History

Fact Explanation
Introduction Primary Thrombophilia is inherited disorders of the haemostatic mechanism leading to thrombi formation (hypercoagulability state). This is commonly affects the venous system ( eg; Deep vein thrombosis, pulmonary embolism). Commonly seen in young population and precautions need to be taken in surgery, pregnancy and prolonged immobilization. Causes of inherited thrombophilia are activated protein c recistance, prothrombin gene mutation, protein C and protein S deficiency and antithrombin deficiency[1][2].
symptoms suggestive of deep vein thrombosis Patient will develop sudden onset severe limb pain with difficulty in moving. limb will be red and swollen. commonly affect lower limbs[3][4].
symptoms suggestive of pulmonary embolism Patient will develop sudden onset shortness of breath, cough, wheezing and haemoptysis following pulmonary embolization[1][5].
Symptoms suggestive of other venous thrombosis Though these presentations are uncommon patients can develop thrombus in other venous systems. eg; Cerebral venous thrombosis patient will be confused, drowsy, may develop seizures due to cerebral venous disease[6]. Hepatic venous thrombosis will present with abdominal distension(ascites), features of liver insufficiency like nausea, vomiting, loss of appetite, yellowish discoloration of eyes, generalized swelling and gastrointestinal bleeding( either as haematemesis/ malena)[7]. Renal vein thrombosis will manifest as loin/ back pain, reduced urine out put and haematuria like symptoms[8]. Mesenteric vein thrombosis will present as abdominal pain and altered bowel habits. In severe ischemic condition bowel ischemia can progress in to bowel perforation causing an acute abdomen[9]. Retinal vein thrombosis leads to vision problems[10].
Past gynacological & obstetric history related to complications of pregnancy Due to the hypercoagulability state these patient can present with/ may have past history of recurrent miscarriages, intra uterine deaths, still births, pre-eclamsia, placental abruption[11][12].
History of sudden onset skin rash (red patches/ brising, skin discoloration) associated with severe ill health. Purpura fulminans can develop in these patients and it can finally lead to skin necrosis (due to thrombi formation in small vessels supplying to skin) and disseminated intravascular coagulation[14][15].
History suggestive of arterial thrombosis There are not much strong evidence to say this condition is associated with arterial thrombosis. But due to the hypercoagulability state it can increased risk of thrombotic complications. Arterial thrombotic complications can damage various systems giving specific features of hypoperfusion. Eg; In cardiac complications, patient will present with chest pain, difficulty in bresthing, dizziness, sweating and other features of myocardial infarction/ angina[16][17]. If thrombotic complications occur in central nervous system, patient will have seizures, paralysis and paresthesia like features[13][19]. If thrombosis occur in a artery supplying to limbs, patients will present with acute limb ischemia (sever pain at rest, coldness, limited movements, numbness) following features of occlusive arterial disease like pain starting few minutes after initiating walking, pain relief with resting and reproduce with walking in a same distance[18][19]. Thrombosis in pulmonary arteries will give features like chest pain, difficulty in breathing, cough and wheezing[5]. Retinal artery thrombosis can leads to sudden onset loss of vision while small thrombi may present with transient loss of vision (amaurosis fugax)[20][21].
History of presence of risk factors for thrombosis There are some well known modifiable/ acquired risk factors for development of arterial and venous thrombosis. Presence of these conditions need to be identify as it is important in management. Risk factors for the development of arterial thrombi are smoking, hypertension, hyperlipidaemia, diabetes mellitus, polycythemia and connective tissue disorders like SLE, APLS. Risk factors for the development of venous thrombi are surgery, trauma, immobilization, pregnancy, use of oral contraceptive pills, hormone replacement therapy, obesity, varicose veins and presence of systemic conditions (heart failure, malignancy, nephrotic syndrome).[16][17][22][23][24].
