Hemostasis

Contents Overview of normal hemostasis Blood vessels Platelets Coagulation system Diagram of coagulation cascade Regulatory mechanisms Fibrinolysis Clinical considerations Laboratory evaluation of platelets Sample collection Tests to evaluate platelets CBC Bone marrow examination Platelet function tests Bleeding time (buccal mucosal bleeding time) Other tests Tests for immune-mediated disease Disorders of platelets Thrombocytopenia Mechanisms Increased destruction of platelets Immune-mediated thrombocytopenia Infection Increased consumption DIC Vasculitis Decreased production Abnormal distribution Hemorrhage Tests Breed differences Thrombocytosis Mechanisms Reactive 3 3 4 5 6 7 7 8 9 9 9 9 9 10 10 11 11

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Regenerative Decreased sequestration Essential thrombocythemia Platelet function disorders Primary Glanzmanns thrombasthenia Others Secondary Von Willebrandd disease Laboratory evaluation of coagulation Sample collection Tests to evaluate coagulation Activated partial thromboplastin time (PTT) Activated clotting time (ACT) Prothrombin time (PT) PIVKA Thrombin time (TT) Fibrinogen Fibrin degradation products (FDPs) D-dimer Antithrombin (AT; ATIII) Specific factor assays Disorders of coagulation Vitamin K antagonism or deficiency DIC Coagulopathy associated with liver disease Inherited coagulation disorders Hemophilia A Hemophilia B Factor XII deficiency Others Bleeding associated with vascular disorders Blank table: Expected test results for different pathologic conditions Recommended reading

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Overview of normal hemostasis Summary of major events in normal hemostasis:

Formation of primary platelet plug (primary hemostasis) Formation of insoluble clot of cross-linked fibrin (secondary hemostasis) Clot retraction Fibrinolysis

The main components of hemostasis are platelets, blood vessels, and the coagulation system. They are highly interconnected, and bleeding disorders may result if any of these systems are perturbed.

Hemostasis: The Big Picture

sub-endothelial collagen
gen ino r fib

endothelium thrombin fibrin plasmin FDPs/D-dimer

vWF GPIb platelet

Factor VIII platelet Fibrinogen receptor (IIb3a)

activation of coagulation cascade

Blood vessels Blood vessles have many key functions in hemostasis, including: Structural framework for hemostasis (subendothelial collagen)
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Neuromechanical (vasoconstriction) Biochemical (endothelial synthesis and metabolism of key regulatory molecules)

Platelets Production regulated mainly by thrombopoietin (TPO) Lifespan = apx. 1 week Structure: o Flat disk shape when quiescent; spherical w/ pseudopodia when activated o Membrane invaginations form a network within the platelet (open canalicular system) involved in release of contents, expansion of surface area when activated o Dense tubular system (modified endoplasmic reticulum) is a reservoir for calcium o Alpha and dense granules contain many bioactive molecules, including calcium, ADP, fibrinogen, von Willebrands factor (vWF), histamine, serotonin o Cytoskeletal components maintain shape, mediate shape change, also involved in release of granule contents and receptor interactions o Surface receptors include GPIIb-IIIa (fibrinogen receptor, aka IIb3a integrin) and GPIb (vWF receptor) Activation of platelets is triggered by soluble agonists (e.g., thrombin), or insoluble agonists (e.g., collagen), followed by: o Adhesion to damaged blood vessel o Shape change and aggregation with other platelets o Release of bioactive substances (granule contents, TXA2)

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o Viscous metamorphosis gel-like mass of platelets fused together and eventually incorporated into the clot Major functions of platelets: o Formation of platelet plug (primary hemostasis) o Localization of coagulation on platelet surface o Clot retraction o Also play a role in inflammation, wound healing

Coagulation system The coagulation system involves interconnected pro- and anti-coagulant pathways that are maintained in a delicate balance to allow for:

Rapid formation of an insoluble fibrin clot only when and where it is

appropriate

Eventual elimination of the clot Prevention of inappropriate clotting during normal homeostasis.
Activation of the coagulation system involves linked enzymatic reactions a series of conversions of inactive proenzymes to activated enzymes as well as other proteins, calcium, and platelet phospholipids. This process eventually results in the formation of thrombin, an enzyme that converts fibrinogen to fibrin. Fibrin is cross-linked to form a stable polymerized clot that also incorporates platelets. The coagulation system is conventionally considered to consist of intrinsic, extrinsic, and common pathways this is an oversimplification, but helps with interpreting test results and localizing defects.

