Ch 7 Haemostasis

Question 1

where platelets from?

Answer 1

derived and released from progenitor megakaryocytes in the bone marrow

Question 2

what do platelets release

major agonist of coagulation (2)

Answer 2

platelets synthesize prostanoids, notably thromboxane A2 (TxA2), from arachidonic acid.

ADP

Question 3

Primary haemostasis (4)

Answer 3

1. adherencce: endothelial disruption > Platelets adhere to subendothelial collagen, either directly or via collagen-bound von Willebrand factor (vWF)
2. resulting in a shape change and activation

3.activation = release of agonists (Txa2 + ADP) from granules and via arachidonic acid metabolism

(4). Agonists recruit and activate additional platelets

(5) and alter the avidity and affinity of fibrinogen binding receptors, leading to aggregation

Question 4

secondary haemostasis

cascade

Answer 4

 Intrinsic and extrinsic pathways
* Extrinsic – initiated by tissue factor
* Intrinsic – initiated through contact activation of fXII

Question 5

A Cell-Based Model of Coagulation

3 PHASES

Answer 5

(1) tissue factor = primary physiologic initiator of coagulation
(2) coagulation is localized to, and controlled by, cellular surfaces

3 overlapping phases
Initiation (on tissue factor-bearing cells)
vascular damage allows contact between plasma and tissue factor
fVII binds to TF (activated)
fVIIa-TF complex activates fX.
fX (cell surface) combines with fVa to produce thrombin.
fVIIa-TF complex also activates fIX, which diffuses into cell

amplification
platelets are fully activated, with cofactors V and VIII bound to their surfaces
thrombin amplifies the original signal

propagation (on platelets)
large scale thrombin generation occurs
fXI binds and activated by thrombin,
fXa generates fIXa.
fIXa complexes with fVIIIa to activate fX fXa-Va complexes activate prothrombin to produce burst of thrombin necessary to produce large quantities of fibrin.

Fibrin then complexed to form fibrin polymers and a stable thrombus

Question 6

• Regulation of hemostasis (3)

Answer 6

1. Platelets do not express tissue factor; coagulation only if tf exposed (localisation)
2. Endothelium controls activated platelets, produces inhibitors i.e prostacyclin limits platelet response to TXA2
3. anticoagulant pathways:

Question 7

3. anticoagulant pathways

Answer 7

:

• **Antithrombin AT **
  inactivates coagulation proteins that escape into the circulation from a site of injury
  exerts potent antiinflammatory effect
• thrombin-thrombomodulin complex activates protein C
  inactivate cofactors fVa and fVIIIa, and this slows the rate of thrombin
  enhances fibrinolysis inactivation of plasminogen activator inhibitor-1 (PAI- 1)
• Tissue factor pathway inhibitor inhibits tissue factor
  abrogates the initiation complex of factor VIIa-TF, as well as factor Xa

Question 8

• Fibrinolysis

2 plasminogen activators?

Answer 8

• Plasminogen activators proteolytically convert the proenzyme, plasminogen, to plasmin
• Plasmin degrades fibrin into soluble degradation products

tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA)

inhibitors or fibrinolysis:
- plasminogen activator inhibitor-1 (PAI- 1: stored in platelet α-granules, inhibits both tPA and uPA
- α2-antiplasmin, synthesized in the liver, inhibits plasmin

Question 9

• Platelet Enumeration and Estimation

Answer 9

Multiply average number of platelets per HPF by 15,000

o Pseudothrombocytopenia is a common artifact

Question 10

• Buccal Mucosal Bleeding Time

prolonged by? 3

Answer 10

o 1-mm deep incisions in the mucosa of the upper lip
o Normal ranges are 1.7 to 4.2 minutes in the dog, and 1.4 to 2.4 minutes in the cat
o prolonged with thrombocytopenia, thrombopathia, and vasculopathy

