History

Fact Explanation
Swollen, reddened limb (unilateral or bilateral) Antiphospholipid syndrome is a disease with following features: arterial or venous thrombosis, recurrent miscarriages occur in a person, laboratory tests positive for antiphospholipid antibodies. The most frequent manifestation in this syndrome is deep vein thrombosis.[1]This is part of diagnosing criteria. [7] This occurs due to transudation of fluid following the venous obstruction and congestion of blood in the affected region.
Pain and tenderness in the calf of the swollen limbs The most frequent manifestation in this syndrome is deep vein thrombosis.[1] This occurs due to transudation of fluid following the venous obstruction and congestion of blood in the affected region.
Acutely developing varicose veins This can be a presentation of DVT. This is due to the opening of collateral veins.
Severe pain and the onset numbness of the affected limb This is due to compartment syndrome created by the increasing pressure resulting in reduced arterial flow causing limb threatening ischemia.
Sudden onset dyspnoea This is due to pulmonary embolism[2]. The thrombi in the limbs and distal veins get dislodged and obstructs the pulmonary arteries. This can be due to a rare complication of respiratory distress syndrome following Pulmonary capillaritis. [1]
Haemoptisis. This is a feature of a larger PE [2].This occurs due to ruptured pulmonary vessels due to increased pressure.
Sudden onset chest pain. This is due to pulmonary embolism [2].The thrombi in the limbs and distal veins get dislodged and obstructs the pulmonary arteries.
Sudden onset Syncope This is a feature of PE [2].This occurs due to reduced cardiac output and diminished cerebral flow.
Sudden onset limb weakness, Difficulty in speech, difficulty in swallowing This due to a cerebrovascular accident (ischemic stroke)[1][3]. Arterial thrombosis is presented in this manner. Valvular damage, vegetation like growth and embolisation [6]can cause strokes. Limb weakness and paresthesia and sphincter dysfunction can be the result of transverse myelopathy (an interaction between aPL and cellular components). [1] Arterial thrombi is part of diagnosing criteria. [7]
Visual disturbance Visual disturbance[6] is due to obstruction of retinal arteries due to thrombosis.
Headache Headache can be a feature due to ischemia following thrombosis.[6]
Obstetric complications: Early and late fetal losses, premature births Early and late fetal losses, premature births frequent fetal and obstetric manifestations. [1][4][5] There are few mechanisms in the pathophysiology. Thrombosis, complement activation and imbalanced angiogenesis [1] Following 3 facts are in the diagnosing criteria[7]: one or more unexplained events of following 2; loss of morphologically normal fetus( more than 10th week of gestation), premature births of a normal neonate before the 34th week of gestation( due to eclampsia, pre-eclampsia), three or more and unexplained event of following and consecutive spontaneous abortions before the 10th week of gestation
Obstetric complications: Pre-eclampsia Pre-eclampsia is a frequent obstetric complication. [1],[4] There are few mechanisms in the pathophysiology. Thrombosis, complement activation and imbalanced angiogenesis. [1]
Dyspnoea, Orthopnoea, and paroxysmal nocturnal dyspnoea This can be the result of myocardial infarction following thrombosis, valvular incompetence( ex-mitral, )[6]
Cutaneous manifestations: Livedo reticularis This occurs due to immune complex deposition inside dermal vessels. [6]
Anuria or oliguria This is due to renal failure following thrombosis of renal vessels.[6]
Severe sepsis like symptoms ( i.e. altered consciousness, collapse) This is due to catastrophic Antiphospholipid Syndrome (systemic inflammatory response syndrome, due to excessive cytokine release from necrotic tissues). This is characterized by multiple microvascular thrombosis and multiorgan failure. [1]
Risk factors associated in developing aPLS Autoimmune conditions (SLE [8] ,Sjogren's syndrome), past history of syphilis, HIV/AIDS, Lyme disease or Hepatitis C, history of using drugs such as hydralazine, quinidine, phenytoin ,amoxicillin or a positive family history.
Risk factors associated in developing thrombosis. Factors such as pregnancy, immobility smoking [8], hyperlipidemia, high BMI[8]and oral contraceptive use can increase the risk of thrombus formation.
References
  1. ESPINOSA G, CERVERA R. Antiphospholipid syndrome Arthritis Res Ther [online] 2008, 10(6):230 [viewed 01 July 2014] Available from: doi:10.1186/ar2536
  2. HWANG HG, SCHULMAN S. Respiratory Review of 2013: Pulmonary Thromboembolism Tuberc Respir Dis (Seoul) [online] 2013 Sep, 75(3):89-94 [viewed 01 July 2014] Available from: doi:10.4046/trd.2013.75.3.89
  3. ETEMADIFAR M, DEHGHANI L, TAHANI S, TOGHIANIFAR N, RAHAIMI M, ESKANDARI N. Neurological manifestations in patients with antiphospholipid syndrome Iran J Neurol [online] 2013, 12(4):172-175 [viewed 01 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829301
  4. MARCHETTI T, COHEN M, DE MOERLOOSE P. Obstetrical Antiphospholipid Syndrome: From the Pathogenesis to the Clinical and Therapeutic Implications Clin Dev Immunol [online] 2013:159124 [viewed 01 July 2014] Available from: doi:10.1155/2013/159124
  5. DUCKITT K, QURESHI A. Recurrent miscarriage Clin Evid (Online) [online] :1409 [viewed 01 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275302
  6. KONIARI I, SIMINELAKIS SN, BAIKOUSSIS NG, PAPADOPOULOS G, GOUDEVENOS J, APOSTOLAKIS E. Antiphospholipid syndrome; its implication in cardiovascular diseases: a review J Cardiothorac Surg [online] :101 [viewed 01 July 2014] Available from: doi:10.1186/1749-8090-5-101
  7. LIM W.. Antiphospholipid antibody syndrome. Hematology [online] December, 2009(1):233-239 [viewed 01 July 2014] Available from: doi:10.1182/asheducation-2009.1.233
  8. QUSHMAQ NA, AL-EMADI SA. Review on Effectiveness of Primary Prophylaxis in aPLs with and without Risk Factors for Thrombosis: Efficacy and Safety ISRN Rheumatol [online] :348726 [viewed 05 July 2014] Available from: doi:10.1155/2014/348726

