Hemostasis and Coagulation

Biology of Hemostasis

Vasoconstriction

initial vascular response to injury
local contraction of vascular smooth muscle is a reflex response to various stimuli
local mediators augment vasoconstriction: thromboxane, endothelin, serotonin, bradykinin

Platelet Plug Formation

platelets are 2-μm fragments of megakaryocytes with a lifespan of 7 - 9 days
injury to the intima exposes subendothelial collagen
subendothelial von Willebrand’s factor (VWF) binds to the exposed collagen
the platelet has a receptor for the bound VWF
VWF serves as a bridge between subendothelial tissue and the platelet
receptor binding activates the platelet, resulting in a release reaction (degranulation)
release reaction results in the recruitment of additional platelets (aggregation), mediated primarily by ADP and serotonin
degranulation also releases thromboxane, a potent vasoconstrictor and platelet aggregator
thromboxane is converted from prostaglandin G2 by cyclooxygenase - this step is irreversibly inhibited by aspirin
activated platelets express receptors which bind fibrinogen, which in turn binds other activated platelets together in an aggregate, forming a platelet plug
aggregation of platelets does not occur in the absence of fibrinogen
surface of the activated platelet plug is a major substrate for the intrinsic coagulation cascade

Coagulation Cascade

results in the formation of insoluble fibrin, which stabilizes the platelet plug
consists of a series of stages in which circulating proenzymes are converted in sequence to activated proteases
all the procoagulants, except VWF, are produced by the liver
factors II, VII, IX, and X are vitamin K dependent
without vitamin K, these proteins do not undergo gamma-carboxylation and are thus inactive

Extrinsic Pathway

initiated by tissue lipoprotein (thromboplastin - extrinsic to blood)
factor VII is activated by thromboplastin and Ca++
activated factor VII activates factor X
causes large amounts of clot to be formed in seconds
monitored by the prothrombin time (or INR)

Intrinsic Pathway

initiated by phospholipids intrinsic to blood
requires several minutes to form a clot
factor XII is activated by binding to subendothelial collagen
prekallikrein and high-molecular-weight kininogen amplify this contact phase
activated factor XII activates factor XI
activated factor XI activates factor IX
activated factor IX acts with factor VIII, phospholipids from the injured platelets, and calcium to activate factor X
monitored by the activated partial thromboplastin time (PTT)

Final Common Pathway

activated factor X converts prothrombin to thrombin
this process is accelerated by activated factor V, tissue lipoproteins, platelet surface phospholipids, and Ca++
thrombin cleaves the fibrinogen molecule into fibrin
fibrin polymerizes both side-to-side and end-to-end, resulting in a latticework
cross-linking of fibrin is catalyzed by activated factor XIII

Control of Coagulation

clot must not form beyond the site of injury

Blood Flow

most important control is the continued rapid flow of blood, which carries away thrombin, procoagulants, products of platelet activation

Endothelium

has a negatively charged surface, which repels clotting factors and platelets
if neither factor XII nor platelets are activated, coagulation cannot be initiated
intact endothelium synthesizes prostacyclin, which inhibits platelet aggregation

Circulating Anticoagulants

Anti-thrombin III

when combined with thrombin, blocks the enzymatic activity of thrombin on fibrinogen
neutralizes all the procoagulant proteases
activity is greatly increased by heparin

Protein C

activated by thrombin
reduces thrombin formation by inactivating factors V and VIII
Vitamin K dependent

Protein S

in conjunction with Protein C, activates plasminogen
Vitamin K Dependent

Fibrinolysis

natural process directed at maintaining the patency of blood vessels by lysis of fibrin deposits
dependent on the enzyme plasmin, which is derived from plasminogen
plasminogen is preferentially absorbed onto fibrin deposits, where it is converted to plasmin by thrombin, activated factor XII, and tissue plasminogen activator (tPA)
plasmin breaks down fibrin, as well as many of the clotting factors found in blood
fibrinolysis can be blocked by epsilon-aminocaproic acid or tranexamic acid

