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Table 22. Heparin-Induced Thrombocytopenia (HIT)

Pathophysiology Immune mediated

Ab recognizes a complex of heparin and platelet factor 4 leading to platelet activation via platelet Fc receptor and

activation of coagulation system

Suspected withintermediate or high probability HUscore

Screen with immunoassays|e.g.HIT ELISA) and conFirm with functional testing (Serotonin Release Assay)

5-14 d (it previously exposed to heparin within100 d.HIT can develop inhours due to an anamnestic response)

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia

( previously known as HIT type II):

immune-mediated reaction following

treatment with heparin leading to

platelet activation and subsequent

coagulation activation

Heparin-associated

thrombocytopenia (previously

known as HIT typeI):transient

thrombocytopenia following

administration of heparin

Diagnosis

Onset of Decreased

Platelets

30 50% (25% of events are arterial) if unhealed

Bleeding complications uncommon

Venous thrombosis:DV1.PE, limb gangrene,cerebral venous sinus thrombosis

Arterial thrombosis:Ml. stroke,acute limbischemia,organ infarct (mesentery, kidney)

Heparin-induced skin necrosis (with LMWH)

Hon-necrotizing erythematous skin lesions

Acute platelet activation syndromes:acute inflammatory reactions (e.g.fever/chills,flushing,etc.)

Transient globalamnesia (rare)

Pretest clinical scoring models can helprule- out HII: 4Ts and the HIIExpert Probability (HEP) score

14C serotonin release assay (tests the functional ability of patient's plasma to activate platelets)

ELISA for Hll-lg (more sensitive,less specific than serotonin assay,faster turnaround time,highnegative predictive

value)

Ultrasound of lower limbveins and upper extremity withcentralvenous catheter for DVT

Clinical suspicion olHit should prompt discontinuation of UFH and LMWH including flushes [specific lesls take several

days)

Initiate anticoagulation witha non-heparin anticoagulant:

e.g.argatroban.danaparoid.fondaparinux.bivalirudin unless there is a strong contraindication (duration depends on

presence or absence of thrombosis)

warfarinshould be started when platelet count >150 x10*/L

DOACs can be started before platelet count recovery

Allergy band and alert inpatient records

Risk of Thrombosis

Clinical Features

Heparin-Associated Thrombocytopenia

(previously known as HIT typeI)

• Direct heparin mediated platelet

aggregation (non-immune)

. Platelets >100 X lO'

Vl

. Self-limited (no thrombotic risk)

• May continue with heparin therapy

• Onset 24-72 h

Specific Tests

Management

LMWH is also associated with HIT.but

the risk is less than unfractionated

heparin (2.6% in UFH vs.0.2%in LMWH)

Table 23. The 4T Pre-Test Clinical Scoring Model for HIT

Category 2 Points 1Point O Points

Thrombocytopenia Platelet count lall >50% Platelet count fall 30-50% Platelet count fall > 30% American Society of Hematology

Choosing Wisely Recommendation

Don 't test or treat for HIT in patients with

low pre-test probability of HIT (4T’s score

of 0-3) as HIT can be excluded

Do not discontinue heparin or start a

non-heparin anticoagulant in these

low-risk patients because of increased

risk of bleeding and increased cost of

alternatives

AND OR OR

platelelnadir >20 x 10

’

/! plateletnadir 10-19 x 10VL platelet nadir <10 xtO

’

/L

liming of Platelet Count Fall Clear onset between 5-10 d ol

heparin exposure

Consistent with fall in platelet count at

5-10 dbut unclear (e.g.missing platelet

counts)

Platelet count fall after

<4d of heparin exposure,

OR and no recent heparin

platelet count fall at <1d if prior

heparin exposure within last 30 d

OR

onset alter 10 d

OR

fall <1d withprior heparin exposure

within 30-100 d

Confirmed new thrombosis, skin

necrosis,or acute systemic reaction

after IV unfractionaled heparin

bolus,adrenalhemorrhage

None apparent

Thrombosis or Other

Sequelae

Progressive or rccurtcnl thrombosis,

non-necrotizing (eiythcmalous) skin

lesions,or suspected thrombosis that

has notbeen proven

Possible

None

OtherCausesfor

Thrombocytopenia

Definite

6-8 points=high probability of HIT:4-5 points= intermediateprobability of HIT:0-3 points = low probability of HIT

Cuket A.Arepally GM. Chong 6H.etal.American Society of Hematology 2018 guidelines lor management ol venous

thromboembolism: heparin-induced thrombocytopenia.Blood Adv. 2018:2:3360-3392

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H31 Hematology Toronto Notes

’

023

Thrombotic Thrombocytopenic Purpura and Hemolytic

Uremic Syndrome

Pathophysiology of TTP

• Normally, large VWF multimers

secreted by endothelial cellsare

rapidly cleaved by ADAMTS13

protease

• Congenital TTP is due to a genetic

deficiency in ADAMTS13

• Acquired TTP (the more common

form) is due to Abs agamst

ADAMTS13

. Without ADAMTS13. undeaved

VWF continuesto promote platelet

adhesion,causing excess platelet

aggregation in small blood vessels

Table 24. TTP and HUS

TTP HUS (see Paediatrics. P82)

Epidemiology Immune form presents predominantly in adults

Congenital form presents predominantly in children

Deficiency of ADAMTS13: metalloproteinase that breaks

down ultra-large VWF multimers

Congenital (geneticabsence of ADAMTS13)

