Physiology of coagulation. Coagulation disorders, evaluation, treatment and anaesthetic implications. Thromboelastography and its relevance to Liver transplant and anaesthetic management of the same. Complete with TEG images of liver transplant patients at various phases of the surgery

1. CLOT KINETICS
CLOT STRENGTH
AND
STABILITY
CLOT
RESOLUTION

2.  0.36 ml of celite-activated whole blood
 A special cylindrical cuvette or cup, which is pre
heated to a temperature of 37 degC
 cuvette oscillates through an angle of 45deg and
each rotation lasts for 10 seconds.
 pin suspended by a torsion wire is lowered into the
blood.
 Development of fibrin strands “couple” motion of
cup to pin
 “Coupling” directly proportional to clot strength

3.  Electrical signal amplified to create TEG
trace
 Result displayed graphically on pen & ink
printer or computer screen
 Deflection of trace increases as clot strength
increases & decreases as clot strength
decreases

5. TEG analyzer measures major parameters of
 clot formation and lysis - R, K, α Angle, MA
and LY 30
 measures TMA and amplitude at a specific
time.
 G (shear elastic modulus strength SEMS)
 coagulation index (CI)

6. •r’ time - represents period of time of latency from start of
test to initial fibrin formation
•normal range 15 - 23 mins (native blood), 5 - 7 mins
(kaolin-activated)
r time ↑ by
• Factor deficiency
• Anti-coagulation
• Severe hypofibrinogenaemia
• Severe thrombocytopenia
r time ↓ by
• Hypercoagulability syndromes

7. ‘k’ time - time from the end of R until a fixed level of clot
strength is reached i.e. amplitude of the trace is 20 mm.
Normal range 5 - 10 mins (native blood) 1 - 3 mins (kaolin-
activated)
k time ↑ by
• Factor deficiency
• Thrombocytopenia
• Thrombocytopathy
• Hypofibrinogenaemia
k time ↓ by
• Hypercoagulability state

8. “α” angle - Measures rapidity of fibrin build-up & cross-linking
(clot strengthening)
assesses rate of clot formation
normal range
• 22 - 38 (native blood)
• 53 - 67(kaolin-activated)
α Angle ↑ by
• Hypercoagulable state
α Angle ↓ by
• Hypofibrinogenemia
• Thrombocytopenia

9. MA is a direct function of the maximum dynamic properties
of fibrin and platelet bonding via GPIIb/IIIa and represents
the ultimate strength of the fibrin clot
Correlates to platelet function 80% platelets 20%
fibrinogen. Normal range 47 – 58 mm (native blood), 59 -
68 mm (kaolin-activated).
MA ↑ by
• Hypercoagulable state
MA ↓ by
• Thrombocytopenia
• Thrombocytopathy
• Hypofibrinogenemia

10. G (SEMS – Shear Elastic Modulus
Strength)
 measured in dyne/cm.2
 It is a measure of clot strength or clot firmness.
5000 A
G = ––––––––––
100 -A
(when A = 50 mm, which is normal value of whole blood, G = 5000
dyne/cm2).
CI (Coagulation Index)
 patient’s overall coagulation is calculated from R, K, MA and a Angle.
 Normal values are from –3.0 to +3.0,
 < –3.0 represent hypocoagulable state
 > +3.0 represent hypercoagulable state.

11. A30 – Amplitude 30 min after MA is reached.
A60 – Amplitude 60 min after MA is reached
LY30 – measures % lysis 30 min after MA is reached.
LY60 – measures % lysis 60 min after MA is reached
gives measure of degree of fibrinolysis
normal range
• < 7.5% (native blood)
• < 7.5% (celite-activated)

12. Clot formation
 Clotting factors -
r, k time
 Clot kinetics
 Clotting factors -
r, k times
 Platelets - MA
 Clot strength /
stability
 Platelets - MA
Clot resolution
 Fibrinolysis - LY30/60;
A30/60

33. Parameters Significance
/deficiency
Correction
Prolonged R coagulation
proteins,
anticoagulants
ffp
↓d α -angle or
prolonged K
fibrinogen cryoprecipitate
↓d MA platelets platelet
concentrate
LY30 more than
7.5%
increased
fibrinolysis
Antifibrinolytic
agents-EACA
tranexamic acid

34. Advantages of TEG
 differential diagnosis of coagulopathy
 Differentiates surgical from non surgical bleeding
 Guides use of blood components
 Guides use of pharmacological agents
Limitations of TEG
TEG cannot identify-
• The individual coagulation factors e.g. VIII, IX, X
• Inhibitors e.g. antithrombin, protein-C, protein S etc.
• Activators e.g. thromboxane A - 2, AD