Assessment of Hemostasis and Coagulation

History and Physical

most important assessment
questions about past surgical or dental history should detect any prior untoward bleeding
a family history should detect any hereditary defects
review medications for oral anticoagulants, aspirin, NSAIDs
complete medical history should detect liver or renal dysfunction

Platelet Tests

Platelet Count

thrombocytopenia is the most common abnormality of hemostasis in surgical patients
spontaneous bleeding only rarely occurs when the platelet count > 40,000
platelet count > 50,000 is usually adequate for hemostasis after surgery or trauma

Bleeding Time

assesses both the interaction between the platelets and damaged blood vessel and the formation of the platelet plug
will be abnormal in patients with thrombocytopenia, qualitative platelet disorders, von Willebrand’s disease
aspirin taken within one week will affect the results
has largely been replaced by more convenient and standardized tests such as the platelet function analyzer test (PFA-100)

Coagulation Tests

Prothrombin Time (PT)

assesses the functional capacity of the extrinsic system (factor VII) and the final common pathway (factors X and V, prothrombin, fibrinogen)
used to monitor patients on Coumadin, and results are reported as an international normalized ratio (INR)

Partial Thromboplastin Time (PTT)

measures the functional capacity of the intrinsic system (factors XII, XI, IX, VIII) and the final common pathway
useful for identifying hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), hemophilia C (factor XI deficiency)
heparin blocks the intrinsic system and results in a prolonged PTT
also used to monitor the effects of the parenteral direct thrombin inhibitors argatroban, bivalirudin, and lepirudin

Thrombin Time

measures the conversion of fibrinogen to fibrin
very sensitive to heparin and direct thrombin inhibitors

Fibrinogen Assays

sensitive test of fibrinogen function
significantly less affected by the presence of heparin or direct thrombin inhibitors than the thrombin time test

Factor Assays

direct immunoassays for most clotting factors are now available

Tests of Fibrinolysis

D-Dimer Assay

D-dimers are fragments of cross-linked fibrin that are produced by lysis of a fibrin clot
marker of clot formation
sensitive test for the presence of DIC and acute thrombosis

Thromboelastogram (TEG)

global test of platelets, coagulation, and fibrinolytic function
particularly useful for detecting hyperfibrinolysis during liver transplantation and cardiac surgery

Interpretation of TEG

R Value

time it takes for clot formation to start
measures coagulation factor activity
prolonged R value could be treated with FFP

K Value

time from the end of R until the clot reaches 20 mm
clot amplification phase
represents thrombin’s ability to cleave fibrinogen into fibrin
elevated with hypofibrinogenemia

Alpha Angle

assesses rate of clot formation and fibrin crosslinking
dependent on fibrinogen

Maximum Amplitude (MA)

represents the strength of the final clot
dependent on platelets (80%) and fibrin (20%)
will be decreased in patients taking ASA or Plavix

LY30

percent clot lysis at 30 minutes
assesses the fibrinolytic phase

Congenital Hemostatic Defects

Factor VIII Deficiency (Hemophilia A)

Inheritance

disease of males
sex-linked recessive trait that occurs in 1 in 5000 male births
spontaneous mutations occur in 20% of cases

Clinical Manifestations

severity of clinical manifestations is related to the degree of deficiency of factor VIII
spontaneous bleeding is rare if the patient has 5% of normal factor VIII activity
spontaneous joint and soft tissue bleeding are the rule if the patient has < 1% factor VIII activity
patients will have a prolonged PTT
diagnosis is confirmed with a factor VIII assay

Replacement Therapy

recombinant (preferred) or plasma-derived factor VIII concentrates are the primary treatment
half-life of factor VIII is 8 to 12 hours
for major surgery, levels of 80 to 100 percent should be obtained preoperatively and maintained for 3 days
levels should be maintained > 50% for the next 10 - 14 days
in mild hemophiliacs, DDAVP increases factor VIII activity and can be used in patients undergoing minor surgery