Examination

Fact Explanation
Swollen erythematous limb This is present in specially lower limb thrombi. The most frequent manifestation in this syndrome is deep vein thrombosis. [1] This occurs due to transudation of fluid following the venous obstruction and congestion of blood in the affected region.
Severe pain in the calf with passive dorsiflexion of the foot. This is positive Homan's sign.It is positive in deep vein thrombosis. The most frequent manifestation in this syndrome is deep vein thrombosis. [1]
Varicose veins This can be a presentation of DVT.this is due to the opening of collateral veins.
Tachypnea This is a common sign in PE. This can be due to poor pulmonary circulation causing cerebral hypoxia and a reflex increase in the respiratory rate.
Tachycardia This is a common sign in PE.Low cardiac output, pain and sympathetic activation can increase the heart rate.
Neck vein dilation This occurs in obstruction of the pulmonary arteries by the thrombus.
Hypotension This is present in massive PE[2].This occurs due to reduced cardiac output following obstruction of the pulmonary arteries.
Cyanosis This is present in massive PE.This occurs due to reduced pulmonary circulation and reduces oxygenation of blood.
Loud P2 on auscultation This is also a feature found in Pulmonary Embolism.
Pansystolic murmur at the apex radiating to the axilla This is due to the regurgitant murmur of Mitral regurgitation. [5]
In a pregnant female: Hypertension This can be due to Pregnancy induced hypertension caused by Antiphospholipid Syndrome.
In a pregnant female: Fundus less than dates This can be caused by placental thrombi resulting in placental insufficiency.
Hemiplegia with increased tone and exaggerated reflexes. This due to a cerebrovascular accident. [1][3]. Arterial thrombosis is presented in this manner. Valvular damage, vegetation like growth and embolisation[5] can cause strokes.
Livedo reticularis This is a net-like, hyperpigmented and violaceous, appearance on the skin that occur due to changes in cutaneous circulation. [4]
References
  1. ESPINOSA G, CERVERA R. Antiphospholipid syndrome Arthritis Res Ther [online] 2008, 10(6):230 [viewed 01 July 2014] Available from: doi:10.1186/ar2536
  2. HWANG HG, SCHULMAN S. Respiratory Review of 2013: Pulmonary Thromboembolism Tuberc Respir Dis (Seoul) [online] 2013 Sep, 75(3):89-94 [viewed 01 July 2014] Available from: doi:10.4046/trd.2013.75.3.89
  3. ETEMADIFAR M, DEHGHANI L, TAHANI S, TOGHIANIFAR N, RAHAIMI M, ESKANDARI N. Neurological manifestations in patients with antiphospholipid syndrome Iran J Neurol [online] 2013, 12(4):172-175 [viewed 01 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829301
  4. ROSE AE, SAGGER V, BOYD KP, PATEL RR, MCLELLAN B. Livedo reticularis. Dermatol Online J [online] 2013 Dec 16, 19(12):20705 [viewed 01 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24364996
  5. KONIARI I, SIMINELAKIS SN, BAIKOUSSIS NG, PAPADOPOULOS G, GOUDEVENOS J, APOSTOLAKIS E. Antiphospholipid syndrome; its implication in cardiovascular diseases: a review J Cardiothorac Surg [online] :101 [viewed 01 July 2014] Available from: doi:10.1186/1749-8090-5-101

