H em a to l o g ic D ise a ses a nd N eop l a sms ● 349

CLINICAL PEARL 9-4

Secondary Hypercoagulable States or Risk Factors
• Malignancy (especially pancreas, GI, lung, and ovaries)
• Antiphospholipid antibody syndrome—the lupus anticoagulant
• Pregnancy—up to 2 months postpartum
• Immobilization, causing stasis of blood
• Myeloproliferative disorders
• Oral contraceptives
• Postoperative state (especially after orthopedic procedures)
• Trauma
• Nephrotic syndrome
• HIT or DIC
• PNH
• Heart failure—causes stasis of blood

b. Protein C is an inhibitor of factors V and VIII, so a deficiency leads to unregu-

lated fibrin synthesis
4. Protein S deficiency—protein S is a cofactor of protein C, so a deficiency leads to

5.
decreased protein C activity
Factor V Leiden (activated protein C resistance) Quick HIT

Hematologic Diseases and Neoplasms

a. A mutation in factor V gene In many cases, inherited
b. Most common hereditary hypercoagulability disorder among Caucasians hypercoagulable diseases
c. Protein C can no longer inactivate factor V, leading to unregulated prothrombin cause thrombotic events
when other risk factors
activation, and thus an increase in thrombotic events
(e.g., immobilization, preg-
6. Prothrombin gene mutation nancy) are also present.
7. Hyperhomocysteinemia

B. Clinical features
1. Venous thromboembolisms (DVT and PE) are the most common sequelae. Such
hypercoagulable disorders are usually not diagnosed until the patient has had sev- Quick HIT
eral episodes of DVT or PE (see Clinical Pearl 9-4). • Check for any second-
2. Suspect an inherited hypercoagulable state if one or more of the following are ary hypercoagulable
present: states or risk factors (see
a. The patient has a family history of DVT, PE, or thrombotic events. Clinical Pearl 9-4) in any
b. The patient has recurrent episodes of DVT, PE, or thrombotic events. patient with a DVT, PE,
or any thrombotic event,
c. The patient’s first thrombotic event was before age 40. especially if recurrent.
d. The patient experiences thrombosis in unusual sites (e.g., in mesenteric veins, Once these are ruled out,
inferior vena cava, renal veins, or cerebral veins). search for an inherited
hypercoagulable state.
C. Diagnosis: Functional assays are available for AT, antiphospholipid antibodies, • It is very important to
protein C, protein S, factor V Leiden, prothrombin gene mutation, and identify the patient with
an inherited hyperco-
hyperhomocysteinemia.
agulable state because
prophylactic anticoagula-
D. Treatment tion should be started
1. Standard treatment for DVT or PE as in patients without primary hypercoagulable and genetic counseling
states. may be appropriate.
2. Patients with any of these disorders who have had two or more thromboembolic
events should be permanently anticoagulated with warfarin.

Anticoagulation
Heparin
A. Mechanism of action
1. Potentiates the action of AT to primarily inhibit clotting factors IIa and Xa
2. Prolongs PTT
 350 ● STEP-UP TO MEDICINE

3. Half-life of standard heparin is 1 hour. It is longer for LMWHs (longer than 3

Quick HIT hours and up to 24 hours, depending on the product)
Options for DVT prophylaxis B. Indications for use
• LMWH
• Low-dose unfractionated 1. Venous thromboembolism: DVT, PE
heparin 2. Acute coronary syndromes: unstable angina, myocardial infarction
• Pneumatic compression 3. Low-dose standard heparin or LMWH for DVT prophylaxis
boots 4. Atrial fibrillation in acute setting
5. After vascular bypass grafting

C. Administration
1. Standard heparin
a. A therapeutic dose is usually given intravenously, initiated with a bolus of 70 to
80 U/kg and followed by continuous IV infusion (15 to 18 U/kg/hr infusion).
Therapeutic PTT is usually 60 to 90 seconds, but this varies depending on the
clinical situation
b. Therapeutic heparin is now often monitored using antifactor Xa levels
c. A prophylactic dose is given subcutaneously—low-dose heparin (5,000 U SC
subcutaneously every 12 hours). PTT monitoring is not necessary with SC dosing
2. LMWH
a. Therapeutic dose—given as a weight-adjusted dose
b. Prophylactic dose—varies depending on type of product
Hematologic Diseases and Neoplasms

D. Adverse effects
1. Bleeding
2. HIT—lower incidence with LMWHs
3. Possible osteoporosis—lower incidence with LMWHs
4. Transient alopecia
5. Rebound hypercoagulability after removal due to depression of AT III