Factor IX Deficiency (Hemophilia B)

clinically indistinguishable from factor VIII deficiency
X-linked recessive mode of inheritance
diagnosis is made with factor IX assay
like factor VIII deficiency, factor IX deficiency can occur in mild, moderate, and severe forms according to the level of factor IX activity in the blood
patients have a prolonged PTT
replacement therapy is with factor IX concentrates
duration of therapy is similar to patients with factor VIII deficiency

von Willebrand’s Disease

autosomal dominant transmission
most common congenital bleeding disorder
vWF is required for platelet binding to subendothelial collagen
clinically, mucosal bleeding (epistaxis, gum bleeding, menorrhagia) predominates
diagnosis is made by the von Willebrand antigen assay
most patients with mild disease (types I and II) can be treated with DDAVP, which causes release of preformed stores of von Willebrand factor
patients with severe disease (type III) should be treated with von Willebrand-containing factor VIII concentrates
cryoprecipitate should be avoided because of its risk of disease transmission
aspirin must be avoided 10 days before an elective procedure

Congenital Platelet Disorders

Glanzmann Thrombasthenia

autosomal recessive disorder
platelet glycoprotein complex (IIb/IIIa) is missing or dysfunctional
normal platelet count
results in poor platelet aggregation and mucocutaneous bleeding
treatment is with platelet transfusions

Bernard-Soulier Syndrome

autosomal recessive deficiency in glycoprotein (GP) Ib, resulting in a defect in the vWF receptor
prevents platelet linking to collagen
treatment is with platelet transfusions

Factor V Leiden

most common inherited thrombophilia or hypercoagulable disorder
autosomal dominant mutation of factor V impairing cleavage by protein C
most common clinical manifestation is VTE and treatment is anticoagulation

Acquired Hemostatic Defects

Platelet Abnormalities

Thrombocytopenia

most common abnormality of hemostasis that results in bleeding in a surgical patient
results from a variety of disease processes:

ITP, TTP, lupus
hypersplenism (splenomegaly, portal hypertension)
chemotherapy
massive transfusions
drugs (heparin, histamine blockers)
viral infection

for an elective operation, a platelet count > 50,000 requires no specific therapy
one unit of platelets will raise the platelet count by 10,000

Impaired Platelet Function

Anti-platelet Drugs

aspirin, clopidogrel (Plavix), and prasugrel (Effient) all irreversibly inhibit platelet function
if possible, the drug should be stopped 5 – 7 days before an elective procedure
in emergency cases, platelet transfusions may be necessary

Uremia

the platelet dysfunction of chronic kidney disease can often be corrected by dialysis or the administration of DDAVP

Acquired Hypofibrinogenemia

Disseminated Intravascular Coagulation (DIC)

caused by the introduction of thromboplastic materials into the circulation, resulting in excessive thrombin generation and diffuse formation of microthrombi
end result is the formation of diffuse microthrombi with consumption of platelets, coagulation factors, and fibrinogen
diffuse hemorrhage usually dominates the clinical picture
many disease processes may activate the coagulation system: sepsis, trauma, burns, obstetric disasters, snakebites
diagnosed by the appropriate clinical setting and lab values (↑ PT, ↑PTT, ↓ platelets, ↓ fibrinogen, ↑ fibrin split products, ↑ D-dimer)
treatment is directed at the causative medical or surgical problem
also important to maintain capillary flow with IV fluids
if there is active bleeding, hemostatic factors should be replaced with fresh frozen plasma and cryoprecipitate
most studies show that heparin is not helpful in acute forms of DIC

