Transcript Thrombin inhibitors

Sam Ibrahim
PGY1 Orthopedic resident
January 19 2016
Objectives
 Physiology of hemostasis
 Bleeding disorders (Acquired and Congenital)
 Transfusion Principles and Complications
 DIC
 Laboratory Coagulation Tests
 Pharmacology of anticoagulants
Hemostasis
 Hemostasis is a complex process whose function is to
limit blood loss from an injured vessel.
 Four major physiologic events participate in the
hemostatic process:
 Vascular constriction,
 Platelet plug formation,
 Fibrin formation
 Fibrinolysis.
Vascular Constriction
 initial response to vascular injury dependent on local
contraction of smooth muscle.
 mediated by
Endothelin - synthesized by injured endothelium
Serotonin - released during platelet aggregation
Thromboxane A2 - produced locally, stimulated by release of
arachidonic acid from platelet membranes
Bradykinin and fibrinopeptides - involved in coagulation
1.
2.
3.
4.
 extent of vasoconstriction varies with
 Degree of injury
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longitudinal injuries may remain open due to physical forces
completely transected vessels may be able to contract fully and stop
bleeding
Platelet Function
 Form a hemostatic plug (The process require vWF)
 subendothelial collagen are exposed in the injured intimal wall
 vWF binds to glycoproteins I/IX/V on platelet membranes
 after adhesion, platelets release ADP and serotonin, which
attract other platelets
 Primary hemostasis – vasoconstriction plus initial platelet
aggregation. Reversible. Not affected by anticoagulants
(heparin, warfarin). Affected by antiplatelet agents.
 Contribute to thrombin formation
First Wave of Platelet Aggregation
 Platelets release arachidonic acid
 Arachidonic is converted by COX(Cyclooxygenase) to prostaglandin
G2, then to prostaglandin H2, then to thromboxane
 thromboxane causes vasoconstriction and platelet aggregation
 Arachidonic acid which is shuttled to adjacent endothelial
cells is converted to prostacyclin
 prostacyclin causes vasodilation and inhibits platelet aggregation
 COX is irreversibly inhibited by aspirin and reversibly
blocked by NSAIDS
 COX-2 inhibitors do not affect platelet COX
Second Wave of Platelet Aggregation
 Platelets release
 ADP
 Ca2+
 Serotonin
 Thromboxane A2
 PF4 which is a potent heparin antagonist
 Platelets compact into a plug
 Fibrinogen bridges the glycoprotein IIB/IIIa receptor on activated platelets
 Thrombospondin from platelet granules strengthens the fibrinogenplatelet bonds
 At this point, thrombosis is irreversible
 Release reactions alter platelet surface phospholipids, allowing binding of
calcium and clotting factors
 This triggers the coagulation cascade
 Second wave of aggregation is inhibited by aspirin, NSAIDS, cAMP, and NO
Coagulation
 The intrinsic pathway begins with the activation of factor XII that
subsequently activates factors XI, IX, and VIII
 In the extrinsic pathway, tissue factor (TF) is released or exposed
on the surface of the endothelium, binding to circulating factor VII,
facilitating its activation to VIIa.
 Common pathway: Each of these pathways continues on to a
common sequence that begins with the activation of factor X to Xa
(in the presence of VIIIa).
 Subsequently, Xa (with the help of factor Va) converts factor II
(prothrombin) to thrombin (IIa)
Fibrin Cross-Linking
 Thrombin is released from platelet membrane
 Thrombin cleaves fibrinogen to fibrin
 Two peptides are removed – fibrinopeptides A and B
 Removal of fibrinopeptide A permits end-to-end
polymerization
 Removal of fibrinopeptide B allows side-to-side
polymerization of the fibrin clot
 Thrombin-activatable fibrinolysis inhibitor (TAFI)
 Activated by thrombin-thrombomodulin complex
 Removes lysine residues from fibrin, preventing
plasminogen from binding
Regulation of Coagulation
1-Feedback inhibition of coagulation cascade Deactivates the enzyme complexes
2-Thrombomodulin (TM) presented by the endothelium form complex with thrombin
no longer available to cleave fibrinogen
Activates protein C
3-Protein C
 binds to protein S on phospholipid surfaces (APC-S complex)
 cleaves Va and VIIIa, deactivating them
 (fV-Leiden) – variant which is resistant to cleavage, resulting in hypercoagulable state
4-Plasmin
 Activated from plasminogen by, tPA, and uPA, ischemia.
 Degrades fibrin clot
 tPA – tissue plasminogen activator. Made by endothelial cells. Main activator of plasminogen. Only acts
on plasminogen which is bound to fibrin (makes its fibrinolyitic activity occur at the clot site only)
 uPA – urokinase plasminogen activator. Produced by endothelial cells and urothelium. Acts on all
plasminogen (not just fibrin-bound)
5-Tissue factor pathway inhibitor (TFPI)
 blocks tissue factor –VIIa complex, preventing activation of X and IX
6-Antithrombin III
 neutralizes all progoagulant serine proteases
 inhibits tissue factor-VIIa complex
Fibrinolysis
 Initiated at the same time as clot formation
 Plasmin
 Activated from plasminogen by tPA, and uPA, and ishemia
 Degrades fibrin mesh
 Alph 2-antiplasmin
 Inhibits plasmin to ensure that clot lysis doesn’t occur too quickly
 Bradykinin
 Endothelium-dependent vasodilator
 Kininogen is cleaved by kallikrein to form bradykinin
 Activated by fXII
 Contraction of nonvascular smooth muscle
 Increased vascular permeability
 Enhances tPA release
 Fibrin degradation products
 E-nodules, D-dimers, Smaller fragments interfere with normal platelet
aggregation.
Testing Coagulation
 PT and INR
 Thromboplastin and calcium are added to plasma, leading to formation
of a fibrin clot
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Variations in thromboplastin activity make it difficult to assess the degree of coagulation based
on PT alone
INR accounts for these variations
 Measures function of fI, II, V, VII, X
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fVII has the shortest half-life of all coagulation factors
 Use to test vitamin K deficiencies, warfarin therapy
 aPTT
 Phospholipid substitute, activator, and calcium are added to plasma,
leading to formation of a fibrin clot
 Measures function of fI, II, V (common pathway) and VIII, IX, X, and XII
(intrinsic pathway)
 Used to monitor heparin therapy – target range 1.5-2.5x the control value
(50-80 sec)

LMW heparin selectively inhibits fXa, may mildly elevate aPTT, but is not
routinely monitored
Testing Coagulation
 Platelet count
 150-400,000/μL
 Dysfunction can occur at either end of the spectrum
 >1,000,000/μL may be associated with bleeding or
thrombotic complications
 <50,000/μL Increased bleeding with major surgical
procedures
 <30,000/μL Increased bleeding with minor surgical
procedures
 < 20,000/μL Spontaneous hemorrhage
Testing Coagulation
 Thrombin time
 Thrombin is added to plasma
 Tests the final steps in the common pathway

Factor I, VIII, X
 If a patient is on heparin, replitase is added instead of
thrombin

Has the same effect, but is resistant to heparin
 Ecarin clotting time
 Ecarin (from leech saliva) added to plasma
 Ecarin cleaves prothrombin to a less-active form of
thrombin