Question 11

• Prothrombin Time and Activated Partial Thromboplastin Time

Answer 11

o Prolongation of the PT indicates defective extrinsic and/or common pathways
o aPTT prolongation indicates defective intrinsic and/or common pathways

o short half-life of factor VII, the PT is very sensitive to vitamin K deficiency

Question 12

• Activated Clotting Time

Answer 12

diatomaceous earth, which serves as a contact activator of factor XII

o normal ACT is less than 110 seconds for the dog, and less than 75 seconds for the cat

affected by: severe thrombocytopenia (<15,000/μL) or thrombopathia, anemia, altered blood viscosity, and assay incubation temperature

Question 13

• d-Dimers

Answer 13

neo-epitope produced when soluble fibrin is crosslinked by fXIIIa

indicate the activation of thrombin and plasmin, and are specific for active coagulation and fibrinolysis

sensitive indicator of thrombotic conditions, such as DIC and thromboembolism

o excellent negative predictive value in that few dogs with DIC or thromboembolism have normal d-dimer concentrations

not specific; DIC, thromboembolism, neoplasia, hepatic disease, renal failure, cardiac failure, or internal hemorrhage, and following surgical procedures

Question 14

• Fibrinogen

Answer 14

endpoint of all clotting assays (PT, aPTT, ACT) is based on the formation of a fibrin clot

prolongation indicating hypofibrinogenemia

Question 15

Viscoelastic Testing: Thromboelastography

global assessment of hemostatic system in whole blood

Answer 15

o reaction time (R) represents the enzymatic portion of coagulation (secondary hemostasis

o The clotting time (K) represents clot kinetics, largely determined by clotting factors, fibrinogen, and platelets

Question 16

• Causes of Surgical Bleeding

o 4 Technical, disorders

Answer 16

o 4 Technical
 Inadequate repair of vessels

 Occult injury to vasculature

 Damage to organs within surgical field

 Damage to organs remote from surgical site

 Primary – result from decreased circulating platelet numbers (thrombocytopenia), from platelet dysfunction (thrombopathia) or rarely, from vascular anomaly (vasculopathy)
 Secondary – low conc or activity of coag factors
 Acquired disorders usually affect both to variable degrees, inherited usually only affect one

Question 17

primary haemostatic disease

Answer 17

decreased production

increased destruction (IMT, 1st - evans and idiopathic and 2nd- drugs, neoplasia)

cosumption (DIC, splenic dz, severe haemorrhage)

aquired (organi dz, drugs )
inherited (vWF)

Question 18

secondary hemostatic disease

Answer 18

Aquired
* Vit K def
* hepatic dz
* DIC
* Drugs
* shock/acid/hypothermia

inherited
* haemophillia A (FVIII)
* Hameophillia B (FIX)
* recessive sex-linked traits

Question 19

predisposing factors for coagulopathies (6)

Answer 19

1. trauma/haemorrhage - tissue injury > TPA release which inhibits PAI-1
2. Hemodilution: hypofibronigenemia thrombocytopenia and reduced factors, also triggered by massive transfusions (1 blood volume in 24 hours or 1/2 blood volume in 3 hours)
3. Hypothermia: platelet adhesion effected

4..Acidemia:

5. Shock: anticoagulant and hyperfibrinolytic state due to unknown mechanisms
6. Critically ill patients:

Question 20

• Preoperative Hemostatic Assessment

Answer 20

Patient-associated factors:
breed, diseased

Procedure bleeding risk

Tests and Their Limitations
* Routine hemostatic screening tests include the basic coagulogram (platelet count, PT, and aPTT) and/or the buccal mucosal bleeding time

Question 21

Clinical signs of primary vs secondary haemostasis

Answer 21

 Primary: ecchymoses, spontaneous bleeding from mucosal surfaces, Petechiae (more indicative of thrombocytopenia then pathia)

 Secondary: hematomas, bleeding into body cavities, SQ, joints, or muscles

Question 22

• Operative and Postoperative Bleeding

Answer 22

 Blood loss of 25% to 30% of blood volume generally results in tachycardia and vasoconstriction