Fibrinolysis

results from release of excessive plasminogen activator
prostate operations can cause the release of urokinase into the circulation
also seen in patients on extracorporeal bypass
treatment is with epsilon-aminocaproic acid (Amicar), which interferes with fibrinolysis by inhibiting plasminogen activation

Liver Failure

hepatic failure is associated with coagulopathy since nearly all the clotting factors are synthesized in the liver
cirrhosis is also associated with thrombocytopenia (hypersplenism)
FFP and cryoprecipitate are the mainstays of treatment for liver coagulopathy
platelet transfusions will often be necessary before invasive procedures, but their effect is only for several hours
proteins C and S, as well as anti-thrombin III, are also made in the liver and may account for a hypercoagulable state in failing livers

Hypercoagulable Disorders

Heparin Induced Thrombocytopenia (HIT)

heparin-associated antiplatelet antibodies develop after exposure to heparin products
clinically, can result in venous or arterial thromboembolism
suspect if platelets <50,000 or decreased >50% and confirm with ELISA or serotonin release assay (SRA)
treatment is to discontinue all heparin products and start a direct thrombin inhibitor

Antiphospholipid Antibody Syndrome

venous or arterial thromboembolism associated with laboratory evidence of antiphospholipid antibodies (anticardiolipin or anti-beta 2 glycoprotein I antibodies)
can occur as a primary condition or associated with autoimmune disease or pregnancy
may present with a prolonged PTT or thrombocytopenia
treatment is anticoagulation

Antithrombin III Deficiency

can be acquired or congenital
associated with increased risk of VTE
diagnosed with decreased levels of ATIII on laboratory evaluation
VTE cannot be treated with heparin; use a direct thrombin inhibitor, warfarin, or direct oral anticoagulant

Antiplatelet Drugs

Aspirin

irreversible inhibitor
long duration of action (7 days)
can be safely continued in low-risk patients

Clopidogrel (Plavix)

most common use is in prevention of coronary or vascular stent thrombosis
often used along with low-dose aspirin (81 mg)
elective surgery should be delayed for at least the minimum recommended duration for each stent type
if emergent surgery is required, 24-hour interventional cardiology should be available
if the risk of bleeding is high, Plavix should be stopped 5 – 7 days before surgery
low-dose aspirin can often be continued
should be resumed as early as possible in the post-op period

Anticoagulant Drugs

Heparin (Unfractionated)

naturally occurring glucosaminoglycan
forms a complex with anti-thrombin III, which inactivates thrombin as well as factors XII, IX, X, XI
half-life is about 1 hour
best monitored by the PTT
clinical situations associated with bleeding include cardiac bypass surgery, hemodialysis, and patients being treated for PE or DVT
effects may be reversed by protamine: 1 milligram of protamine neutralizes 100 units of heparin
continuous infusion technique reduces the risk of spontaneous bleeding
can be given SQ for DVT prophylaxis
thrombocytopenia can be a limiting factor (HIT)

Low Molecular Weight Heparin (LMWH)

Lovenox (enoxaparin), Fragmin (daleparin)
binds to and activates antithrombin III
inhibits factor Xa, but not thrombin
may be used prophylactically or therapeutically
clinical bleeding usually occurs in patients being treated for DVT or PE who develop worsening renal function
can’t be monitored by the PTT
protamine reverses a variable amount of LMWH activity (Lovenox 54%)
causes less HIT than heparin
SQ use only

Fondaparinux (Arixtra)

IV agent
indirect inhibitor of Xa; does not inhibit thrombin
used in acute coronary syndromes and the treatment of VTE
no lab monitoring available

Warfarin (Coumadin)

is used for chronic anticoagulation (atrial fibrillation, mechanical cardiac valves, VTE)
inhibits the activation of the vitamin K-dependent factors (II, VII, IX, X)
numerous drug – drug interactions and variable bioavailability makes dosing difficult and unpredictable
factor VII function is the most sensitive indicator of the warfarin effect, since it has the shortest half-life (2 - 4 hrs)
monitored by the prothrombin time/INR
protein C and protein S are also vitamin K-dependent anticoagulants
if these proteins are affected to a greater degree than the clotting factors, then a hypercoagulable state can arise
rapid reversal can be achieved with IV vitamin K and prothrombin complex concentrate
FFP reversal is slow and requires large volumes
oral vitamin K will reverse Coumadin within 24 hours

