Thank you for all the contributions to the case this week!
This week we discussed a 45 year old man who presented with a recurrent pulmonary embolism (PE) whilst on rivaroxaban. He had had a PE 2 years prior to his current admission.
- From our history/examination we established:
- He had no overt risk factors for venous thromboembolism (VTE) with no recent immobility, surgery and no symptoms/signs suggestive of malignancy/autoimmune disease.
- He was compliant with his rivaroxaban and taking it with meals (reduced absorption of rivaroxaban with fasting state) and was not on any interacting medications.
- • He had no family history of VTE.
- He was haemodynamically stable with no evidence of right heart strain / pulmonary hypertension on echo.
As he had had failed to be adequately anticoagulated whilst on rivaroxiban he was initially switched to therapeutic low molecular weight heparin whilst being loaded with warfarin.
On discharge follow up was arranged in the anticoagulation clinic (warfarin monitoring) and thrombosis clinic for review and follow up of the extensive investigations that we had requested (see below). Unfortunately only 3 days later he represented with confirmed extension of his PE and renal/liver dysfunction.
The following are the results of the multiple investigations we requested throughout our complicated case:
- Progressive thrombocytopenia (nadir 75) and new anaemia (Hb 103)
- Deranged LFTs with mixed conjugated and unconjugated bilirubin
- Stage 1 AKI
- USS liver: Suggestive of sinusoidal obstructive syndrome
- CT CAP: No evidence of malignancy
- JAK2 negative
- No PNH clone
- No Factor V leiden / FII genetic mutation (NB other aspects of thrombophilia screen not requested as recent event and on anticoagulation)
- Antiphospholipid antibodies: Positive
- Lupus anticoagulant final ratio: 2.1 (<1.2 normal)
- Note this was performed on anticoagulation so could be a false positive
- IgG and IgM cardiolipin antibodies: <10 U/ml.
- Anti IgG B2 glycoprotein antibodies 347 U/ml (0-7).
- Autoantibody screem negative.
- Therapeutically anticoagulated
- Peak anti-Xa levels on re-admission: 0.84. INR 2.2 on readmission
- HIT pre-test probability score: low risk therefore no further HIT investigations performed.
To summarise our patient had rapidly recurrent thrombosis despite adequate anticoagulation, AKI, evidence of sinusoidal obstructive syndrome, MAHA. The investigations demonstrated strongly positive anti IgG B2 glycoprotein antibodies. The clinical and laboratory features are all consistent with Catastrophic Antiphospholipid Syndrome.
Antiphospholipid syndrome (APS)
APS is an acquired autoimmune condition. It is a clinicopathological diagnosis characterised by thrombosis / pregnancy morbidity and the persistence of antiphospholipid antibodies. It affects approximately 1% of the population and the median age of onset is 31 years. It can be primary (idiopathic) or secondary (commonly associated with other autoimmune conditions, malignancy).
APS Diagnostic criteria
APS syndrome is present if at least one of the following clinical criteria AND at least one of the laboratory criteria are met.
- Vascular thrombosis
- ≥1 arterial, venous or small vessel thrombosis
- Pregnancy morbidity
- ≥1 unexplained deaths of a morphologically normal fetus ≥10th week of gestation
- ≥1 pre-term births of a morphologically normal neonate <34th week of gestation secondary to eclampsia/pre-eclampsia or recognised placental insufficiency
- ≥3 unexplained consecutive spontaneous miscarriages <10th week of gestation
- Lupus anticoagulant (LA) on ≥2 occasions at least 12 weeks apart
- IgG / IgM aCL antibodies present in medium/high titre on ≥2 occasions at least 12 weeks apart
- IgG / IgM Anti-β2-glycoprotein antibody on ≥2 occasions at least 12 weeks apart
Antiphospholipid antibodies (aPL)
Incidental findings of aPL is reasonably common and found in approximately 1% of the general population. aPL are frequently temporary, for example following infection. It is believed that additional factors contribute to the thrombotic / pregnancy morbidity – a ‘second hit phenomenon’ and indeed the majority of people with aPL do not develop the clinical features of APS.
• Two tests based on different principles should be performed. DRVVT should be one of these tests and the other is typically be an APTT using a reagent with lupus anticoagulant sensitivity. Patients should be regarded as lupus anticoagulant positive if one test is positive.
• Testing for lupus anticoagulant is not accurate when on the patient is anticoagulation (VKA antagonists, DOACs and heparin) and should be avoided.
• Testing for coagulation factors in the presence of lupus anticoagulant can be misleading especially those for intrinsic pathway factors based on 1-stage methods.
• Monitoring of oral anticoagulants in patients with lupus anticoagulant can be misleading and a baseline PT /APTT should be performed. If this is prolonged an alternative PT reagent for which the baseline is normal should be used. Point-of-care devices should be used with caution for INR determination. Anti-Xa levels should be used to monitor heparin if the APTT is prolonged.