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Intrinsic Pathway
Negatively charged surface (e.g., collagen) XII XI VIII XIIa + PK + HMWK XIa IX VIIIa IXa

Extrinsic Pathway

Tissue factor VIIa VII

(VIIa + Tissue factor + Ca+2 + PL )

(IXa + PL + VIIIa + Ca+2) X Va Xa

Common Pathway

(Xa + Va + PL + Ca+2) Prothrombin (II) Thrombin (IIa) Fibrin XIIIa XIII

Fibrinogen

Calcium (Ca2+) and platelet phospholipid (PL) are cofactors for several reactions

Cross linked fibrin

Activation of the intrinsic pathway begins with the activation of factor XII by contact with a negatively charged surface. Once activated, factor XIIa quickly binds and activates prekallikrein (PK), high molecular weight kininogen (HMWK), and factor XI forming a cohesive complex. The extrinsic pathway is initiated by the release of tissue factor (TF) by damaged tissue or activated endothelial cells and macrophages. Tissue factor binds factor VII forming an active complex that not only activates factor X but also factor IX of the intrinsic pathway. The intrinsic and extrinsic pathways have common endpoints that result in the activation of factor X, the beginning of the common pathway. Factors VIII and V are cofactors that accelerate coagulation; both are predominantly activated by thrombin. Factor XIII is also activated by thrombin and functions in the crosslinking of fibrin resulting in an insoluble clot. Platelet phospholipid (PL) is expressed on activated platelet membranes and provides a structure upon which coagulation factor activation is greatly accelerated. Ca2+ links negatively charged surfaces of vitamin-K dependent factors to PL, positioning these enzymatic clotting factors for efficient reactions on their substrates; Ca2+ also facilitates the binding of other factors.

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Regulatory mechanisms are critical to the prevention of inappropriate or excessive clotting, and eventual dissolution of the clot (fibrinolysis). Pro- and anti-coagulant pathways are normally maintained in a balance that avoids hyperor hypocoagulable states. Anticoagulant and fibrinolytic pathways provide critical checks & balances these pathways are intitiated simultaneously with activation of the coagulation system. Regulators of hemostasis include: Antithrombin (AT; also known as antithrombin III or ATIII) inactivates thrombin; heparin potentiates activity of AT Protein C (w/ its cofactor, Protein S) inactivates Factors Va and VIIIa Thrombin in addition to its procoagulant and platelet activating activities, thrombin also: Converts plasminogen to plasmin, which lyses fibrin Activates Protein C Stimulates production of prostacyclin, a platelet inhibitor and vasodilator Thrombomodulin binds thrombin, promotes thrombin-Protein C interactions Tissue factor pathway inhibitor (TFPI) diminishes factor VIIa/TF complex activity

Fibrinolysis refers to dissolution of the fibrin clot, which results from the action of plasmin on fibrin Inactive plasminogen is converted to plasmin by: Tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) Factor XIIa Thrombin Fibrin degradation products (FDPs; also known as fibrin split products, FSPs) Assays for FDPs used to detect inappropriate coagulation

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 FDPs can impair hemostasis by inhibiting fibrin polymerization and inhibiting platelets D-dimer is a specific type of FDP resulting from breakdown of crosslinked fibrin Regulators of fibrinolysis Inhibition of plasminogen Inhibition of plasmin

Clinical considerations Signalment, history, clinical signs are important in evaluating the cause of bleeding. Age, sex, breed may be important in distinguishing acquired v. hereditary diseases History e.g., trauma, rodenticide exposure, family history of bleeding tendency Signs - Disorders of primary hemostasis typically result in small bleeds (e.g., petechiation, mild ecchymosis, bleeding from mucous membranes, bleeding immediately after venipuncture) - Disorders of secondary hemostasis typically result in big bleeds (e.g., hemorrhage into body cavities/joints, marked ecchymosis, large hematomas, delayed bleeding after venipuncture) Basic principles:

Obtain diagnostic samples before initiating therapy Use appropriate collection and handling techniques (including using the
right blood tube, filled properly if youre not sure, check 1st with the lab)