Direct Factor Xa Inhibitors

bind directly to factor Xa, rather than enhancing the activity of antithrombin, as is done by heparin
only oral agents are available
most common indication is for stroke prevention in patients with atrial fibrillation
other uses include treatment of venous thromboembolism, ischemic heart disease, and heparin-induced thrombocytopenia
contraindicated in patients with prosthetic heart valves, severe kidney or liver disease, or pregnancy
very predictable bioavailability, so lab monitoring of drug levels is not required
most agents have a half-life of 12 hours, but this may be prolonged in older patients
rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban are the most common agents in use
andexanet alfa is now available as a reversal agent

Direct Thrombin Inhibitors

prevent thrombin from converting fibrinogen to fibrin

IV Agents

bivalirudin, argatroban
short half-lives
may be monitored by the PTT
primarily used in patients undergoing percutaneous coronary interventions
may also be used in patients with heparin-induced thrombocytopenia
no reversal agents available

Dabigatran (Pradaxa)

oral agent
used in stroke prevention in patients with atrial fibrillation, in prevention and management of VTE, and in ischemic heart disease
half-life of 12 - 17 hours
no routine laboratory monitoring is necessary
renally excreted, so dialysis can be used in cases of life-threatening bleeding
Idarucizumab is available as a reversal agent

Thrombolytics

activate plasminogen to facilitate clot breakdown
tPA (tissue plasminogen activator) is most commonly used, but streptokinase and urokinase are also available
keep fibrinogen level > 100 mg/dL to minimize risk of bleeding

Perioperative Management of Patients Receiving Anticoagulants

a balance between reducing the risk of thromboembolism and preventing excessive bleeding must be reached for each patient

Estimating Thromboembolic Risk

conditions that increase thromboembolic risk include atrial fibrillation, prosthetic heart valves, recent venous or arterial thromboembolism, coronary artery disease, and stroke
clinician must estimate the risk of a thromboembolic event occurring if the antithrombotic agent is discontinued perioperatively
mortality rate for mechanical heart valve thrombosis is 17.5%, and for ischemic stroke, 37%
mortality from major bleeding while on antithrombotic agents is ~ 6% - 10%

Nonvalvular Atrial Fibrillation

most common indication for chronic anticoagulation
individual patient risk factors determine thromboembolic risk
important risk factors include congestive heart failure, hypertension, age ≥ 75, diabetes, previous stroke/TIA
points can be assigned to risk factors to calculate an overall thrombotic risk score (CHADS₂)
low risk patients have a < 5% annual risk of VTE while on anticoagulation; moderate risk patients have a 5% - 10% annual risk; and high risk patients have > 10% annual risk
the VTE risk can be used to determine whether heparin bridging is indicated preoperatively

Prosthetic Heart Valves

Mechanical Valves

patients with bileaflet aortic valves without previous stroke or atrial fibrillation have a low annual risk of thromboembolism (< 5%) while anticoagulated
aortic valve patients with atrial fibrillation have moderate risk (5% - 10%)
high risk factors (> 10% annual risk) include patients with mitral valve prostheses, caged-ball or tilting-disk aortic valves, or previous thromboembolic events

Bioprosthetic Valves

porcine or bovine valves do not require long-term anticoagulation (3 – 6 months)
all percutaneous aortic valves are bioprosthetic
elective operations should be delayed for 3 – 6 months after implantation
for emergent operations in the 3 – 6 month window, coumadin can be stopped without any heparin bridging