Acquired (drugs,malignancy, transplant.HIV-associated,

and idiopathic)

1.Thrombocytopenia

2.MAHA/TMA

3. Neurological symptoms:headache,confusion,focal

defects, and seizures

4.Symptoms can be mild and non-specific

CBC and blood film:decreased platelets and increased schstocytes

PT. PTT.fibrinogen:normal

Markers of hemolysis:increased unconjugated bilirubin,increased IDH.and decreased haptoglobin

Negative Coombs test/DAT

Creatinine and urea to follow renal function (TTP has nearly no kidney injury vs.HUS'drug mediated TTP which induces

severe injury that issudden in onset)

ADAMTS13 gene,activity or inhibitor testing (TTP)

Medical emergency: TTP mortality '•90% if untreated

Plasma exchange tsteroids

Platelet transfusion avoided unless life-threatening bleed Possible role of ecnlizumab (C5Ah blocks complement

(associated with microvascular thrombosis)

Plasma infusion if plasmapheresis is not immediately

available

Caplacizumab in certain cases of acquired TTP

Predominantly children and elderly

Etiology Shiga toxin (f.coll serotype 0157:H7) in 90%

Other bacteria,viruses,genetic causes,and drugs

Clinical Features 1.Severe thrombocytopenia

2.MAHATMA

3.Acute kidney injury

4.Bloody diarrhea

5.Gl prodrome

Investigations

( both TTP, HUS)

Differential Diagnosis of TTP

• DIC

. HUS

• aHUS

• HELLP

• Catastrophic APS

• Evanssyndrome (AJHA + (TP)

Supportive therapy (fluids.RBC transfusion, nutribon.etc.)

Some evidence for plasma exchange

Management

activation) for neurologic symptoms

Note:oHUS is a complex disease with ditterent etiology,treatment depends on genetic abnormalities

von Willebrand Disease

Pathophysiology

• most common inherited bleeding disorder (prevalence of 1%)

• usually autosomal dominant (types 2N and 3 are autosomal recessive)

• women more commonly diagnosed (heavy menstrual bleeding, peripartum bleeding)

• qualitative defect or quantitative deficiency of VWF depending on type

VWF mediates platelet adhesion/aggregation and acts as a chaperone for Factor Vlll (extending

its half-life in circulation);abnormal VWF can affect both primary and secondary hemostasis

VWF exists as a series of multimers ranging in size

largest multimers are most active in mediation of platelet adhesion/aggregation

both large and small multimers complex with Factor VIII

VWF levels vary according to blood group (lowest in group O patients) and other factors

(pregnancy, hormonal medication, acute inflammation)

Classification

• type 1: mild quantitative deficiency (decreased amount ofVVVF and proportional decrease in VWF

activity) - 80% of cases

• type 2: qualitative defect (VWF activity disproportionally lower than quantity) - 20% of cases

• type 2A:reduced V WF-dependent platelet adhesion due to high and intermediate molecular

weight VWF multimer deficiency

type 2B: increased affinity for platelet GPlb

• type 2M:reduced V WF-dependent platelet adhesion with normal VWF multimer levels

• type 2N:decreased affinity for Factor VIII

• type 3:severe total quantitative defect (virtually no VWF produced) - 1 in 1000000

Clinical Features

• bleeding history is the single most important predictor of an underlying bleeding disorder

• validated,standardized bleeding assessment tools (e.g.1STH-BAT) to facilitate exploration of the

bleeding history

• mucocutaneous bleeding (easy bruising, epistaxis (>10 min), heavy menstrual bleeding, peripartum

bleeding, post-dental extraction bleeding, excessive postoperative bleeding, and unexplained

gastrointestinal bleeding)

• type 3 V WD patients can experience musculoskeletal bleeding due to significant deficiency in

Factor Vlll (lack of Factor Vlll chaperoning as VWF is absent)

• family history of a bleeding disorder (a negative family history cannot be used to exclude the

diagnosis)

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Investigations

• CBC, platelet, VWh'

tAntigen (determine how much VWF is present), VWF:Ristocetin cofactor activity

(determine how well VWF bindsto platelet), Factor VIII (determine how well VWF chaperones Factor

VIII), and F IT

• tests to further categorize tvpe/subtype of VWD:multimer analysis, ristocetin induced platelet

agglutination, and genetic studies

Table 25. Investigations in VWD

Test Expected Result Test Expected Result Consider VWD in all women with heavy

PTT N/» von Willebrand antigen menstrual bleeding

Ristocetin activity

Factor VIII

N,

'

» (can be low intype 2B)

Affects antigen quantification (t in group 0)

Rule out secondary iron deficiency due lobleeding VWF multimer analysis

Pit Count » (cofactor for VWF-PIt binding)

Blood group

Ferritin

V

Multimer

*

variants

VWD

Q

is the most common heritable

bleeding disorder Treatment

• DDAVP* is effective treatment for 85-90% of patients with type 1 VWD and for some subtypes of type

2 VWD

» causes release of VWF and Factor VIII from endothelial cells

variable efheaev depending on disease type;tachyphylaxis occurs after 4 consecutive doses

• need to document responsiveness with “DDAVP* challenge"

• caution in children due to hyponatremia

• tranexamic acid (Cyklokapron*, antifibrinolytic) to stabilize clot formation

• VWF:Factor VIII concentrate (Hurnate P*, Wilate’) if DDAVP* unresponsive/clinically ineffective or

for severe bleeding episode

» need to monitor VWF and factor Vlll levels (very high factor VIII level can be prothrombotic)