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Laboratory evaluation of platelets Sample collection Good venipuncture technique to avoid activating platelets, which may cause false test results (e.g., aggregation may cause false decrease in platelet concentration) In most species, blood collected into an EDTA (purple top) tube for a CBC is fine for routine evaluation of platelets Some specialized platelet tests require collection of blood into sodium citrate (light blue top tube) or other anticoagulant

Tests to evaluate platelets

Complete blood count (CBC) In most clinical settings, the platelet

concentration (# per microliter) and mean platelet volume (MPV, expressed in fL) values will be determined as part of the routine CBC, using an automated hematology analyzer. The technology of these instruments continues to improve. Estimating platelet number from a blood smear: est. # platelets/uL = [avg. #/HPF (100x objective)] x (20,000) Scan the feathered edge of the smear for platelet clumping (esp. common in cats), which may cause a falsely low platelet count and platelet estimate MPV (fL) tends to increase with a regenerative response Platelet morphology (blood smear) evaluate size, shape, granularity of platelets; verify that values determined by automated counter are consistent with the blood smear

Bone marrow examination (aspirate for cytology and/or core biopsy for
histopathology) to assess thrombopoiesis, particularly in the case of unexplained thrombocytopenia

Tests to evaluate platelet function

Bleeding time aka buccal mucosal bleeding time (BMBT) or template bleeding time) assesses platelet plug formation by measuring time
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interval between inflicting of standardized wound and cessation of bleeding; usually performed on oral buccal mucosa - Prolonged time may be due to primary or secondary platelet function defect, von Willebrands disease, vascular defect, decreased number of platelets - Low sensitivity test - Reference interval is species- and site-dependent; can do a normal control - Contraindicated in patient is thrombocytopenic (cannot interpret results) Other tests to characterize platelet function abnormalities some of these are only available through specialized laboratories - Clot retraction test crude test; results will be abnormal (lack of normal retraction) in some types of primary platelet function defects - PFA-100 instrument, simulates a damaged blood vessel uses whole blood, measures time for a platelet plug to occlude an aperture - Platelet aggregometry assesses platelet aggregation in response to physiologic agonists - Flow cytometry to assay for expression of surface molecules - Thromboelastography (TEG) global test of hemostasis that evaluates platlets, coagulation, and fibrinolysis

Tests for immune-mediated disease

Flow cytometry detects immunoglobulin bound to the platelet surface, using a fluorescent-labeled antibody Immunofluorescent antibody (IFA) sometimes referred to as the antimegakaryocyte antibody test (AMAT), this test actually detects the presence of immunoglobulin non-specifically: a smear of a bone marrow aspirate is incubated with a fluorescent-labeled antibody to speciesspecific immunoglobulin; positive staining of megakaryocytes supports a diagnosis of IMT.

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Disorders of platelets A. Thrombocytopenia 1. Signs severe thrombocytopenia (< 20,000/L) may result in spontaneous hemorrhage; uncomplicated mild or moderate thrombocytopenia typically does not 2. Mechanisms of thrombocytopenia a. Increased destruction of platelets i. Immune-mediated thrombocytopenia (IMT) usually severe thrombocytopenia (often < 10,000 /L) Primary (idiopathic) IMT Most commonly in young to middle-aged female dogs Concurrent IMT and IMHA = Evans syndrome Secondary IMT Drugs Infection Neoplasia Vaccination? Isoimmune IMT (neonatal pigs, foals)

ii. Infection FeLV A. platys

b. Increased consumption of platelets i. Disseminated intravascular coagulation (DIC) usually moderate (> 50,000/L) thrombocytopenia Definition: syndrome caused by continuous activation of coagulation and fibrinolysis, resulting in thrombosis of the microvasculature and hemorrhage due to depletion of coagulation factors and platelets; also called consumptive coagulopathy
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Underlying disorder(s)

Systemic activation of coagulation

Intravascular deposition of fibrin

Depletion of platelets & coagulation factors

Thrombosis of small & midsize vessels

Bleeding

Organ failure

Adapted from: M. Levi & H.T. Cate, NEJM, 341(8), 1999

Laboratory diagnosis classically based on a triad of findings: Thrombocytopenia Prolonged coagulation time(s) Decreased fibrinogen +/or increased fibrin degradation products