This is inhibited by hirudin and other direct thrombin inhibitors
Testing Coagulation
 Thromboelastography
(TEG)
 Blood is induced to clot in a
low-shear environment
(resembles sluggish venous
flow)
 Monitors viscoelastic
properties of blood, revealing
strength and stability of the
clot
 Monitors time to clotting,
revealing adequacy of
coagulation factors and
platelets
CONGENITAL FACTOR DEFICIENCIES
 Coagulation Factor Deficiencies
 Hemophilia
 Von Willebrand’s Disease
 Factor XI Deficiency
 Factor II, V, and X Deficiency
 Factor VII Deficiency
 Factor XIII Deficiency
 Platelet Functional Defects
• GlanzmannThrombasthenia
• Bernard-Soulier syndrome
• Storage pool disease
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Hemophilia
Sex-linked recessive ( affect males almost exclusively)
Platelets are normal, therefore initial vasoconstriction and platelet plug formation are normal, but mature
clot formation is impaired.
Labs: prolonged PTT, normal PT/INR, bleeding time and vWF:Ag (antigenic level of vWF which rules out
vW disease.)
Clinical severity corresponds to measureable level of factor VIII (A) or IX (B) in the plasma
Severe
 <1% of normal factor activity
 Spontaneous bleeds
 Hemarthrosis ,Intramuscular and retroperitoneal hematoma, GI, GU, retropharyngeal bleeding
 Oral and intracranial bleeding may be life threatening
 Moderate
 1-5% of normal factor activity
 Severe bleeds after trauma or surgery
 Mild
 5-30% of normal factor activity
 Often only have mild bleed after trauma or surgery

Treatment
 Recombinant fVIII concentrate
 Recombinant high purity fIX concentrate
Active bleeding
 fVII, given q2h
Adjuncts
 aminocaproic acid (Amicar) – inhibits fibrinolysis
 desmopressin acetate (DDAVP)
Von Willebrand’s Disease
 Most common congenital bleeding disorder
 Autosomal dominant
 Presentation:similar to bleeding from platelet dysfunction, ie:
mucosal bleeding, petechiae, epistaxis, and menorrhagia
 vWF
 glycoprotein which carries fVIII
 improves platelet adhesion to endothelium
 Type I – partial quantitative deficiency
 Treat with intermediate-purity fVIII concentrate
 Desmopressin - triggers release of vWF from endothelial cells
 Type II – qualitative defect
 May or may not respond to desmopressin
 Type III – total deficiency
 Usually don’t respond to desmopressin
Factor XI Deficiency
 Autosomal Recessive
 aka “hemophilia C”
 Ashkenazi Jewish population
 Bleeding after surgery, trauma
 Treat bleeding or pre-operatively with FFP
 Plasma contains 1 unit of fXI/mL
 Adjunct - desmopressin
Factor II, V, and X Deficiency
 Rare, autosomal recessive
 Significant bleeding with <1% normal activity
 Treat bleeding with FFP
 fV is unstable, therefore need daily transfusions

Goal 20-25% activity
 fII half life is 72h

Goal 25% activity
 May inherit fV and fVIII deficiency together
 Treat with fVIII concentrate and FFP
 Prothrombin complex concentrates
 Treat II and X deficiencies
 fV deficient patients may also have fV-deficient platelets,
and require platelet transfusions
Factor VII Deficiency
 Rare autosomal recessive disorder
 Wide variation in clinical bleeding, does not
always correlate with level of fVII activity
 Spontaneous bleeding uncommon unless <3%
 Easy bruising, mucosal bleeding, postop bleeding in
30% of procedures
 Treatment
 FFP
 Recombinant fVIIa – half life is only 2h therefore need
multiple transfusions (1/2-life of fVII in FFP is 4h)
Factor XIII Deficiency
 Rare, autosomal recessive
 Severe bleeding diathesis
 Tends to be delayed, because clots form normally but are
susceptible to fibrinolysis
 Umbilical stump bleeding
 Intracranial bleed
 Spontaneous abortion
 Treatment
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Goal 1-2% activity
FFP
Cryoprecipitate
fXIII concentrate
Platelets Defects
 Abnormalities of platelet surface proteins
 Glanzmann Thrombasthenia
 Rare, autosomal recessive
 Glycoprotein IIb/IIIa complex is absent or dysfunctional,
resulting in faulty platelet aggregation
 Agglutination with ristocetin cofactor assay..
 Treat bleeding with platelet transfusions
 Bernard-Soulier syndrome
 Defect in glycoprotein Ib/IX/V receptor for vWF
 Platelets unable to adhere to subendothelium
 Treat with platelet transfusion
 No agglutination on ristocetin cofactor assay.
Platelets Defects
 Abnormalities of platelet granules – “Storage pool disease”
 Most common intrinsic platelet defect
 Granules contain products which normally would attract more
platelets, aid in aggregation, and activate the clotting cascade
 Alpha Granules

Grey platelet syndrome – see platelets on Wright’s stain
 Dense granules – contain ADP, ATP, calcium, phosphate
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May occur with partial albinism (Hermansky-Pudlak syndrome)
Variable bleeding
 Treatment
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Desmopressin
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Stimulates high vWF levels, which compensates for the dysfunctional platelets
Platelet transfusion
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For severe bleeding
Acquired haemostatic defect
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Platelet Abnormalities
Acquired Hypofibrinogenemia
Myeloproliferative Diseases
Coagulopathy of Liver Disease
Coagulopathy of Trauma
Acquired Coagulation Inhibitors
Platelets – Quantitative Defects
 Immune thrombocytopenia
 petechiae, purpura, epistaxis
 Primary
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Idiopathic – aka idiopathic thrombocytopenic purpura (ITP)
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Children – acute and short-lived, often follows a viral illness
Adults – insidious and chronic
Platelets are young and functional
Decreased platelet numbers due to impaired production and T-cell-mediated
destruction
Associated with other autoimmune disorders (IgG autoantibody)
Associated with low-grade B-cell malignancies
 Secondary
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Viral infection
Drug-related
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HIT
Peripheral smear shows large platelets
Platelets – Quantitative Defects
 Immune thrombocytopenia
 Treatment
 Goal to maintain platelets >20-30 x 10 ^9/L
 First Line
a. Corticosteroids: The majority of patients respond but only a few long
term
b. Intravenous immunoglobulin (IVIG) or anti-D immunoglobulin:
indicated for clinical bleeding
 Second Line. Required in most patients
a. Splenectomy: open or laparoscopic. Criteria include severe
thrombocytopenia, high risk of bleeding, and continued need for steroids.
Failure may be due to retained accessory splenic tissue.
b. Rituximab, an anti-CD 20 monoclonal antibody
c. Thrombopoietin (TPO) receptor agonists such as romiplostim and
eltrombopag
 Third Line. To be used after failure of splenectomy and rituximab
a. TPO receptor agonists
b. Immunosuppressive agents. For failure of TPO receptor Agonists
Platelets – Quantitative Defects
 Heparin-induced thrombocytopenia (HIT)
 antibodies against (platlet factor 4)PF4 form during exposure to heparin
 5-7d after heparin is started
 1-2d after reexposure
 more common with full-dose unfractionated heparin
 17% develop anti-PF4 antibodies, but only 1-3% get HIT
 Affects platelet activation and endothelial function
 Results in thrombocytopenia and intravascular thrombosis
 Diagnosis
Suspect if platelet count falls <100,000/L or drops by 50% from baseline after Heparin
 Serotonin release assay(SRA)
 High specificity, low sensitivity
 ELISA
 Low specificity, high sensitivity
 Treatment
 Stop heparin
 Add another anticoagulant to prevent subsequent thrombosis.
 Lepirudin, argatroban, bivalirudin, danaparoid
 Don’t use warfarin, because early on it induces a hypERcoagulable state!
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Platelets – Quantitative Defects
 Thrombotic thrombocytopenic purpura (TTP)
 Immune inhibition of metalloproteinase enzyme
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(ADAMTS13) which normally cleaves vWF
Large vWF molecules activate platelets
Thrombi form and thrombocytopenia results
Microangiopathic hemolytic anemia, fever, renal and
neuro signs and symptoms
Peripheral smear shows schistocytes
Treatment
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Plasmapheresis
DO NOT transfuse platelets
Rituximab –monoclonal antibody against B lymphocytes may
help
Platelets – Quantitative Defects
 Hemolytic uremic syndrome (HUS)
 Secondary to infection by Escherichia coli 0157:H7 or
other Shiga toxin–producing bacteria
 usually associated with some degree of renal failure