• gynaecologic focused care for heavy menstrual bleeding (N.B. estrogens have the added benefit of

increasing VWF levels)

Prognosis

• patients with mild type 1 VWD usually have auto-correction of VWF deficiency in pregnancy

• most cases are mild-moderate, and only -10% of cases require long-term prophylactic therapy

Disorders of Secondary Hemostasis

Definition

• inability to form an adequate fibrin clot

• disorders of coagulation factors or cofactors

• disorders of proteins associated with fibrinolysis

• characterized by delayed bleeding, deep muscular bleeding,and spontaneous hemarth roses

Table 26. Classification of Secondary Hemostasis Disorders

Hereditary Acquired

Factor Vllldeficiency:Hemophilia A.VWD

Factor IX deficiency:Hemophilia B(Christmas Disease)

Factor XI deficiency:Hemophilia C

Other (actor deficiencies are rare

Liver disease

DIC

Vitamin K deficiency

Acguued inhibitors [Factor Vlll most corrmon)

Hemophilia A (Factor Vlll Deficiency)

Pathophysiology

• X-linked recessive disorder where factor Vlll is absent or deficient, 1 in 5000 males

• mild (>5% of normal factor level), moderate (1-5%),severe (< 1%)

Clinical Features

• see Table 19, H27

• patients may have also acquired HIV or HCV from contaminated blood products(no cases observed

from transfusions in Canada since 1985)

Investigations

. CBC

• prolonged PTT, normal 1NR ( FI )

• decreased factor Vlll (<40% of normal)

• VWF antigen and ristocetin activity testing to rule out VWD

Treatment

• DDAVP* in mild hemophilia A

• factor Vlll concentrate for:

prophylaxis (recommended for patients with severe hemophilia A)

• on-demand (i.e.to treat a bleed)

• antifibrinolytic agents(e.g. tranexamic acid),especially for mucosal bleeds

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Hemophilia B (Factor IX Deficiency)

• X-linked recessive, 1 in 30000 males;approximately half have severe disease (factor IX activity <1% of

normal)

• clinical and laboratory features identical to hemophilia A (except decreased factor IX)

• treatment:factor IX concentrate ( prophylaxis or on-demand), antifibrinolytic agents

Factor XI Deficiency

• autosomal recessive; more common in Ashkenazi Jewish population

• usually mild, often diagnosed in adulthood

• factor XI level does not correlate proportionally with bleeding risk - risk of bleeding correlates with a

previous history or family history of bleeding

• treatment: antifibrinolytic agents, FP, Factor XI concentrate, DDAVP*

Liver Disease

• see (

iastroenterolonv.G32

Pathophysiology

• thrombocytopenia secondary to: hypersplenism, nutritional deficiency,direct B.M toxicity related to

alcohol, diminished production from chronic viral infections(e.g. HCV),and decreased production of

TPO

• deficiency in synthesis of all factors except Vlll (also made in endothelium)

• aberrant or diminished synthesis of fibrinogen (factor 1)

• diminished synthesis of natural anticoagulants and altered regulation of fibrinolysis

Investigations

• CBC, peripheral blood film:thrombocytopenia, target cells

• primary hemostasis affected

thrombocytopenia

• secondary hemostasis affected

elevated 1NR (FI),FIT,TT

low fibrinogen in end-stage liver disease

Treatment

• supportive, treat liver disease, blood products if active bleeding (FP, platelets,cryoprecipitate)

Investigationsin Liver Disease

Factor V.VIL Vlll.Expect decreased V

and VII because they have the shortest

half-life.Factor Vlll will be normal or

increased because it is produced in the

endothelium

Vitamin K Deficiency

Etiology

• drugs

vitamin K antagonist (e.g.warfarin) -diminished production of functional FactorsII,VII,IX X,

proteinsC and S

• antibiotics eradicating gut flora, altering vitamin K uptake

• poor diet:e.g. prolonged fasting orstarvation (especially due to chronic alcohol consumption )

• biliary obstruction

• chronic liver disease (decreased stores)

• fat malabsorption (e.g. celiac disease, disorders of bile or pancreatic secretion, intestinal disease, and

cystic fibrosis)

• vitamin K deficiency bleeding,see Paediatrics. P52

Investigations

• IN R (P

'

l ) is elevated out of proportion to elevation of the PIT

• decreased Factors II, VII, IX, X (vitamin K-dependent)

Treatment

• hold anticoagulant if vitamin K antagonist on board

• vitamin K PO if no active bleeding

• if bleeding,give vitamin K 10 mg IV (reversal may take up to 12 h)

• if life-threatening bleeding and vitamin k antagonist used,give PCC or FP if PCC contraindicated

PCCs are relatively contraindicated in liver disease or if there is a previous history of HIT (PCC

product contains heparin)

(§>

Vitamin K Dependent Factors

Vitamin K antagonists(e.g.warfarin)

affect function of these factors:

1972Canada vs.Soviets"

X.DC, VII.II. proteinsC and S

PT should improve within 24 h of

adequately dosed vitamin K repletion

(onset isin 6-12 h):if not.search for

other causes

American Society of Hematology

Choosing Wisely Recommendation

Do not administer plasma or

prothrombin complex concentratesfor

non-emergent reversal of vitamin K

antagonists(e.g. outside of the setting of

major bleeding,intracranial hemorrhage,

or anticipated emergentsurgery)

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H3-I Hematology Toronto Notes 2023