Family history of similer symptoms primary thrombocytopenia is occur following inherited conditions. So there will be Family history of similer symptoms especially young relatives with recurrent spontaneous thrombosis[1][25].
References
  1. KHAN S, DICKERMAN JD. Hereditary thrombophilia Thromb J [online] :15 [viewed 08 November 2014] Available from: doi:10.1186/1477-9560-4-15
  2. SALMELA B, HARTMAN J, PELTONEN S, ALBäCK A, LASSILA R. Thrombophilia and Arteriovenous Fistula Survival in ESRD Clin J Am Soc Nephrol [online] 2013 Jun 7, 8(6):962-968 [viewed 08 November 2014] Available from: doi:10.2215/CJN.03860412
  3. OFRI D. Diagnosis and treatment of deep vein thrombosis West J Med [online] 2000 Sep, 173(3):194-197 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071067
  4. BONGIOVANNI SL, RANALLETTA M, GUALA A, MAIGNON GD. Case Reports: Heritable Thrombophilia Associated with Deep Venous Thrombosis after Shoulder Arthroscopy Clin Orthop Relat Res [online] 2009 Aug, 467(8):2196-2199 [viewed 08 November 2014] Available from: doi:10.1007/s11999-009-0895-6
  5. KONECNY F. Inherited trombophilic states and pulmonary embolism J Res Med Sci [online] 2009, 14(1):43-56 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129068
  6. MERCURIO A, ALTIERI M, SARACENI VM, PAOLUCCI T, LENZI GL. Cerebral Venous Thrombosis Revealing Primary Sj?gren Syndrome: Report of 2 Cases Case Rep Med [online] 2013:747431 [viewed 08 November 2014] Available from: doi:10.1155/2013/747431
  7. RODRíGUEZ-LEAL GA, MORáN S, CORONA-CEDILLO R, BROM-VALLADARES R. Portal vein thrombosis with protein C-S deficiency in a non-cirrhotic patient World J Hepatol [online] 2014 Jul 27, 6(7):532-537 [viewed 08 November 2014] Available from: doi:10.4254/wjh.v6.i7.532
  8. WILES KS, HASTINGS L, MUTHUPPALANIAPPAN VM, HANIF M, ABEYGUNASEKARA S. Bilateral renal artery thrombosis in inherited thrombophilia: a rare cause of acute kidney injury Int J Nephrol Renovasc Dis [online] :35-38 [viewed 08 November 2014] Available from: doi:10.2147/IJNRD.S50948
  9. EASTWOOD KA, VAUGHAN A, MCCUNE KH. Mesenteric vein thrombosis associated with anti-thrombin III deficiency Ulster Med J [online] 2009 Jan, 78(1):53-55 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629022
  10. REHAK J, REHAK M. Branch Retinal Vein Occlusion: Pathogenesis, Visual Prognosis, and Treatment Modalities Curr Eye Res [online] 2008 Feb, 33(2):111-131 [viewed 08 November 2014] Available from: doi:10.1080/02713680701851902
  11. KUPFERMINC MJ. Thrombophilia and pregnancy Reprod Biol Endocrinol [online] :111 [viewed 08 November 2014] Available from: doi:10.1186/1477-7827-1-111
  12. ABU-HEIJA A. Thrombophilia and Recurrent Pregnancy Loss: Is heparin still the drug of choice? Sultan Qaboos Univ Med J [online] 2014 Feb, 14(1):e26-e36 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916273
  13. HAYWOOD S, LIESNER R, PINDORA S, GANESAN V. Thrombophilia and first arterial ischaemic stroke: a systematic review Arch Dis Child [online] 2005 Apr, 90(4):402-405 [viewed 08 November 2014] Available from: doi:10.1136/adc.2004.049163
  14. KNOEBL PN. Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications Biologics [online] 2008 Jun, 2(2):285-296 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721356
  15. Guidelines on the investigation and management of thrombophilia. The British Committee for Standards in Haematology. J Clin Pathol [online] 1990 Sep, 43(9):703-709 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC502744