• Lupus anticoagulant is more strongly associated with thrombosis in comparison to the other antiphospholipid antibodies.
- Detected using an ELISA technique
- Can be reliably tested for when on anticoagulation
- IgG isotype and higher titres are more associated with thrombosis.
Anti-β 2 glycoprotein 1 antibodies
- Detected using an ELISA technique
- Can be reliably tested for when on anticoagulation
- The IgG isotype is more commonly associated with thrombotic sequelae but overall β 2 glycoprotein 1 antibodies are less commonly associated with pathological sequelae than the other aPL.
Who should be tested for aPL?
It should be tested for in individuals in which it’ll alter there management.
- Unprovoked proximal DVT / PE
- Young adults (<50 years) with ischaemic stroke
- Obstetric morbidity / mortality
Management of APS?
There is limited evidence to guide upon the management of APS. It is important to modify other risk factors for thrombosis / pregnancy morbidity.
Standard dosing of anticoagulation. Patients with APS have a higher risk of recurrence and if VTE is unprovoked anticoagulation should be longterm. If there is a contributory risk factor for thrombosis in addition to APS then the individual risks/beenfits need to reviewed. To decide upon duration of the anticoagulation.
Patients with ischaemic stroke / MI with APS may be at higher risk of recurrence and cohort studies suggest that anticoagulation with warfarin should be considered but there is no strong evidence that it is better than antiplatelet therapy
Recurrent (≥3) pregnancy loss: Antenatal administration of heparin combined with low dose aspirin is recommended throughout pregnancy and should be initiated as soon as pregnancy is confirmed.
History of pre-eclampsia or fetal growth restriction: Low dose aspirin.
Women with aPL should be considered for post-partum thromboprophylaxis
Catastrophic Antiphospholipid Syndrome (CAPS)
Life threatening condition with acute onset characterised by multiple organ thrombosis commonly involving the microvasculature. This is a rare condition affecting <1% of APS cases. It can be a diagnostic challenge as it is the first presentation of APS in ~50% of adults and can affect any organ or tissues although does tend to have a predilection for the kidneys, lungs and brain. It also shares similarities with other conditions such as thrombotic microangiopathies, HITT, etc. Mortality rates of CAPS is high at approximately ~37% in the acute setting.
In particular relevance to our case CAPS has multiple abdominal manifestations including sinusoidal obstructive syndrome. It also one the many causes of MAHA. According to the CAPS Classification criteria our patient had ‘probable CAPS’ as we did not have a biopsy confirming small vessel occlusion.
CAPS Classification Criteria
- Evidence of involvement of ≥3 organs, systems, tissues
- Development of manifestations simultaneously or <1 week
- Confirmation by histopathology of small vessel occlusion
- Laboratory confirmation of the presence of aPL
Definite CAPS: All four criteria
- All 4 criteria, except only 2 organs, systems, tissues
- All 4 criteria, except for the absence of laboratory confirmation of aPL
- Criteria 1,2 and 4
- Criteria 1, 3 and 4 with the development of a 3rd event ≥1 week <1 month of presentation, despite anticoagulation
Management of CAPS
There is only limited data to guide on the management of CAPS. It requires an multidisciplinary approach and prompt treatment is essential to reduce morbidity and mortality.
- Therapeutic anticoagulation
- Due to critical illness unfractioned heparin is often instituted
- If recurrent VTE then target INR / anti-Xa level should be increased
- Corticosteroids – initially high dose methylprednisolone for 3 days following by slow wean of prednisolone.
- Plasma exchange – there is an approximate >20% increase in survival with the addition of plasma exchange to anticoagulation and steroids.
- If patients aren’t responding adequately IVIg can be considered. If the patient is undergoing plasma exchange IVIg should be instituted when this has finished.
Immunosuppressive therapies– there are no large, prospective trials to guide upon which immunosuppressive therapy to use. The following are used:
- Associated with improved survival if CAPS is in association with SLE.
- Tending to be increasing used.
- Not licensed but experts have used as a last resort.
● Keeling et al. Guideline on the investigation and management of APS. British Journal of Haematology. 157 (1): 47-58. 2012.
● Galli et al. Lupus anticoagulants are stronger risk factors for thrombosis than aCL antibodies in the antiphospholipid syndrome: a systemic review of the literature. Blood. 101 (5). 1827-1832. 2003
● Giannakapoulos et al. How I treat APS. Blood. 114 (10). 2020-2031. 2009
● Ortel et al. How I treat CAPS. Blood 126: 1285-1293. 2015.
● Kazzaz et al. Treatment of antiphospholipid syndrome. https://www.ncbi.nlm.nih.gov/pubmed/26927441