Question 23

what % needs transfusion

Answer 23

 blood pressure can be preserved until as much as 40% blood volume loss

Question 24

determining cause of coagulopathies

Answer 24

 Perform coag studies
* Normal TEG > indicates a technical cause of bleeding
 Check for hypothermia and acidosis
 Review medications
 Review history
 Additional coag studies : platetelt dysfunction with BMBT/smear. consider hyperfibrinolysis

Question 25

management for coagulopathies | prevent bleeding

Answer 25

 treat shock  Rule out technical  Restore normal hemostasis with medications and transfusions  Monitor coag parameters  Monitor for ongoing blood loss  Monitor for complications  “Damage control resuscitation” – aggressive correction of coagulopathies, while reducing hypoperfusion, hemodilution, and hypothermia  “Hypotensive resuscitation therapy”

Question 26

Plasma transfusion options (3)

Answer 26

FFP: all (factors, Vwf, albumin) cryoprecipitate: (vWf, fVII, fibrinogen) crysupernatant: all but (vWf, fVII, fibrinogen)

Question 27

o Platelet Transfusion

Answer 27

FWB: 10ml/kg Platelet rich plasma: short self life, limited availability

Question 28

hemostatic agents

Answer 28

 Desmopressin: induces release of vWF via V2 receptors. lasts 2 hours. (type 1 Wonvillibrands); 1-4 ug/kg SQ  Antifibrinolytics: aminocaproic acid and treanexamic acid (block activation of plasminogen)  Recombinant factor VIIa-

Question 29

o Thrombocytopenia

Answer 29

 Spontaneous bleeding generally does not occur until platelet counts fall below 50,000/μL IMT  nonpathologic thrombocytopenia is reported in Cavalier King Charles Spaniels  majority of thrombocytopenic cats have underlying disease,

Question 30

von Willebrand Disease Dx: prolonged BMBT + normal platelet count. Antigen assay (VWF:Ag (below 50%) are predicted at risk) genetic test | type 1,2,3

Answer 30

 multimeric plasma glycoprotein that **facilitates platelet adhesion** to exposed subendothelium  participates in platelet **aggregation** and **binds fVIII** Hereditary VWD is an autosomal trait. 1 x abnormal gene increase risk. Antigen screening test required > * <50% are considered deficient Type 1 **all multimers,** but in reduced concentrations Doberman Pinschers, Poodles, Shetland Sheepdogs, GSD Type 2 disproportionate loss of **high-molecular-weight** multimers GSP Type 3 quantitative deficiency, almost complete **absence of vWF** (<0.1%) * Shetland Sheepdogs, Scottish Terriers | Tx: FFP, cryopreciptate (4hr life) desmopressin b4 surgery

Question 31

o Other Thrombopathies

Answer 31

requires the administration of platelets

Question 32

o Vitamin K Deficiency | anticoagulant rodenticide toxicity

Answer 32

factors II, VII, IX, and X, as well as for the synthesis of proteins C and S  PT prolongation occurs first, reflecting the short half-life of fVII (4 to 6 hours).  aPTT follows when other factors are depleted (approximately 2 days  Vitamin K1 therapy is initiated at 2.5 to 5.0 mg/kg SC or IM

Question 33

o Hepatic Disease

Answer 33

 synthesizing clotting factors (with the exception of fVIII), coagulation inhibitors (AT, protein C), and fibrinolytic protein significantly decreased functional hepatic mass (>70%)  Vitamin K deficiency due to malabsorption of fat-soluble vitamins or biliary obstruction  Hyperfibrinolysis + Thrombocytopenia 80-90% have bleeding anomoly, but unpredicatble bleeding risk

Question 34

THROMBOEMBOLIS | venous or arterial

Answer 34

macrovascular obstruction by a thrombus that develops locally (primary thrombosis), or that translocates from a distant site (embolism). Arterial > aortic (FATE) Venous > PTE, hepatic/portal, caudal venacava