  16. SYKES TC, FEGAN C, MOSQUERA D. Thrombophilia, polymorphisms, and vascular disease Mol Pathol [online] 2000 Dec, 53(6):300-306 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1186984
  17. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 08 November 2014] Available from: doi:10.2450/2010.0066-10
  18. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 08 November 2014] Available from: doi:10.2450/2010.0066-10
  19. NG KW, LOH PK, SHARMA VK. Role of Investigating Thrombophilic Disorders in Young Stroke Stroke Res Treat [online] :670138 [viewed 08 November 2014] Available from: doi:10.4061/2011/670138
  20. NAGY V, TAKACS L, STEIBER Z, PFLIEGLER G, BERTA A. Thrombophilic screening in retinal artery occlusion patients Clin Ophthalmol [online] 2008 Sep, 2(3):557-561 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694013
  21. CHAK M, WALLACE G, GRAHAM E, STANFORD M. Thrombophilia: genetic polymorphisms and their association with retinal vascular occlusive disease Br J Ophthalmol [online] 2001 Jul, 85(7):883-886 [viewed 08 November 2014] Available from: doi:10.1136/bjo.85.7.883
  22. KHALAFALLAH AA, IBRAHEEM AR, TEO QY, ALBARZAN AM, PARAMESWARAN R, HOOPER E, PAVLOV T, DENNIS AE, HANNAN T. Review of Management and Outcomes in Women with Thrombophilia Risk during Pregnancy at a Single Institution ISRN Obstet Gynecol [online] :381826 [viewed 08 November 2014] Available from: doi:10.1155/2014/381826
  23. CAINE GJ, STONELAKE PS, LIP GY, KEHOE ST. The Hypercoagulable State of Malignancy: Pathogenesis and Current Debate Neoplasia [online] 2002 Nov, 4(6):465-473 [viewed 08 November 2014] Available from: doi:10.1038/sj.neo.7900263
  24. GIOVANNINI L, DONADIO C. Fingertips Ischemia, Nephroangiosclerosis, and Focal Segmental Glomerulosclerosis: Is Genetic Thrombophilia the Unique Explanation? Case Rep Med [online] 2014:832592 [viewed 08 November 2014] Available from: doi:10.1155/2014/832592
  25. SAUKKO PM, ELLARD S, RICHARDS SH, SHEPHERD MH, CAMPBELL JL. Patients' understanding of genetic susceptibility testing in mainstream medicine: qualitative study on thrombophilia BMC Health Serv Res [online] :82 [viewed 14 November 2014] Available from: doi:10.1186/1472-6963-7-82

Examination

Fact Explanation
General examination ill health (appearance of the illness will give an rough idea about the level of severity of the illness), pain (this will help in managing the patient),temperature ( this will be important in excluding the differentials like cellulitis and pyrexia will be a symtom in thrombosis like pulmonary embolism), icterus (icterus will be a symptom in associated hepatic vein thrombosis) and level of hydration of the patient[1][2][3]. There will be a skin rash (purpura fulminans) with petechiae and ecchimotic patches. In severe condition there will be skin necrosis causing skin discoloration. There will be features of disseminated intravascular coagulation, like extensive bruising and increased bleeding tendency (eg: spontaneous haematuria, gum bleeding, nasal bleeding, puncture site bleeding)[4][5].
Limb examination for deep vein thrombosis If the patient present with limb pain limb examination need to be done. In DVT limb will be swollen, red and very tender. patient will have limited movements due to the pain[6][7].
Respiratory system examination for pulmonary embolism patient will be febrile, cyanosed, dyspnoic, coughing, wheezing, sputum will be blood staining. Jvp can be elevated. There will pleural rub and pleural effusion on lung examination[1][2].
