Naresh

ACQUIRED HYPERCOAGULABLE STATES

Presenter: Dr. Naresh MonigariModerator: Dr. M.M.PRABHU

DEFINITION :

• Hypercoagulability is any alteration in the coagulation pathway that predisposes to thrombosis: venous , arterial or both.

Virchow's triad:

COAGULATION CASCADE

TYPES OF HYPERCOAGULABLE STATES

Three types are known


Venous thromboembolic disease is the most common clinical manifestation resulting from 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.


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.

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

.

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).

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.

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

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

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.


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.


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.

.

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.

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

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).

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.

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

“Non-criteria” APS findings

Clinical: Livedoreticularis

Thrombocytopenia (usually 50,000-100,000 /mm3)

Autoimmune hemolytic anemia

Cardiac valve disease

Multiple sclerosis–likesyndrome, chorea, or other myelopathy

Laboratory: IgA aCL antibody

IgA Anti– ß2gpi

Antiphosphatidylserine

Antiphosphatidyl ethanolamine

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.

Properties of aPLs

Blood, Vol 93, No 7 (April 1), 1999: pp 2149-2157

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

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.

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.

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.

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.

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

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.

LUPUS ANTICOAGULANT TESTSCOAGULATION ASSAYS

• Perform coagulation screen to detect prolongationin 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

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

DILUTED RUSSELLS VIPER VENOM TEST

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 phospholipidinhibiting the action of the RVV and prolonging the clotting time.

• More affected by anti –cardiolipin antibodies.

KAOLIN CLOTTING TIME [KCT]

• The most sensitive test for the detection of circulating anticoagulants.

• Is essentially an activated partial thromboplastintime test but without any added phospholipid.

• The KCT relies on small quantities of phospholipidin the patient’s plasma and so is particularly sensitive to platelet contamination of the plasma sample, which greatly reduces the sensitivity of the test.


• 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.


• 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

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.

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.

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.

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.

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.

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.

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.

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% -

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)

RISK FOR THROMBOSIS

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


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.

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

PATHOGENESIS AND THERAPEUTIC INTERVENTIONS

3) Activation of receptors by anti-β2GPI antibodies: relevant target receptors

On platelets are ApoE receptor and glycoprotein IbaOn 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


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


5)Disruption of the annexin A5 shield:Decrease in annexin A5shown in

antiphospholipid antibody–treated endothelial cells.

Hydroxychloroquine inhibits anti-β2GPI disruption ofthe Annexin A5 shield in vitro and attenuates thrombosis associated with APS in mice.


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


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


8)BAFF B-cell activating factor:

BAFF inhibitor BELIMUMAB is

protective against thrombosis.

CLINICAL MANIFESTATIONS

Central Nervous SystemCerebrovascular ischemiaStrokeCerebral venous thrombosisDementiaTransverse myelitisChoreaMigraineMultiple sclerosis like illness

Cardiovascular SystemArterial thrombosisVenous thrombosisMyocardial ischemiaCardiac valvular vegetationsAccelerated atherosclerosis

RespiratoryPulmonary thrombosisPulmonary hypertension

HematologicalThrombocytopeniaAutoimmune hemolytic anemia

DermatologicalLivedo reticularisChronic leg ulcers

ObstetricalRecurrent pregnancy lossPlacental insufficiency

OtherAdrenal insufficiencyAseptic necrosis of boneBudd–Chiari syndrome

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.

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.

http://www.uptodate.com/contents/aspirin-drug-information?source=see_link

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 orUnderlying 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.

http://www.uptodate.com/contents/aspirin-drug-information?source=see_link

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

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.

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.


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.


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 heparinSpecial considerations:a) If cumarin is reintroduced, this must occur from the 2nd

trimester of pregnancy onwardb) If breast-feeding is desired, treatment with low molecular

weight heparin must be maintained because cumarin passes into breast milk.


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)

Naresh

Health & Medicine

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