Often require dialysis
 May have neurologic symptoms
 Treatment
 Plasmapheresis
May get both TTP and HUS with autoimmune disease (esp. SLE),
HIV, and certain drugs (ticlopidine, mitomycin C, gemcitabine,
cyclosporine, tacrolimus)
Platelets – Quantitative Defects
 Sequestration
 Enlarged spleen secondary to portal hypertension, sarcoidosis,
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lymphoma, Gaucher’s disease
Total body platelet count is normal, but a larger percentage of the
platelets are in the enlarged spleen
Mild decrease in platelet survival
Bleeding is less severe than anticipated from the count because of
mobilization of sequestered platelets
Treatment
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Splenectomy
Don’t do a splenectomy in patients with portal hypertension – can
predispose to portal vein thrombosis
Transfused platelets are relatively ineffective because they will also be
sequestered
Platelets – Qualitative Defects
 Massive transfusion
 Impaired ADP-
stimulated aggregation
after transfusion of >10
units of packed red
blood cells
• Uremia
Inhibits platelet aggregation
treat with dialysis or desmopressin
Platelets – Qualitative Defects
Myeloproliferative disorders
 thrombocythemia, polycythemia vera, or myelofibrosis
 Impaired platelet aggregation and secretion
 Treat by reducing platelet count to normal range – function tends to improve
 *risk of thrombosis as well as bleeding
 Thrombosis consumes platelets as well as coagulation factors
 Myeloproliferative Diseases
 Polycythemia may result in spontaneous thrombosis (increased viscosity, increased
platelet count, increased stasis)
 Thrombosis consumes coagulation factors, and may lead to bleeding
 In addition, patients have abnormalities of platelet aggregation and release and
may have spontaneous hemorhage even without coagulation factor consumption
 Postpone surgery until blood volume, hematocrit (<48%), and platelet count
(<400,000/L) are within normal levels
 If emergent surgery is required, perform phlebotomy and blood replacement with
ringer’s lactate
 Treatment of thrombocytosis
 Hydroxyurea, anagrelide
 Liver disease
Platelets – Qualitative Defects
 Drugs
 aspirin, clopidogrel, dipyridamole, and glycoprotein
IIb/IIIa inhibitors
 Aspirin

irreversible acetylation of platelet prostaglandin synthase
 Clopidogrel
 irreversible inhibition of ADP-induced platelet aggregation
 Evidence for when to stop aspirin and clopidogrel
preoperatively is poor

General recommendation to stop 7d before an elective surgery
Acquired Hypofibrinogenemia
 DIC
 Primary Fibrinolysis.
DIC
 Intravascular activation of coagulation
with loss of localization
 Excessive thrombin generation leads to
microthrombi and then clot propagation
 Coagulation factors and platelets are
consumed, leading to diffuse bleeding
 Fragments D and E interpose themselves
between fibrin and polymers forming a
weak fibrin clot thereby inhibiting the
normal coagulation of blood.
 Predisposing factors
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Infection
Trauma
Malignancy
Embolization of brain matter, bone
marrow, or amniotic fluids
Organ injury (ex severe pancreatitis)
Liver failure
Vascular abnormalities (ex large
aneurysms)
Snakebites
Illicit drugs
Transfusion reactions
Transplant rejection
 Diagnosis
 Inciting cause
 Thrombocytopenia
 Elevated INR and PTT
 Low fibrinogen levels
 Increased d-dimer, FDPs
 Treatment
 Treat causative problem
 Maintain adequate perfusion
 FFP for active bleeding, may also
need platelets and cryoprecipitate
 Heparin is not helpful acute DIC
 Epsilon-aminocaproic acid (or
tranexamic acid) to inhibit
fibrinolysis, which releases
fagments D and E that interfere
with normal clot formation
Primary Fibrinolysis
 Accelerated clot breakdown
 The release of excessive plasminogen-activating
substances leads to primary pathologic fibrinolysis
 Occurs in
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Prostate resection – urokinase is released, and breaks down
fibrin
Extracorporeal bypass
Coagulopathy of trauma – PAI-1 consumption
 Treatment

aminocaproic acid – inhibits plasminogen activation
Coagulopathy of Liver Disease
 Impaired coagulation
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Prolonged INR
Decreased production of factors
synthesized in the liver
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Vitamin K-dependent factors (II, VII, IX, X)
Fibrinogen (I)
Factor V, VIII, XI, XII, XIII
Antithrombin III
Plasminogen
Protein C
Protein S
Decreased vitamin K absorption