Central nervous system examination Either with cerebral venous thrombosis or arterial thrombi formation, patients can develop neurological symptoms. On examination patient will be confused, drowsy, may develop seizures and there will be motor/ sensory involvement or signs of imbalance with cerebellar involvement[8][9].
Abdominal examination There will be icterus, generalized oedema, ascites with hepatic vein thrombosis[3]. In mesenteric ischemia there will be tender abdomen and with perforation there will be garding and rigidity[10]. In renal vein thrombosis there will be haematuria on urine examination and patients will have generalized oedema[11].
Fundoscopic examination Stormy sunset can be seen in central retinal vein occlusion. wedge changes ( tortuous veins, oedema) are occur in branched retinal vein occlusion. Retinal haemorrhages, disk pallor and oedema can be seen in retinal artery occlusion.[12][13][14].
Gynaecological and obstetric examination In miscarriages/ there will be per vaginal bleeding, pains and OS can be opened/ closed. In a placental abruption patient may be haemodynamically unstable (shock), PV bleeding will present. Uterus will be tender. In an intra uterine deaths foetal movements and foetal heart sound will be absent. Pre-eclamsia, Patient will have hypertension, generalized body swelling and urine examination will reveal proteinuria. [15][16]
References
  1. KHAN S, DICKERMAN JD. Hereditary thrombophilia Thromb J [online] :15 [viewed 08 November 2014] Available from: doi:10.1186/1477-9560-4-15
  2. KONECNY F. Inherited trombophilic states and pulmonary embolism J Res Med Sci [online] 2009, 14(1):43-56 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129068
  3. RODRíGUEZ-LEAL GA, MORáN S, CORONA-CEDILLO R, BROM-VALLADARES R. Portal vein thrombosis with protein C-S deficiency in a non-cirrhotic patient World J Hepatol [online] 2014 Jul 27, 6(7):532-537 [viewed 08 November 2014] Available from: doi:10.4254/wjh.v6.i7.532
  4. Guidelines on the investigation and management of thrombophilia. The British Committee for Standards in Haematology. J Clin Pathol [online] 1990 Sep, 43(9):703-709 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC502744
  5. KNOEBL PN. Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications Biologics [online] 2008 Jun, 2(2):285-296 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721356
  6. OFRI D. Diagnosis and treatment of deep vein thrombosis West J Med [online] 2000 Sep, 173(3):194-197 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071067
  7. BONGIOVANNI SL, RANALLETTA M, GUALA A, MAIGNON GD. Case Reports: Heritable Thrombophilia Associated with Deep Venous Thrombosis after Shoulder Arthroscopy Clin Orthop Relat Res [online] 2009 Aug, 467(8):2196-2199 [viewed 08 November 2014] Available from: doi:10.1007/s11999-009-0895-6
  8. HAYWOOD S, LIESNER R, PINDORA S, GANESAN V. Thrombophilia and first arterial ischaemic stroke: a systematic review Arch Dis Child [online] 2005 Apr, 90(4):402-405 [viewed 08 November 2014] Available from: doi:10.1136/adc.2004.049163
  9. NG KW, LOH PK, SHARMA VK. Role of Investigating Thrombophilic Disorders in Young Stroke Stroke Res Treat [online] :670138 [viewed 08 November 2014] Available from: doi:10.4061/2011/670138
  10. EASTWOOD KA, VAUGHAN A, MCCUNE KH. Mesenteric vein thrombosis associated with anti-thrombin III deficiency Ulster Med J [online] 2009 Jan, 78(1):53-55 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629022
  11. WILES KS, HASTINGS L, MUTHUPPALANIAPPAN VM, HANIF M, ABEYGUNASEKARA S. Bilateral renal artery thrombosis in inherited thrombophilia: a rare cause of acute kidney injury Int J Nephrol Renovasc Dis [online] :35-38 [viewed 08 November 2014] Available from: doi:10.2147/IJNRD.S50948
