Thrombophilia or hypercoagulability, means an increased risk for thrombosis (blood clotting). It is well established that a hypercoagulable state exists in thalassemia.
A definitive article on this subject can be seen at
http://bloodjournal.hematologylibrary.org/cgi/content/full/99/1/36 Some excerpts are below.
The hypercoagulable state in thalassemia
Amiram Eldor and Eliezer A. Rachmilewitz
From the Institute of Hematology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and Department of Hematology, Edith Wolfson Medical Center, Holon, Israel.
...profound hemostatic changes have been observed in patients with beta -thalassemia major (beta -TM) and beta -thalassemia intermedia (beta -TI) and also in patients with alpha thalassemia (hemoglobin H disease). The presence of a higher than normal incidence of thromboembolic events, mainly in beta -TI, and the existence of prothrombotic hemostatic anomalies in the majority of the patients, even from a very young age, have led to the recognition of the existence of a chronic hypercoagulable state in thalassemic patients.
There have been numerous reports of thromboembolic complications associated with thalassemia, many describing cerebral thrombotic events.[Stroke]
Studies of the coagulation proteins provide strong evidence for the existence of a chronic hypercoagulable state in thalassemia. Several investigators have reported profound changes in the levels of coagulation factors, coagulation factor inhibitors, and components of the fibrinolytic system...In conclusion, it seems that the low levels of protein C and free protein S seen in thalassemic patients may be acquired at an early age. The extent to which the imbalance between coagulation inhibitors and clotting factors contributes to the hypercoagulable state in thalassemia remains to be determined.
A range of laboratory tests has provided solid evidence for the existence of a chronic hypercoagulable state in thalassemia and, particularly, in splenectomized patients with beta -TI who do receive regular transfusions. Thalassemic patients have low levels of protein C and protein S, show enhanced platelet consumption, and show ongoing platelet, monocyte, granulocyte, and endothelial activation. Increased plasma levels of activation peptides, TAT, F1,2, FPA, and D-dimer, are suggestive of continuous thrombin generation and enhanced fibrinolysis. The presence of a persistent hypercoagulable state combined with the infrequent occurrence of significant thrombotic events suggests that thrombosis is largely a subclinical process in thalassemia and has been associated with autopsy findings of platelet and fibrin thrombi in the microvasculature in the lungs and the brain.20,21 These thrombi could contribute to the pulmonary hypertension, low lung capacity, hypoxemia, and diffusion defects associated with right heart failure (cor pulmonale)22-27 and to the high frequency of ischemic brain lesions associated with asymptomatic brain damage as detected by MRI.14
Venous thrombosis is more prevalent in beta -TI patients who are not receiving regular transfusions and who have undergone splenectomy. These patients may be more susceptible to thromboembolism because they have more circulating damaged RBCs and increased platelet counts. The beneficial role of regular blood transfusions is illustrated by the observation that thromboembolic manifestations are more frequently recorded in less developed countries with limited transfusion resources and ex vivo and in vitro experiments that show that normal RBCs can eliminate the abnormal aggregation observed with thalassemic RBCs.
The addition of prophylactic antithrombotic therapy has only recently been suggested for high-risk patients with beta -TI who are exposed to transient thrombotic risk factors (eg, surgery, immobilization, pregnancy).19 Thalassemia major patients who had developed an acute thrombotic event should be considered for prolonged antithrombotic therapy, as for any patients with thrombophilia, in view of their profound hemostatic anomalies. What remains to be seen is whether lifelong treatment with antithrombotic agents is indicated in patients with thalassemia to prevent any subclinical thrombosis in the lungs and brain. It is noteworthy that some thalassemic patients responded to treatment with platelet inhibitor drugs (aspirin and dipyridamole) with a rise in their arterial oxygen content.
Some general notes include, that the clotting is more common in non-transfused intermedias and splenectomized patients. It is also well known that an increased risk of the hypercoagulable state in pregnant intermedias and majors, but our anecdotal evidence within this group suggests that this is also common in thal minors and accounts for multiple miscarriages in many thal minor women.
Testing.