Differential Diagnoses

Fact Explanation
Thrombotic thrombocytopenic purpura (TTP) The following features will be present: central nervous system (eg, confusion, visual disturbance, seizure, aphasia, hemiparesis and coma), acute kidney injury , cardiac conduction defects, congestive cardiac failure and bleeding manifestations such as bruising, petechiae, menorrhagia, epistaxis, hematuria, and gastrointestinal hemorrhage, fever and hemolytic jaundice. [3]
Heparin induced thrombocytopenia (HIT) It occurs in patients treated with Unfractionated Heparin during cardiac catheterization, angioplasty, cardiopulmonary bypass and the treatment of unstable angina and myocardial infarction. It typically occurs within 4-15 days after initiating treatment. There is multiple and recurrent arterial and venous thromboembolic events. [4]
Disseminated intravascular coagulation (DIC) DIC is common in patients with malignancies, trauma, obstetric complications (placental abruption), and in sepsis. [5] In these patients bleeding manifestations occur[5] such as bleeding from cannula sites, uncontrolled bleeding during surgery.
Antithrombin III Deficiency There are recurrent episodes of venous thrombosis and a positive family history. This is rare (0.2%), but it is common 0.5–7.5% in patients with venous thromboembolism.[6]
Protein C Deficiency Protein C(with the cofactor protein S) inactivates factors Va and VIIa. Its association with venous thrombosis. This is seen in 0.2% of the community and 2.5–6% of the patients with venous thrombosis.[6]
Protein S Deficiency Protein S deficiency occurs in 1.35% of the patients with venous thrombosis. Only one-third of the patients develop venous thrombosis by 60 years.[6]
Activated Protein C Resistance and Factor V Leiden It was found that factor V allele was resistant to the proteolytic effect of protein C. 10% of the patients with venous thrombosis have factor V Leiden.It is rare in people of African and Asian descent. Factor V Leiden by itself is a low-risk factor for venous thrombosis.The risk increases with events such as perioperative periods after surgery[6]
Factor II Prothrombin Gene Mutation There is a mutation at base 20210 of the prothrombin gene. Incidence of thrombosis is lower than other conditions. [6]
Increased levels of Factors VIII, IX, and XI Patients with history of venous thrombosis have shown increased levels of factors VIII, IX, and XI.[6]
References
  1. LIM W.. Antiphospholipid antibody syndrome. Hematology [online] December, 2009(1):233-239 [viewed 01 July 2014] Available from: doi:10.1182/asheducation-2009.1.233
  2. HUNT,Beverley J. AMES, Paul R.J Antiphospholipid Syndrome: Differential Diagnosis.[online]2006[viewed 2 July 2014]. Available form: http://link.springer.com/chapter/10.1007%2F1-84628-009-5_22#page-1
  3. BLOMBERY P, SCULLY M. Management of thrombotic thrombocytopenic purpura: current perspectives J Blood Med [online] :15-23 [viewed 02 July 2014] Available from: doi:10.2147/JBM.S46458
  4. KOTWAL J, CHAUDHARY S, MANOJ MG, HASNAIN S, NAIR V, LUTHRA M. Heparin: Induced thrombocytopenia: Incidence and laboratory approach to diagnosis in Indians. Indian J Pathol Microbiol [online] 2014 Jan-Mar, 57(1):31-8 [viewed 02 July 2014] Available from: doi:10.4103/0377-4929.130886
  5. KANEKO T, WADA H. Diagnostic criteria and laboratory tests for disseminated intravascular coagulation. J Clin Exp Hematop [online] 2011, 51(2):67-76 [viewed 02 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22104305
  6. PINJALA RK, REDDY LR, NIHAR RP, PRAVEEN GV, SANDEEP M. Thrombophilia - How Far and How Much to Investigate? Indian J Surg [online] 2012 Apr, 74(2):157-162 [viewed 02 July 2014] Available from: doi:10.1007/s12262-011-0407-2