Disseminated intravascular Coagulation

DIC is a spectrum which may include

thrombosis,bleeding,or both

Definition

• excessive, dysregulated release of piasmin and thrombin leading to intravascular coagulation and

fibrinolysis

• depletion of platelets, coagulation factors, and fibrinogen

• risk of life-threatening hemorrhage and/or thrombosis

Etiology

• occurs as a complication of many other severe medical,surgical,or obstetrical conditions

• widespread endothelial damage and extensive inflammatory- cytokine release

Factor Levelsin Acquired

Coagulopathies

Factor Liver Vitamin DIC

Disease KDef

V N *

a

Table 27.Etiology of DIC

n « a »

Activation of Procoagulant

Activity

Endothelial Injury Reticuloendothelial Vascular Stasis

Injury

Other

VH Kt N *

APS Infections/sepsis

Vasculitis

Metastatic

adenocarcinoma

Liver disease

Splenectomy

Hypotension

Hypovolemia

Acule hypoxia

'

'acidosis

Intravascular hemolysis (check lactate)

e.g.incompatible blood,malaria

Tissue injury

e.g.obstetric complications,trauma. Aortic aneurysm

Giant hemangioma

PE

Important Etiologies of DIC

burns,crushinjuries

Malignancy

e.g.solid tumours,hematologic

malignancies (especially APL)

Snake venom,fat embolism,heat

OMITS

Obstetric complications

Malignancy

Infection

Trauma

Shock

stroke

Clinical Features

• presence ofboth hemorrhage and clotting

Table 28.Clinical Features of DIC

Clinical Prediction of DIC - International

Society of Thrombosis and Hemostasis

(ISTH) Calculator

Presence of an underlying, predisposing

condition is a requirement

Signs of Microvascular Thrombosis Signs of Hemorrhagic Diathesis

Neurological:multifocal infarcts,delirium,coma, seizures

Skin:focal ischemia.superficial gangrene,purpura fulminans

Renal:oliguria,azotemia,cortical necrosis

Pulmonary:ARDS

Gl:acute ulceration,liver dysfunction

Adrenal failure:adrenalhemorrhage or infarction

SBC:m

'

croangiopathic hemolysis (schistocytes)

General:Bleeding from any site in the body (secondary lo decreased

platelets and coagulation factors)

Neurologic intracranial bleeding

Skin:petechiee.eahymosis.oozingfrom puncture sites

Renal:hematuria

Mucosal:gingival oozing,eprstaxis.massive bleeding

DIC diagnosisis defined as >5 points

Points 0 12 3

PSsSet >«0 <50

KM Investigations

• peripheral blood smear:schistocytes

• primary hemostasis:CBC, decreased platelets

• secondary hemostasis: prolonged INR ( FT), F I T

'

,

'

IT,decreased fibrinogen and other factors

• fibrinolysis:increased FDPs or D-dimers and short euglobulin lysis time (i.e. accelerated fibrinolysis)

• extent of fibrin deposition: urine output and RBC fragmentation

Treatment

• individualize supportive therapy according to underlying condition:recognize early and treat

underlying disorder-supportive measures:hemodynamic and /or ventilatorsupport, aggressive

hydration,and RBC transfusion if severe bleed

• in bleeding phase (recommendations from 1STH Guidance Statement 2013):

treat the underlying condition

transfuse platelets in patients with active bleeding if platelet count <50 x 109/L or in those with a

high-risk of bleeding and a platelet count of <20 x lGr/L

• TP may be useful in patients with active bleeding with either prolonged PT/aPTT (>1.5 times

normal) or decreased fibrinogen (<1.5 g/L).TP should be considered in DIG patients requiring an

invasive procedure with similar laboratory abnormalities

• fibrinogen concentrate or cryoprecipitate may be recommended in actively bleeding patients with

persisting severe hvpofibrinogenemia (<1.5 g/L) despite TP replacement

PCC may be considered in actively bleeding patients if TP transfusion is not possible

• in thrombotic phase:

• LMWH preferred over UTH in critically ill, non-bleeding patients

»T

Morierate Strong

increase increase

Ladof lo

Ftn crest

sarkm <5i :5i

Mceror UU IIIH

W)

Pmloageti <3 >36 >{

ns

Arsogea >10 <10

HU

Table 29. Differential Diagnosis for Abnormal Coagulation Testing

r ~t

Increased PT/INR Only Increased PTT Only Both Increased t

_ J

Warfarin

Vitamin K deficiency

Factor VIIdeficiency

Liver disease

factor VIIinhibitors

Intrinsic factor deficiency:Factor VIII

(Hemophilia A),factor IX (Hemophilia S).

Factor XI.FactorXIl

Heparin.DOACs

Antiphospholipid Ab

Intrinsic factor inhibitors (e_g.Factor VIII)

Deficiency of common pathway factors:

Prothrombin (Factor II),fibrinogen.FactorV.

Factor X

Severe liver disease

FactorV.FactorX.prothrombin, and fibrinogen

inhibitors

Excessive anticoagulation

Severe vitamin K deficiency

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H35 Hematology Toronto Notes 2023

Hypercoagulable Disorders Differential Diagnosis of Elevated

D-Dimer

. Arterial thromboembolic disease (e.g.

