Philip C. Hoffman, M.D.

Wed, Nov 15th 2017

I. Hypercoagulable States
Composed of inherited and acquired risk factors for thrombosis that have been identified and
associated with venous or arterial thromboembolism

A. Acquired
1. Related to Stasis
a) Immobilization. Venous stasis associated with bed rest or prolonged immobilization
(congestive heart failure, stroke, myocardial infarction, leg injury, prolonged sitting) is
an important risk factor for venous thrombosis
b) Hyperviscosity. Can be related to increased plasma viscosity (hypergammaglobinemia),
increased number of red or white cells (polycythemia, myeloid leukemia) or decreased
deformability of cells (sickle cell disease)

2. Related to blood activation

a) Major surgery/trauma. Orthopedic surgery on the hip and knee, major abdominal or
pelvic surgery (e.g., gynecological or prostate) can significantly increase the risk of
thrombosis. The risk of thrombosis also increases to 50-60% in patients in major
trauma: head, spinal injury, pelvic fracture, femoral fracture and tibial fracture.
b) Malignancy. Venous thrombosis occurs often in cancer patients. The result of multiple
factors may contribute to thrombogenesis including: direct production of procoagulants
by the tumor, low-grade DIC, venous obstruction by the tumor itself, and indirect
consequences of being ill or the effect of treatments like surgery or chemotherapy.
(i) Pregnancy and puerperium. 1 in 2000 women will develop thrombosis
during pregnancy. This risk may be higher in the puerperium (six-week
period following delivery.) Pregnancy is associated with a six-fold increase
in thrombosis. Causative factors include hormonal influences, stasis from
uterine compression of IVC.
c) Antiphospholipid antibody syndrome (APLS)
(i) The antiphospholipid syndrome is characterized by vascular thrombosis
(arterial or venous), and/or pregnancy morbidity in association with medium
to high titers of antibodies against phospholipids or phospholipid-binding
cofactors in the blood
(ii) Clinical manifestations include venous or arterial thrombosis, recurrent fetal
loss, thrombocytopenia, or livedo reticularis. May occur in patients with
systemic lupus erythematosus, but also in patients with cancer, infections,
and certain drugs. Commonly idiopathic, as well.
d) Oral contraceptives. Likely increase the risk of thrombosis is 4-fold. This is particularly
an issue in older women and smokers. This risk is significantly increased in carriers of
Factor V- Leiden mutations or women with a family history of thrombosis.
e) Postmenopausal estrogen replacement therapy. Also associated with a 4- to 8 fold risk
of thrombosis. Carriers of Factor V Leiden taking estrogen replacement therapy are at
significantly increased risk of VTE.
f) Nephrotic syndrome. There is an increased risk of both arterial and venous
thromboemboli. The mechanism may be decreased levels of plasma antithrombin due to
urinary excretion, platelet hyperactivity or increased blood viscosity may contribute.

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Philip C. Hoffman, M.D.
Wed, Nov 15th 2017

g) Age. Increases the risk of thrombosis.

h) Hyperhomocysteinemia. May be both an acquired and inherited state.
(i) Acquired-- Associated with nutritional deficiencies: cobalamin, folate,
pyridoxine. Currently replacement with these vitamins are recommended,
although it is unknown if lowering homocysteine levels reduces the risk of
thrombosis
(ii) Inherited—homozygous deficiency of cystathione beta-synthase causes high
levels of plasma homocysteine, atherosclerosis, arterial disease and venous
thrombosis at a young age.
(iii) Contributes to both venous and arterial thrombosis and atherosclerosis.
j) Congestive heart failure, especially right-sided
k) Myeloproliferative disorders—p.vera, essential thrombocythemia

B. Inherited
1. Antithrombin (AT III) deficiency
a) Inherited in autosomal dominant fashion. Antithrombin primarily inactivates thrombin,
as well as factor Xa and factor IXa. It is a heparin cofactor.
b) Prevalence. Frequency is estimated as high as 0.5-1% in pts with venous
thromboembolism; particular risk during pregnancy

