This document discusses acquired hypercoagulable states, specifically focusing on those associated with malignancy. It describes how malignancies can induce a hypercoagulable state through the production of tissue factor and cancer procoagulant. This predisposes patients to both venous thromboembolisms and arterial thrombosis. The document outlines treatment recommendations including inpatient, outpatient, and perioperative thromboprophylaxis for cancer patients.

1. ACQUIRED HYPERCOAGULABLE
STATES
Dr. Naresh Monigari

2. DEFINITION :
• Hypercoagulability is any alteration in the
coagulation pathway that predisposes to
thrombosis: venous , arterial or both.
Virchow's triad:

3. COAGULATION CASCADE

4. TYPES OF HYPERCOAGULABLE STATES
Three types are known

5. ACQUIRED HYPERCOAGULABLE STATES
Venous thromboembolic disease is the most
common clinical manifestation resulting from
hypercoagulable states.

6. ACQUIRED HYPERCOAGULABLE STATES
Acquired conditions that have been associated
with both VTEs and arterial thrombosis are :
Malignancy
Myeloproliferative syndromes
Antiphospholipid antibodies (APAs)
Hyperhomocysteinemia and
Heparin-induced thrombocytopenia.

7. ACQUIRED HYPERCOAGULABLE STATES
MALIGNANCY :
 Hypercoagulable state is due to production of substances
with procoagulant activity (tissue factor and cancer
procoagulant).
 The risk of thrombosis may be further increased in patients
with malignancy and a central venous catheter, in which
situation the prevalence of a venous thrombotic event may be
as high as 12 percent.

10. PATHOGENESIS IN MALIGNANCY
• The substances that have been isolated from animal and
human tumors with procoagulant activity fall into two major
categories:
Tissue factor-like procoagulant
Cancer procoagulant
.

11. TISSUE FACTOR PROCOAGULANT
Tissue factor expression by malignant cells ( sarcoma,
melanoma, neuroblastoma, lymphoma, pancreatic and
colorectal cancer, ovarian cancer and acute promyelocytic
leukemia (APL).
 Tissue factor (TF) forms a complex with factor VII to activate
factor X, thereby initiating blood coagulation.
 Tissue factor-bearing micro particles result from alternative
splicing of TF mRNA, and lack the Transmembrane
domain(seen in patients with pancreatic carcinoma).

12. CANCER PROCOAGULANT
• It is a CALCIUM-DEPENDENT CYSTEINE PROTEASE that has
been found in malignant and fetal tissue, but not normally
differentiated tissue
• It activates factor X directly, independent of the
tissue factor/factor VIIa complex.
• It has been reported to be present in extracts of cells obtained
from patients with acute promyelocytic leukemia, malignant
melanoma, and cancers of the colon, breast, lung, and kidney.

13. TROUSSEAU'S SYNDROME
Trousseau's syndrome (migratory superficial
thrombophlebitis)
• A rare variant of venous thrombosis
• Characterized by a recurrent and migratory pattern
• Involvement of superficial veins, frequently in unusual sites
such as the arm or chest.
• Usually has an occult tumor which is not always detectable
• Usually an adenocarcinoma

14. TREATMENT
INPATIENT PROPHYLAXIS:
1) Hospitalized patients with active malignancy with acute
medical illness or reduced mobility should receive
pharmacologic thromboprophylaxis in the absence of
bleeding or other contraindications.
2) Hospitalized patients who have active malignancy
without additional risk factors may be considered for
pharmacologic thromboprophylaxis in the absence of
bleeding or other contraindications.
3) Data are inadequate to support routine
thromboprophylaxis in patients admitted for minor
procedures or short chemotherapy infusion.
American Society of Clinical Oncology 2013

15. TREATMENT
OUTPATIENT PROPHYLAXIS:
1) Routine pharmacologic thromboprophylaxis is not
recommended in cancer outpatients.
2) Based on limited RCT data, clinicians may consider LMWH
prophylaxis on a case-by-case basis in highly selected
outpatients with solid tumors receiving chemotherapy.
.
3)Patients with multiple myeloma receiving thalidomide- or
lenalidomide-based regimens with chemotherapy and/or
dexamethasone should receive pharmacologic
thromboprophylaxis with either aspirin or LMWH for lower-
risk patients and LMWH for higher-risk patients.
American Society of Clinical Oncology 2013