Ml. cerebrovascular accident, acute

limb ischemia.AFib. intracardiac

Hypercoagulability Workup -Venous Thrombosis

• workup for hypercoagulable state is controversial and should be considered ONLY if it will alter

treatment decisions

• includes inherited or acquired thrombophilia

hypercoagulability workup may be considered in patients with:

multiple recurrent thromboses

warfarin-induced skin necrosis or neonatal purpura fulminans(protein C or S deficiency)

thrombosis at an unusual venoussite

abnormal blood work, constitutionalsymptoms, or physical exam findingssuggestive of

cancer

arterial thrombotic events due to a hypercoagulable state are typically associated with APS, HIT,

IAK2+ MPNs, and PNH, not hereditary thrombophilias

• workup (if indicated)

• initial

CBC, blood smear, coagulation studies,liver/renal function tests, urinalysis,and hemolysis

markers(if anemic)

malignancy history, age appropriate cancerscreening

serology"APLA (lupus anticoagulant will be affected by anticoagulation)

depending on CBC, consider JAK2

post-treatment (or >6 wk, as protein levels are depleted/consumed by dot)

antithrombin activity'(not on heparin)

proteins C,Sactivity (not on warfarin)

• note:most of these tests do not change management, and a negative test does not rule out a

hypercoagulable state

• decision to pursue hypercoagulability workup should be made in consultation with a hematologist

thrombus)

• Venous thromboembolic disease

(e.g.DVT.PE)

• Abnormal fibrinolysis (e.g.use of

thrombolytic agents)

• Surgery/trauma (e.g.tissue ischemia,

necrosis)

• Vaso-ocdusive episode of SCD

• Renal disease (nephrotic syndrome,

acute/chronic renal failure)

• Pregnancy-related (e.g. normal

pregnancy, preedampsia.eclampsia)

. Cardiovascular-related (e.g.

cardiovascular disease.CHF)

• Severe infection/sepsis/inflammation,

systemic inflammatory response

syndrome

. DIC

. Malignancy

. Severe liver disease

• Venous malformation

• Isolated prolonged INR is most

commonly due to Factor VII

deficiency in the extrinsic pathway

since it has the shortest half-life

• Isolated elevated PTT is usually due

to factor deficiency or inhibitors in

the intrinsic pathway

SELECTED CAUSES OF HYPERCOAGULABILITY

Activated Protein C Resistance (Factor V Leiden)

• most common cause of hereditary thrombophilia

• 3-7% of European White population are heterozygotes

- point mutation in the Factor V gene (R506Q) results in resistance to inactivation of Factor Va by

activated protein C

Prothrombin Gene Mutation (PT) G20210A

• 1-3% of European White population are heterozygotes

• G to A transposition at nucleotide position 20210 of the prothrombin gene promoter region results in

increased levels of prothrombin, thusincreased thrombin generation

Protein C and Protein S Deficiency

• protein C inactivates Factors Va and Villa using protein S as a cofactor

• protein C deficiency

homozygous or compound heterozygous:neonatal purpura fulminans

heterozygous

type1:decreased protein C levels

type II:decreased protein C activity

acquired:liver disease,sepsis, DIC,warfarin, and certain chemotherapeutic agents

• 1/3of patients with warfarin necrosis have underlying protein C deficiency

• protein S deficiency

type I:decreased free and total protein Slevels

type 11:decreased protein S activity

type Ill:decreased free protein S levels

acquired:liver disease, DIC, pregnancy, nephrotic syndrome, inflammatory conditions, and

warfarin

Antithrombin Deficiency

• in absence of heparin: antithrombin slowly inactivatesthrombin.In the presence of heparin:

antithrombin rapidly inactivatesthrombin

• causes/etiology:autosomal dominant inheritance,urinary losses in nephrotic syndrome, or reduced

synthesisin liver disease

• diagnosis must be made outside window of acute thrombosis and anticoagulation treatment (acute

thrombosis, heparin,systemic disease all decrease antithrombin levels)

• deficiency may result in resistance to UFH ( LMWH may be considered, with monitoring of anti-Xa

levels)

• heparin resistance:suspect if >35000 IU of UFH required during 24 h use

Elevated Factor VIII Levels

• an independent marker of increased incident and recurrent thrombotic risk,but levels can also be

increased in numerous states as an acute phase reactant, therefore its clinical use is controversial

American Society of Hematology

Choosing Wisely Recommendations

1Do not testforthrombophilia

in adult patients with venous

thromboembolism occurring in the

setting of major transient risk factors

ji.e.surgery, trauma,or prolonged

immobility)

2. Do not use inferior vena cava filters

routinely in patients with acute venous

thromboembolism

Common Causes of Hypercoagulability

CALM APES

Protein C deficiency

APS

Factor V Leiden

Malignancy

Antithrombin deficiency

Prothrombin G20210A

Increased Factor VIII (Bght)

Protein Sdeficiency

Causes of Both Venous and Arterial

Thrombosisindude:

APS

MPN

HIT

Distal venous dot with patentforamen

ovale r »

PNH L J

decreased

Protein C. protein

during

S

acute

.and

thrombosis

AT1II are + -

therefore to testfor deficiency,they

must be tested outside of thistime

period

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H36 Hematology Toronto Notes 2023

Congenital Dysfibrinogenemia

• may predispose to thromboembolic disease, bleeding, or both

Disorders of Fibrinolysis

• includes congenital plasminogen deficiency, tPA deficiency, but association with VTE risk is not dear

Antiphospholipid Antibody Syndrome

• definition: I clinical and £ I laboratory criteria

• clinical: arterial or venous thrombosis, recurrent (>3) early pregnancy losses <10 wk, one late fetal

loss £10 wk (morphologically normal),or premature birth before 34 wk due to (pre)eclampsia or

placental insufficiency

laboratory (must be confirmed on two occasions, tested £12 wk apart):anticardiolipin IgG and