absorption is bile-dependent, so patients
with impaired bile production will have low
vitamin K levels
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Increased destruction
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Treat if there is active bleeding or
upcoming surgery
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FFP can achieve partial correction
Cryoprecipitate if fibrinogen is <100mg/dL
 Thrombocytopenia
 Hypersplenism
 Decreased production of
thrombopoietin
 Immune-mediated platelet
destruction
 Especially with hepatitis C and
primary biliary cirrhosis
 Usually no treatment is required
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Don’t base decision for treatment
solely on platelet count
Platelet transfusions only last
several hours
IL-11 stimulates hematopoietic
stem cells, but has significant
side effects
Splenectomy can reduce portal
vein flow and predispose to
portal vein thrombosis
Transjugular intrahepatic
portosystemic shunt (TIPS) –
mixed results
Coagulopathy of Trauma
 Early coagulopathy
 Present on arrival in ED
 Induced by shock - hypoperfusion
causes activation of
thrombomodulin
 Systemic activation of anticoagulant
and fibrinolytic pathways
 Thrombin-thrombomodulin
complex deactivates protein C and
consumes plasminogen activator
inhibitor 1 (PAI-1)
 PAI-1 consumption deinhibits
tPA, which enhances fibrinolysis
 Other causes of coagulopathy in trauma
 Acidosis
 Hypothermia
 Dilution of coagulation factors
during resuscitation
Acquired coagulation inhibitor
 Antiphospholipid syndrome (APLS)
 Lupus anticoagulant and anticardiolipin antibodies
 Must be present persistently
 Arterial and/or venous thrombosis
 Bleeding may occur in conjunction with other hypocoagulable states
 Investigate all patients who show recurrent thrombosis
 Associated with SLE, RA, Sjogren’s syndrome
 May develop transiently in response to infections or drugs
 Prolonged aPTT but increased risk of thrombosis in vivo
 Treatment
 Warfarin
Anticoagulants and Bleeding
 Heparin
 Activates antithrombin, which deactivates thrombin and fXa
 Decreased risk of spontaneous bleeding if a continuous infusion is
used
 UFH
 Requires monitoring via aPTT or anti-fXa activity
 Risk of Heparin-induced thrombocytopenia (HIT)—development of
IgG antibodies against heparin bound platelet factor 4 (PF4).
Antibody-heparin-PF4 complex activates platelets Ž
thrombosis and
thrombocytopenia.
 For rapid reversal (antidote), use protamine sulfate (positively charged
molecule that binds negatively charged heparin).
Anticoagulants
 LMWH
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Tinzaparin, enoxaparin,
more reliable therapeutic anticoagulation – inhibits fXa
Lower HIT risk
No monitoring unless patient has renal insufficiency or severe
obesity
 Determine drug effect with an assay for anti-Xa activity
 Thrombin inhibitors
 Argatroban, lepirudin, bivalirudin, dabigatran
Injection
 Can be used in anticoagulation after HIT
 No reversal agent (the only method is emergent dialysis)
 No need for monitoring
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Anticoagulants
 Direct factor Xa inhibitors Apixaban, rivaroxaban.
 MECHANISM: Bind to and directly inhibit factor Xa.
 CLINICAL USE
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Treatment and prophylaxis for DVT and PE (rivaroxaban); stroke
prophylaxis in patients with atrial fibrillation.
Oral agents do not usually require coagulation monitoring.
Can be held for 36 to 48 hours prior to surgery
TOXICITY: Bleeding
Reversed: by prothrombin complex concentrates(four-factor
concentrates only: II, VII, IX, and X).
Anticoagulants
 Warfarin
 MECHANISM: Interferes with γ-carboxylation of vitamin K-
dependent clotting factors II, VII, IX, and X, and proteins C and
S.
 Cytochrome p-450 system
 Clinical Use: Chronic anticoagulation (e.g., venous
thromboembolism prophylaxis, and prevention of stroke in
atrial fibrillation).
 Not used in pregnant women (because warfarin, unlike
heparin, crosses placenta). Follow PT/INR.
 Antidote: give vitamin K. For rapid reversal, give fresh frozen
plasma or prothrombin complex concentrate(preferred in
elderly with intracranial hemorrhage).
Anticoagulants
Common drugs that 
warfarin effectiveness
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Alcohol
Azathioprine
Barbiturates
Carbamazepine
Cortisone
Corticotropin
Cyclophosphamide
Dicloxacillin
Haldol
Phenytoin
Prednisone
Ranitidine
Rifampin
Spironolactone
Sucralfate
Trazodone
Vitamin C (high dose)
Common drugs that 
warfarin effectiveness
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Allopurinol
5-ASA
Amiodarone
ASA
Azole antifungals
Cephalosporins
Clarithro/erythro
5-FU
Flagyl
Heparin
NSAIDs
Neomycin
PPIs
Penicillins
Prednisone
Propranolol
Quinolones
Ranitidine
Thyroxine
TMP/SMX
Tylenol
Thrombolytics
Antiplatelet Agents
 Glycoprotein IIb/IIIa inhibitors
 Abciximab, Eptifibatide, Tirofiban
 ADP receptor/P2Y12 inhibitors
 thienopyridines
 Clopidogrel, Prasugrel, Ticlopidine
 Ticagrelor
 Prostaglandin analogue (PGI2)
 Beraprost, Prostacyclin, Iloprost, Treprostinil
 COX inhibitors
 Acetylsalicylic acid/Aspirin
 Aloxiprin
 Carbasalate calcium
 Indobufen
 Triflusal
 Thromboxane inhibitors
 thromboxane synthase inhibitors (Dipyridamole, Picotamide)
 receptor antagonist (Terutroban†)
 Phosphodiesterase inhibitors
 Cilostazol, Dipyridamole, Triflusal
Surgical intervention in anticoagulation
patients

Bleeding complications
 Hematuria
 Soft tissue bleeding
 Intracerebral bleeding
 Skin necrosis
 Abdominal bleeding intraperitoneal, extraperitoneal, or retroperitoneal
*most common cause of abdominal pain in patients receiving anticoagulation therapy
 Preoperative concerns
 aPTT <1.3 and INR <1.5 do NOT require reversal of anticoagulation therapy unless
working in high-risk areas (CNS, eye)
 Discontinue warfarin, administer vitamin K, use FFP in emergent situations
 Bridge patients with heparin if they are at high risk for thrombosis


The primary indication is patients with mechanical heart valves. Other indications
include a recent (within 30 days) myocardial infarction, stroke, or pulmonary
embolism
heparin infusion should be held for 4 to 6 hours before the procedure Restarted
within 12 to 24 hours of the end of its completion.
 Discontinue heparin and administer protamine sulfate for rapid reversal


Adverse reactions - hypotension, flushing, bradycardia, nausea, and vomiting
Protamine also has anticoagulant effects, so aPTT may still be prolonged
Thrombolytics
Alteplase (tPA), reteplase (rPA), streptokinase, uPA.
 MECHANISM: Directly or indirectly aid conversion
of plasminogen to plasmin, which cleaves thrombin
and fibrin clots. •PT, •PTT, no change in platelet
count.
 CLINICAL USE: Early MI, early ischemic stroke,
direct thrombolysis of severe PE.
 TOXICITY: Bleeding.
 Antidote: Treat toxicity with aminocaproic acid, an
inhibitor of fibrinolysis. Fresh frozen plasma and
cryoprecipitate can also be used to correct factor
deficiencies.
Cardiopulmonary Bypass
 Predisposes to excessive bleeding via contact with circuit tubing and
membranes
 Abnormal platelet and clotting factor activation,
 activation of inflammatory cascades, which lead to excessive fibrinolysis
 Platelets undergo reversible alterations in morphology and their ability to
aggregate, which causes sequestration in the filter fragments.
 Measurement of bleeding by: activated clotting time and blood gas.
Treatment
 Platelets
 FFP and cryoprecipitate
 ε-aminocaproic acid and tranexamic acid, at the time of anesthesia
induction
 Aprotinin – protease inhibitor, acts as an antifibrinolytic agent
 Desmopressin
Local Hemostasis
 Significant surgical bleeding is usually caused by
ineffective local hemostasis
 Management


Interrupt blood flow to involved area
Direct closure of blood vessel wall defect
Local Hemostasis
 Mechanical Procedures
Digital pressure
Extremity tourniquet
Pringle maneuver for liver bleeding
Hemostatic clamp – usually more damaging to the vessel than digital
pressure
 Simple ligature for small vessels
 Transfixion suture and ligature for large arteries with pulsation
 Bone wax
 Thermal Agents
 Heat denatures protein, resulting in coagulation of large areas of
tissue
 Electrocautery – alternating current
 Can also use direct current and argon gas to control diffuse bleeding
 A negative grounding plate should be placed beneath the patient to
avoid severe skin burns




Topical Hemostatic Agents
 Ideal agent: hemostatic action, minimal tissue reactivity,
nonantigenic, biodegrades in vivo, easy to sterilize, inexpensive, can be
tailored to specific needs
 Absorbable agents
 Gelatin foams (Gelfoam), oxidized cellulose (Surgicel), and microfibrillar collagens (Avitene).
 (Gelfoam) and (Surgicel), provide a physical matrix for clotting
initiation
 (Avitene). facilitate platelet adherence and activation.
 Biologic agents
 Topical thrombin, fibrin sealants (FloSeal), and platelet sealants (Vitagel)
 Facilitate formation of fibrin clots and several clotting factors
 Human or recombinant thrombin No foreign body or inflammatory reactions
 Risk of DIC if product is introduced in large caliber vessel
 Bovine thrombin derivatives used with caution due to the potential
immunologic response
Transfusion
 Compatibility
 A, B, O, and Rh serologic compatibility are routinely
tested
 15% of the population is Rh-negative

Give Rh-positive blood if no Rh-negative is available UNLESS the
patient is a premenopausal woman
 Transfuse O-negative blood to all patients in emergency
situations

