melena

Secondary Coagulopathy
-Hemoabdomen, hemothorax
-Pericardial effusion
-Pulmonary
hemorrhage
-Melena less commonly

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Primary Coagulopathy
-Thrombocytopenia
-Thrombocytopathia

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Importance of a Blood Smear
-Automated thrombocytopenia should be verified with a blood smear
-Manual platelet estimate
-# platelets in 10 fields, averaged
-X 15,000/uL = platelet estimate
-Assess for clumping, adequate blood smear technique

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Primary Coagulopathy - Thrombocytopenia
Decreased Production
Estrogens, chemotherapeutics, azathioprine, sulfas, leflunomide
Cats- methimazole, griseofulvin

Increased Destruction IMT, neoplasia, vasculitis, DIC
Sequestration Splenic torsion
Loss Acute blood loss > 20% blood volume
Breed Related Cavalier King Charles spaniels - macroplatelets
Greyhounds

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Clinical Diagnosis in the ER
-Is thrombocytopenia the cause of hemorrhage?
-Platelet < 50K = spontaneous hemorrhage common
-Platelet >75-100K = without trauma/surgery
hemorrhage is unlikely unless concurrent secondary coagulopathy OR thrombocytopathia
Platelets < 75,000/uL
-Increased destruction
-Decreased production
Platelets > 75,000/uL
-Loss
-Consumption

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If Thrombocytopenia is Not the Cause...
-vWD?
-Thrombocytopathia?
-Acquired -Inherited
-Severe hypertension
-Hemoptysis -Hyphema
-Epistaxis -Gingival hemorrhage
-Less commonly petechiation
-Secondary coagulopathy?

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Is it vWD? Tentative Diagnosis in the ER
-Is bleeding due to von Willebrand's disease?
-Normal PLT count
-Normal PT/PTT
-Rarely PTT is mildly prolonged from associated deficiency in factor VIII
-Prolonged buccal mucosal bleeding time (BMBT)
-Breed predisposition
-Prolonged BMBT
-NO history of NSAIDs or other known PLT inhibitors

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Von Willebrand's Disease
vWF Concentration
vWF Structure/ Function
Clinical Severity
Breeds
Type I Low Normal Variable Airedale, Akita, Bernese
Mtn dog, Dachshund, Doberman, GSD, Golden Retriever, Greyhound, Irish Wolfhound, Manchester Terrier, Schnauzer, Pembroke Welsh Corgi, Poodle, Sheltie, others
Type 2 Low Abnormal Severe German Shorthaired Pointer, German Wirehaired PointerType 3 Markedly reduced or absent Severe Chesapeake Bay Retriever, Scottish Terrier, Shetland Sheepdog, Dutch Koolier

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vWD Diagnostics
Von Willebrand factor antigen assay -Measures concentration of vWF compared to 100% standard (% vWF:Ag)
-Normal (70-180%)
-Borderline (50-69%)
-Abnormal (0-49%)
-Clinical signs often not unless vWF <20% unless invasive procedure or trauma
-Value fluctuates with pregnancy and disease (liver, inflammatory)

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vWD Diagnostics
DNA
-Clear
-Affected
-Carrier
-Cheek swab
-Bernese Mountain Dog, Coton de Tulear, Doberman Pinscher, German Pinscher, Kerry Blue Terrier, Manchester Terrier, Papillion, Pembroke Welsh Corgi, Poodle, Stabyhoun, Drentsche Patrischond -VetGen (www.vetgen.com) or Vetnostic Laboratories (www.vetnostic.com)
-10-14 day turnaround

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Clinical Diagnosis in the ER
Is bleeding due to thrombocytopathia?
-Normal platelet count
-Normal PT/PTT -Normal vWf (or not a predisposed breed)
-Prolonged BMBT (>4-5 min)
-Definitive diagnosis does require a normal vWF level

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Buccal Mucosal Bleeding Time

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Buccal Mucosal Bleeding Time