IgM, anti-p2 glycoprotein-!Ab, or lupus anticoagulant

• mechanism: not well understood, Abs interact with platelet membrane phospholipids causing

increased activation; can also interfere with thrombin regulation, fibrinolysis, and inhibit the protein

C pathway

• see Rheumatology.RH13

Malignancy

9

is a Common Cause ol

Acquired Hypercoagulability

Workup should include:

Complete history and physical

Age appropriate screening:

Mammogram. Pap. PSA. colonoscopy

Additional imaging/laboratory testing

based on clinical suspicion

Close follow-up

Screening tor Occult Cancer in Unprovoked VIE

(SOME)

ICJM 2015:373:697-704

Purpose:In assessthe efficacy of a screen ing

program for occult cancer that employs CT of the

abdomen and pelvis in patients experiencing their

hist unpranked episode ol VIE.

Methods:Patients(i

-854|were randomly assigned

to limited occult-cancer screening or limited occultcancerscreening plus Cl.

Results: 3.2% ol patientsin the limited-screening

group and 4.5% oi patients in the limited-screening

pbsCl gioup received a new diagnosis of occult

cancer between the randomliation point and 1-year

followup (P-0.28).Four occult cancers were missed

by the tailed screening strategy, whip live occult

cancers were missed by the limited screening plusCI

strategy|PM.O).

Conclusion: Routine screening with CT In patients

who hada first unprovokedVIE dldnol provide a

clinically significant benefit.

Venous Thromboembolism

Definition

• thrombusformation and subsequent inflammatory response in a superficial or deep vein

• includessuperficial thrombophlebitis, DVT,and PE

• thrombi propagate in the direction of blood flow (commonly originating in calf veins)

• DVT is more common in lower extremity than upper extremity (upper extremity DVT are increasing

due to more central venous accesslines)

• incidence -1% if age >60 yr

• most important sequelae of DVT are PE (

-50% chance with proximal DVT) and chronic venous

insufficiency

• acutely, PE can result in cardiorespiratory failure and death (rare in treated patients), most severe

chronic sequela of PE is chronic thromboembolic pulmonary hypertension (CTEPH)

Etiology (Virchow’s Triad)

• endothelial damage

• exposure of procoagulant proteins on dysfunctional endothelium promotes thrombosis

• decreases inhibition of coagulation and local fibrinolysis

• changes to vessel wall integrity may result in turbulent blood (low

• venous stasis

Although lupus anticoagulant prolongs

PTT, this is a misnomer, as its main

clinical feature is thrombosis immobilization (e.g. post-Ml,CHE,stroke, and postoperative) inhibits clearance and dilution of

coagulation factors

• hypercoagulability

• inherited (see Hypercoagulable Disorders, H35)

acquired

age (risk increases with age)

surgery (especially orthopaedic, thoracic,Gl, and GU)

trauma (especially fractures ofspine, pelvis, femur,or tibia, and spinal cord injury)

neoplasms (especially pancreas,stomach,lung,lymphoma, bladder, testicular, colorectal, and

gynaecologic - based on the Khorana score)

blood dyscrasias(MPNs, especially PV, ET),PNH, hyperviscosity (multiple myeloma,

polycythemia, leukemia, and SCD), hemolytic anemias

prolonged immobilization (e.g. CH1

;

,stroke, Ml, and leg injury)

hormone related (combined OCP, hormone replacement therapy, and selective estrogen receptor

modulators)

• pregnancy

• APS

• heart failure (risk of DVT greatest with right heart failure and peripheral edema)

New York Heart Association ( NYHA) Class III and IV

• idiopathic (10-20% are later found to have cancer)

Risk uf VIE in Hospitalized Patients Receiving

Ineffective Antitbiombotic Therapy

Risk Factor RR (95% Cl) P-value

Age >75yr 1.79 (1.18-2.71) 0.M7

1.58 (1.01-2.51)

1.67 (1.01-2.77) 0.08

0.94(0.59-1.51) 0.91

Cancer

Previous VIE

Obesity

Hocmone therapy 0.51 (0.08-3.38) 0.70

Heart failure 1.08 (022-1.62) 0.82

0.89 (0.55-1.43) 0.72

1.48 (0.84-2.6) 0.27

Acute infectious 1.50 (1.00-2.26) 0.06

disease

Acute rheumatic 1.45 (0.84-2.50) 0.27

disease

NYHA III

NYHA IV

Source: JAMA 7004:1&4:963 Clinical Features of DVT -HB

• absence of physical findings does not rule out disease

• unilateral leg edema, erythema, warmth, and tenderness; purple-blue colour may indicate severe

linib-threatening thrombus

• palpable cord (i.e. thrombosed vein)

• phlegmasia alba dolens (white appearance) and phlegmasia cerula dolens (acute pain and edema) with

massive thrombosis

• Homan ssign (pain or resistance with foot dorsiflexion) is unreliable

Virchow's Triad

Endothelial damage

Blood stasis

Hypercoagulability

+

Differential Diagnosis of DVT

• muscle strain or tear, lymphangitis or lymph obstruction, venous valvular insufficiency,ruptured

popliteal cysts, cellulitis,and arterial occlusive disease

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H37 Hematology Toronto Notes 2023

Investigations for DVT

• D-dimer test only useful to rule out DVT if negative with low clinical suspicion of disease (Modified