35. BY : DR. ARATI M. BADGANDI
MODERATOR: DR.SOWMINI

36.  Hereditary

37.  Acquired

38.  Hereditary deficiency of factor VII rare autosomal recessive
disease with highly variable clinical severity.
 Only homozygous deficient patients have factor VII levels
generally low enough (<15%) to have symptomatic
bleeding.
 Easily recognized from their unique laboratory pattern of a
prolonged PT but normal PTT.
ANAESTHEIC CONSIDERATIONS
 Rx of single-factor deficiency state depends on severity.
 Most patients with mild to moderate factor VII deficiency
can be treated with infusions of FFP.

39.  Patients with factor VII levels <1% generally require
treatment with a more concentrated source of factor VII.
 Preferred product for prophylaxis is Proplex T (factor IX
complex) because of its high level of factor VII.
Treatment of factor VII deficiency with active bleeding
 Proplex T or the activated form,
 Recombinant factor VIIa (NovoSeven), usually beginning
with dose of 20-30 μg/kg, with redosing according to PT
results.

40.  Congenital deficiencies in factors X, V & prothrombin
are inherited as autosomal recessive traits & severe
deficiencies are quite rare, on the order of one in one
million live births.
 Pts with severe deficiencies in any of these factors
demonstrate prolongations of PT & PTT.
 Congenital factor V deficiency - prolonged bleeding time
because of relationship btwn factor V & platelet function
in supporting clot formation.

41. ANAESTEHTIC CONSIDERATIONS
 Can be corrected with FFP.
 Conc of vit K–dependent factors in FFP is approx. same
as normal plasma in vivo. (to obtain significant increase
in level of any factor, considerable volume infused)
 At least 4-6 units of FFP needed to attain 20-30%
increase in any missing factor level.
 This level represents considerable volume of plasma
(800–1200 mL) - significant CVS challenge.
 Duration of effectiveness of replacement depends on
turnover of each factor, dictating how often repeated
infusions of FFP needed for maintenance.

42.  Factor V is stored in platelet granules. (particularly
in bleeding patient, platelet transfusion ideal)
 Severe deficiency in pt facing surgery with
significant risk of blood loss, several prothrombin
complex concentrates (PCCs) available.
 Adv - factor levels of 50% or higher can be
achieved without risk of volume overload.
 Disadv - PCCs are risk induction of widespread
thrombosis, thromboembolism & DIC.
 Important to recognize variation in factor levels in
different products.

43.  Defects in propagation phase of coagulation convey a
significant bleeding tendency, ass. with isolated prolongation
of activated partial thromboplastin time (aPTT).
 X-linked recessive disorders hemophilia A & B principal eg. of
this type.
 Marked reduction in either factor VIII or IX associated with
spontaneous & excessive hemorrhage, especially
hemarthroses & muscle hematomas.
 Deficiency in factor XI (gene on chromosome 4), prolongs
aPTT but less severe bleeding tendency.
 Not all deficiencies with prolongation of aPTT associated with
bleeding.

44.  Initial activation stimulus surface contact activation of
factor XII (Hageman factor) to produce XIIa, facilitated by
HMW kininogen & conversion of prekallikrein to active
protease kallikrein.
 Deficiency in any of these 3 factors causes prolongation
of aPTT.
 These factors play no role in initiation / propagation phase
of clotting in vivo - deficiencies of factor XII, HMW
kininogen & prekallikrein not associated with clinical
bleeding.
 Deficiencies in these factors - no special management
except alteration of coagulation testing to allow accurate
measurement of physiologic factors critical to in vivo
hemostasis.

45.  Factor VIII gene is very large gene on X chromosome.
 Most severe hemophiliacs generally have inversion/deletion of
major portions of X chromosome genome or missense
mutation, resulting in factor VIII activity < 1% of normal.
 Point mutations & minor deletions - milder disease with factor
VIII levels > 1%.
 In some patients, functionally abn protein is produced -
causes discrepancy btwn immunologic measurement of factor
VIII antigen (protein) & coagulation assay of factor VIII
activity.
 Clinical severity of hemophilia A best correlated with factor
VIII activity level.