2. Protein C deficiency
a) Protein C is a Vitamin K-dependent anticoagulant protein produced by the liver.
Inherited autosomal dominant trait in heterozygotes, with a prevalence in the population
of 1 in 200-500. Protein C becomes activated to aPC.
b) Pathogenesis: the primary effect of aPC is to inactivate coagulation factors Va and
VIIIa, which are necessary for efficient thrombin generation and factor X activation.
The inhibitory effect of aPC is markedly enhanced by protein S, another vitamin K-
dependent protein.
(i) Homozygous deficiency--Purpura fulminans in neonates causing severe
clotting throughout the body leading to death
(ii) Heterozygous deficiency—more commonly seen
(a) Type I: Results from an inadequate amount of protein C.
The protein C that is present is functional
(b) Type II: Results from functionally defective protein C molecules.
The antigenic amount of protein C present is normal.
(iii) Warfarin-induced skin necrosis. This is associated with heterozygous
protein C deficiency that can occur during the first several days of warfarin
therapy, particularly with high doses of the medication. Necrotizing skin
lesions can occur in the extremities, breasts, and trunk. Initiation of
warfarin can cause protein C (vitamin K-dependent anticoagulant) to
decrease to low levels before there is reduction of the vitamin K-dependent
procoagulants (II, VII, IX, X). This produces a transient hypercoagulable
state. This is prevented by giving warfarin slowly, and maintaining heparin
therapy for several days of overlap during transition to warfarin.

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Philip C. Hoffman, M.D.
Wed, Nov 15th 2017

3. Protein S deficiency
a) Protein S is another Vitamin K-dependent protein produced by the liver, which serves
as a cofactor for the action of protein C. Inherited as autosomal dominant trait in
heterozygotes. It confers a similar risk of thrombosis as protein C deficiency.
b) Protein S deficiency may also be acquired, in pregnancy, with oral contraceptive use,
and in patients with HIV infection.

4. Factor V Leiden mutation

a) Mutation at one of the cleavage sites in Factor V gene located on chromosome 1. Leads
to resistance to activated protein C. Accounts for 40-50% of cases of inherited
thrombophilia
b) Prevalence: This is the most common genetic defect predisposing to thrombosis among
Caucasians, with a prevalence of 5% with regional variation. The prevalence is highest
in Greece, Sweden, and Lebanon where it approximates 15 percent in some areas. The
mutation is apparently not present in African blacks, Chinese, or Japanese populations.
The mutation increases the risk of venous thrombosis in heterozygous carriers by 3- to
8-fold and 50- to 80-fold in homozygous carriers.

5. Prothrombin 20210 gene mutation

a) Prevalence. The prevalence of this mutation is found in 3% of Caucasians with regional
variation. There is a 3-fold risk of thrombosis with this mutation. Thought to be
mediated by elevated prothrombin levels.
b) Pathogenesis. Transposition (guanine to adenine) at nucleotide 20210 in the 3'
untranslated region of the prothrombin gene is associated with increased prothrombin
levels and increased risk of thrombosis. Increased risk of deep vein and cerebral venous
thrombosis

C. Hints about the workup

1. Is it venous or arterial?
a) Arterial clotting has a much shorter differential (e.g., platelet excess,
myeloproliferative disorders, hyperhomocysteinemia, antiphospholipid syndrome)
b) Factor V-L, Prothrombin gene mutation, AT III, and Protein C and S are all risk
factors for venous thromboembolism

2. Clues to an inherited prothrombotic state

a) young age
b) recurrent episodes
c) unusual locations of thrombosis (mesenteric, cerebral sinus)
d) family history

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Philip C. Hoffman, M.D.
Wed, Nov 15th 2017