However, DIC may occur in less fulminant forms that do not meet all of these diagnostic criteria. More complex scoring systems are used to characterize DIC in human medicine. Pathogenesis: Release of thromboplastin (tissue factor) generation of thrombin Defective inhibition of coagulation (e.g., ATIII, protein C) Defective fibrinolysis (e.g., PAI-1) Always secondary to another disease process, for example: Neoplasia Sepsis Endotoxemia Shock Heat stroke Intravascular hemolysis Obstetrical complications
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DIC is a common condition in veterinary medicine

ii. Vasculitis Inflammation & damage to blood vessels platelet adhesion and activation Vasculitis may have various underlying causes (e.g., RMSF, immune-mediated)

c. Decreased production of platelets Immune-mediated destruction of precursors Space occupation of the marrow Drug-induced (e.g., chemotherapy, estrogen toxicity, chloramphenicol, streptomycin, sulfonamides) Infection (e.g., Ehrlichia, FeLV, BVD, EIA) Toxic (bracken fern poisoning in cattle)

d. Abnormal distribution of platelets Splenic sequestration of platelets

e. Hemorrhage Blood loss alone usually does not result in thrombocytopenia If so, usually only mild decrease

3. Test for thrombocytopenia (in addition to CBC): a. Bone marrow examination is indicated with any unexplained cytopenia, including thrombocytopenia In cases of IMT, marrow usually has megakaryocyte hyperplasia In cases of decreased production, typical bone marrow finding is megakaryocyte hypoplasia

b. +/- additional tests as clinically indicated Test for platelet-bound immunoglobulin (e.g., flow cytometry) Tests for underlying or related disease Immune-mediated disease (ANA, Coombs test) Ehrlichia titers
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FeLV test Coagulation panel

4. Breed differences: Cavalier King Charles Spaniels often have macrothrombocytopenia (lower than normal numbers of abnormally large platelets) Greyhounds tend to have lower platelet numbers than other breeds (in addition to RBC differences) B. Thrombocytosis 1. Mechanisms of thrombocytosis: a. Reactive fairly common, non-specific - Inflammation - Iron deficiency b. Regenerative - Recovery from thrombocytopenia c. Decreased sequestration - Splenic contraction (esp. horses), splenectomy (transient thrombocytosis) d. Essential thrombocythemia - Leukemia of platelet precursors, extremely rare C. Platelet function disorders (aka thrombocytopathies, thrombopathies) 1. Primary intrinsic platelet function defect - Glanzmanns thrombasthenia (Great Pyrenees, otterhounds; also reported in some horse breeds) absent, markedly decreased, or abnormal expression of fibrinogen receptor - Other rare conditions are also described in veterinary species

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2. Secondary platelet function defects - IMT (may cause impaired function in addition to destruction) - Hyperglobulinemia (excess protein coats platelet surface) - Uremia (bleeding tendency correlates with severity of azotemia) - Drugs (e.g, NSAIDs or aspirin cause reversible or irreversible inhibition of arachidonic acid metabolism) - Increased fibrinolytic products in plasma (increased production, as in DIC; decreased clearance, as in liver failure) 3. von Willebrands disease (vWD) deficiency of von Willebrand factor (vWF), a soluble factor that mediates binding of platelets to collagen and stabilizes factor VIII; synthesized mainly by endothelium. vWD is often considered a platelet disorder, but technically it is not rather it is a disorder of a soluble factor that influences platelet function. The most common canine heriditary bleeding disorder, also described in most domestic species Variable severity of disease: Type I: partial quantitative deficiency (<50%) variable bleeding tendency (Doberman pinschers, others) Type II: qualitative abnormalities moderate to severe bleeding tendency (GSHPs, German wirehaired pointers) Type III: severe quantitative deficiency (<0.1%) severe bleeding tendency (Chesapeake Bay retrievers, Scotties, Shelties, others) Inheritance is autosomal (Types 2 & 3 recessive; Type 1 thought to be recessive, maybe incompletely dominant)Variable modes of inheritance Laboratory findings: Normal platelet count Prolonged bleeding time

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PTT, ACT often normal, may be prolonged if factor VIII level is low enough Normal PT Specific assays for vWF require specialized laboratory