  12. REHAK J, REHAK M. Branch Retinal Vein Occlusion: Pathogenesis, Visual Prognosis, and Treatment Modalities Curr Eye Res [online] 2008 Feb, 33(2):111-131 [viewed 08 November 2014] Available from: doi:10.1080/02713680701851902
  13. NAGY V, TAKACS L, STEIBER Z, PFLIEGLER G, BERTA A. Thrombophilic screening in retinal artery occlusion patients Clin Ophthalmol [online] 2008 Sep, 2(3):557-561 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694013
  14. CHAK M, WALLACE G, GRAHAM E, STANFORD M. Thrombophilia: genetic polymorphisms and their association with retinal vascular occlusive disease Br J Ophthalmol [online] 2001 Jul, 85(7):883-886 [viewed 08 November 2014] Available from: doi:10.1136/bjo.85.7.883
  15. KUPFERMINC MJ. Thrombophilia and pregnancy Reprod Biol Endocrinol [online] :111 [viewed 08 November 2014] Available from: doi:10.1186/1477-7827-1-111
  16. ABU-HEIJA A. Thrombophilia and Recurrent Pregnancy Loss: Is heparin still the drug of choice? Sultan Qaboos Univ Med J [online] 2014 Feb, 14(1):e26-e36 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916273

Differential Diagnoses

Fact Explanation
Non communicable diseases leading to thrombophilic complications Non communicable diseases like hypertension (with high pressure causing endothelial damage) , hyperlipidaemia (with atherosclerotic plaques causing endothelial damage) and diabetes mellitus (endothelial dysfunction) can cause thrombophilic complications [1][2].
Causes of polycythemia With both primary (eg; polycythemia rubra vera) and secondary polycythemia (eg: secondary to high altitude, COPD, Congenital cyanotic heart diseases, heavy smoking) there will be hyperviscosity, thrombocytosis and altered platelet membrane responses causing hypercoagulability. From full blood count polycythemia and primary thrombophilia can differentiate[3][4].
Connective tissue disorders Connective tissue disorders like Systemic lupus erythematosus, anti phospholipid syndrome can associated with systemic thrombi formation (secondary to vasculitis) especially causing recurrent abortions and intrauterine deaths. With special screening tests (eg; Lupus anticoagulant test) these conditions can be excluded[5][6].
Other causes for the development of venous thrombosis Risk factors for the development of venous thrombi are surgery, trauma, immobilization, pregnancy, use of oral contraceptive pills, hormone replacement therapy, obesity, varicose veins, presence of systemic conditions (heart failure, malignancy, nephrotic syndrome) and inflammatory conditions (inflammatory bowel disease, systemic tuberculosis). In the absence of these primary causes and genetic risk factors leads to the diagnosis of Primary Thrombophilia. Majority can be excluded from the history[7][8].
paroxysmal nocturnal haemoglobin urea In this condition red blood cells are sensitive to compliment mediated dystruction due to the inherited loss of surface glycosylphosphatidylinositol. This is characterized with Intra vascular haemolysis, pancytopenia and increased thrombosis. Urine analysis (urinary haemosiderin) will useful to diagnose the condition[9][10].
Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic Purpura is a haematological disorder. It is characterized by thrombus formation in small blood vessels of the body. As thrombus consume platelets in the blood it causes reduction in platelet count (thrombocytopenia). So there is a bleeding tendency associated with this disease which can not be seen in Primary thrombophilia[11][12].
Sickle cell disease This is a one of haemoglobinopathy characterized by mutation in the beta-globin Chain(single amino acid molecular disorder). This is an inherited condition. This can present with systemic hypoperfusion symptoms due to microvascular blockage with abnormal (sickled) red bloods cells. Here patient will be anaemia and blood picture will diagnose the condition[13][14].