Question 35

Virchow’s triad | risk factors for thromboembolism

Answer 35

1. abnormalities of the vessel wall (endothelial injury) 2. abnormalities of blood flow (vascular stasis) 3. abnormalities of blood constituents (hypercoagulability)

Question 36

Hypercoagulability

Answer 36

imbalance between prothrombotic and anticoagulant activities * Hypoalbuminemia increases TxA2 synthesis * Acquired AT deficiencies * Activated protein C deficiency,

Question 37

hypercoagulable state | causes

Answer 37

**IMHA and surgery** > venous thromboembolism others: Neoplasia, pancreatitis, HyperA, sepsis, DM | TEG ~ diagnosis of hypercoagulability

Question 38

* Postoperative Thromboembolism | 82% THR have PTE

Answer 38

 imaging studies  (1) the exclusion of other potential causes; (2) laboratory evidence of hypercoagulability, if possible; and (3) identification of an underlying disorder

Question 39

Pulmonary Thromboembolism pulmonary hypertension > heart failure, reduced CO and death

Answer 39

xray radiolucency, hypovascular lung regions blood gas increased A-a gradient, hypoxemia, hypocapnia, and decreased oxygen responsiveness d-dimer increased Dx: CT pulmonary angiography (CTPA) Tx: Antiplatelet drugs aspirin: irreversible functional defect in platelets by inactivating COX-1 * ultralow-dose standard primary thromboprophylaxis Anticoagulants: inhibit 2nd hemostasis, venous thromboprophylaxis * Unfractionated Heparin (needs monitoring) * Low-molecular-weight heparin * Warfarin oxygen supplementation (patient support) | reduce sx risk: minimise trauma, hypoperfusion and compression

Question 40

DISSEMINATED INTRAVASCULAR COAGULATION

Answer 40

systemic activation of coagulation, leading to widespread microvascular thrombosis that compromises organ perfusion and can contribute to organ failure > progress to consumption and bleeding CS: organ dysfunction Dx: hypercaog (TEG), thrombocytopaenia, increased PT, aPTT, hypofibrinogen, and d-dimers Tx: underying dz, o Adequate perfusion must be restored and maintained via appropriate fluid therapy +/- transfusion

Question 41

Preoperative autologous blood donation and transfusion in dogs undergoing elective surgical oncology procedures with high risk of hemorrhage **Sharma 2020** Vet Surg

Answer 41

Study design: Prospective study. Animals: Twelve dogs. minimum of 6 days mandibulectomy, maxillectomy, chest wall resection, and liver lobectomy Ten of the 12 dogs received autologous transfusion. No dog developed transfusion-related complications

Question 42

Prospective evaluation of the utility of cross-matching prior to first transfusion in cats: 101 cases Humm 2020

Answer 42

Transfusion reactions occurred in 20 cats, most commonly febrile non-haemolytic transfusion reactions (n = 9) and haemolytic transfusion reactions (n = 7)

Question 43

Twelve autologous blood transfusions in eight cats with haemoperitoneum Cole 2019

Answer 43

retrospective descriptive study Autologous transfusion appears to be a safe and effective technique for stabilising cats with haemoperitoneum.

Question 44

Xenotransfusion of canine blood to cats: a review of 49 cases and their outcome Gal 2020

Answer 44

Xenotransfusion of canine packed red blood cells to cats is possible but haemolysis should be expected between 1 and 6 days after transfusion

Question 45

Evaluation of viscoelastic coagulation monitoring parameters and fibrinogen concentrations in healthy dogs undergoing stifle arthroscopy and tibial plateau leveling osteotomy Mackenzie Grace 2024 | AVJR

Answer 45

Prospective study of 37 client-owned dogs Stifle arthroscopy and TPLO surgery was not associated with significant effects on viscoelastic coagulation The findings of this study suggest that similar preoperative prophylactic antithrombotic intervention is not needed for canine patients.