46.  Severe hemophiliacs (activity <1%, <0.01 U/mL) usually
diagnosed during childhood - frequent, spontaneous hges into
joints, muscles, & vital organs.
 Frequent Rx with factor VIII replacement, risk of developing
progressive, deforming arthropathy.
 Factor VIII levels 1-5% of normal enough to reduce severity of
disease - increased risk of hge with surgery/trauma, much
less spontaneous hemarthroses/hematomas.
 Factor levels 6-30% only mildly affected, may go undiagnosed
well into adult life - at risk for excessive bleeding with a major
surgical procedure.

47.  Female carriers also at risk with surgery.
 Severe hemophilia A patients prolonged PTT, whereas
milder disease PTT may be only few sec > normal.
 Since TF VII–dependent (extrinsic) pathway of laboratory
clotting is intact, PT is normal.
ANAESTHETIC CONSIDERATIONS
 If major surgery necessary, factor VIII level must be brought
to near normal (100%).
 Initial inf of 50-60 U/kg (3500–4000 units in 70kg pt).
 T1/2 approx. 12hrs in adults, repeated infusions of 25-30
U/kg every 8-12 hrs needed to keep level > 50%.
 For each unit/kg infused, plasma VIII level will increase
approx 2%.

48.  In children, t1/2 factor VIII as less as 6hrs -more
frequent inf & lab assays to confirm efficacy.
 Peak & trough factor VIII levels measured to confirm
dosing level & interval.
 Rx continued upto 2 wks to avoid postoperative
bleeding (disrupts wound healing).
 Longer periods required in patients who undergo bone
or joint surgery (4-6 wks of replacement therapy).
 Up to 30% of severe hemophilia A patients exposed to
factor VIII concentrate or recombinant product develop
inhibitor Abs.
 Newer recombinant preparations not resulted in
reduction in incidence of inhibitor formation.

49.  Hemophilia B pts similar spectrum of disease as A.
 Factor IX levels <1% - severe bleeding, moderate
disease seen with levels of 1-5%.
 Pts with factor IX levels of between 5-40% generally
have very mild disease.
 Milder hemophiliacs (>5% activity) may not be
detected until Sx performed / dental extraction.
 Similar to lab findings with hemophilia A - prolonged
PTT & normal PT.

50. ANAESTHETIC CONSIDERATIONS
 General guidelines do not differ significantly from
hemophilia A patients.
 Recombinant/purified product or factor IX–PCC used to
treat mild bleeding episodes/prophylaxis with minor
procedures.
 In amounts sufficient to increase factor IX levels to 50%+
increased risk of TE complications, especially in
orthopedic procedures.
 Essential to use only recombinant IX Rx pts undergoing
major orthopedic Sx / severe traumatic injuries / liver
disease.
 Purified factor IX conc/recombinant IX over several days
to treat bleeding in hemophilia B.

51.  Recovery of factor IX is approx. half of factor VIII - dosing
approximately double that for factor VIII concentrates.
 To achieve 100% plasma level in severe hemophilia B
patient, 100 U/kg (7000 units in a 70-kg patient) needs to
be administered.
 Factor IX has a half-life of 18-24 hrs - repeated infusions
at 50% of original dose every 12-24 hrs usually sufficient
to keep plasma level >50%.
 Like factor VIII recommendations, doses of 30-50 U/kg
will give mean factor IX levels of 20%-40%, adequate for
less severe bleeds.

52.  Hemophilia A patients Significant risk of developing circulating
inhibitors to factor VIII, incidence of 30%-40% in patients severely
deficient in factor VIII.
 Hemophilia B patients are less likely. (3%-5%)
 Severe hemophilia-like syndrome can occur in genetically normal
individuals 2ndary to appearance of acquired autoAb to factor VIII
or IX.
 Patients usually middle-aged or older with no personal or family
history of abnormal bleeding with sudden onset of severe,
spontaneous hemorrhage.
 Mixing study - presence of inhibitor. By mixing pt plasma & normal
plasma 1:1 ratio to determine whether prolonged PTT shortens.
Hemophilia A (deficiency in factor VIII but no inhibitor) - shortening
of PTT to < 4 s of normal PTT control.

53.  In contrast, patient with factor VIII inhibitor will not correct PTT
to that extent, if at all. Also important to quantitate factor VIII
activity level, & using modification of PTT called Bethesda
assay to measure inhibitor titer.
 In general, factor VIII inhibitor patients fall into one of two
groups according to the level of inhibitor.
 High responders (>10 U/mL) demonstrate marked inhibitor
response after any factor infusion (cannot be neutralized by
high-dose replacement Rx). Typical of induction of an
alloantibody, & pt constantly at risk of anamnestic response
when re-exposed to factor.
 In contrast, low responders develop & maintain low levels of
inhibitor, constant despite repeated exposure to factor VIII
replacement.