References
  1. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 12 November 2014] Available from: doi:10.2450/2010.0066-10
  2. GACKA MA, MAłECKI R, ADAMIEC R. Participation of protein Z-dependent protease inhibitor and protein Z system in the pathomechanism of thrombotic complications Int J Angiol [online] 2010, 19(4):e120-e125 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285951
  3. MERRIMAN L, GREAVES M. Testing for thrombophilia: an evidence-based approach Postgrad Med J [online] 2006 Nov, 82(973):699-704 [viewed 12 November 2014] Available from: doi:10.1136/pgmj.2006.048090
  4. STERGIOPOULOS K, BRENNAN JJ, MATHEWS R, SETARO JF, KORT S. Anabolic steroids, acute myocardial infarction and polycythemia: A case report and review of the literature Vasc Health Risk Manag [online] 2008 Dec, 4(6):1475-1480 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663437
  5. BOEY ML, COLACO CB, GHARAVI AE, ELKON KB, LOIZOU S, HUGHES GR. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed) [online] 1983 Oct 8, 287(6398):1021-1023 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1549560
  6. CHOUDHARY MM, HAJJ-ALI RA, LOWDER CY. Gender and Ocular Manifestations of Connective Tissue Diseases and Systemic Vasculitides J Ophthalmol [online] 2014:403042 [viewed 12 November 2014] Available from: doi:10.1155/2014/403042
  7. SIGEL B, IPSEN J, FELIX WR JR. The epidemiology of lower extremity deep venous thrombosis in surgical patients. Ann Surg [online] 1974 Mar, 179(3):278-290 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1355887
  8. FENNERTY A. Venous thromboembolic disease and cancer Postgrad Med J [online] 2006 Oct, 82(972):642-648 [viewed 12 November 2014] Available from: doi:10.1136/pgmj.2006.046987
  9. MUSHTAK A, YOUSEF KHAN F, ALDEHWE B, ABDULRAHMAN AL-ANI A. THREE DIFFERENT PRESENTATION OF SAME PATHOPHYSIOLOGY Acta Inform Med [online] 2012 Sep, 20(3):190-191 [viewed 12 November 2014] Available from: doi:10.5455/aim.2012.20.190-191
  10. MEMON AR, KHAN R, RAUF MU, SHAFIQUE K. Paroxysmal nocturnal hemoglobinuria presenting as cerebral venous sinus thrombosis: a case report Int Arch Med [online] :39 [viewed 12 November 2014] Available from: doi:10.1186/1755-7682-7-39
  11. TSAI HM. Mechanisms of microvascular thrombosis in thrombotic thrombocytopenic purpura Kidney Int Suppl [online] 2009 Feb:S11-S14 [viewed 12 November 2014] Available from: doi:10.1038/ki.2008.610
  12. TSAI HM. Pathophysiology of thrombotic thrombocytopenic purpura Int J Hematol [online] 2010 Jan, 91(1):1-19 [viewed 12 November 2014] Available from: doi:10.1007/s12185-009-0476-1
  13. DE MONTALEMBERT M, MAUNOURY C, ACAR P, BROUSSE V, SIDI D, LENOIR G. Myocardial ischaemia in children with sickle cell disease Arch Dis Child [online] 2004 Apr, 89(4):359-362 [viewed 12 November 2014] Available from: doi:10.1136/adc.2003.027326
  14. QUINN CT, MCKINSTRY RC, DOWLING MM, BALL WS, KRAUT MA, CASELLA JF, DLAMINI N, ICHORD RN, JORDAN LC, KIRKHAM FJ, NOETZEL MJ, ROACH ES, STROUSE JJ, KWIATKOWSKI JL, HIRTZ D, DEBAUN MR. Acute Silent Cerebral Ischemic Events in Children with Sickle Cell Anemia JAMA Neurol [online] 2013 Jan, 70(1):58-65 [viewed 12 November 2014] Available from: doi:10.1001/jamaneurol.2013.576

Investigations - for Diagnosis

Fact Explanation
Full Blood count To detect any polycythemia/ anaemia assocciated with, WBC counts and Platelet counts will also helpful in deciding the diagnosis[1][2].