After 4 or more units, there is a significant increase in the risk of
hemolysis
 Cross-matching between donors' red blood cells and
recipients' sera
Banked Whole Blood
 Once gold standard
 rarely available
 shelf life 42 days
 Recent evidence has demonstrated that the age of red cells
may play a significant role in the inflammatory response and
incidence of multiple organ failure
 During storage, intracellular ADP and 2,3-DPG are depleted,
which results in decreased ability to transport oxygen
 stored blood is acidotic, which may impair coagulation
Red Blood Cells
 Packed
 plasma is removed by centrifugation, which reduces but does not eliminate
reaction to plasma components
 Frozen
 useful in patients with known sensitizations
 Theoretically, ATP and 2,3-DPG stores should be maintained
 Leukocyte-Reduced and Leukocyte-Reduced-Washed RBC
 99.9% of WBC and most platelets are removed
 Leukocyte reduction prevents almost all febrile, nonhemolytic
transfusion reactions, alloimmunization to HLA class I antigens, and
platelet transfusion refractoriness. Prevents CMV transmission
 This is the standard RBC transfusion product in most places
 Most evidence supporting this is poor quality, although there is one
large retrospective Canadian study suggesting that leukocyte-reduced
transfusions decreased mortality and infections
Platelet Concentrates
 Indications for platelet transfusion
Massive blood loss and replacement with platelet-poor products
Inadequate platelet production
Qualitative platelet disorders
Target >50,000/μL for elective surgery
 Newer evidence suggests targets can be lowered in patients who have
no signs of hemostatic deficiency and no history of poor tolerance of
low platelet counts
 Each unit is 50mL
 1 unit of platelets contains 5.5 × 1010platelets – increases the platelet
count by 10,000/μL in an average 70kg person




 Shelf-life 120h from time of donation
 Leukocyte reduction can help prevent HLA alloimmunization
 Rarely will need HLA-matched platelets in patients who are sensitized
due to previous transfusion or pregnancy
 Complications
 Allergic reactions
 Disease transmission
Fresh-Frozen Plasma
 prepared from freshly donated blood
 source of the vitamin K–dependent factors
 the only source of factor V
 Infectious risks
 Short shelf-life
 Needs refrigeration
Concentrates
 Most clotting factors and albumin are available as
concentrates
 Decreased infection risk
 Virucidal technologies
Tranexamic Acid
 An antifibrinolytic agent that inhibits both plasminogen activation and






plasmin activity, thus preventing clot breakdown rather than promoting
new clot formation.
It is excreted in urine and has a half-life of about 2 hours .
Used In coronary artery bypass grafting (CABG), liver transplantation, hip
and knee arthroplasty, and other surgical settings.
The greatest benefit of TXA administration occurred when patients
received the medication soon after injury.
Adverse events:
 Acute gastrointestinal disturbances
 Visual disturbances
 Occasional thromboembolic events
Contraindication:
 acquired defective color vision
 active intravascular clotting.
 Aneurysmal subarachnoid hemorrhage;
TXA should not be given with activated prothrombin complex concentrate
or factor IX complex concentrates because these may increase the risk of
thrombosis.
Indications for Replacement of Blood
 Improvement in Oxygen-Carrying Capacity
RBC
Transfused cells have decreased oxygen carrying capacity
compared to native cells(The decrease in 2,3-DPG and P50 impair
oxygen offloading)
 Treatment of Anemia
 Transfuse if <7 g/dL

Target levels are higher for patients with CAD
 Data is poor
 Volume Replacement
 Loss up to 20% (Class I or II hemorrhage) can be treated with
crystalloids
 Blood loss over 20% may require transfusion of red cells, and in massive
transfusion, require additional blood products
Damage Control Resuscitation
 Previous strategy:
sequential




Several litres crystalloid
Up to 6 units pRBC
Plasma after 6 units pRBC
Platelets
 This practice was based on
old blood products, which
contained more plasma than
current products
 May exacerbate the initial
coagulopathy of trauma
 Damage control
resuscitation strategy
 Aim to halt and/or prevent
the lethal triad of
coagulopathy, acidosis, and
hypothermia
 Plasma is given earlier and in
larger amounts

1:1 plasma to pRBC ratio
 One study showed decreased
30-day mortality
 Military studies are showing
success

They also add platelets (1:1:1
ratio) and recombinant afVII
Complications of Transfusion
 10% of all transfusions
 <0.5% are serious
 Deaths are rare
 16-22% are due to (Transfusion related acute lung injury) TRALI
 12-15% due to ABO hemolytic reactions
 11-18% due to bacterial contamination of platelets
 Primarily related to blood-induced proinflammatory responses
 Types





Nonhemolytic
Allergic
Respiratory
Hemolytic
Infectious
Nonhemolytic Reactions
 Febrile nonhemolytic reactions
 Increase in temperature >1°C
associated with transfusion
 1% of all transfusions
 Cause uncertain
 ?Cytokines in donated
blood
 ?recipient and donor
antibodies reacting
 Reduced with
 leukocyte-reduced blood
products
 Pretreatment with tylenol
 Bacterial contamination


Rare
Gram negatives which can grow at 4°C are
most common


Y. enterocolitical
Pseudomonas

Usually occurs in platelets stored at at 20°C or
apheresis platelets stored at room temperature

Up to 25% of patients will have sepsis and
death

fever and chills, tachycardia, hypotension, and
GI symptoms

hemoglobinemia, hemoglobinuria, and
disseminated intravascular coagulation

Treatment





Stop transfusion
Draw blood cultures
Give O2
Adrenergic blocking agents
Antibiotics
Allergic Reactions
 Common
 1% of all transfusions
 Usually mild
 rash, urticaria, fever within 60-90 min of start of transfusion
 Anaphylactic shock is rare
 Caused by transfusion of
 Antibodies from hypersensitive donors
 Antigens to hypersensitive recipient
 Treatment
 Antihistamine
 Epinephrine
 Steroids
Respiratory Complications

Transfusion-related Circulatory overload (TACO) 
 Avoidable!
Caution in patients with
underlying heart disease
 Consider CVP monitoring when
large amounds of fluid are
administered
 Increased venous pressure, dyspnea,
and cough
 Crackles
 Treatment
 Diuresis
 Slow the rate of transfusion
 Stop other fluids during
transfusion

Transfusion-related acute lung injury (TRALI)
 noncardiogenic pulmonary edema related to
transfusion
 Occurs with administration of any plasmacontaining blood product
 symptoms are similar to those of circulatory
overload with dyspnea and associated
hypoxemia
 accompanied by fever, rigors, and bilateral
pulmonary infiltrates on chest radiograph
 1-2h after onset of transfusion
 Most cases are undiagnosed
 Etiology uncertain
 May be related to anti-HLA or anti–human
neutrophil antigen antibodies in
transfused blood that primes neutrophils
in the pulmonary circulation
 Multiparity of the donor is considered a
major risk factor for the development of
TRALI
 Treatment
 Stop transfusion
 Supplemental oxygen
 Mechanical ventilation if needed
Hemolytic Reactions

Acute
 ABO-incompatible blood
 6% are fatal
 Intravascular destruction of RBCs
 Hemoglobinemia and hemoglobinuria,
DIC, acute renal insufficiency and ATN
Pain at site of transfusion, facial flushing,
back and chest pain
 Fever, respiratory distress, hypotension,
tachycardia, diffuse bleeding


High index of suspicion is required
Labs
 Hemoglobinuria
 Positive Coomb’s test is diagnostic
(transfused cells coated with patient
antibody)
 Treatment
 Stop transfusion
 Send patient and donor samples to lab
 Monitor urine output
 Maintain hydration to prevent
hemoglobin precipitation in renal
tubules