54. ANAESTHETIC CONSIDERATIONS
 Mx of Hemophilia A with inhibitor varies according to whether
high/low responder.
 Low responders (titers <5-10 Bethesda U/mL) – no anamnestic
response to factor VIII conc, whereas high responders (titers of
several 1000units) dramatic anamnestic responses.
 Low-responder category managed with factor VIII concentrates.
 Larger initial & maintenance doses of factor VIII required &
frequent assays of factor VIII levels essential to guide therapy.
 When titer of the factor VIII inhibitor >5-10 U/mL (high
responder category), Rx with factor VIII conc is not feasible.

55.  Major life-threatening bleeds treated with products such as
activated PCCs/recombinant factor VIIa.
 Rx with activated PCCs - risk of initiating DIC or widespread
thromboembolism - recombinant factor VIIa becoming
treatment of choice for acquired inhibitors.
 Hemophiliacs can generate Xa via factor VIIa binding to
tissue factor in initiation phase, but in propagation phase
unable to generate Xa & thrombin burst on platelet surface
without factor VIII or IX.
 Recombinant factor VIIa in high concentrations replaces
VIIIa/IXa Xase complex requirement by binding to platelet
surface & increasing both Xa generation & thrombin burst.
 Active bleeding – 90-120 μg/kg IV every 2-3 hrs until
hemostasis achieved.

56.  Only other defect causing isolated prolongation of PTT &
bleeding tendency - Rosenthal's disease.
 Autosomal recessive trait, affects males & females
equally.
 Much rarer than hemophilia A or B, affects up to 5% of
Jews of Ashkenazi descent from Eastern Europe.
 Generally, bleeding tendency, if at all, quite mild & may
only be apparent following Sx.
 Hematomas & hemarthroses very unusual, even in
patients with factor XI levels <5%.
 Homozygous for type II mutation - very low levels of factor
XI & develop a factor XI inhibitor when exposed to plasma
therapy.

57. ANAESTHETIC CONSIDERATIONS
 Treatment depends on severity of deficiency & bleeding h/o.
 Most patients' factor XI deficiency treated with infusions of
FFP.
 Treatment of active bleeding is either PCCs/recombinant
factor, usually beginning with a dose of 20-30 μg/kg, with
redosing according to prothrombin time results.
 Management of factor XI inhibitors is comparable to that of
hemophilia A & B inhibitors.

58.  Interferes with final step in generation of fibrin clot.
 Hypo/afibrinogenemia, relatively rare conditions,
autosomal recessive traits.
 Afibrinogenemia - severe bleeding diathesis with
spontaneous & posttraumatic bleeding.
 Since bleeding can begin during first few days of life,
may be initially confused with hemophilia.
 Hypofibrinogenemic pts usually no spontaneous
bleeding, but difficulty with Sx.
 Severe bleeding anticipated in patients with plasma
fibrinogen levels <50-100 mg/dL.

59.  Fibrinogen is synthesized in liver under control of 3
genes on chromosome 4. >300 mutations producing
dysfunctional & reduced amounts of fibrinogen reported
– autosomal dominant traits.
 Hypodysfibrinogenemia exhibit excessive bleeding.
 Heterozygous pts although have abnormal coagulation
tests do not have bleeding tendency.
 Approx. 60% clinically silent, while remainder present
with bleeding diathesis / paradoxically thrombotic
tendency.
 Lab evaluation of fibrinogen - measurements of
fibrinogen concentration & function.

60.  Most accurate quantitative measurement by
immunoassay/protein precipitation technique.
 Other screening tests for fibrinogen dysfunction - thrombin
time (TT), CT using retiplase.
 Definitive diagnosis & subclassification - fibrinopeptide
chain analysis by Na dodecyl sulfate–polyacrylamide gel
electrophoresis & amino acid sequencing.
ANAESTHETIC CONSIDERATIONS
 Cryoppt Rx - to increase fibrinogen level by at least 100
mg/dL in average-size adult, 10-12 units of cryoprecipitate
infused, followed by 2-3 units/day. (fibrinogen catabolized
at rate of 25%/day).
 Dysfibrinogenemia pts with a thrombotic tendency require
long-term anticoagulation.