E. Contraindications to heparin
1. Previous HIT
2. Active bleeding, GI bleeding, intracranial bleeding
3. Hemophilia, thrombocytopenia
4. Severe HTN
5. Recent surgery on eyes, spine, brain

F. Reversing the effects of heparin and LMWHs

1. The half-life of standard heparin is short, so it will cease to have an effect within
Quick HIT 4 hours of its cessation.
2. One can give protamine sulfate to reverse the effects of heparin if necessary (effec-
Administer FFP if severe
bleeding occurs (for tiveness is not proven, but it is the only potential antidote that exists in the case of
patients on either warfarin severe bleeding).
or heparin). 3. LMWH has a longer half-life than standard heparin, so it takes longer for the
effects to fade.

Low-molecular-weight Heparin
A. Mechanism of action
1. LMWHs mostly inhibit factor Xa (equivalent inhibition of factor Xa as standard
heparin), but have less inhibition of factor IIa (thrombin) and platelet aggregation.
2. They cannot be monitored by PT or PTT because they do not affect either.
3. Examples include enoxaparin, dalteparin, and tinzaparin.

B. Indications for use

1. LMWHs are being used more now because of their greater convenience compared
with standard heparin, as well as a decreased risk of side effects (HIT, osteoporosis).
a. They are given subcutaneously (no IV administration).
b. PTT monitoring is not necessary.
 H em a to l o g ic D ise a ses a nd N eop l a sms ● 351

c. They are easier to use as an outpatient—the patient may be discharged if stable,

and the patient can continue LMWH until the level of long-term anticoagula-
tion (warfarin) is therapeutic.
2. Excreted via kidneys—use cautiously in patients with renal dysfunction.
3. It is much more expensive than standard heparin, but often more cost-effective in
the long run due to reduced testing, nursing time, and length of hospital stay.

Warfarin
A. Mechanism of action
1. A vitamin K antagonist—leads to a decrease in vitamin K-dependent clotting fac-
tors (II, VII, IX, X) and proteins C and S
2. Causes prolongation of PT (and increase in INR)
3. It takes 4 to 5 days for the anticoagulant effect to begin. Therefore, start heparin as
well if the goal is acute anticoagulation because heparin has an immediate effect.
Once warfarin is therapeutic (check by INR), then stop the heparin and continue
warfarin for as long as necessary

B. Indications for use: Same as heparin but used for long-term anticoagulation.
C. Administration
1. Given orally.

Hematologic Diseases and Neoplasms

2. Heparin is initiated first—as soon as PTT is therapeutic, initiate warfarin.
Continue heparin for at least 4 days after starting warfarin. Once INR is therapeu-
tic on warfarin, stop the heparin.
3. The level of anticoagulation is monitored by the INR. In most cases, an INR of 2
to 3 is therapeutic. However, patients with mechanical heart valves need coagula-
tion with goal INR of 2.5 to 3.5.

D. Adverse effects
1. Hemorrhage.
2. Skin necrosis is a rare but serious complication. It is caused by rapid decrease in
protein C (a vitamin K-dependent inhibitor of factors Va and VIIIa).
3. Teratogenic—avoid during pregnancy!
4. Should not be given to alcoholics or to any patient who is prone to frequent falls
because an intracranial bleed in a patient on warfarin can be catastrophic.

E. Reversing the effects of warfarin

1. Discontinue warfarin and administer vitamin K.
2. The half-life of warfarin is much longer than that of heparin—it takes 5 days to
correct the effects of warfarin on stopping the medication. Vitamin K infusion Quick HIT
corrects an abnormal PT within 4 to 10 hours if the patient has normal liver
If rapid reversal of acute
function. bleeding from warfarin is
3. Giving vitamin K makes it difficult to return the patient to therapeutic INR levels indicated, give FFP.
if anticoagulation is to be continued.

Clopidogrel
A. Mechanism of action
1. Blocks the binding of ADP to a specific platelet ADP receptor P2Y12, which
reduces platelet activation and aggregation
2. Increases the bleeding time

B. Indications for use

1. Acute coronary syndromes: unstable angina, myocardial infarction, NSTEMI
2. Pretreatment for patients undergoing PCI
3. After PCI—patients should typically receive at least 1 year of clopidogrel (and
aspirin) after stent placement
4. Peripheral artery disease
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C. Administration
1. Given orally
2. For patients with STEMI who will undergo treatment with primary PCI, a load-
ing dose of clopidogrel is associated with better outcomes than pretreatment with
placebo. There is some debate about the appropriate dose, but 600 mg seems to
provide the best ratio of benefit to associated bleeding risk
3. Patients should receive daily clopidogrel after receiving a stent for any indication.
The dose is typically 75 mg/day for at least 12 months, with the first 6 months
being the most important