From
http://peir.path.uab.edu/coag/article_208.shtml
From UAB Coagulation Service (http://coag.path.uab.edu)
Guidelines
Thrombophilia Guidelines
Thrombophilia, or hypercoagulability, means an increased risk for thrombosis. Thrombophilia may be congenital or acquired. Thrombosis may be cardiovascular, including angina, myocardial infarction (MI), and peripheral vascular disease (PVD); cerebrovascular, including transient ischemic attack (TIA) and stroke, or venous thromboembolic disease, including deep venous thrombosis (DVT) or pulmonary embolism (PE). Cardiovascular and cerebrovascular diseases are highly dependent on platelet aggregation while venous thromboembolic diseases may be related to coagulation system abnormalities and are the focus of the following discussion:
Why Perform Thrombophilia Testing?
Circumstantial Thrombophilia Risk Factors
Disease-Related Thrombophilia Risk Factors
Circumstances that Require a Workup for Thrombophilia
Primary Thrombophilia Laboratory Test Profile
Acute Thrombophilia Test Profile
Lupus Anticoagulant Testing Algorithm
Lupus Anticoagulant Testing
Anti-cardiolipin Antibodies Testing
Antiphospholipid Syndrome (APS)
Relative Risk of Initial DVT or PE for Acquired Thrombophilia Factors
Prevalence of Congenital Thrombophilia
Relative Risk of First DVT or PE in Congenital Thrombophilia
Why Perform Thrombophilia Testing?
* To establish the pathologic basis of the thrombotic event and provide the opportunity to communicate etiologic factors to patients
* To influence duration of therapy during a thrombotic episode
* To offer prophylaxis for high risk patients during periods of potentially in-creased stimulus (see "Circumstantial Thrombophilic Risk Factors" below)
* To alert the patient's kindred to the presence of inherited risk factors
* To determine the need for alternative laboratory testing when condition affects primary testing mode such as heparin monitoring in patients with a pro-longed PTT due to LA
Refer to the acute thrombophilia test profile for UAB assays to order during thrombotic episodes.
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Circumstantial Thrombophilic Risk Factors
*
Age, previous thrombosis, smoking
*
Pregnancy, contraceptive therapy, hormone replacement therapy (HRT)
*
Immobilization: travel, bedfast, wheelchair, sedentary lifestyle
*
Diet, obesity = lipids and immobilization
*
Orthopedic surgery, neurosurgery, trauma, fractures
*
Blood group non-O with increased VWF and VIII
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Disease-Related Thrombophilic Risk Factors
*
Autoimmune disorders: systemic lupus erythematosus; antiphospholipid syndrome
*
Malignancies: Adenocarcinoma; myeloproliferative diseases such as CML or PV; acute myeloid leukemia, especially M3, M5
*
Paroxysmal nocturnal hemoglobinuria (PNH)
*
Chronic inflammatory diseases: chronically elevated factor VIII and fibrinogen
*
Congestive heart failure
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Circumstances That Require a Laboratory Workup For Thrombophilia
*
Venous thrombosis before 40-50 years of age
*
Unprovoked thrombosis at any age
*
Recurrent thromboses at any age
*
Unusual sites such as cerebral, mesenteric, portal, or hepatic veins
*
Positive family history for thrombosis
*
Thrombosis during pregnancy, oral contraceptives, or hormone replacement therapy (HRT)
*
Unexplained abnormal laboratory test such as prolonged PTT
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Primary Thrombophilia Laboratory Test Profile
Order the following series of assays when the patient is not taking an anticoagulant such as Coumadin® (warfarin) or heparin and has taken no anticoagulant or has not had a thrombotic event for at least ten days:
*
Activated protein C resistance (APCR)
o
Perform factor V Leiden mutation assay when the APCR ratio is below the cutoff, indicating resistance
*
Lupus anticoagulant testing
*
Anticardiolipin antibodies IgG and IgM
*
Antithrombin activity
o
Perform antithrombin antigen assay when activity is consistently low
*
Fasting homocysteine
*
Factor VIII activity
*
Protein C activity
o
Perform protein C antigen assay when activity is consistently low
*
Protein S activity
o
Perform free and total protein S antigen when activity is low
*
Prothrombin 20210 mutation assay
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Acute Thrombophilia Test Profile
Order the following assays when the patient is currently taking an anticoagulant such as Coumadin® (warfarin) or heparin, has had a thrombotic event, or has taken an anticoagulant within the last ten days:
*
Activated protein C resistance (APCR)
o
Perform factor V Leiden mutation assay when the APCR ratio is below the lower limit of the reference interval, indicating resistance
*
Fasting homocysteine
*
Anticardiolipin antibodies IgG and IgM
*
Prothrombin G20210A mutation assay
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Lupus Anticoagulant Testing Algorithm
Click to enlarge
Click to enlarge
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Lupus Anticoagulant Testing
LA testing requires two clot-based assays . Laboratories may choose to perform a low phospholipid PTT reagent designed to detect LA (PTT-LA) and the dilute Russell viper venom time (DRVVT) test (see figures above and table below). Warfarin prolongs the DRVVT and heparin affects the PTT-LA.