Investigations - for Diagnosis

Fact Explanation
Lupus Anticoagulant If Lupus Anticoagulant is present (detected according to the guidelines of International Society on Thrombosis and Haemostasis) on 2 occasions (12 weeks apart) the diagnosis of Antiphospholipid syndrome can be made.[1][2]
Anticardiolipin antibody If Anticardiolipin antibody (IgG and/or IgM isotype) is present with titer greater than 40 GPL or MPL, or greater than the 99th percentile (measured by a standardized ELISA) in 2 occasions( 12 weeks apart)[1] [2], then diagnosis of aPLS can be made.
Anti-beta2-glycoprotein-1 antibody If Anti-beta 2-glycoprotein-1 antibody ( IgG and/or IgM isotype)-is present in titer greater than the 99th percentile, (measured by a standardized ELISA test) in 2 occasions( 12 weeks apart)[1] [2]then diagnosis of aPLS can be made.
Duplex scan of the legs This scan is commonly used to detect deep vein thrombosis[3], because in aPLS, the commonest presentation is Deep Vein Thrombosis.
Venography This scan is commonly used to detect deep vein thrombosis [3], because in aPLS, the commonest presentation is DVT.
Arterial angiograms Arterial thrombi can be presented with CNS symptoms or rarely with peripheral symptoms).This method is used in diagnosing arterial thrombi in both situations.
Full blood count In some patients there can be a co-existent thrombocytopenia. [1]
References
  1. LIM W.. Antiphospholipid antibody syndrome. Hematology [online] December, 2009(1):233-239 [viewed 02 July 2014] Available from: doi:10.1182/asheducation-2009.1.233
  2. RAND JH, WOLGAST LR. Dos and don'ts in diagnosing antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program [online] 2012:455-9 [viewed 02 July 2014] Available from: doi:10.1182/asheducation-2012.1.455
  3. DEL PAPA N, VASO N. Management of Antiphospholipid Syndrome Ther Adv Musculoskelet Dis [online] 2010 Aug, 2(4):221-227 [viewed 02 July 2014] Available from: doi:10.1177/1759720X10365969

Investigations - Followup

Fact Explanation
PT-INR Long-term warfarin treatment needs monitoring of the PT- INR, the target range PT- INR is 2.0 to 3.0. [1]
Haemoglobin long-term warfarin treatment needs monitoring of hemoglobin levels to detect any asymptomatic decrease in hemoglobin that might indicate bleeding that can be unnoticed to the patient. [1]
References
  1. LIM W.. Antiphospholipid antibody syndrome. Hematology [online] December, 2009(1):233-239 [viewed 01 July 2014] Available from: doi:10.1182/asheducation-2009.1.233

Management - General Measures

Fact Explanation
Counsel the patient. Explain the importance of identifying symptoms and signs of complications(DVT) and the compliance with treatment. Symptoms of DVT are acute onset leg swelling,erythema and calf pain (usually not associated with fever or local trauma.There may be acute onset varicose veins in some patients Patient should be explained about the possibility of a pulmonary embolism and the high mortality rates.So acute onset chest pain, Dyspnoea, Haeoptysis should prompt urgent hospitalisation. To minimize the above mentioned problems and prevent recurrence, adherence to treatment should be emphasized.
Explain the issues regarding the use of Warfarin Warfarin has some adverse effects Ex1. Bleeding(GI, CNS,) so drugs such as NSAIDS should be avoided.[1] 2.Drug interactions Drugs such as Azoles,Sulpanomides[1],SNRIs and Antiarrhthmics(Amiaderone increase the action of Warfarin so dose adjustment is required. Drugs such as anticonvulsents decrease the action of Warfarin. Drugs such as Omeprazole, Cimetadine reduce the absorption so has to be substituted. Avoid Warfarin in First trimester due to Teratogenicity.
References
  1. LINDH JD, ANDERSSON ML, MANNHEIMER B. Adherence to Guidelines for Avoiding Drug Interactions Associated with Warfarin - A Nationwide Swedish Register Study PLoS One [online] , 9(5):e97388 [viewed 03 July 2014] Available from: doi:10.1371/journal.pone.0097388