D. Adverse effects
1. Bleeding
2. Bruising/purpura
3. Some animal models suggest that proton pump inhibitors (PPIs) interfere with the
conversion of clopidogrel to its active metabolite, decreasing the effectiveness of
clopidogrel. For this reason, many people suggest not using clopidogrel with PPIs

Next Generation Anticoagulants

A. Direct factor Xa inhibitors—rivaroxaban, apixaban, edoxaban
1. Inhibit factor Xa directly (as opposed to stimulating AT like heparin)
2. Currently approved for DVT prophylaxis in surgical patients and stroke prophy-
Hematologic Diseases and Neoplasms

laxis in patients

B. Direct thrombin (factor II) inhibitors—lepirudin, argatroban, dabigatran

1. Inhibitor thrombin directly
2. Lepirudin, argatroban, and dabigatran are used currently for treatment of HIT

Oncology
• A detailed description of many cancers can be found in the appropriate anatomical
chapter of this book (i.e., lung cancers in pulmonary chapter, colon cancer in GI).

Epidemiology
• In order of occurrence, the most common cancers in males are prostate, lung, and colon.
The cancers with the highest mortality in males are lung, followed by prostate and colon.
• In order of occurrence, the most common cancers in females are breast, lung, and
colon. The cancers with the highest mortality in females are lung, followed by breast
and colon.
• The number one avoidable risk factor for most cancers is smoking. All patients should
be encouraged to stop smoking.
• Other etiologic agents in cancer include viruses (Hepatitis B/C for hepatocellular car-
cinoma, HPV in cervical cancer), chemicals (asbestos, ethanol, aflatoxin, cadmium,
silica), and UV light.

Cancer Prevention and Screening

• Breast cancer—annual mammogram beginning at age 40 years for females.
• Cervical cancer—Quadrivalent HPV vaccine (Gardasil) protects against high-risk HPV,
approved in females ages 9 to 26 years old. Begin annual pap smears at age 21 even if
not sexually active.
• Colorectal cancer (CRC)—begin colonoscopy screening (q10 years) for average risk
people. If first-degree CRC, begin screening at age 40 or 10 years before the age of
diagnosis of relative (whichever earlier).
• Prostate cancer—despite ongoing trials, currently there is no consensus that screening
with measuring prostate-specific antigen (PSA) levels decreases mortality.
• Lung cancer—screen any previous or current smoker (with minumum 30 pack years
history) for lung cancer using low-dose CT between ages 55 to 80, annually (NLST
trial showed 20% reduction in mortality in CT cohort vs. chest x-ray cohort).
TREATMENT OPTIONS FOR PE
Supportive Anticoagulant therapy Fibrinolytic therapy Surgery
therapy
For everyone For everyone unless CI For hemodynamically Last resort (or as a
unstable (massive PE) , prophylaxis)
unless CI
ABC check Heparin tPA Thrombectomy
(DVT)
Oxygen Warfarin Alteplase Embolectomy (PE)
IV fluids Factor Xa inhibitors Reteplase IVC filter
Dobutamine Direct thrombin inhibitors Tenecteplase
lepirudin, desirudin,
bivalirudin and argatroban.

Note: What defines massive?