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Thrombocytopathia - Acquired Platelet Dysfunction
-More common than hereditary PLT disorders
-NSAID
-Synthetic colloids
-Acepromazine
-Antiplatelet medications
-Liver disease
-Renal failure

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Inherited Platelet Disorders by Breed
Thrombocytopathia Breeds Reported
Glanzmann's thrombasthenia
Scott syndrome
Chediak-Higashi syndrome
Breeds Reported
Great Pyrenees
Otter hound
Greater Swiss Mountain dog
Scott syndrome German Shepherds
Persian cats
Collies
American Cocker Spaniels

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Thrombocytopathia - Inherited Platelet Disorders
-Glanzmann's thrombasthenia (GT)
-Defect in GP IIb/IIIa (fibrinogen) receptor on platelet
-Great Pyrenees, Otter hound, Greater Swiss Mountain dog
-Scott syndrome
-Inability of platelets to generate a procoagulant platelet surface (phospholipases)
-German Shepherds

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Thrombocytopathia - Inherited Platelet Disorders
-Chediak-Higashi Syndrome
-Lack of dense granules (procoagulant)
-Persian cats (blue flame)
-Concurrently impaired neutrophil function
-Collies, American Cocker Spaniels
-UPenn Genetics Lab
(research.vet.upenn.edu/penngen)

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Thrombocytopathia
Treatment of Inherited Platelet Disorders
-Platelet transfusion if active severe hemorrhage and ongoing blood loss
-Ideally FWB, PRP or PC
-WB or pRBC if severe secondary anemia
-If chronic blood loss (low grade) iron supplementation may be necessary

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Primary Coagulopathy - ITP
-Is bleeding due to ITP?
-Platelet count often << 50,000/uL
-There is often subcutaneous PLUS GI blood loss

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---Platelets for Treatment of ITP?
-GI blood loss is very unrewarding to treat with platelet concentrates
-Often don't appreciate any improvement in amount of GI blood loss with a therapeutic dose of platelets -Ongoing hemorrhage results in LOSS of the transfused platelets rapidly -Immune mediated destruction results in rapid loss of transfused platelets
-pRBC or FWB to maintain adequate HCT for O2 delivery while immunosuppressants take effect
-5-7 days for bone marrow response

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Correcting a Primary Coagulopathy

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Platelet Transfusion Guidelines-Humans
-Platelet Transfusion Indications
-Prophylaxis against hemorrhage (PLT <10K)
-Prior to invasive procedure (PLT <50K)
-Actively hemorrhaging patient (PLT <20K)
-Avoided in IMT unless life threatening hemorrhage
-Drug induced or hereditary PLT dysfunction prior to invasive procedure
-Fresh platelet concentrate (plasmapharesis) -Up to 38% of patients have febrile reactions
-Up to 2% have severe reactions

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Platelet Transfusion Guidelines - Vet
-Consider if:
-Platelet count is <50,000/uL
AND
-Active hemorrhage into life threatening location
-Brain
-Lungs
OR
-Emergency surgical intervention needed

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%MONO 31.1%
%EOS 1.4%
%BASO 0.0%
NEU 0.04K/microlitre 2.95 - 11.64 LOW
LYM 0.46K/microlitre 1.05 - 5.10 LOW
MONO 0.23K/microlitre 0.16 - 1.12
EOS 0.01K/microlitre 0.06 - 1.23 LOW
BASO 0.00K/microlitre 0.00 - 0.10
PLT 110K/microlitre 148 - 484 LOW
MPV 11.9fL 8.7 - 13.2
PDW 12.9fL 9.1 - 19.4
PCT 0.13% 0.14 - 0.46 LOW

%EOS 0.0%
%BASO 0.0%
NEU 0.01K/microlitre
LYM 0.21K/microlitre
MONO 0.03K/microlitre
EOS 0.00K/microlitre
BASO 0.00K/microlitre
PLT 0K/microlitre
MPV 13.4fL
PDW --.--fL
PCT 0.00%