Wells'

Pre-test Probability 1) and no other acute medical issues; positive result may be non-specific

• doppler ultrasound is most useful diagnostic test for DVT

95%

Wells’ Score for Predicting DVT

• Paralysis,paresis,or recent

orthopaedic casting of lower

extremity (1)

» Recently bedridden (>3 d) or major

surgery within past 4 wk (1)

• Localized tenderness in deep vein

system (1)

• Swelling of entire leg(1)

• Calf swelling >3 cm compared to the

other leg(measured10 cm below the

tibial tuberosity) (1)

• Pitting edema greater in the

symptomatic leg (1)

• Collateral non-varicose superficial

veins (1)

• Active cancer or cancer treated

within 6 mo (1)

. Alternative diagnosis more likely

than DVT (e.g. Baker's cyst,cellulitis,

muscle damage, superficial venous

thrombosis) (-2)

sensitivity and specificity for proximal DVT -

• sensitivity for calf DV T -70%

• venography is the gold standard, but is expensive,invasive, and higher risk

• CT pulmonary angiogram or V/Q scan if PE suspected

Post-Thrombotic Syndrome

• development of chronic venousstasissigns and symptomssecondary to a deep venous thrombosis

• symptoms:pain,venous dilatation, edema, pigmentation,skin changes, and venous ulcers

• clinical severity can be assessed using the Villalta score

• large impact on quality of life following a DVT

• treatment: extremity elevation, exercise, compression stockings, and skin/ulcer care

• for clinical features and treatment of PE,see Respirolocv, R19

Approach to Treatment of Venous Thromboembolism

Purpose

• prevent further clot extension (minimum 3 mo duration)

• prevent acute PE (occurs in up to 50% of untreated patients)

• reduce the risk of recurrent thrombosis (duration depends on presence of other risk factors)

• treatment of massive iliofemoral thrombosis with acute lowerlimb ischemia and/or venous gangrene

(phlegmasia cerulea dolens)

• limit development of late complications (e.g.post-thrombotic syndrome, chronic venous insufficiency,

and chronic thromboembolic pulmonary HTN)

Total Score Interpretation

3-8:High probability.1-2:Moderate

probability,-2-0:Low probability

Modified Wells’ Score

Same as above except with 1additional

point for a history of DVT or major

surgery within past12 wk.and the

interpretation is DVT likely for >2 points

and DVT unlikely for <1point.D-dimer

is ordered for DVT unlikely patients to

fully rule out DVT which can help reduce

unnecessary ultrasounds

i:::e

Initial Treatment

• consider empiric treatment in patient with moderate/high suspicion of DVT and low-risk of bleeding,

if diagnostic imaging will be delayed (definitive imaging should be obtained at first opportunity)

. DOACs

apixaban or rivaroxaban alone (with loading dose)

• dabigatran or edoxaban require 5- 10 d of parenteral anticoagulation (usually LMWH) prior to

initiation

See landmark Hematology Inalsfor more informalion

on IlieClOT trial. It detailsthe efficacy of ton

m olecularweight heparin o.oral antkoagglanl

agents in preventing recurrent thrombosis in patients

with cancer.

contraindications: during pregnancy, in breastfeeding women

there remains limited evidence in severe renal deficiency and some clinicians do not use DOACs

in this population

• LMWH

administered SC,at least as effective as UEH with a lower bleeding risk

advantages:predictable dose response and fixed dosing schedule,lab monitoring not require,

HIT,safe and effective outpatient therapy (including pregnant and cancer patients)

disadvantages: only partially reversible by protamine,long-term use associated with osteoporosis

renally cleared - may require dose adjustment in patients with renal dysfunction

<1%

Duration of Treatment with Vitamin X Antagonists

jVKA] in Symptomatic Venous Thromboembolism

Cuch.

-ane DB Syst Rev 2014X0001367

Purpose: lo evaluate the efficacy and safety of

va nous durations of theiapy w ith VKA In patients with

symptomatic VIE.

Study Selection: dels comparing various durations

of therapy with VKA m patientssymptomatic VIE.

Results: II studies(total 3716 pari c pan Is) were

Included. A significant leducbon in the (Ask ol

recurrent VIE was observed during prolonged VKA

treatment (tl 0.20.95% Cl.0.11 toO.38)*

dependent

ol Use lime elapsed since the imdex thrombotic event.

Patientsreceiving prolonged treatment were at

increased risk of bleeding coinpicalwos(U 2.(0.

95% Cl 1.51 to 4.49).

Conclusion:Treatment with VKAstrongly reduces

the risk of recurrentVIE for aslong astheyare used.

Therapy should he discontinued when the risk of harm

from major bleeding (which remains constant orei

time)isof greater concern than the absolute risk of

reament VIE (which declines over time).