When the PTT-LA is prolonged, perform a thrombin time to detect heparin. If present, treat specimen with Hepzyme® before further testing.
* When heparin is ruled out, the next step is to check for the presence of an inhibitor by a mixing study, which should fail to correct.
* LA is confirmed by correction of the prolonged PTT-LA and/or DRVVT with a high phospholipid reagent. If LA only affects PTT-LA, rule out factor VIII inhibitor by checking a factor VIII level.
Click to enlarge
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Anti-cardiolipin Antibodies Testing
Anti-cardiolipin antibodies of IgG or IgM isotype are measured in immunologic assays (ELISA) and do not prolong clot-based tests. Results of medium or high titer on two or more consecutive occasions at least 12 weeks apart are evidence for chronicity and possible APS.
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Antiphospholipid Syndrome (APS)
APS is the most common acquired thrombotic disease. Anti-phospholipid antibodies (APLs) in the form of lupus anticoagulant, anti-cardiolipin antibody, or anti-beta 2 glycoprotein 1 are found in 5% of unselected individuals, and 2% remain on repeat testing . They are in 10 to 50% of people with autoimmune disorders. The relative risk of thrombosis for people with primary APLs is 1.6 to 3.2.
APS is diagnosed when a patient has a history of thrombosis or pregnancy complications AND a positive LA or anticardiolipin antibody which persist for 12 weeks.
Vascular thrombosis
* One or more clinical episodes of arterial or venous thrombosis in any tissue con-firmed by imaging, Doppler, or histopathology without evidence of vessel wall in-flammation is evidence for APS.
Obstetric morbidity
* APS is suspected if a patient has a history of one or more unexplained documented fetal deaths beyond ten weeks of gestation, one or more premature births of normal neonates at or before 34 weeks dues to eclampsia or placental insufficiency, or three or more unexplained consecutive spontaneous abortions before 10 weeks.
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Relative Risk of Initial DVT or PE for Acquired Thrombophilia
· Femoral and tibial fractures
80%
· Hip, knee, GYN, prostate surgery
50%
· Adenocarcinoma
20x
· Chronically elevated factor VIII
6x
· Oral contraceptives (30 mg)
4-6x
· Pregnancy
3-5x
· Hormone replacement (5 mg)
2-4x
· Homocysteinemia due to vitamin deficiency
2-7x
· Chronic APL without a known autoimmune disorder
1.6-3.2´
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Prevalence of Congenital Thrombophilia
Factor
General
Population
People With
Thrombosis
· APCR: factor V Leiden mutation
3-8% of Caucasians
20-25%
· Prothrombin G20210A
2-3% of Caucasians
4-8%
· Antithrombin deficiency
1 in 2-5000
1-1.8%%
· Protein C deficiency
1 in 300
2.5-5.0%
· Protein S deficiency
Unknown
2.8-5.0%
· Hyperhomocysteinemia
11%
13.1-26.7%
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Relative Risk of First DVT or PE in Congenital Thrombophilia
Factor
Odds of Thrombosis
· APCR: heterozygous factor V Leiden mutation
3x
· APCR: homozygous factor V Leiden mutation
18x
· Prothrombin G20210A heterozygotes
2-4.8x
· Antithrombin deficiency heterozygotes
10-20x
· Protein C deficiency heterozygotes
6.5x
· Protein S deficiency heterozygotes
1.6 to 11.5x
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