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Platelet Transfusion Options
-Fresh Whole Blood
-Fresh Platelet Rich Plasma
-Fresh Platelet Concentrate
-Frozen Platelet Concentrate
-Lyophilized Platelets

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Platelet Transfusion Options
-Fresh whole blood
-Maintain at room temperature with gentle agitation until transfusion
(<8 hr)
-10 ml/kg expected to increase PLT by 10 K/uL but post
transfusion platelet count can't be predicted
-Potential for hypervolemia particularly if patient is not actively hemorrhaging-ITP without significant hemorrhage
-Congenital thrombocytopenia/thrombocytopathia
-Correcting HCT alone during treatment of thrombocytopenia has been shown to be beneficial...

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Role of RBC in Primary Coagulation
-pRBC transfusion improves hemostasis in anemic
thrombocytopenic human patients -RBC help disperse PLT from center of vessels to increase PLT- endothelial contact in the periphery
-Increased release of ADP leading to PLT activation
-Nitric oxide scavenging
-Increased PLT production of thromboxane
-Anemia is shown to increase bleeding time by 60%
-15% reduction in HCT resulted in bleeding time prolongation BUT 32% decrease in PLT count did not
-Human recommendation
-Correct HCT to >35% before correcting platelet dysfunction in anemic thrombocytopenic patients requiring PLT transfusion

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Platelet Transfusion Options
-Fresh platelet rich plasma (PRP)
-Crossmatch is recommended prior to administration
-1 U/ 10 kgs
-Fresh platelet concentrates (PC)
-Canine PC = ~ 8 x 1010 PLT
-Human PC has 3.3 x 1011 PLT/uL (apharesis)
-1 U/10 kg --> maximum PLT rise = 40 K/uL
-Both PRP and PC
-Prepared & maintained at room temperature (22 C) up to 5 days
-Gentle agitation continuously to minimize in vitro PLT deterioration

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Platelet Rich Plasma & Platelet Concentrate
-500 ml FWB processed within 8 hours
-Soft spin (1000 Xg for 4 min)
-Express supernatant into satellite bag = PRP
-Mean PLT = 8 x 1010 -Hard spin (2000 Xg x 10 min) = PC
-Mean PLT = 8 x 1010
-80% have PLT >5.5 x 1010 and 24% have PLT >1 x 1011
-~26% of platelets in FWB are lost in processing
-HCT of unit 0.1% - 26.2%
-Reduce HCT <1% if stop expression of PRP 1 cm from the RBC- plasma interface
-Crossmatch

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Platelet Transfusion Options
-Frozen platelet concentrate
-Thaw at room temperature (22C) and use within 4 hrs
-Gentle rotation every 5 min and rest for 15 min after thawing PRIOR to administration (filter)
-1 U/10 kg over 1-2 hours (1 U = 1 x 1011 PLT)
-Expected PLT rise is 20,000/uL
-New recommendation is ~2.5X this dose due to 35% PLT loss during freeze-thaw & low (45%) PLT recovery from cryopreservation
-DMSO decreases PLT viability, PLT aggregation, and clinical efficacy
-6 mo shelf life

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Platelet Transfusion Options
-Lyophilized platelets
-Reconstituted with 0.9% saline
-Rare transfusion reactions
-Store up to 24 months

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Lifespan of Transfused Platelets
-3.5 - 7 days
-Fresh whole blood - Fresh platelet rich plasma
-Fresh platelet concentrate
-2 days
-Frozen platelets
-Minutes
-Lyophylized platelets
-Dependent upon the primary disease process!