Venous Thromboembolism

thromboembolism within 3 months is a high risk factor for recurrent thromboembolism if anticoagulation is stopped
after 3 months of anticoagulation, the annual risk of recurrent VTE is 15%
elective surgery should be deferred for at least 3 months after a VTE
additional risk factors such as cancer or inherited thrombophilias will also need to be considered

Coronary Artery Disease

dual antiplatelet therapy is prescribed after coronary stent placement, and discontinuation is a strong risk factor for stent thrombosis
elective surgery should be delayed for > 14 days after balloon angioplasty, 30 days after bare-metal stent placement, and 1 year after drug-eluting stent placement
for emergency procedures, the cardiologist should be involved in risk/benefit decisions regarding stopping the antiplatelet medications

Stroke

low-dose aspirin and/or Plavix is recommended for the treatment of acute stroke and secondary prevention after ischemic stroke or TIA
stroke patients also have an increased risk for cardiovascular complications
the elevated risk for cardiac complications plateaus at 9 months after an ischemic stroke; therefore, elective surgery should be deferred for at least 9 months, if possible

Estimating Procedure Bleeding Risk

bleeding risk is determined based on the invasiveness of the procedure and the sequelae of bleeding if it occurs
spinal anesthesia, cardiac, vascular, and intracranial procedures are especially risky
low risk procedures (skin surgery, hernias, elective cholecystectomy) do not usually require discontinuation of antithrombotic agents
patient comorbidities (liver, kidney disease) may also contribute to bleeding risk
the surgeon is responsible for assessing bleeding risk based on the patients individual anatomy, pathology, risk factors, and their own experience with the procedure

Deciding Whether to Interrupt Anticoagulation

decisions must be made on a case by case basis – no scoring system can substitute for clinical judgement
in general, if surgical bleeding risk is high, anticoagulants must be discontinued
the period off anticoagulation should be as short as possible
in lower risk cases, anticoagulants should usually be continued

Timing of Anticoagulant Interruption

Coumadin

discontinue 5 days before surgery
check INR on the day before surgery
surgery when INR < 1.5
low dose vitamin K may be necessary
high risk patients (recent stroke, mechanical valve) may require a bridging agent started 3 days before surgery
Coumadin can usually be resumed 12 – 24 hours after surgery
it takes 5 – 10 days to get INR > 2.0, so a heparin bridging agent may be required

Direct Oral Anticoagulants (DOACs)

Dabigatran (Pradaxa), Apixaban (Eliquis), Rivaroxaban (Xarelto)
for minimal bleeding risk, discontinue on the day of surgery only
for low/moderate bleeding risk, discontinue the day before surgery and restart the day after surgery
for high bleeding risk, discontinue 2 days before surgery and restart 2 days after surgery
if the GI tract is unavailable post-surgery, bridging with LMWH is necessary

Bridging Anticoagulation

requires using a short-acting agent (LMWH) during the interruption of a long-acting agent (Coumadin or DOACs)
intent is to minimize the time the patient is not anticoagulated
can cause increased risk of bleeding
bridging can be used pre-op, post-op, or both
indications for bridging include:

embolic stroke or arterial embolus within previous 12 weeks
mechanical mitral valve, mechanical aortic valve and additional stroke risk factors
atrial fibrillation and high risk of stroke
venous thromboembolism within the last 12 weeks
recent coronary stenting

LMWH is discontinued 24 hours before surgery; IV heparin is discontinued several hours before surgery
post-op bridging is restarted once hemostasis is assured
resumption of bridging too soon can result in increased risk of major bleeding
Coumadin is generally restarted on the same day as the heparin

Hemostasis and Coagulation

Biology of Hemostasis

Control of Coagulation

Assessment of Hemostasis and Coagulation

Congenital Hemostatic Defects

Acquired Hemostatic Defects

Antiplatelet Drugs

Anticoagulant Drugs

Perioperative Management of Patients Receiving Anticoagulants

References