PE : give heparin Hemodynmic instability as :
Massive PE : give tPA 1)Hypotension: give IV bolus fluid
2)Hypoxemia : give O2
3)Bradycardia : give Dobutamin
4)Pulselessness
Anti-coagulant therapy:
1)Heparin:
a)UFH
b)LMWH
As Enoxaparin , Dalteparin , Tinzaparin
2) Warfarin
3) Others :
a) Factor Xa inhibitor as FondaparinuX , ApiXaban , RivaroXaban
b)Direct thrombin inhibitors as : Dabigatran , Argatroban
lepirudin, desirudin,
bivalirudin and argatroban.
Once you suspect or confirm PE : give anticoagulant unless CI
Which drug should you give?
Heparin or FondaparinuX …or factor Xa inhibitors or direct
thrombin inhibitors …why? Because it is rapid acting
What about giving warfarin first?
There are 2 major problems:
1)WR is slow acting .. As it is oral and it has to go to the liver then
start it inhibitory action of gamma carboxylation “vitamin K
dependent” then the liver will eliminate its production of VK
dependent serine proteases (coagulation factors) , protein S&C ,
Factor II, VII, IX & X
2)WR inhibit protein C&S before it even inhibit factor II, VII, IX, &
X ie WR inhibit the anticoagulant before it inhibit the pro-
coagulants , therefore , in the beginning , WR is PRO-Coagulant
(by inhibiting the anti-coagulant : protein C&S that is why WR
causes skin necrosis.
So ,there are 2 problems with starting WR:
1)The patient is literally dying and we have the audacity to give a
slow –acting oral drug
2)The patient is having a clot and we are giving him a PRO-
coagulant (at least in the beginning)
What is the solution?
v Bridge with heparin (called heparin bridge) heparin first and
WR 4 days then stop heparin and continue WR alone
ØHeparin will anti-coagulate until WR can stop being pro-
coagulant and start being anticoagulant (about 4 days)
ØWhen should stop heparin and leave WR alone (How we
know WR start working)? When INR reaches 2
Once we suspect , or confirm pulmonary embolism , we need anticoagulant
unless contraindication
CI to anticoagulant:
1) Major bleeding diathesis that is not corrected as hemophilia ,
thromboasthenia , liver failure(cirrhosis) , renal failure
2) Active or potentially active bleeding disorders : as active GI-bleeding or
PU, Dissecting aortic aneurism , cerebral aneurism , esophageal varices ,
recent major surgery , recent stroke , recent trauma
3) Severe , uncontrolled HTN (malignant HT) as systolic pressure more
than 200 , and diastolic more than 140
Heparin CI:
All above plus:
History of heparin induced thrombocytopenia
Severe thrombocytopenia
Life-threating allergy
Uncontrolled , active bleeding except DIC
CI to Warfarin: all above plus:
Life-threatening allergy
Pregnancy
Cancer (LMWH is ideal)
CI to tPA:
Absolute :
Previous hemorrhagic stroke at any time
Other cerebrovascular events in the last year
Active internal bleeding
Intracranial neoplasm
Suspected aortic dissection
Relative CI:
Persistent HT more than 180/110
Current anticoagulant use INR more than 2-3
Remote non-hg CVA
Recent major surgery or trauma within 2-4 wks
Previous streptokinase exposure
Active PU
Pregnancy
Don’t give to acute coronary syndrome (ACS) patient with no ST elevation
Primary percutaneous coronary intervention (PPCIs) are superior to
fibrinolytic therapy for the treatment of ST segment elevation myocardial
infarction (STEMI)
Which one is better ;UFH or LMWH?
It depends:
For DVT : LMWH better than UFH
For PE: UFH=LMWH
If we afraid of the risk of bleeding : LMWH better than UNH (less
bleeding risk )
If we want to reach the therapeutic level faster : give LMWH
Which one can monitor by PTT? UFH only
Which one can cause HIT ? Both but more with UFH
Which one has higher risk of osteoporosis? UFH
Which one better during pregnancy ? LMWH
Which one better for cancer patient? LMWH
Which one better for RF patient? UFH
Which one is preferred if a patient who is hemodynamically unstable ?
UFH as :
1)LMWH has a relatively –delayed onset of action 20-30 mint while UFH
is rapid onset and immediate
2)LMWH requires adequate & optimal blood pressure and adequate
perfusion while UFH just bind to ANTI-III no matter what
Once we suspect PE we start anticoagulant (heparin or
FondaparinuX) BUT many patients has CI to anticoagulant (as
recent stroke…) what shall we do?
1)Thromboectomy for DVT and emolectomy for PE
2)IVC filter (if hemodynamically stable)

What if we gave too much heparin (UFH , LMWH)?

Give antidote : protamine sulfate

What if heparin caused HIT ( Thrombocytopenia and or

thrombocytosis)?
a)Do not give UFH , LMWH
b)Do give a direct thrombin inhibitor ( Argatroban or Lepirudin)
c)Do not give Lepirudin to a renal failure patient just Argatroban

Can we give warfarin to HIT? Only when the platelets start to go

over 100.000
Once you suspect or confirm PE:
1)ABCs FOR STABILIZE
2)Anticoagulant (heparin or fondaparinuX)
3)Give WR and continue the heparin bridge (for at least 4 days ad
when the INR reaches at least 2)
4)If massive PE and unstable hemodynamically you can give tPA

IVC filter: indicated for:

Recurrent venous thromboembolism (DVT/PE) despite adequate
anticoagulant therapy or
Recurrent venous thromboembolism (DVT/PE) and anticoagulant
therapy is CI
FondaparinuX:
It is factor Xa INHIBITOR
Does not cause HIT
Contraindicated in RF
No antidote