61.  Factor XIII (fibrin-stabilizing factor) deficiency rare autosomal
recessive disorder (prevalence of 1 in five million).
 At birth persistent umbilical / circumcision bleeding.
 Adults - severe bleeding diathesis - recurrent soft-tissue
bleeding, poor wound healing, high incidence of intracranial
hge.
 Blood clots form but weak & unable to maintain hemostasis.
 Fetal loss in women with factor XIII deficiency approachES
100%, suggesting a critical role in maintaining pregnancy.
 Factor XIII deficiency considered in severe bleeding diathesis
with normal screening tests (PT, PTT, fibrinogen, platelet count,
BT).

62.  Clot dissolution in 5M urea used as a screen.
 Definitive diagnosis after abnormal screen accomplished by
enzyme-linked immunosorbent assay.
 Severe hemorrhage at levels of 1% of normal. Heterozygotes
(factor XIII levels of approximately 50%) usually no bleeding
tendency.
ANAESTHETIC CONSIDERATIONS
 Rx with FFP/cryoprecipitate/plasma-derived factor XIII
concentrate/Fibrogammin P.
 Preop prophylaxis - IV inj 10-20 U/kg at 4-6wk intervals
(depending on preinfusion level).
 Acute hge - infusion of 50-75 U/kg.
 Factor XIII long circulating half-life of 7-12 days, adequate
hemostasis achieved with even low plasma concentrations
(1%–3%).

63.  Production disorders may be caused by
megakaryocyte aplasia or hypoplasia in bone marrow.
 Congenital hypoplastic thrombocytopenia with absent
radii (TAR syndrome) usually inherited in autosomal
recessive manner.
 Thrombocytopenia develops in 3rd trimester/early after
birth, often initially severe (<30,000/μL), slowly
improves over time nearing normal range by age 2.
 Patients often have obvious bilateral radial anomalies &
abnormalities of other bones may also occur.

64. Fanconi Syndrome
 Hematologic manifestations do not usually appear until
approx. 7 yrs of age, although thrombocytopenia reported
in neonates.
 Bone marrow - reduced cellularity & reduced numbers of
megakaryocytes.
 Treatment rarely necessary in neonatal period & stem cell
transplantation curative once severe bone marrow failure
has developed.
May-Hegglin Anomaly
 Giant platelets in circulation & Döhle bodies (basophilic
inclusions) in WBCs.
 Platelet production variably ineffective; 1/3rd
significantly
thrombocytopenic & at risk of bleeding.

65. Wiskott-Aldrich Syndrome
 X-linked disorder that presents with a combination of
eczema, immunodeficiency, and thrombocytopenia.
 Circulating platelets smaller than normal, function poorly
because of granule defects & have a reduced survival.
The latter, however, is not enough to explain the
severity of the thrombocytopenia; ineffective
thrombopoiesis is the principal abnormality.
Autosomal Dominant Thrombocytopenia
 Increased megakaryocyte mass with ineffective
production & in some cases, release of macrocytic
platelets into circulation.
 Many have nerve deafness & nephritis (Alport's
syndrome).

66.  Failure in platelet production from marrow damage
where all aspects of normal hematopoiesis are
depressed even to the point of marrow aplasia (aplastic
anemia).
 Reductions megakaryocyte mass seen in pts receiving
radiationRx/ Ca chemoRx, due to exposure to benzene
& insecticides, common drugs such as thiazide
diuretics, alcohol, & estrogens, or complication of viral
hepatitis.
 Infiltration of marrow by malignant process will also
disrupt thrombopoiesis.

67.  Hematopoietic malignancies - multiple myeloma,
acute leukemias, lymphoma, & myeloproliferative
disorders produce platelet production defect;
metastatic Ca & Gaucher's disease (rarer).
 Ineffective thrombopoiesis seen in pts with vit B12 or
folate deficiency, including patients with alcoholism
& defective folate metabolism.
 Identical to maturation defect in RBC & WBC lines.
Marrow megakaryocyte mass is increased, but
effective platelet production is reduced.
 Rapidly reversed by appropriate vit therapy.

68. ANAESTHETIC
CONSIDERATIONS
 Platelet transfusions mainstay.
 Patients with ineffective thrombopoiesis 2ndary to
intrinsic abnormality of megakaryocytes treated
similarly to those with production disorder when need
for urgent surgery of a bleeding episode.
 Ineffective thrombopoiesis associated with either vit B12
or folate deficiency immediately treated with
appropriate vit therapy.
 Recovery of platelet count to normal occurs within a
matter of days, making platelet transfusion
unnecessary in all but acute situations.