II. Principles of Anticoagulation

A. Medications used in the prophylaxis and treatment of both arterial or venous thrombosis
1. Unfractionated Heparin (UFH)
a) Binds to antithrombin and alters the conformation of antithrombin and accelerating
inhibition of thrombin and factor Xa. Thrombin that is bound to fibrin is resistant to
inhibition by heparin-antithrombin complexes, which is why larger doses of heparin are
needed to prevent extension of pre-existent thrombosis compared with smaller doses
used in prophylaxis
b) Pharmakokinetics of heparin can be complex for multiple reasons. Therefore, close
laboratory monitoring is necessary
(i) heparin binds to platelets and other cells (macrophages, endothelial cells)
avidly and residual heparin clears slowly thru the kidneys
(ii) UFH consists of a mixture of glycosaminoglycans ranging widely in molecular
weights (5,000-30,000). This high molecular weight heparin is cleared faster
than low molecular weight heparin
c) Acute treatment of VTE. Heparin is given intravenously by continuous infusion after
an initial bolus, using weight-adjusted dosing.
(i) Typical weight nomogram: 80U/kg bolus followed by an infusion of
18U/kg/hour
(ii) heparin dose is adjusted every 6 hours to maintain the aPTT in a therapeutic
range of 1.5-2.5 x baseline
d) The main complication of heparin is bleeding. Bleeding can occur either when the aPTT
is in the desired therapeutic range (if there is a nidus for bleeding), or if the aPTT is
supratherapeutic.
e) The most feared complication of heparin is heparin-induced thrombocytopenia (HIT), a
severe immune-mediated drug reaction that can occur in any patient exposed to heparin.
It is a potentially devastating prothrombotic disease caused by heparin-dependent
antibodies that develop after a patient has been on heparin. Platelets are activated,
leading to thromboses, both venous and arterial. It is more common in surgical patients,
especially those undergoing cardiovascular surgery; women; and patients receiving
UFH.
f) Osteoporosis is another, though uncommon complication of heparin, particularly in
pregnancy.
g) Heparin is the drug of choice in pregnant women for treatment or prophylaxis for
thrombosis because it does not cross the placenta
For bleeding emergencies requiring rapid neutralization of heparin, protamine sulfate is
available, though it is uncommonly used. If minor bleeding occurs, stopping heparin is
usually sufficient, as the half-life of the drug is so short (1-1.5 hours)
h) Despite the need for careful monitoring and the risk of HIT, unfractionated heparin still
has many advantages, particularly its flexibility in patients in hospital undergoing
procedures, etc.

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Philip C. Hoffman, M.D.
Wed, Nov 15th 2017

2. Low molecular weight heparins-LMWH (enoxaparin, dalteparin, tinzaparin)

a) These fractionated heparins have a low molecular weight (4,000-8,000), bind to ATIII
and inhibit specifically FXa to a greater extent than thrombin. They do not bind to
plasma proteins so they have a more predictable and consistent anticoagulant response.
Therefore, they do not require laboratory monitoring. Dosing for treatment of VTE is
weight-based, and fixed for VTE prophylaxis.
b) If monitoring is necessary, such as in patients with renal insufficiency or major obesity,
anti-factor Xa levels (“LMWH level”) should be measured, as LMWH has no
significant effect on the aPTT. The therapeutic range is between 0.5 to 1.2 units/mL
when measured 3 to 4 hours after administration of drug.
c) LMWH is administered subcutaneously once or twice daily in a fixed dose because of a
long biologic half life of 4 to 6 hours after injection; they are cleared almost exclusively
by the kidneys and should be avoided in renal failure
d) Complications are similar to those of unfractionated heparin, including risk of bleeding,
HIT, and osteoporosis. The risk of developing HIT is much less with LMWH than with
UFH, but there is cross-reactivity with LMWH and antibodies from HIT; therefore,
LMWH is not a suitable alternative to heparin if HIT develops.
e) Treatment of choice in pregnant patients requiring anticoagulation—has the advantage
of outpatient convenience.
f) Protamine sulfate incompletely neutralizes LMWH and therefore is not generally used
to reverse its anticoagulant effects. Thus, LMWH is not as flexible as UFH.

3. Warfarin (Coumadin®)
a) Oral anticoagulant that acts as a vitamin K antagonist, reducing the functional activity
of vitamin K-dependent proteins (Factors II, VII, IX and X, and Proteins C and S). The
effect is mediated through inhibition of the vitamin K-dependent gamma-carboxylation
of coagulation factors II, VII, IX, and X. This results in the synthesis of
immunologically detectable but biologically inactive forms of these coagulation
proteins.
b) Warfarin is rapidly absorbed by the GI tract and reaches peak blood levels in 90
minutes and half-life of 36-42 hours.
c) Warfarin circulates and binds to albumin, and only 3% of warfarin is in free form and
biologically active. It accumulates in the liver where it is metabolized into an inactive
metabolite.
d) Many drugs affect the response to warfarin in the body, by interfering with binding to
albumin, or by affecting the absorption of vitamin K (e.g., effect of antibiotics on gut
flora)