Delayed
 2-10 days after transfusion
 Extravascular hemolysis, mild anemia,
and indirect (unconjugated)
hyperbilirubinemia

They occur when an individual has a low
antibody titer at the time of transfusion
but the titer increases after transfusion



Fever
Recurrent anemia
Jaundice

Labs
 Decreased haptoglobin
 Low-grade hemoglobinemia and
hemoglobinuria

Treatment
 No specific intervention needed
Transmission of Disease
 Malaria



All blood components
Incubation 8-100 days
Shaking chills and spiking fever
 Chagas' disease
 CMV
 Hepatitis B

1/100 000 in non-immune recipients
 Hepatitis C

 Brucellosis
<1/1000 000
 HIV-1
 Syphilis

<1/1000 000
 Prions
 "pathogen inactivation systems"


Under study
reduce infectious levels of all viruses and
bacteria known to be transmittable by
transfusion
Evaluation of Excessive Intraoperative or
Postoperative Bleeding
 Causes
 Ineffective hemostasis
 Results in bleeding from the operative field but no bleeding from other sites
 Blood transfusion
 Causes hypothermia, dilutional coagulopathy, platelet dysfunction, fibrinolysis, and
hypofibrinogenemia
 Hemolytic transfusion reaction may cause diffuse bleeding due to ADP release from
hemolyzed RBCs, resulting in diffuse platelet aggregation and resultant
thrombocytopenia
 Transfusion purpura – rare. Recipient forms antibodies to foreign platelet antigens.
Foreign antigens are transferred to the patient’s own platelets, and these are also
destroyed by antibodies. Thrombocytopenia and bleeding may continue for several
weeks. Corticosteroids may help, although the disease is self-limiting. Transfusion is
not helpful because new donor platelets will also be destroyed.
 Undetected hemostatic defect
 Consumptive coagulopathy
 DIC
 Fibrinolysis
 Gram-negative sepsis (meningococcemia, Clostridium perfringens sepsis, and
staphylococcal sepsis)
Question 1
 With regard to normal hemostasis, which of the following
statements is true?
A. Vascular disruption is followed by vasoconstriction
mediated by vasoactive substances released by
activated platelets.
B. Platelet adhesion is mediated by fibrin monomers.
C. The endothelial surface supports platelet adhesion
and thrombus formation.
D. Heparin inhibits adenosine diphosphate (ADP)stimulated platelet aggregation.
E. A prolonged bleeding time may be due to
thrombocytopenia, a qualitative platelet defect, or
reduced amounts of von Willebrand factor.
Question 2
 With regard to drug effects and platelet function, which of
the following statements is true?
A.Vasoconstricting agents such as epinephrine,
prostaglandin G2 and H2 (PGG2 and PGH2), and
thromboxane A2 reduce levels of cyclic adenosine
monophosphate (cAMP) and induce platelet aggregation.
B.Vasodilators such as prostaglandin E1 (PGE1),
prostacyclin (PGI2), theophylline, and dipyridamole
elevate cAMP levels and block platelet aggregation.
C.Aspirin and indomethacin interfere with platelet release
of ADP and inhibit aggregation.
D.Furosemide competitively inhibits PGE2.
E.The effect of aspirin is reversible in 2 to 3 days.
Question 3
 With regard to blood coagulation, which of the
following statements is true?
A.The principal complex initiating blood coagulation
is the tissue factor (TF)–factor VIIa complex.
B.Coagulation is initiated in the fluid phase of blood.
C.Only endothelial cells express TF.
D.The factor Xa-Va complex converts fibrinogen to
fibrin in quantities sufficient to activate platelets.
E.Antithrombin is the main regulator of blood
coagulation.
Question 4
 With regard to fibrinolysis, which of the following
statements is true?
A.Plasmin is not a significant factor in fibrinolysis.
B.Plasminogen deficiency results in a clinical bleeding
disorder.
C.Plasmin acts only on cross-linked fibrin polymers.
D.Ischemia is a potent activator of the fibrinolytic
system.
E.Physiologic fibrinolysis does not occur.
Question 5
 Which of the following conditions is associated with an
isolated prothrombin time (PT) prolongation?
A.von Willebrand disease
B.Factor VIII deficiency (hemophilia A)
C.Common pathway factor deficiencies (factors II, V,
and X and fibrinogen)
D.Therapeutic anticoagulation with warfarin
(Coumadin)
E.Therapeutic anticoagulation with heparin
Question 6
 All of the following statements regarding complications of
transfusion are false except:
A. Febrile reactions are rare.
B. Gram-positive organisms are the most common
contaminants of stored blood.
C. Screening for minor antigens should be repeated every
week when multiple transfusions are given.
D. A small amount (more than 0.1 cc) of intravenous air is
well tolerated.
E. Malaria, Chagas disease, human T-cell leukemia virus I
(HTLV-I), acquired immunodeficiency syndrome
(AIDS), and hepatitis can be transmitted by blood
transfusions.
References
 Schwartz’s Principles of Surgery, 10th edition.
 Rush University Medical Center Review of Surgery 5th
 First aid Usmle step 1 2015
 Previous presentation
Thanks
Hypercoagulable States
 Thrombosis frequently results from an interplay of
genetic and acquired factors
Hypercoagulable States
 Inherited (Primary) Hypercoagulable
States

Activated protein C resistance






factor V Leiden Mutation
Prothrombin gene mutation
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Dysfibrinogenemias (rare)
 Acquired (Secondary) Hypercoagulable
States
Pregnancy and postpartum period
Estrogen use
Immobilization
Trauma
Postoperative state
Advancing age
Obesity
Lupus anticoagulant or antiphospholipid
antibody syndrome
 Malignancy














Disease-related or treatment-related
Nephrotic syndrome
HIT
Myeloproliferative disorders
PNH
DIC
Inherited (Primary) Thrombotic Disorders
 Almost exclusively venous thrombosis
 APC resistance secondary to fVLeiden is most
common (12-40% of patients presenting with DVT)
 Prothrombin mutation is second most common
APC Resistance and fV Leiden
 Variant fV is resistant to cleavage by activated Protein C

90% caused by a mutation of arginine to glutamine at position 506 (the cleavage site)
 More common in caucasian poplulation (1-8.5%)
 Absent from black, Chinese, Japanese, first nations populations
 In 20-50% of venous thrombosis patients
 7x the risk of venous thrombosis compared to normal population
 More severe if homozygous or if coinherited with antithrombin III deficiency
 Risk of arterial and venous thrombosis
 3x risk of late fetal loss due to intervillous or spiral artery thrombosis resulting in
preeclampsia, placental abruption, stillbirth
 Increased risk of MI if patients are also smokers
 aPTT-based assay


Perform aPTT using factorV-deficient plasma
Nearly 100% sensitivity and specificity
 Confirm via genetic testing
Prothrombin Gene Mutation
 G to A substitution at nucleotide 20210 in the 3′-untranslated region of
the prothrombin gene
 results in increased prothrombin synthesis in the liver
 In 2% of whites and 3% of southern Europeans, rare in Asian and
African populations
 In 18% of people with DVT and positive family history
 40% of those also hade fVLeiden
 Increased risk (2.8x) of venous thrombosis
 Increased risk with use of OCP
 PCR
 No functional assays or immune assays because of significant overlap
with normal values
Antithrombin III Deficiency
 Autosomal dominant (most important plasma protease inhibitor)
 1/250-1/500 in the general population
 Antithrombin III is a serine protease inhibitor of thrombin (II), VIIa, IXa, Xa, XIa,
and kallikreinin.
 Types:
 Type I – reduced synthesis
 Type II – defective protein
 50% of patients may experience venous thrombotic episodes