Management - Specific Treatments

Fact Explanation
Venous Thromboembolism: initial treatment If there are no contraindications to heparin therapy such as active bleeding, allergy or documented HIT, unfractionated heparin, low molecular weight heparin or pentasaccharide (least 4 to 5 days) with warfarin overlap can be started as the initial therapy. [1][4]
Venous Thromboembolism: long-term treatment Warfarin (or other vitamin K antagonists) administered with a target international normalized ratio (INR) of 2.0 to 3.0 is recommended In patients with APS and thrombocytopenia. [1].[4] The duration of treatment is indefinite. [1][2] With recurrent thrombosis, lifelong treatment is needed.
Management of arterial thrombosis. In a patient with stroke, aspirin is typically the first choice. Warfarin can be started in an ischemic stroke due to the risk of thrombosis. Myocardial infarction and peripheral arterial thromboembolism need long-term warfarin therapy. [1] [4]
Antithrombotic recommendations during pregnancy Women with antiphospholipid syndrome, with no history of thrombosis low-dose aspirin with prophylactic unfractionated heparin or low molecular weight heparin, should be given in the antepartum period. [1][3][4] One of the commonest obstetric complications of aPLS is pre-eclampsia[6].
Treatment of associated thrombocytopenia Treatment should be initiated with overt bleeding or with increased risk of bleeding. If platelet level is less than 20 to 30 × 109/L or if patient presents with bleeding, treatment can be considered.[1] Changing the intensity of anticoagulant therapy in individual patient basis can be considered. Glucocorticoids, intravenous immune globulin (IVIgG), immunosuppressive agents (azathioprine, cyclophosphamide) are used.
Treatment of associated bleeding The antithrombotic agent needs to be discontinued first. [1] The specific antidotes should be administered. i.e. Protamine sulfate for heparin, Vitamin K for warfarin. [1] Administration of frozen plasma for heparins or warfarin, prothrombin complex concentrates for warfarin can be done in the acute management.[1] Red cell transfusions for symptomatic anemia can be considered.[1] If thrombocytopenia is detected, or if the patient is on aspirin, platelet transfusions may be given.[1]
References
  1. LIM W.. Antiphospholipid antibody syndrome. Hematology [online] December, 2009(1):233-239 [viewed 01 July 2014] Available from: doi:10.1182/asheducation-2009.1.233
  2. DEL PAPA N, VASO N. Management of Antiphospholipid Syndrome Ther Adv Musculoskelet Dis [online] 2010 Aug, 2(4):221-227 [viewed 02 July 2014] Available from: doi:10.1177/1759720X10365969
  3. LOCKSHIN MD. ANTICOAGULATION IN MANAGEMENT OF ANTIPHOSPHOLIPID ANTIBODY SYNDROME [APS] IN PREGNANCY Clin Lab Med [online] 2013 Jun, 33(2):367-376 [viewed 02 July 2014] Available from: doi:10.1016/j.cll.2013.01.001
  4. GIANNAKOPOULOS B., KRILIS S. A.. How I treat the antiphospholipid syndrome. Blood [online] December, 114(10):2020-2030 [viewed 03 July 2014] Available from: doi:10.1182/blood-2009-05-220756
  5. QUSHMAQ NA, AL-EMADI SA. Review on Effectiveness of Primary Prophylaxis in aPLs with and without Risk Factors for Thrombosis: Efficacy and Safety ISRN Rheumatol [online] :348726 [viewed 05 July 2014] Available from: doi:10.1155/2014/348726
  6. MARCHETTI T, COHEN M, DE MOERLOOSE P. Obstetrical Antiphospholipid Syndrome: From the Pathogenesis to the Clinical and Therapeutic Implications Clin Dev Immunol [online] 2013:159124 [viewed 05 July 2014] Available from: doi:10.1155/2013/159124