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Philip C. Hoffman, M.D.
Wed, Nov 15th 2017

e) Dose-response to warfarin depends on pharmacokinetics (difference in absorption or

metabolic clearance), pharmacodynamics (differences in hemostatic response to given
doses of warfarin), and technical factors: lab errors, poor compliance, poor
communication between care giver and patient. There is increasing evidence that
genetic polymorphisms affect dose-response to warfarin, and analysis of these can help
predict a patient’s required dose
f) Prothrombin (i.e., Factor II) half-life is 72 hours and thus anticoagulation with warfarin
takes at least 3 days. Lowering factor VII, the vitamin-K dependent factor with the
shortest half life, will raise the INR quickly (since the INR is so dependent on Factor
VII) but the patient is not truly anticoagulated until all the factors are reduced, at least 3
days.
g) Prothrombin time (PT) is the test to monitor warfarin therapy, standardized and reported
as PT/INR (International Normalized Ratio)
INR= (Patient PT/Mean normal PT)ISI
The ISI (International Sensitivity Index) is the adjustment for the particular
thromboplastin reagent used in the laboratory
h) Warfarin is started within 24 hours of starting heparin or LMWH, and overlap with
heparin for 3-5 days is needed until full antithrombotic effect of warfarin is achieved
i) The usual starting dose of warfarin is 5 mg. The dose is then titrated to a goal INR
which is usually 2-3 for VTE. Because of the narrow therapeutic window, frequent
monitoring is needed. After stabilization of INR, monitoring should still continue every
2 to 4 weeks. Any new medication or a change in diet requires closer monitoring.
Patients should not be advised to avoid vitamin-K containing foods; rather, they should
be advised to be consistent in their diet, and allow the physician to adjust the dose
around the diet.
j) The most common complication of warfarin is bleeding, which is higher in older
patients
k) Warfarin is a vitamin K antagonist. Therefore, vitamin K is an antidote, though it takes
24-36 hours for it to fully reverse the PT/INR. In emergencies, fresh frozen plasma
(FFP), prothrombin complex concentrate (PCC, Proplex®) or recombinant Factor VII
(Novo-Seven®) can reverse the effect and halt bleeding.
l) Warfarin can cross the placenta and can cause fetal abnormalities especially when taken
during the first trimester of pregnancy. In later pregnancy, maternal bleeding
complications are of concern. Therefore it should be avoided during pregnancy.
m) A rare complication is warfarin skin necrosis, which can be seen in patients with protein
S or C deficiency in the first few days of warfarin therapy. The vitamin-K dependent
anti-coagulants (protein C and protein S) fall quicker than the pro-coagulants (Factors
II, VII, IX, X), so if heparin overlap is not continued during the first days of warfarin
initiation, thrombosis can occur.

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Philip C. Hoffman, M.D.
Wed, Nov 15th 2017

4. Direct Thrombin inhibitors (argatroban, bivalirudin, dabigatran)

a) Class of drugs that bind to the active site of thrombin. These can be administered
intravenously.
b) Advantages over heparin include:
(i) Do not bind to PF4 released from activated platelets
(ii) Can inactivate thrombin bound to fibrin, unlike heparin
(iii) Heparin induced thrombosis will not occur
c) Can be used to anticoagulate patients with HIT. Argatroban is monitored using the
PTT, similar to what is done with UFH. Argatroban can be used in patients with renal
insufficiency, but may require dose reduction with liver disease.
d) Dabigatran (Pradaxa) is an oral DTI approved for prevention of stroke in non-valvular
atrial fibrillation, and treatment of DVT/PE.
e) Except for dabigatran, for which idarucizumab was just approved as an antidote, the
direct thrombin inhibitors have no antidote (analogous to protamine for heparin).
Hence, careful calculation of dose is essential, and starting low and gradually working
up is prudent.

5. Factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban)

a) Fondaparinux (Arixtra)—subcutaneously administered medication; indicated for
prevention of venous thromboembolism in orthopedic or abdominal surgery; treatment
of DVT or pulmonary embolism. It carries a very low risk of platelet activation, so has
also been used as alternative anticoagulant in patients with HIT
b) Rivaroxaban (Xarelto)—oral inhibitor indicated for postoperative thromboprophylaxis
in patients who have undergone hip or knee replacement surgery; prevention of stroke
and systemic embolism in patients with nonvalvular atrial fibrillation; treatment of
DVT/PE; reduction in the risk of recurrence of DVT and pulmonary embolism
following initial 6 months of treatment for DVT and/or pulmonary embolism.
c) Apixaban (Eliquis)—oral inhibitor, same indications as rivaroxaban.
d) Edoxaban (Savaysa)—oral inhibitor, same indications as rivaroxaban, after initial
parenteral anticoagulation.

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