69. Drug-induced Autoimmune Thrombocytopenic
Purpura
 Quinine, quinidine & sedormid are best known & studied
extensively.
 Pts present with severe thrombocytopenia, with platelet
counts <20,000/μL.
 Drugs act as haptens to trigger Ab formation & serve as
obligate molecules for Ab binding to platelet surface.
 Can also occur within hrs of 1st exposure to drug due to
preformed antibodies - varying frequency (0%–13%) with
abciximab (ReoPro) & other glycosylphosphatidyl glycan Ib/IIIa
inhibitors.
 α-methyldopa, sulfonamides, gold salts, also stimulate autoAb .

70. Heparin-induced Thrombocytopenia
 Modest decrease in platelet count, HIT type I
(nonimmune) observed in majority of patients within 1st
day of full-dose unfractionated heparin (UH) therapy.
 Relates to passive heparin binding to platelets - modest
shortening of platelet life span, transient & clinically
insignificant.
 HIT type II (immune-mediated) - In patients receiving
heparin for >5 days, Ab to hep-platelet factor 4 complex
- capable of binding to platelet Fc receptors - platelet
activation & aggregation.
 Results in further release of hep-platelet factor 4 &
appearance of platelet microparticles in circulation -
magnify procoagulant state.

71.  Hep-platelet factor 4 complex binding to endothelial cells
stimulates thrombin production - leads to increased
clearance of platelets with venous &/or arterial thrombus
formation - loss of limbs/stroke/ MI/ unusual sites of
thrombosis (adrenal, portal vein, skin).
 Incidence of HIT type II varies with type & dose of heparin
used & duration of Rx.
 10-15% of pts receiving bovine UH develop Ab, <6% of
patients receiving porcine heparin.
 <10% who develop Ab to hep–platelet factor 4 complex will
exhibit thrombotic event.
 Risk varies (40%+ in postop setting when high circulating
levels of both activated platelets & thrombin are present,
eg.orthopedic surgery).

72.  HIT antibody +ve pts undergoing CABG/hep therapy for
unstable angina reported to have significant increase in
adverse events .
 Pts on full-dose UH for >5 days/previously received heparin
should be monitored with every other day platelet counts.
 >50% decrease in platelet count, even if absolute count within
normal range - appearance of HIT type II Ab & mandates
stopping hep & substituting direct thrombin inhibitor
(lepirudin/argatroban).
 If heparin continued, (even LD SC hep/LMWH), significant risk
of major thromboembolic event.
 Acute form of HIT type II can occur in patients restarted on
heparin within 20 days of a previous exposure - sudden onset
of dyspnea, shaking chills, diaphoresis, hypertension,
tachycardia.

73.  Platelet transfusions appropriate if pt experiencing life-
threatening hge or bleeding into a closed space.
 In autoimmune thrombocytopenia 2ndary to drug
ingestion, most imp management step is to discontinue
drug.
 Corticosteroid therapy may speed recovery in patients
with ITP–like picture, as seen in pts reacting to
sulfamethoxazole.
 Rate of recovery depends on clearance rate of drug &
ability of marrow megakaryocytes to proliferate & increase
platelet production.

74.  Approx. 60% pts show response, upto 50% have
long-lasting improvement in counts, effect not
immediate.
 Splenectomy can help in >85% if done early in
disease.
 Substitution of LMWH not an option (significant cross-
reactivity.)
 In thrombotic event/when continued anticoagulation is
required, HIT patients should be started on direct
thrombin inhibitor.
 After baseline PTT, lepirudin given as IV bolus of 0.4
mg/kg, followed by infusion at rate of approx. 0.15
mg/kg/hr, to keep PTT 1.5-2.5 times normal.
 Argatroban given as infusion of approx.2.0 μg/kg/min,
titrated to keep PTT between 1.5-3 times normal.

75. Myeloproliferative Disease
 PV, myeloid metaplasia, idiopathic myelofibrosis, essential
thrombocythemia & CML - abnormal platelet function.
 High platelet counts - abnormal bleeding/tendency for arterial
or venous thrombosis/both.
 In PV, expansion of TBV, increase in blood viscosity ->
thrombotic risk. (splenic, hepatic, portal, & mesenteric
BVs)
 BT may be prolonged - poor predictor of abnormal bleeding.
 Defects in epinephrine-induced aggregation, dense & α-
granule function.
 Bleeding due to an acquired form of vWD may also be
observed in these disorders.