16. TREATMENT
PERIOPERATIVE PROPHYLAXIS :
1) All patients with malignant disease undergoing major surgical
intervention should be considered for pharmacologic
thromboprophylaxis with either UFH or LMWH unless
contraindicated because of active bleeding or a high bleeding
risk.
2) Prophylaxis should be commenced preoperatively.
3)Mechanical methods may be added to pharmacologic
thromboprophylaxis, BUT SHOULD NOT BE USED AS
MONOTHERAPY for VTE prevention unless pharmacologic
methods are contraindicated because of active bleeding or
high bleeding risk.
American Society of Clinical Oncology 2013

17. TREATMENT
5) Thromboprophylaxis for patients undergoing major
surgery for cancer should be continued for at least 7-10
days post operatively.
Extended prophylaxis with LMWH for up to 4 weeks
postoperatively should be considered for patients
undergoing
major abdominal or pelvic surgery for cancer who have
high-risk features such as restricted mobility, obesity,
history of VTE, or with additional risk factors.
.

18. Treatment & Secondary Prophylaxis
1 )LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation
with newly diagnosed VTE who does not have severe renal impairment
(defined as creatinine clearance < 30 mL/min).
2) For long term anticoagulation, LMWH for at least 6 months is preferred due
to improved efficacy over Vitamin K antagonists. Vitamin K antagonists are
an acceptable alternative for long-term therapy if LMWH is not available.
3)Anticoagulation with LMWH or Vitamin K antagonist beyond the initial 6
months may be considered for select patients with active cancer, such as
those with metastatic disease or those receiving chemotherapy.
4)The insertion of a vena cava filter is only indicated for patients with
contraindications to anticoagulant therapy (see Table 4). It may be
considered as an adjunct to anticoagulation in patients with progression of
thrombosis (recurrent VTE or extension of existing thrombus) despite
optimal therapy with LMWH.

19. Absolute Contraindications To Therapeutic
Anticoagulation In Cancer Patients With Vte
• Active major, serious or potentially life-threatening
bleeding not reversible with medical or surgical
intervention, including active bleeding in a critical site.
• Severe, uncontrolled malignant hypertension
• Severe, uncompensated coagulopathy ,Severe platelet
dysfunction or inherited bleeding disorder
• Persistent, severe thrombocytopenia (< 20,000/μL)
• Surgery or invasive procedure including lumbar puncture,
spinal anesthesia, epidural catheter placement

20. ANTIPHOSPHOLIPID SYNDROME
• The antiphospholipid syndrome (APS) is
characterized by the occurrence of
Venous thrombosis
Arterial thrombosis
pregnancy related morbidity,
In the presence of laboratory evidence of
antiphospholipid antibodies (aPL).

21. ANTIPHOSPHOLIPID SYNDROME
• Also known as HUGHES SYNDROME.
• Autoimmune disorder.----acquired thrombophilic disorder.
• Mostly associated with SLE.
• Responsible for frequent miscarriages in young females
(15%).
• CATASTROPHIC APS---Asherson’s syndrome.
• MC thrombotic defect leading to fetal wastage.

22. Antiphospholipid Syndrome Criteria
Sydney revision of Sapporo criteria 2006
CLINICAL CRITERIA
• Vascular Thrombosis
• Pregnancy Morbidity:
a) death of normal fetus
at > 10 wks
b) premature birth at < 34
wks due to preeclampsia
c) >3 consecutive abortions
at <10wks
d) placental insufficiency at
< 34 wks
LABOARATORY CRITERA
• anti-Cardiolipin IgG
• anti-Cardiolipin IgM
• Lupus anticoagulant (LAC)
- medium - high
titer - at least X 2
- 12 wks apart
Definite APS: 1 Clinical + 1 Lab criteria

24. “Non-criteria” APS findings
Clinical:
 Livedoreticularis
 Thrombocytopenia
(usually 50,000-100,000
/mm3)
 Autoimmune hemolytic
anemia
 Cardiac valve disease
 Multiple sclerosis–like
syndrome, chorea, or other
myelopathy
Laboratory:
 IgA aCL antibody
 IgA Anti– ß2gpi
 Antiphosphatidylserine
 Antiphosphatidyl
ethanolamine

25. Antiphospholipid antibodies
Antiphospholipid antibodies are heterogeneous family
of immunoglobulins :
• Do not bind to phospholipids
• And are directed at plasma proteins with affinity for
anionic (phospholipid) surfaces.
• Best known are
Anti–cardiolipin antibodies
Anti prothrombin antibodies.