(*however this number may be based on old data with high-risk families)
Tend to occur in deep veins of legs, mesenteric veins
42% are spontaneous
60% are recurrent
40% have clinical signs of PE
Onset usually after puberty, increasing risk of thrombosis with advancing age
58% are related to pregnancy, childbirth, OCP, surgery, trauma
 First-degree relatives of symptomatic individuals have 8-10x increased risk of
thrombosis over noncarriers
Antithrombin III Deficiency
 Screening – antithrombin III-heparin cofactor assay
 Measures factor Xa inhibition
 Antithrombin III activity assay
 For type II
 Test interpretation
 Normal range – excludes antithrombin III deficiency
 Low levels – confirm with another sample at a later time when
patient is well, clot-free, and on no medications which may
interfere with antithrombin levels
 Treatment
 1) antithrombin III concentrates (if available) or FFP while on
heparin followed by
 2) oral anticoagulants as per usual.
Acquired Antithrombin III Deficiency
 Transiently reduced concentration of
antithrombin III
 Acute thrombosis
 DIC
 Liver disease
 Nephrotic syndrome
 OCP and HRT use
 Pregnancy-induced hypertension
 Infusions of L-asparaginase
 Heparin
Protein C Deficiency

autosomal dominant

Rare, more severe form is autosomal recessive





7x the risk of a DVT
70% are spontaneous
63% are recurrent
40% get PE
Usually asymptomatic until early 20s

Tends to affect lower extremity and mesenteric veins


0.5-4% of patients with DVT
1 : 16,000 - 1 : 32,000 within the general population

May have a higher incidence with poorer penetrance


Type I – reduced quantity and activity
Type II – reduced activity

Testing


ELISA – quantified
Functional activity assays
Protein C Deficiency
 Warfarin
 Reduces quantity and activity of protein C



Makes diagnosis difficult
Can use a ratio of protein C to prothrombin or factor X, but this only
works if the patient is in a stable phase of anticoagulation
Delay testing until 2 weeks post-anticoagulant therapy, or test while on 2
weeks of bridging heparin
 Warfarin-induced skin necrosis






During first several days of therapy
Due to transient hypercoagulable state – protein C levels are decreased
to 50% of normal within one day
Lesions on extremities, breasts, trunk, penis
Extend over a period of hours from an initial central erythematous
macule
Progress to edema, purpura, and necrosis
Treatment – rapid administration of protein C
Protein S Deficiency
 autosomal dominant

A rarer severe form is autosomal recessive
 10% of all cases of inherited thrombophilia
 1-7% of patients with DVT
 Presentation is similar to antithrombin III and protein C deficiencies
 Venous thrombosis
 Immunosorbent assays measure total Protein S, while functional assays measure free
Protein S


Normally, 60% is complexed to C4b binding protein
Free 40% is active
 Type I – decreased quantity and activity
 Type II – normal quantity but decreased functional activity
 Type III – normal quantity but decreased free protein
Acquired Protein S Deficiency
 Acquired protein S deficiency












Pregnancy
OCP
DIC
Acute thromboembolic disease
Inflammation (C4b binding protein is an acute phase protein)
HIV
Nephrotic syndrome – increased plasma levels bt reduced
functional activity
Liver disease
L-asparaginase chemotherapy
Antiphospholipid antibodies
Warfarin
Newborns
Dysfibrinogenemias
 Autosomal dominant
 Heterogeneous group of disorders
 Defect in cleavage of fibrinopeptides A or B (proteolytic cleavage of fibrinogen to




fibrin by thrombin)
Defect in fibrin molecule itself
Abnormality of binding of thrombin to fibrin, leading to excess circulating
thrombin, leading to thrombosis
Some cause abnormal fibrin polymerization
Resistance to fibrinolysis by plasmin
 Presentation
 Asymptomatic
 Bleeding
 Recurrent venous or arterial thromboembolism
 Investigations
 Prolonged thrombin and reptilase times
 Functional fibrinogen measurements are usually low
 Occasionally may have elevated INR or PTT
Inherited Abnormalities of Fibrinolysis
 Rare
 Many affected persons never experience a
thrombotic event
 May not actually predispose to thrombosis at all
 Heterogeneous
 Abnormal plasminogen
 Plasminogen deficiency
 Defective synthesis or release of tissue-type
plasminogen activator
 Increased plasminogen inhibitor
Factor XII Deficiency
 Involved in blood coagulation in vitro but likely
unimportant in vivo
 Prolonged PTT, but no bleeding disorder
 8-20% incidence of thromboembolism, including
several MIs in young people
 Severe deficiency may predispose to venous thrombosis,
but the association is unclear
Hyperhomocysteinemia
 Sulfur-containing amino acid formed from methionine
 Vitamin B6 and 12 are cofactors in conversions
 Impaired intracellular metabolism allows accumulation in the blood
 Premature atherosclerosis, venous thromboembolism, mental retardation,
ectopic lenses, skeletal abnormalities
 Folic acid, vitamins B6 and B12 can reduce plasma levels
 However do not reduce thrombotic events
 No intervention exists, therefore there is no point in testing
 Acquired hyperhomocysteinemia




Smoking
Elderly
Renal failure
Deficiency of folate, B6, B12
Hypercoagulability in Pregnancy
 Pregnancy
6x increased risk of venous
thromboembolism
 Affect 1% of pregnant women
 Cause 12% of fatalities

 Causes


 Puerperium

6-week period following delivery
Increased risk of thrombosis than in
pregnancy itself
 Increased risk with








Increasing age
C-section
Prolonged immobilization
Obesity
Previous thromboembolism
Coexistant thrombophilia
Pregnancy-induced alteration in
hemostasis – goal is to provide adequate
hemostasis at the time of placental
separation. Coagulation profile returns to
normal 4 weeks post-delivery.


Placenta is rich in tissue factor
Increased procoagulant factors
Decreased free and total Protein S
Decreased fibrinolytic activity




Returns to normal within hours of delivery
Increased platelet activation and increased
platelet turnover
However, 8% have mild thrombocytopenia
Venous stasis in lower extremities
secondary to compression by the uterus

Right iliac artery also compresses the left
iliac vein, resulting in more left-sided DVTs
Trauma to pelvic veins during vaginal
delivery
 Tissue injury during C-section

Oral Contraceptives and Hormone
Replacement Therapy
 OCP
 Increased venous and arterial thrombosis
 Venous – related to dose of estrogen and type of progestin
 Increased risk in women with fVLeiden and with family history of thrombosis
 Unclear if there is an increased risk of MI
 Actual mechanism of prothrombotic activity unclear
 Increases fI, II, VII, VIII, X
 Decreases antithrombin III, protein S
 Acquired APC resistance
 HRT
 2-4x risk of DVT
 Remember that the baseline risk is higher because these patients tend to be older
than those on OCP
 Increased risk if also have fVLeiden
 14x risk of DVT compared to noncarriers with no HRT
 Raloxifene – SERM – also has an associated risk of increased venous
thromboembolic events
Postoperative State
 Depends on type of surgery
 DVT is often asymptomatic
 Need imaging
 Higher rates of thrombosis in







Older age
Previous thromboembolism
Malignancy
Medical illness
Thrombophilia
Long surgical time
Pre or post-op immobilization
 Increased thrombotic risk persists
for several weeks after surgery
 Mechanism
 Exposure of tissue factor from
injured vessels
 Monocytes activated by
inflammatory response
 Post-op