. Ul H

in patients with high-risk of bleed, or requiring rapid interruption for surgical procedures; use

hospital-based nomograms that use bleeding risk and patient weight to determine appropriate

dose

advantages: rapidly reversible by protamine

• disadvantages: must monitor aPIT or heparin levels with adjustment of dose to reach therapeutic

level (~2x normal value); higher risk for development of HIT

Long-Term Oral Treatment

• anticoagulation therapy

warfarin

should be initiated with heparin overlap:dual therapy for at least 48 h with INR >2,due

to initial prothrombotic state secondary to warfarin’sinhibition of natural anticoagulants

protein C/S, half-life of vitamin K factors and risk of warfarin-induced skin necrosis

dosed to maintain INR at 2-3, monitor twice weekly for 1-2 wk

discontinue heparin after INR >2.0 for 2 consecutive days

- DOACs

apixaban or rivaroxaban: INR not used, patients with CrCl >15 mL/min

dabigatran (factor lla inhibitor) or edoxaban: LMWH or IV heparin for at least 5 d before

initiating dabigatran, INK not used, patients with CrCl >30 mL/min

important drug interactions to consider for DOACs

cancer patients; LMWH more effective than warfarin at preventing recurrence of venous

thrombosis In cancer patients; DOACs are as effective as LMWH (more bleeding observed for

patients with Cii cancer taking rivaroxaban or edoxaban)

r

^ Common Medications that Interact

with Warfarin

Acetaminophen (interference with

vitamin K metabolism)

Allopurlnol

NSAIDs (Gl injury)

Fluconazole

Metronidazole

Sulfamethoxazole

Tamoxifen

+

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H38 Hematology Toronto Notes >023

LMWH

typically reserved as long term therapy for patients unable to tolerate oral anticoagulants

(e.g. unable to absorb oral medications, high risk bleeding patients with intraluminal G1

malignancy)

•duration of anticoagulant treatment

provoked V I E with transient risk factor:3mo

provoked V I E with ongoing risk factor:consider indefinite therapy with annual reassessment

first unprovoked proximal DVT or PE: >3 mo, consider indefinite therapy with annual

reassessment

second unprovoked VTE: consider indefinite therapy

cancer-associated DVT:consider indefinite therapy for aslong patient has active malignancy (in

patients who have cancer in remission, anticoagulation is usually extended for 3-6 mo post last

treatment)

inferior vena cava filters

temporary filter indicated only if acute DVT (<4 wk) with significant contraindications to

anticoagulant therapy (i.e. active bleeding) or if anticoagulation must be interrupted (i.e.for

urgent surgery')

must be retrieved once safe to do so as filter is pro-thrombotic in the long-term and associated

with other complications(migration of filter,etc.)

•special considerations

pregnancy: treat with LMWH during pregnancy, then LMWH or warfarin for 6 wk post-partum

(minimum total anticoagulation time of 3-6 mo, but must include 6 wk post-partum, asthisis a

high-risk period)

avoid warfarin in pregnancy due to teratogenicity outside ofselect patient populations(e.g.may

be used by some thrombosis experts during the second and third trimestersin woman with

mechanical heart valves)

avoid DOAC in pregnancy (due to lack of data) and if breastfeeding in postpartum period

surgery:avoid elective surgery'in the first 3 mo after a venous thromboembolic event

preoperatively:IV heparin may be used up to 4-6 h preoperatively

perioperatively:warfarin or DOACs discontinued for at least 2-5d preoperatively (consider

mechanism of drug clearance)

postoperatively:IV heparin, LMWH, DOAC can be used for anticoagulation (consult with

surgeon prior to re-initiation)

for patients at high-risk for thromboembolism (VTE <12 wk, recurrent VTE,APS,AFib

with priorstroke, and mechanical heart valve),IV heparin or LMWH (bridging) may be

considered before and after the procedure while the1NR is below 2.0.Bridging not required

for DOACs

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In Flospital Prophylaxis

•consider for those with a moderate to high-risk of thrombosissvithout contraindications

•non-pharmacological measuresinclude: early ambulation, elastic compression stockings (TEDs), and

intermittent pneumatic compression (1PC)

•LMWH as per hospital protocol (e.g.enoxaparin 40 mg SC once daily,dalteparin 5000 U SC once

daily),or rarely UEH 5000 IU SC BID, UFH 50001U SC TID

•DOACs for orthopaedic surgery thromboprophylaxis

Initiation of Warfarin Therapy Requires

Bridging with Heparin Therapy for

4-5Days

10 mg loading dose of warfarin causes

a precipitous detine in protein C levels

in first 36 h resulting in a transient

hypercoagutable state

Warfarin decreases Factor VI levels

in first 48 h.INR is prolonged (most

sensitive to Factor VII levels),however fid

antithrombotic effect is not achieved until

Factor IX X and II are sufficiently reduced

(occurs after <4 d|

Table 30. Contraindications of Anticoagulant Therapy

Absolute Contraindications toTreatment Relative ContraindicationstoTreatment

Active bleeding

Severe bleeding diathesis or platelet count <20 x10

’

/L

|<20000/mm]

)

Mild-moderate bleeding diathesis or thrombocytopenia

Recent major trauma

Recentstroke

Major abdominalsurgery within past 2 d

GI/6U bleeding within14d

Endocarditis

Neurosurgery or ocularsurgery within 10d

Treatment of Pulmonary Embolism

• see Kespirologv, K21

Low-Risk Surgical Patients

<40 yr.no risk factorsfor VTE.geaeral

anesthetic (GA) <30 min.minor elective,

abdominal or thoracic surgery

Moderate-Risk Surgical Patients

>40 yr.>1risk factor foe VTE.GA >30 min

High-Risk Surgical Patients

>40 yr.surgery for malignancy or lower

extremity orthopaedic surgery lasting

>30 min.inhbitor deficiency,or other risk

factors

High-Risk Medical Patients

Heart failure,severe respiratory disease,

ischemic stroke or lower limb paralysis,

confined to bed.and have >1adcktional

risk factor (e.g.active cancel previous

VTE.sepsis,acute neurologic disease.ISO)

+