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Cryoprecipitate
-Indications
-Active hemorrhage or planned invasive procedure -Rich in vWF, Factors VIII and XIII, Fibrinogen, Fibronectin
-vWD
-Hemophilia A (Factor VIII deficiency)
-FFP can be used for cats with Hemophilia A
-Dose = 1 U/10-12 kg in dogs
-1 U Cryo = 250-300 ml FFP
-Administration rate: 2-5 ml/kg/hr within 2-4 hr of procedure
-Repeat every 30 min if needed for invasive procedures

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A dog receiving a transfusion

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Secondary Coagulopathy - Clinical Picture
-Hemoabdomen
-Hemothorax
-Pulmonary hemorrhage
-Pericardial effusion
-Hyphema
-Less commonly melena, hematuria

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TF-VIIa-Ca2+
IXIXa
XProthrombin Xa Trace
Thrombin
VIII, V
VIIIa, Va VIIIa, IXa
Xa, Va
Prothrombin Thrombin

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Clinical Diagnosis in the ER
-Is hemorrhage due to secondary coagulopathy?
-Normal platelet count or > 75-100 K
-PT or PTT prolonged
-Citrated PTT is sensitive to sampling or testing errors
-PTT is not often out of range with a normal PT = consider repeat PTT to confirm

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Secondary Coagulopathy
Prolonged PT with normal PTT
Early rodenticide toxicity (PT>25% prolonged)
Hereditary Factor VII Deficiency
Liver disease
Prolonged PTT with normal PT
Sepsis, severe SIRS (<25% prolonged)
Hemophilia A or B
Liver disease
Dilutional coagulopathy
Spurious result

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Secondary Coagulopathy - Anticoagulant Rodenticide
Short Acting Anticoagulant Rodenticide
Warfarin
Long Acting Anticoagulant Rodenticide
Brodifacoum, Bromadiolone,
Chlorophacinone, Diphacinone,
Indandione, and Pindone.
-Clinical hemorrhage 48-72 hr post ingestion
-Factor VII half life is 7 hrs
-Hemorrhage when F-VII activity < 30-40% normal
-Don't confuse with other rodenticides
-*Bromethalin (Neurotoxin)
-Cholecalciferol (Renal failure)

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Vitamin K Anticoagulant Rodenticide Clinical Diagnosis
-Is bleeding due to Anticoagulant Rodenticide?
-PT >> PTT
-If active hemorrhage, PT and PTT both severely prolonged
-Sometimes mild thrombocytopenia
-Consumptive coagulopathy (+/- blood loss)
-Normal PCV in acute hemorrhage with disproportionately LOW total protein
-Compatible history

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Vitamin K Anticoagulant Rodenticide Clinical Management
-Confirmatory Diagnosis
-Vitamin K deficiency coagulation panel
-Antemortem citrated plasma OR stomach contents/ urine/postmortem blood
-Cornell Comparative Coagulation, 24 hour turn around

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Vitamin K Anticoagulant Rodenticide - Treatment
-Known ingestion within 4 hrs
-PT will be normal
-If emesis is induced within 2-4 hr and activated charcoal administered, can recheck PT in 48 hr to confirm it is still normal
-No need to treat with Vitamin K1 (adequate decontamination)
-Ingestion > 2 hrs ago or inadequate decontamination
-Normal PT/PTT OR no hemorrhage with prolonged PT
-Vitamin K1 5 mg/kg PO ideally (or SQ) once then 2.5 mg/kg PO with a meal (SID or divided BID) x 28-30 days

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Vitamin K Anticoagulant Rodenticide - Treatment
-Hemorrhage or PT/PTT severely prolonged
-Vitamin K1 5 mg/kg PO (or SQ) once then 2.5 mg/kg PO (SID or divided BID) x 28-30 days
-FFP or Frozen plasma 10-15 ml/kg IV over = 4 hr; recheck PT 1 hr after completion
-Monitoring for ALL treated patients
-PT 2 days after last dose of Vitamin K1
-If normal, no additional therapy
-If prolonged, treat with 2 additional weeks of Vitamin K1 and recheck PT 2 days after last dose