26. Properties of aPLs
Blood, Vol 93, No 7 (April 1), 1999: pp 2149-2157

28. Antiprothrombin antibodies inhibit the activation of factor X and prothrombin
Anticardiolipin antibodies inhibit prothrombin but not factor X activation.
Sites of action of antiprothrombin and anticardiolipin antibodies along the blood
coagulation cascade:
Blood, Vol 93, No 7 (April 1), 1999: pp 2149-2157

29. Anti prothrombin antibodies
• The synergistic effect of antiprothrombin antibodies on two
consecutive phospholipid-dependent coagulation reactions is
shown mainly by overall clotting tests, such as
Kaolin clotting time (KCT) or
Colloidal silica clotting time (CSCT)
which proceed through the generation of factor Xa and
activation of prothrombin.

30. Anticardiolipin antibodies
Anticardiolipin antibodies
• Inhibit prothrombin activation
• strictly b2-glycoprotein I–dependent fashion, with
no effect on factor X
• Presence affects the dRVVT
more than the KCT or other overall clotting assays.

31. Comparison of the ratios of the KCT and the
dRVVT:
• If the ratio of the KCT exceeds that of the
dRVVT, it is considered a coagulation profile
associated with antiprothrombin antibodies.
• If the relationship is reversed it is considered a
‘‘dRVVT’’ coagulation profile that may be
associated with anticardiolipin antibodies.

32. Suspicion of APS
• when to suspect APS:
 Occurrence of one or more otherwise unexplained
thrombotic or thromboembolic events.
 One or more specific adverse outcomes related to
pregnancy.
 Unexplained thrombocytopenia or prolongation of a
test of blood coagulation.

33. INITIAL LABORATORY EVALUATION
• IgG and IgM anticardiolipin antibodies (aCL) by
enzyme-linked immunosorbent assay (ELISA)
• IgG and IgM anti-ß2-glycoprotein I (anti-β2GPI)
antibodies by ELISA..
• Lupus anticoagulant testing

34. LUPUS ANTICOAGULANT
• The lupus anticoagulant phenomenon refers to the
ability of aPL to cause prolongation of in vitro clotting
assays such as the
Activated partial thromboplastin time (aPTT)
dilute Russell viper venom time (dRVVT)
Kaolin clotting time
Infrequently, the prothrombin time.

35. LUPUS ANTICOAGULANT TESTS
COAGULATION ASSAYS
• Perform coagulation screen to detect prolongation
in phospholipid dependent coagulation assay (usually
use: APTT)
• If APTT is prolonged: Mix with normal plasma
- If due to factor deficiency: corrected
- If due to inhibitor (antibody) not corrected
• Confirm inhibitor is phospholipid dependent :
corrected by mixing with platelets or phospholipids
• Perform second test: KCT or DRVVT

36. TESTS FOR LAC
• APTT:
- variability in reagents result in inconsistent sensitivity.
- acute phase reaction and pregnancy may shorten APTT
and mask
a weak LAC
A normal APTT does not exclude LAC
• KCT- Kaolin clotting time
more sensitive to presence of anti-factor II
• DRVVT- Dilute Russell’s viper venom time
more sensitive to presence of b2 GPI
• TTI - Tissue thromboplastin inhibition test
No LAC shows 100%
specificity and sensitivity
because aPLs are
heterogeneous.
More than 1 test system is
needed

37. DILUTED RUSSELLS VIPER VENOM TEST

38. DILUTED RUSSELLS VIPER VENOM TEST
• RVV directly activates factor X, the test is
unaffected by deficiencies of factors XII, XI, IX
or VIII
• In individuals with a lupus anticoagulant [LA]
the antibody binds to the phospholipid
inhibiting the action of the RVV and
prolonging the clotting time.
• More affected by anti –cardiolipin antibodies.