Laboratory evaluation of coagulation Sample collection Most tests require citrated plasma Good venipuncture technique; studies indicate that is clinically acceptable to collect blood from an IV catheter if proper technique is used Plastic or siliconized syringes, tubes Anticoagulant - sodium citrate (light blue top) tube, except for ACT, FDP tests - ratio of anticoagulant:blood must be 1:9 need to fill the tube properly

Tests to evaluate coagulation Activated partial thromboplastin time (aPTT or PTT) Required sample: citrated plasma Measures time for fibrin clot formation after addition of a contact activator, calcium, and a substitute for platelet phospholipid Deficiencies/dysfunction in intrinsic and/or common coagulation pathway (all factors except for VII and XIII) will cause prolongation of PTT Insensitive test prolongation requires 70% deficiency Other causes of prolongation include polycythemia (less plasma per unit volume, so excess amount of citrate available to chelate calcium), heparin therapy Activated clotting time (ACT) Required sample: non-anticoagulated whole blood in special ACT tube (diatomaceous earth as contact activator) Used in practice setting performed by warming sample to body temp, monitoring for clot formation; normal times are 60-90 seconds in dogs, < 165 seconds in cats Less sensitive version of PTT prolongation requires 95% deficiency Severe thrombocytopenia may cause prolongation
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 One stage prothrombin time (OSPT or PT)

Required sample: citrated plasma Measures time for fibrin clot formation after addition of tissue factor (TF, thromboplastin), calcium, and a substitute for platelet phospholipid Deficiencies/dysfunction in extrinsic (factor VII) and/or common coagulation pathway will cause prolongation of PT Insensitive test prolongation requires 70% deficiency

PIVKA (proteins induced by vitamin K antagonism or absence) test

Required sample: citrated plasma PIVKA are inactive (uncarboxylated) vitamin-K dependent factors; an increase in PIVKA is not specific for vitamin K antagonism, but may be the earliest and most sensitive detector The name of this test is misleading because the one available in veterinary medicine is essentially a version of the PT using an especially sensitive thromboplastin reagent

Thrombin time (TT)

Required sample: citrated plasma Measures time for fibrin clot formation after thrombin (factor IIa) is added; two kinds of assays with or without calcium Defects directly involving formation and/or polymerization of fibrin will prolong this test i.e., if the lesion is upstream of the conversion of fibrinogen to fibrin, the TT will be normal

Fibrinogen
Required sample: citrated plasma Fibrinogen concentration measured based on time to clot formation after addition of thrombin; this is essentially the same as the thrombin time, above, and is a more accurate method than the heat precipitation method Decreased fibrinogen may be due to increased consumption (DIC) or decreased production (liver disease) Increased fibrinogen is associated with inflammation, renal disease, dehydration

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 Fibrin degradation products (FDPs)

Required sample: special FDP tube (get from lab) Used in the practice setting (Thrombo-Wellcotest) Performed by adding blood to a special tube containing thrombin and a trypsin inhibitor (sample clots almost instantly in normal dogs and cats), and incubating two dilutions of serum (1:5 and 1:20) with polystyrene latex particles coated with sheep anti-FDP antibodies (should be negative in normal dogs and cats, but positives have been reported in normal cats)

D-dimer test
Required sample: citrated plasma Latex agglutination test Validated in dogs but not cats Assays for a specific type of FDP resulting from breakdown of crosslinked fibrin; often used as part of a DIC panel; can be used as a negative predictor to rule out pathologic thrombosis (e.g., pulmonary thromboembolism); will also be increased when there is appropriate clotting

Antithrombin (AT; aka antithrombin III, ATIII)

Required sample: citrated plasma Decreased due to decreased production (liver disease), loss (protein losing nephropathy or enteropathy), consumption (DIC), chronic heparin therapy

Specific factor assays

Required sample: citrated plasma Performed at specialized laboratories

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Disorders of coagulation A. Vitamin K antagonism or deficiency 1. Causes: Poisoning with coumarin derivatives (e.g., rodenticides, mycotoxin from moldy sweetclover in cows) Fat malabsorption (uncommon) Dietary deficiency (rare) Antibiotics that cause decreased absorption or utilization by the liver