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Secondary Coagulopathy - Factor VII
-Hereditary Factor VII deficiency
-Beagles, Alaskan Klee Kai dogs -Prolonged PT with normal PTT
-Low Factor VII activity on clotting factor analysis

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Secondary Coagulopathy - Liver Failure
-Hepatic synthesis and carboxylation of factors II, VII, IX, X
-Intrahepatic and post hepatic cholestasis
-Impairs bile acid release into SI
-Vitamin K deficiency
-Hyperfibrinolysis
-PT/PTT prolongation there is <30-40% functional liver capacity
-PTT is often prolonged 1st

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Secondary Coagulopathy - Hemophilia
Factor Deficiency
Breeds
Clinical Signs
Diagnosis
Hemophilia A
IX
German wirehair pointer, 25 other breeds
**GWP have mild CS
-Teething
-Surgical
-Spontaneous hemarthrosis
-Cavitary hemorrhage
-SQ hematomas
-Severe hemorrhage during teething or OHE/castration
-Prolonged PTT with normal PLT and PT
-Factor IX assay - Normal >50%, - Affected <20% - Severe <2%
-DNA

Hemophilia B
VIII Any
-Spontaneous hemarthrosis
-Cavitary hemorrhage
-SQ hematomas
-Severe hemorrhage during teething or OHE/castration
-Prolonged PTT with normal PLT and PT
-Factor VIII assay
-Pedigree analysis

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Clinical Diagnosis - Hemophilia
-Could hemorrhage be due to hemophilia?
-Normal platelet count
-Mild thrombocytopenia if hemorrhage present -Normal PT
-Prolonged PTT
-Treatment
-FFP for A and B
-Cryoprecipitate for B

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Secondary Coagulopathy-Cats
-Factor XII deficiency (Hageman factor)
-Autosomal recessive- DSH, DLH, Siamese, Himalayan
-Marked PTT prolongation but no in vivo bleeding tendency recognized
-F-XII level can be measured
-Hemophilia A or Hemophilia B
-DSH, Birman, Himalayan
-Factor VIII (A) or IX (B) levels < 5%
-Factor I deficiency (fibrinogen)
-Maine Coon cats
-Hereditary Vitamin K responsive coagulopathy
-Devon Rex cats

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Trauma Induced Coagulopathy (TIC)
-Platelet dysfunction in 45% of human trauma patients at admission and 91% during hospitalization
-40-70% of human deaths are due to massive hemorrhage within 6 hr of trauma
->30% of severely traumatized veterinary patients
-Elevated PTT, decreased fibrinogen
-Correlated to severity of trauma

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Dilutional Coagulopathy (DC)
-Replacement of acute blood loss with crystalloids and pRBC
-Thrombocytopenia and depleted clotting factors
-Coagulopathy compounded by acidosis and hypothermia in critical illness
-Massive Transfusion
-Treatment Options
-FFP
-Likely doses > 15 ml/kg based on experimental data
-Recombinant factor VIIa
-Fibrinogen concentrate
-Prothrombin complex concentrate

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Effect of Synthetic Colloids on Coagulopathy
-Factor VIII
-Decreased VIII levels
-Accelerated elimination of the complexed HES:vWF: FVIII by the reticuloendothelial system
-vWF
-Decreased circulating levels found in high molecular weight HES
treated dogs
-Platelet dysfunction
-Decreased activation and expression of integrin
-Decreased platelet agonist expression
-HES molecules coat the PLT surface

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Disseminated Intravascular Coagulation (DIC)
-DIC is a HYPERcoagulable syndrome from acute
widespread activation of coagulation
-Hypercoagulable phase --> Thromboembolic
complications
-Intravascular formation of fibrin
-Hypocoagulable phase --> Diffuse hemorrhage
-Consumption of platelets and coagulation factors

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DIC
-Is hemorrhage due to DIC?
-PLT < 75K -PT/PTT prolongation (subclinical)
-Fulminant hemorrhage and simultaneous microvascular thrombosis
-Diagnosis
-Thrombocytopenia, + FDPs, hypofibrinogenemia, + D-Dimer, Prolonged PT/PTT
-Treatment options
-Treat the underlying disease
-Anticoagulate?
-Correct the coagulopathy?