39. KAOLIN CLOTTING TIME [KCT]
• The most sensitive test for the detection of
circulating anticoagulants.
• Is essentially an activated partial thromboplastin
time test but without any added phospholipid.
• The KCT relies on small quantities of phospholipid
in the patient’s plasma and so is particularly
sensitive to platelet contamination of the plasma
sample, which greatly reduces the sensitivity of
the test.

40. KAOLIN CLOTTING TIME [KCT]
• There is no phospholipid correction step for the KCT.
• Instead factor deficiency for a prolonged KCT is
excluded by repeating the test with the addition of
relatively large quantities of normal plasma.
• This will shorten the KCT by replacing any deficient
clotting factor but in the presence of a coagulation
inhibitor there will be no or limited correction.

41. KAOLIN CLOTTING TIME [KCT]
• A test comprising 100% normal plasma and
80% normal:20% patient plasma is used and a
ratio derived using the formula:
• A ratio of ≥1.2 is considered positive for a
lupus anticoagulant

42. CONFORMATORY ASSAYS
• Upon addition of excess phospholipid, the clotting
time shortens toward normal.
• A routine PTT may or may not be prolonged by a
lupus anticoagulant, depending on the amount of
phospholipid in the PTT reagent.
• PTT-based lupus anticoagulant assays are designed to
have a low concentration of phospholipid to enhance
sensitivity.
• Samples should be depleted of platelets prior to
freezing, platelet phospholipid will decrease the
sensitivity of the tests.

43. ANTI-CARDIOLIPIN TEST
• Advantages
– Overwhelming majority of APS patients are anti cardiolipin
positive
– Test can be performed reproducibly.
– Clinicians and laboratories generally familiar with units of
measurement.
• Disadvantages
– Relatively nonspecific (particularly low positive, IgM
positive).
– Intra-laboratory and Inter-laboratory variability.
– Problems with false positive results: aCL positive in a wide
variety of infectious diseases and in non-APS related
autoimmune diseases.

44. ANTI CARDIOLIPIN ANTIBODY
• Commercially available enzyme-linked
immunosorbent assays (ELISA):
Cardiolipin, is bound to a solid phase.
If anticardiolipin antibody is present in sample,
antibody will bind to the cardiolipin
It will be detected by a second antibody that is
labeled for colorimetric quantitation.

45. ANTI-ß2GLYCOPROTEIN I
• More specific than anticardiolipin test for diagnosis of
Antiphospholipid Syndrome (but not 100% specific)
• Not as sensitive as anticardiolipin test (70-90% sensitivity)
• Efforts of standardization continuing
• Useful in diagnosis of doubtful cases of APS. Some APS
patients negative for aCL and positive for anti-b2GPI.

46. REPEAT TESTING
• In patients with initial positive testing for aPL, the test
should be repeated after at least 12 weeks to confirm
persistence of the aCL, anti-β2GPI, or LA test.
• In patients with a strongly suggestive clinical history
whose initial test result is a positive LA or a high titer aCL
(>40) or anti-β2GPI, but whose second test is negative,
we perform a third test after several weeks and use the
third result to help guide decision-making.
• If the first test was a minimally positive aCL or anti-β2GPI
and the second test was negative. the result is
considered negative and do not perform third
test.Testing should be repeated if the patient has a
clinical event.

47. ADDITIONAL TESTING
• Testing for additional aPL:
In case of strong clinical suspicion of APS and negative
aPL tests (IgG and IgM aCL and anti-β2GPI, and
testing for LA),
IgA aCL or IgA anti-β2GPI may occasionally be positive.

48. ADDITIONAL TESTING
Testing for heritable and acquired thrombophilias:
• In patients with venous thrombosis testing for
hereditary thrombophilia has to be done for the
identification of patients at elevated risk of
thrombosis over that which occurs with aPL alone.
• In patients with arterial thrombosis Complete
testing is not justified since Hereditary thrombophilia
is principally a risk factor only for venous thrombosis.