76. Dysproteinemia
 AbN platelet function, defects in adhesion, aggregation &
procoagulant activity.
 1/3 pts with Waldenström macroglobulinemia, IgA myeloma
-demonstrable defect; IgG multiple myeloma pts less affected.
 Conc. of monoclonal protein spike correlates with abn. in
platelet function.
 Functional defect in pts with DIC & fibrin/fibrinogen breakdown
- Fibrin fragments impair polymerization & platelet aggregation.
 Failure of platelet thrombus formation in DIC multifactorial –
1. Thrombocytopenia
2. Hypofibrinogenemia
3. Loss of dense & α-granule function 2ndary to platelet
activation.

77. Uremia
 Untreated pts defect in platelet function correlating with severity of
uremia & anemia.
 Uncleared metabolic product guanidinosuccinic acid - inhibitor of
platelet function by inducing endothelial cell NO release.
 Platelet adhesion, activation & aggregation are abnormal, TXA2
decreased.
 Prolonged BT >30 min - corrected by HD. (may also relate to
anemia since BT shortens with transfusion/erythropoietin)
 Acute bleeding – DDAVP can improve platelet function transiently.
Infusion of conjugated estrogens (0.6 mg/kg per day) for 5 days
shortens BT (normalization of plasma levels of nitric oxide
metabolites.)
 Improvement several days to appear, lasting for upto 2 wks.

78. Liver Disease
 Usually hge due to discrete defect - bleeding varices/
gastric/duodenal ulcer.
 If widespread bleeding – ecchymoses, oozing from IV,
coagulopathy considered.
 Multifaceted defect in coagulation.
 Thrombocytopenia due to hypersplenism, failed
thrombopoietin response.
 Platelet dysfunction 2ndary to high levels of circulating fibrin
degradation products.
 Reduced production of factor VII (principal cause of
prolonged PT) low-grade, chronic DIC with increased
fibrinolysis.

79. Nephrotic Syndrome Patients
 Risk of TE disease including renal vein thrombosis.
 Explanation for this is unclear.
 Attributed to
1. < normal levels of ATIII or PC, 2ndary to renal loss of
coagulation protein
2. factor XII deficiency
3. platelet hyperactivity
4. abnormal fibrinolytic activity
5. >normal levels of other coagulation factors.
 Hyperlipidemia & hypoalbuminemia also been proposed
as etiologic factors.

81.  Can be divided into 2 major classes:
1. Congenital predisposition caused by one or more
genetic abn. (thrombophilia)
2. Acquired/environmental hypercoagulability.
 Hereditary conditions predisposing to venous
thromboembolism (VTE) conceptually be divided into
1. Conditions that decrease endogenous antithrombotic
proteins
2. Increase prothrombotic proteins

82. Hereditary Antithrombin Deficiency
 AT III most imp of body's defenses against clot
formation in healthy BVs/perimeter of active bleeding.
 AT III deficiency autosomal dominant trait, 1/1000-5000
individuals.
 Homozygous AT deficiency is generally not compatible
with life.
 Heterozygote AT III level 40-70% of normal, 20 times
more likely to develop VTE at some point – usually with
some triggering event that further increases their
hypercoagulability.

83. Hereditary Protein C and Protein S Deficiency
 Adversely affect thrombin regulation.
 Hampers ability to limit rates of thrombin generation.
 Heterozygous deficiencies - relative surplus of factors Va &
VIIIa from defective inactivation ensures & prothrombinase
complexes act with enhanced kinetics - overabundance of
thrombin.
 Synthesis of PC & PS vit K dependent, PC shorter t1/2.
 PC deficient particular risk of thrombosis if warfarin therapy
initiated in absence of protective previous anticoagulation by
heparin.
 Specifically, 1st days of warfarin Rx, before inhibition of vit K
has decreased factors VII, IX, & XI to provide anticoagulation
- paradoxically hypercoagulability.

84. Factor VLeiden
 Factor VLeiden gene, differs from normal gene by single
nucleotide, producing AA substitution at 1 site where APC
normally cleaves factor Va - rendering it refractory to inactivation.
 VaLeiden stays active in circulation > normal - increased
thrombin generation.
 Low - intermediate procoagulant risk.
 Heterozygous 5-7fold increased risk of VTE, homozygous
carriers 80-fold.
 Approx. 5% of northern European descent, rarely in African or
Asian descent.

85. Antiphospholipid Antibodies
 Tendency for venous & arterial thrombosis in circulating LAC
Abs (antiphospholipid/ACL Abs).
 APL Abs mix of several IgG, IgM, IgA directed at phospholipid-
associated proteins, esp. prothrombin & β2-glycoprotein I.
 LAC Abs detected by prolongation of PTT & PT, while ACL
Abs measured directly by immunoassay.
 ACL Ab defined by its reactivity to cardiolipin, β2-glycoprotein
I.
 Increases binding of WBCs & platelets to endothelial surface -
thrombus formation. Other MOAs - interference with PC
activation, reduction in PS levels, development of a HIT-like
platelet defect.