2. Pathophysiology of rodenticide toxicity Vitamin K-dependent coaguation factors are II, VII, IX, and X; activation of these factors requires post-translational carboxylation; vitamin K is an essential cofactor for this reaction, and is oxidized (to vitamin K1 epoxide) in the process Anticoagulant rodenticides are vitamin K antagonists; they inhibit vitamin K epoxide reductase, the enzyme that converts vitamin K back to its active form; effect lasts until rodenticide is metabolized and cleared examples: warfarin (1st generation), bromodiolone and brodifacoum (2nd generation more potent, longer t1/2)

Inactive factors (II, VII, IX, X, also Protein C and Protein S

carboxylase

active factors (carboxylated)

vitamin K (active)

vitamin K epoxide (inactive)

X
UST 2008 - Hemostasis

X
= inactivation of vitamin K epoxide reductase, the enzyme that maintains vitamin K in the active form
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3. Laboratory features of rodenticide toxicity Factor VII has the shortest t1/2, so initially prolonged PT may be the only abnormality on the coagulation panel; eventually, PTT and ACT will also be prolonged PIVKA are inactive (uncarboxylated) vitamin-K dependent factors; they are carboxylated to active form within 8-12 hours of vitamin K administration In uncomplicated cases, platelet count is usually within the reference interval

B. DIC Definition, pathophysiology, diagnosis are covered above, in section on thrombocytopenia due to increased consumption of platelets. Note that coagulation factors are also depleted due to consumption in DIC. C. Coagulopathy associated with liver disease The liver is the site of synthesis and clearance of most clotting factors and inhibitors, and fibrinolytic agents and inhibitors (factor VIII produced mainly by endothelium, including hepatic sinusoids). Pathogenesis: Decreased synthesis of coagulation factors (except factor VIII), ATIII Production of abnormal coagulation factors Decreased clearance of FDPs, activated clotting factors These factors may lead to hypo- or hypercoagulable states

D. Inherited coagulation disorders Many inherited disorders of coagulation have been reported in animals. Signalment may provide important information. Recall that PT and PTT are relatively insensitive and may not be prolonged in an animal with a factor deficiency. Examples: 1. Hemophilia A deficiency of factor VIII (not vWF) Described in dogs, cats, horses, cattle Mode of inheritance: X-linked recessive in dogs, horses Variable severity of disease Laboratory findings:
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Normal platelet count, bleeding time PTT, ACT prolonged if deficiency is severe enough Normal PT Specific assay requires specialized laboratory (Cornell)

2. Hemophilia B deficiency of factor IX

Similar disease and inheritance pattern to Hemophilia A

3. Factor XII deficiency

The most common congenital bleeding disorder in cats Affected animals typically do not have clinical bleeding tendencies Prolonged PTT or ACT, other tests within normal limits
4. Inherited deficiencies of most other coagulation factors have also been reported (e.g., factor VII deficiency in beagles, factor XI deficiency in Kerry Blue Terriers).

Bleeding associated with vascular disorders Pathogenesis: failure to support collagen-platelet interactions and adhesion initiating hemostasis Causes: Vasculitis Collagen disorders (e.g., Ehler-Danos syndrome, reported in boxers, springer spaniels, cats)

Clinical features are those of the underlying disorder, mucosal surface bleeding, prolonged bleeding time. These types of conditions generally require histologic evaluation.

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Expected laboratory test results for different pathologic conditions

Platelet count BMBT PT ACT/ PTT Fibrinogen FDP/ D-dimer AT

Condition

Thrombocytopenia

vWD

Platelet function defect (1 or 2)

DIC

Vitamin K antagonism/ deficiency Severe liver disease

Extrinsic pathway deficiency Intrinsic pathway deficiency Common pathway deficiency Fibrinogen deficiency/ dysfunction

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Recommended reading Stockham SL, Scott MA. 2008. Hemostasis. In Fundamentals of Veterinary Clinical Pathology, 2nd edition. Ames: Blackwell Publishing. Stockham SL, Scott MA. 2008. Platelets. In Fundamentals of Veterinary Clinical Pathology, 2nd edition. Ames: Blackwell Publishing. Topper MJ, Welles EG. 2003. Hemostasis. In Duncan & Prasses Veterinary Laboratory Medicine: Clinical Pathology, edited by KS Latimer, EA Mahaffey, KW Prasse, 4th edition. Ames: Iowa State Press.

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