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When to Treat Secondary Coagulopathy?
-PT, PTT > 25% prolonged
% prolonged = (Patient value - high end reference range) / (high end reference range)
-Invasive procedure is planned OR active blood loss
-Understand the underlying disease process to tailor treatment to that patient

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Clotting Factor Replacement
Fresh Whole Blood
Stored Whole Blood
Fresh Frozen Blood
Frozen Plasma
Provides ALL clotting factors + PLT + albumin + RBC
Deficient in Factors V, VIII, vWF and platelets
No platelets
Deficient in von, Willebrand's factor, Factors VIII and XIII, fibrinogen, and fibronectin
-Rodenticide, Hemophilia B, hepatic failure
10-20 ml/kg
10-20 ml/kg
10-15 ml/kg
10-15 ml/kg
-Recheck PT/PTT after completion of transfusion

p.58

FFP vs. Frozen Plasma
-What if FFP is thawed for a patient, and the unit is not used?
-Can be refrozen within 2 hrs of thaw and maintains all factor efficacy
-Relabel as "Frozen plasma"
Yaxley PE. Freeze-thaw-cycled FFP. JVECC 20(5) 2010.

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Administration Guidelines
-Cats
-All cats require blood type specific plasma
-Type A, Type B
-Type AB

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Administration Guidelines
-Dogs
-No need to type dogs prior to plasma or cryoprecipitate
-Crossmatch is suggested prior to platelet transfusions especially if multiple transfusions expected
-DEA 1.1 positive or negative
-There are > 13 blood types in dogs including dal

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Administration Guidelines
-FFP, WB, PRBC
-Filter
-Administration over 4 hours or divide the transfusion aseptically into volumes that can be administered over 4 hours
-Transfusion monitoring
-Initial 15-30 min at 0.25 ml/kg/hr or 5 ml in 1st 15 min
-Remainder of transfusion over = 4 hours
-Detailed guidelines in Transfusion Medicine - Part I

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Image of two dogs

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Diagnostic Evaluation of Coagulopathy
-CBC
-Spurious thrombocytopenia is very common in the ER
-Always verify with a manual platelet estimate
-Manual platelet estimate
-# platelets in 10 fields, averaged X 15,000/uL = platelet estimate
-Assess for clumping, adequate blood smear technique
-Buccal mucosal bleeding time (BMBT)
-Assesses primary coagulopathy
-Thrombocytopenia AND thrombocytopathia
-Normal= 2-5 minutes
-Correct technique is important

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Diagnostic Evaluation of Coagulopathy
-PT/PTT
-Citrated vs. whole blood assessment in hospital
-Citrate: blood ratio -Allow sample to'rest' for minimum of 5 minutes prior to running sample
-Whole blood cartridges -Minimum sample 0.2 uL blood
-Run immediately
-Coagulation Panel: PT, PTT, fibrinogen, antithrombin, D- dimer
-Reference Laboratory = Less ideal for emergent patients
-Activated Clotting Time (ACT)
-< 2 min canine
-< 1.5 min cats

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Diagnostic Evaluation of Coagulopathy
-Thromboelastography (TEG)
-Whole blood assessment of global coagulation
-Primary AND secondary coagulopathies
-Fibrinolytic system
-Limited availability in practice

p.66

Treatment Goals Prior to Emergency Invasive Procedures
-Normalization of PT/PTT
-<20% prolonged with normal platelet count
-Platelet count > 100,000/uL
-Surgical site: spleen, GI, bladder
-Platelet count >80,000/uL
-PCV > 20%
-BMBT < 2-4 min

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Complimentary information in Part I of this lecture series

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Complimentary information in Part I of this lecture series
© DVM STAT 24/7
2019