Hereditary and Acquired Thrombophilias
The primary aim is to identify existing hereditary or acquired pro-thrombotic conditions that increase susceptibility to VTE. This testing serves to evaluate the likelihood of recurring VTE in individuals following their initial unprovoked occurrence. Rather than focusing primarily on thrombophilias, it’s more useful to identify whether a DVT is provoked or unprovoked, and to consider patient sex and age when determining the risk of recurrent DVT and the need for long-term anticoagulation. Hospital-acquired VTEs, accounting for up to two-thirds of all VTE events, highlight the importance of recognizing situations where recurrent risk is low, thus requiring only a three-month anticoagulation regimen. Thrombophilia testing’s necessity remains controversial, with current consensus suggesting it should be conducted when patient management will be influenced.
When to consider Thrombophilia testing:
1. Patients with their first unprovoked DVT, testing can help identify a high recurrence risk, especially in younger patients (up to 40-45 years) where thrombophilia is more prevalent. A negative test shouldn’t necessarily lead to discontinuing anticoagulation after three to six months of treatment. However, severe thrombophilia might support extended treatment.
2. DVT at unusual sites (e.g., cerebral veins) without apparent provocation, especially when combined with a strong family history of VTE, particularly in those under 45 years old.
3. Females with histories of recurrent miscarriages or obstetric morbidities related to placental ischemia can be suspected of DVT, and antiphospholipid antibody testing can be useful.
Timing for Thrombophilia testing:
Thrombophilia testing should be avoided in the acute period following a recent VTE, especially if the patient is on anticoagulants. Plasma level assays are best performed at least two weeks after stopping VKAs or three days after discontinuing a DOAC. Genetic testing can be done at any time. Abnormal plasma thrombophilia tests should be repeated on a different day for confirmation. Patients studied while on anticoagulants should be retested later, as protein C and S levels and routine lupus anticoagulant testing are affected by VKAs and DOACs.
| Hereditary | Antithrombin deficiency | 1. Autosomal dominant 2. 10-15% Familial Thrombophilias | Heterozygous trait leads to 5-20 fold increase in risk for VTE | 1. Type 1 - Parallel reduction in biochemical activity and antigen concentration 2. Type 2 - Only functional defect (biochemical activity reduced), with normal antigen concentration 3. Homozygous trait is incompatible with life |
| Protein C deficiency | Homozygotes and compound heterozygotes are just compatible with life. - Protein C < 0.01 U/ml - spontaneous skin necrosis in neonatal life (neonatal purpura fulminans) - Protein C ~ 0.04-0.06 U/ml - 7-10 fold increase in risk for VTE in later life. | 1. Vitamin K dependent protease (synthesized in liver) 2. Activated by thrombin and cause proteolytic degradation of activated factor V and VIII 3. Purpura fulminans - protein C replacement by Fresh frozen plasma and Protein C concentrate 4. Warfarin induced skin necrosis - half life of Protein C < other vitamin K dependent coagulation factors leads to hypercoagulable rate |
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| Protein S deficiency | 1. Reduced concentration of free protein S - 2-10 fold increased risk of VTE, | 1. Vitamin K dependent protease (synthesized in liver) 2. Co-factor for the anticoagulant function of APC (Free Protein S) 3. Bound Protein S (40%) - bound to complement 4b binding protein 4. Increased risk of skin necrosis during VKA therapy. |
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| Factor V Leiden | Single point mutation at nucleotide position 1691 in the factor V gene (substitution of arginine by glutamine) | 1. Heterozygotes - 5 fold increase in VTE risk 2. Homozygotes - 80 fold increase in VTE risk | 1. Most common cause of APC resistance. 2. Amino acid substitution prevent APC from recognizing a cleavage site on factor V causes resistance to anticoagulation action of APC |
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| Activated protein C (APC) resistance | ||||
| Prothrombin G20210A variants | Single point mutation at nucleotide position 20210 in the prothrombin gene (substitution of glutamine by arginine) | 30% increase in prothrombin antigen or activity assay | Carriers - increased risk of DVT | |
| Dysfibrinogenaemia | ||||
| Factor XIII 34val | ||||
| Fibrinogen (G) 10034T | ||||
| A and/or B alleles of the ABO blood group | ||||
| Prothrombin Yukuhashi (II R596L) | ||||
| Acquired | Antiphospholipid syndrome (APS) | Antiphospholipid antibodies (aPL) | 1. Thrombosis in vascular bed and DVT 2. Aggressive variant of APS causes multi-organ system involvement | 1. Test to be performed on two occasion more than 12 week apart because transient antibodies can occur 2. All three assay are to be performed: - Lupus anticoagulant - Anticardiolipin antibodies - anti-beta-2 glycoprotein I antibodies 3. Stroke at young age, thrombotic myocardial infarction and placental dysfunction |
| Paroxysmal nocturnal haemoglobinuria | Stomatic mutations in phosphatidylinositol glycan A gene (PIGA) in hematopoietic stem cell. | PNH with history of VTE - maintain anticoagulation indefinitely | 1. Eculizumab (anti C5 monoclonal antibody) 2. Supportive care - Transfusion and anticoagulation 3. Allogenic stem cell transplant |
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| Myeloproliferative syndromes with JAK2V617F mutation | ||||
| Other causes | Hemolytic states | Sickle cell crisis | ||
| Any inflammatory disease | 1. Infection e.g pneumonia 2. Rheumatoid arthritis 3. Inflammatory bowel disease 4. Systemic lupus erythematosus 5. Adamantiades-Behcet disease |
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| Nephrotic Syndrome | Loss of antithrombin in the urine |