49. Frequency of antiphospholipid
antibodies in different populations
Population aCL LAC
Normal individuals: 2-5% 0-1%
Normal pregnancy: 1-10% -
Elderly (>70 years of age): >50% -
Patients with SLE: 17-86% 7-
65%
Family members of patients with
APS:
8-31% -

50. RISK FOR THROMBOSIS
• A positive test for lupus anticoagulant is a stronger
risk factor for thrombosis and adverse pregnancy
outcomes after 12 weeks of gestation than positivity
for either anti–β2-glycoprotein I or anticardiolipin
antibodies. (BLOOD, 15 OCTOBER 2003 .VOLUME 102, NUMBER 8)
• The deep veins of the lower limbs and the cerebral
arterial circulation are the most common sites of
venous and arterial thrombosis, respectively.
( n engl j med 368;11 nejm.org march 14, 2013)

51. RISK FOR THROMBOSIS

52. Pathogenesis and therapeutic
interventions
Homeostatic regulation of blood coagulation is altered
1) Increased oxidative stress: Levels of oxidized β2GPI were
increased in patients with APS.
Free thiol form of β2GPI protects
endothelium fromROS;
Antiphospholipid antibodies promote
an increase in intracellularROS.
Possible therapeutic intervention:
• NAC inhibits ROS-mediated thrombosis;
• coenzyme Q10 inhibits antiphospholipid antibody–mediated ROS
generation

53. Pathogenesis and therapeutic
interventions
2)Impaired function of eNOS: impaired endothelial nitric
oxide–dependent vascular relaxation and decreased plasma
nitrite levels in patients with APS.
Statins up-regulate eNOS activity.

54. PLEIOTROPIC EFFECTS OF STATINS
• - TPA and  PA inhibitior-1 expression
• - Expression of adhesion molecules
• - Pro-inflammatory cytokines
• - Expression of tissue factor
• - Thromboxane A2 synthesis and platelet reactivity
• - Endothelin 1 synthesis
• - NF-kB activation
• - MHC class II antigen expression

55. PATHOGENESIS AND THERAPEUTIC
INTERVENTIONS
3) Activation of receptors by anti-β2GPI antibodies: relevant
target receptors
On platelets are ApoE receptor and glycoprotein Iba
On monocytes, annexin A2, TLR2, andTLR4 and
On endothelial cells, annexin A2,TLR2,and TLR4
A1 analogues of ApoE receptor2 and synthetic domain Iinhibit anti-
β2GPI–mediated effects

57. Pathogenesis and therapeutic
interventions
4)Increased expression and activation of tissue
factor: Up-regulation of tissue factor by
antiphospholipid antibodies has been shown in
monocytes and neutrophils and on endothelial cells.
• PDI ( protein disulfide isomerase)inhibitors attenuate
murine thrombosis
• Statins inhibited thrombosis in a murine model of
tissue factor–dependent APS

58. Pathogenesis and therapeutic
interventions
5)Disruption of the annexin A5 shield:
Decrease in annexin A5
shown in
antiphospholipid antibody–treated
endothelial cells.
Hydroxychloroquine inhibits anti-β2GPI disruption of
the Annexin A5 shield in vitro and attenuates thrombosis
associated with APS in mice.

59. Pathogenesis and therapeutic
interventions
6)Antibody-mediated activation of complement
C3 and C5:
C5a binds and activates neutrophils, inducing
upregulation of tissue factor.
C5 inhibitor eculizumab ameliorates
catastrophic APS

60. Pathogenesis and therapeutic
interventions
7)Increased expression of TLR7 and TLR8 and
sensitization to TLR7 and TLR8 agonists:
Antiphospholipid antibodies induce up-regulation of
TLR7 and TLR8 in plasmacytoid dendritic cells,
sensitizing them to the effects of TLR7 and TLR8
agonists.
Hydroxychloroquine inhibits TLR7 activation in vitro

61. Pathogenesis and therapeutic
interventions
8)BAFF B-cell activating factor:
BAFF inhibitor BELIMUMAB is
protective against thrombosis.

63. CLINICAL MANIFESTATIONS
Central Nervous System
Cerebrovascular ischemia
Stroke
Cerebral venous thrombosis
Dementia
Transverse myelitis
Chorea
Migraine
Multiple sclerosis like illness
Cardiovascular System
Arterial thrombosis
Venous thrombosis
Myocardial ischemia
Cardiac valvular vegetations
Accelerated atherosclerosis
Respiratory
Pulmonary thrombosis
Pulmonary hypertension
Hematological
Thrombocytopenia
Autoimmune hemolytic anemia
Dermatological
Livedo reticularis
Chronic leg ulcers
Obstetrical
Recurrent pregnancy loss
Placental insufficiency
Other
Adrenal insufficiency
Aseptic necrosis of bone
Budd–Chiari syndrome

67. MANAGEMENT OF APS
Therapy is not primarily directed to the
elimination or reduction in the levels of
antibodies through plasma exchanges,
intravenous gammaglobulin or
immunosuppresants
(except in catastrophic APS),
because of lack of a clear correlation between
APLA titers and thrombotic episodes.