Increased fibrinogen and vWF,
decreased antithrombin III and
protein C
Venous stasis in legs
 In patients over 40 without
thromboprophylaxis, DVT risk is
 20-25% after general or gyne
procedures (1-2% have clinically
significant PE)
 10% after transurethral procedure
 40% for radical prostatectomy
 45-70% after total knee arthroplasty
(fatal PE in 1-3% of total hip
arthroplasty)
Trauma
 Up to 58% of polytrauma patients have lower
extremity DVT
 2-22% have PE
 This is the third most common cause of death in
patients who survive 24h
 Increased risk in





Advanced age
Need for surgery
Blood transfusions
Lower extremity fractures
Spinal cord injury
Air Travel
 Air travel >3000 miles
 Likely secondary to stasis
 Increased risk with other predisposing thrombotic risk
factors
Malignancy
 In up to 11% of cancer patients

High association with pancreas, GI tract, ovary, prostate, and lung tumors
 40% have post-op thromboembolic events

Prophylaxis is very important!
 Cancer may first present with a thrombotic event

One study found malignancy in 22.6% of patients with idiopathic DVT, 6% of patients with
secondary thrombosis, and 11% of patients with PE

High numbers because of aggressive malignancy workup
 Contributing factors in thrombotic tendency







obstruction of blood flow by the tumor
patient immobility
hepatic involvement and dysfunction
Sepsis
advanced age
other comorbid conditions
certain antineoplastic agents


l-asparaginase, mitomycin
thalidomide or lenalidomide in conjunction with high doses of dexamethasone
Malignancy
 DIC – the cardinal coagulopathy associated with
malignancy
 In up to 15% of cancer patients
 Rarely acute – minor bleeding from mucosal or cutaneous surfaces
or extensive life-threatening hemorrhage involving visceral sites.
Labs show increase INR, PTT, thrombin time, and reptilase time,
low fibrinogen, thrombocytopenia, increased fibin degradation
concentration
 usually chronic- often asymptomatic, labs show less pronounced
change in fibrinogen, platelets, d-dimer. Minimal change in INR
and PTT
 DVT
 Trousseau syndrome - migratory superficial phlebitis of
extremities
Nephrotic Syndrome
 excessive kidney glomerular leakage of plasma proteins into the urine
 edema, proteinuria, hypoalbuminemia, and hyperlipidemia
 Renal vein thrombosis occurs in 35%
 Distant thrombosis occurs in 20%
 Arterial thrombosis can be seen in children, resulting in stroke, mesenteric
infarction, limb ischemia
 Variable findings in blood coagulation parameters







Often have low antithrombin III (due to urinary excretion)
Increased Protein C and S
Decreased XII, XI, and X
Elevated XIII, X, VIII, VII, and V characteristically are elevated in these patients
?platelet hyperreactivity
increased whole blood viscosity
abnormal fibrin clot architecture related to hypofibrinolysis
Hemolytic Anemias

Paroxysmal Nocturnal Hemoglobinuria

rare acquired clonal disorder of bone marrow stem cell


Chronic intravascular hemolysis with episodes of gross hemoglobinuria and leukopenia
Thrombocytopenia… yet thrombosis is more common than bleeding



Tends to occur in intraabdominal and cerebral vessels rather than leg and lung
Labs




Increased sensitivity to complement-mediated lysis
Pancytopenia
Increased reticulocyte count
Iron deficiency
Treatment

Acute



Chronic


Oral anticoagulation
Sickle cell disease

Increased blood viscosity contributes to microvascular occlusion


Causes tissue ischemia and infarction
Platelet activation, thrombin generation, fibrinolysis


Heparin or LMWH
Fibrinolytics
Increased large vessel thrombosis
Thalassemia

Increased risk of cerebral thrombosis, deep vein thrombosis, pulmonary embolism, and recurrent arterial
occlusions
Hyperviscosity
 Multiple causes
 Increased plasma viscosity
 hypergammaglobulinemia or hyperfibrinogenemia
 Increased number of red or white blood cells
 Polycythemia vera
 Leukemia
 Decreased deformability of cells
 Sickle cell disease
 Results in stasis and platelet dysfunction, leading
to thrombosis
Drug-Induced Thrombosis
 Chemotherapy
 L-asparaginase – causes deficiencies of pro- and
anticoagulant factors
 cyclophosphamide, methotrexate, and 5-fluorouracil –
may decrease protein C and S levels
 Estrogen therapy for prostate carcinoma
 Tamoxifen
 Thalidomide or lenalidomide

Especially with high-dose dexamethasone
Lupus Anticoagulants and the
Antiphospholipid Syndrome
 Antiphospholipid syndrome (APLS)
 Lupus anticoagulant and anticardiolipin antibodies
 Must be present persistently
 Arterial and/or venous thrombosis
 Bleeding may occur in conjunction with other hypocoagulable states
 Investigate all patients who show recurrent thrombosis
 Associated with SLE, RA, Sjogren’s syndrome
 May develop transiently in response to infections or drugs
 Prolonged aPTT but increased risk of thrombosis in vivo
 Treatment
 Warfarin
Investigating Hypercoagulability
 Routine tests
 For all patients with thrombosis
 INR, aPTT
 CBC
 Peripheral smear




DIC and thrombotic microangiopathies (TTP, HUS) – red cell fragmentation or schistocytes
Tumor – Leukoerythroblastic smear – nucleated RBCs and immature WBCs
LFTs
Urinalysis
 Screen for lupus anticoagulants – periodically re-evaluate, because these are only risk
factors for thrombosis if they are present for several months

Cardiolipin, β2-glycoprotein-I antibodies – elevated in some patients with lupus
anticoagulants
 Idiopathic DVT
 CT chest, abdo, pelvis if other symptoms support malignancy
 Ensure age-appropriate screening tests are done (mammogram, pap smear,
colonoscopy)
Investigating Hypercoagulability
 Tests for Specific Biologic Risk Factors
 Guide based on whether event was arterial or venous
 antithrombin III, protein C, and protein S
 Venous clot
 age <50
 Recurrent thrombosis
 Family history
 factor V Leiden mutation and the prothrombin G20210A mutations
 Venous clot
 Not as strongly associated with increased age, recurrent thrombosis, and family
history as are antithrombin and protein C&S deficiencies
 Lupus anticoagulant – venous or arterial thrombosis
 Test for all biologic risk factors in patients with clots in unusual locations
 Mesenteric vein
 Cerebral veins
Investigating Hypercoagulability
 Factor V Leiden
 Screen – clotting assay using factor V-deficient plasma
 Confirm – genetic test for fV Leiden
 Prothrombin gene mutation
 Genetic test
 Antithrombin III deficiency
 Functional assay (heparin-cofactor assay)
 Protein C deficiency
 Functional assay
 May get false positives if the patient has fVLeiden
 Protein S deficiency
 Functional assay
 May get false positives if the patient has fVLeiden
 Immunological assay
 Dysfibrinogenemia
 Immunologic and functional assays of fibrinogen
 Thrombin time
 Lupus anticoagulant
 Clotting assay
 Serologic tests for antiphospholipid antibodies and cardiolipins
*functional assays detect quantitative and qualitative defects, while serologic assays only
detect quantitative defects
Timing of Laboratory Testing
 Acute thrombosis, comorbid illness, and anticoagulant therapy can result
in false lab results
 Heparin – may get 30% drop in antithrombin III levels
 Warfarin – decreased functional activity of protein C and S; rarely elevates
antithrombin III
 Wait 2 weeks after patient has completed the initial course of oral
anticoagulants following a thrombotic event
 If the patient is at a high risk for recurrent thrombosis, discontinue
warfarin for 2 weeks and bridge with heparin before testing for protein
C and S deficiency
 Consider testing first-degree family members