86.  Isolated VT/TE 2/3 of cases; cerebral thrombosis accounts for
1/3.
 Coronary, renal, retinal, subclavian, & pedal artery occlusions
less common.
 Along with factor VLeiden & prothrombin gene mutation, APL
Ab considered 1 of top causes of TE in young.
 Can also present with catastrophic APL syndrome
characterized by multiorgan failure 2ndary to
1. widespread small vessel thrombosis
2. Thrombocytopenia
3. ARDS
4. DIC
5. Autoimmune hemolytic anemia.
 Clinical picture is indistinguishable from of TTP (Bacterial
infections triggering events)

87.  Current strategies range from simple management
approaches (early ambulation) to combination of SC heparin
with elastic stockings followed by conversion to warfarin with
ass. lab monitoring.
 VTE risk factors must be considered when balancing degree
of thrombotic risk costs (monetary & bleeding risk) of
aggressive perioperative anticoagulation.
 Prophylaxis strategies may take form of pharmacologic or
physical methods.
 Drugs proven to suitable for VTE prophylaxis include UH,
LMWH, oral anticoagulant warfarin, direct thrombin inhibitors
(hirudin), factor Xa inhibitors (fondaparinux).

88.  Physical methods of prophylaxis - graded compression
elastic stockings 40-45% risk reduction, intermittent
pneumatic compression risk reduction approaches that of
UH.
 Inv late 70s & 80s presented convincing evidence that RA
(usually neuraxial blockade) - decreased incidence of
postoperative VTE, esp for lower extremity jt replacement.
 RA thus preferred technique for this Sx & procedures with
high VTE risk.
 Postop prophylactic anticoagulation with warfarin & SC
heparin std for high-risk operations.
 With advent of routine antithrombotic prophylaxis, adv of
RA over GA less clear.

89.  In conclusion, no particular anesthetic technique is
mandated for antithrombotic prophylaxis, & except in
special circumstances, LMWH not be withheld in
postop period to allow continued use of epidural.
 In absolute CI to anticoagulation / major bleeding,
placement of VC filter used to prevent recurrent PE.
 Available filters - Greenfield, bird's nest, Simon nitinol,
Vena Tech, Gunther Tulip Retrievable Vena Caval
Filter.
 Filters reduce incidence of PE to <4%, but not more
effective than long-term anticoagulation.
 Complications - insertion site (20-40%) & IVC
thrombosis, tilting / migration of filter, damage to wall
IVC, filter fracture.

90. Anesthetic Considerations for Patients on
Long-Term Anticoagulation
 Periop Mx of pts receiving long-term anticoagulation
requires special consideration.
 Risk of thrombosis when preop pt not effectively
anticoagulated weighed against risk of bleeding during
& after surgery if anticoagulation continued periop.
 Risks of recurrence of thrombosis greatest if inciting
thrombus arterial, esp if associated with AF (recurrent
embolism 40% mortality).
 In contrast, recurrent lower-extremity VTE risk of
associated sudden death of 6%.

91.  Time elapsed since inciting thrombus also critical (for
arterial & venous thrombi).
 Most anticoagulated pts managed on warfarin,
anticoagulation gradually abates after stopping drug.
 INR does not fall for approx 29hrs, then decreases with
t1/2 approx 22hrs. (If high risk without anticoagulation,
bridging in form of therapeutic doses of UH / LMWH
considered approx 60hrs after last dose of warfarin).
 In IV UH, window of 6drug-free hrs allowed prior to
surgery.
 For LMWH, SC, doses given once / twice daily for 3 days
before Sx, with last dose no <18hrs preop for twice-daily
dose (i.e., 100 U/kg of LMWH) 30hrs for once-daily
regimen (i.e., 150–200 U/kg of LMWH). Add. 6-hr drug-
free interval if RA planned.

92.  Postop resumption of anticoagulation requires
evaluation of risk of recurrent thrombosis & degree to
which Sx increases patient's hypercoagulability (e.g.,
minor vs major orthopedic Sx).
 Since delay of approx 24 hrs after warfarin
administration before the INR increases, warfarin
resumed asap except in high bleeding risk.
 Consideration for bridging therapy with IV or SC
anticoagulation until the INR becomes therapeutic.