68. PRIMARY THROMBOPROPHYLAXIS
• Antiphospholipid Antibody Acetylsalicylic Acid
(APLASA) study:
Conclusions were:
• Asymptomatic individuals who are persistently
positive for aPL have a low annual incidence of
acute thrombosis.
• These individuals do not benefit from low-
dose aspirin.
• Thrombotic events in this population are unlikely
in the absence of additional risk factors for
thrombosis.

69. SLE WITH APL
In the absence of any contraindication to the use
of aspirin, prophylactic therapy with a low-dose
(81 mg/day) of aspirin is advised for
Patients with SLE or
Underlying connective tissue disorder,
If other risk factors for thromboembolic disease,
such as cardiovascular or genetic risk factors, are
present.
• Women with aPL should avoid oral
contraceptives, particularly those with high
estrogen content.

70. PRIMARY THROMBOPROPHYLAXIS
Common clinical practice is to treat with
• Low dose aspirin all patients with persistently
positive LA or aCL, especially if they are of the
IgG isotype and have medium or high titers,
• Strict control the existence of other associated
risk factors
• In patients with SLE, an alternative to aspirin
can be the use of hydroxycloroquine.
R. Cervera / Reumatol Clin. 2010;6(1):37–42

71. SECONDARY THROMBOPROPHYLAXIS
• A characteristic common to most patients with APS is
thrombosis tends to recur
in the same vascular territory,
Venous thrombosis recurrence tends to be venous
and
Arterial thrombosis recurs in arteries in almost 80% of
cases.

73. PROPHYLAXIS OF PREGNANCY LOSS IN PATIENTS
WITH ANTIPHOSPHOLIPID SYNDROME
1) PREGNANT WITH APLA AND NORMAL PRIOR PREGNANCIES:
Optional: aspirin (100 mg/day) from the moment the patient finds
out she’s pregnant and throughout pregnancy.
2) FIRST WITH APLA:
a) No associated disease:
Optional: aspirin (100 mg/day) from the moment the patient finds
out she’s pregnant and throughout pregnancy.
b) Associated SLE:
Recommended: aspirin (100 mg/day) from the moment the patient
finds out she’s pregnant and throughout pregnancy.

74. PROPHYLAXIS OF PREGNANCY LOSS IN PATIENTS
WITH ANTIPHOSPHOLIPID SYNDROME
3) PREGNANT WITH APLA AND ASSOCIATED OBSTETRIC
DISEASE BUT NO HISTORY OF THROMBOSIS:
Recommended: aspirin (100 mg/day) from the moment the
patient finds out she’s pregnant and throughout pregnancy.
Prednisone: only for non obstetric reasons (SLE activity or
intense thrombocytopenia), preferably under 30 mg/day.

75. PROPHYLAXIS OF PREGNANCY LOSS IN PATIENTS WITH
ANTIPHOSPHOLIPID SYNDROME
4) PREGNANT WITH APLA AND HISTORY OF THROMBOSIS:
Interrupt cumarin before 6th week of pregnancy (maximum
risk for teratogenesis is between 6th and 11th weeks)
Administer aspirin ( 100 mg/day) associated to low molecular
weight heparin
Special considerations:
a) If cumarin is reintroduced, this must occur from the 2nd
trimester of pregnancy onward
b) If breast-feeding is desired, treatment with low molecular
weight heparin must be maintained because cumarin
passes into breast milk.

76. PROPHYLAXIS OF PREGNANCY LOSS IN PATIENTS WITH
ANTIPHOSPHOLIPID SYNDROME
5) THERAPEUTIC FAILURE WITH ABOVE MENTIONED
GUIDELINES:
a) If the patient only received aspirin during the
previous pregnancy:
Add low molecular weight heparin to aspirin at the
moment the pregnancy is confirmed
b) If this fails:
Evaluate adding intravenous gammaglobulin (400
mg/kg/day for 5 days, repeating monthly until
pregnancy ends)