ESR/ CRP These inflammatory markers will also useful in identifying any ongoing inflammmatory condition[3][4].
Blood film This will be useful in excluding malignancies like myeloproliferative disorder and other differential diagnosis like sickle cell disease[1][5].
Thrombin time and reptilase test This will assess the fibrinogen activity and these tests will be prolonged in the abnormal fibrinogen activity[6][7].
Prothrombin time and APTT tests will assess the clotting status/ clotting factor activity of the patient. these will be shorten in Thrombophilia[8].
Activated protein C resistance test and DNA analysis (PCR) These tests will assess the factor V Leiden as factor V Leiden gene mutation (activated protein C resistance) is the most common inherited cause of venous thrombosis[9][10].
Protein C and protein S immunological assay These are to assess any protein C and/ or protein S deficiency[11][12].
Prothrombin gene analysis Prothrombin allele G20210A is a condition with increased levels of prothrombin. Prothrombin gene analysis will useful in assessing the presence of this condition. This condition will also have high levels of factor VIII, IX and XI [13][14].
Plasma homocysteine estimation In hyperhomocycteinaemia, there will be higher levels of plasma homocycteinse[15][16].
Test for CD59 and CD55 expression This tests will be useful in excluding the differencial diagnosis, paroxysmal nocturnal haemoglobinuria[17][18].
Lupus anticoagulant assay and anticardiolipin antibody and anti-β2 glycoprotein 1 antibody This will assess the prothrombotic status of the patient[19][20].
fibrinogen tests, factor VIII, plasminogen and factor XII levels High levels of fibrinogen, and other clotting factors can associated with arterial thrombosis[21][22].
Antithrombin immunological and functional assay (cromogenic heparin cofactor assay) This is helpful in assessing antithrombin III deficiency[11][12].
References
  1. MERRIMAN L, GREAVES M. Testing for thrombophilia: an evidence-based approach Postgrad Med J [online] 2006 Nov, 82(973):699-704 [viewed 12 November 2014] Available from: doi:10.1136/pgmj.2006.048090
  2. ABDUL-RAHMAN AM, GILHOTRA JS, SELVA D. Dynamic focal retinal arteriolar vasospasm in migraine Indian J Ophthalmol [online] 2011, 59(1):51-53 [viewed 12 November 2014] Available from: doi:10.4103/0301-4738.73717
  3. CASTRO C, GOURLEY M. Diagnostic Testing and Interpretation of Tests for Autoimmunity J Allergy Clin Immunol [online] 2010 Feb, 125(2 Suppl 2):S238-S247 [viewed 12 November 2014] Available from: doi:10.1016/j.jaci.2009.09.041
  4. NAGY V, TAKACS L, STEIBER Z, PFLIEGLER G, BERTA A. Thrombophilic screening in retinal artery occlusion patients Clin Ophthalmol [online] 2008 Sep, 2(3):557-561 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694013
  5. SOKOLOVA M, TSVETAEVA N, SUKHANOVA G, VASILIEV S, MISURIN A, SANATKO M, NAREIKO M, RUDAKOVA V, SEMENOVA E, KHOROSHKO N. Ph-Negative Chronic Myeloproliferative Neoplasm (Primary Myelofibrosis) - as One of the Reasons of the Budd-Chiari Syndrome Mediterr J Hematol Infect Dis [online] , 4(1):e2012047 [viewed 12 November 2014] Available from: doi:10.4084/MJHID.2012.047
  6. NAKASHIMA MO, ROGERS HJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants Blood Res [online] 2014 Jun, 49(2):85-94 [viewed 12 November 2014] Available from: doi:10.5045/br.2014.49.2.85
  7. KOOPMAN J, HAVERKATE F, LORD ST, GRIMBERGEN J, MANNUCCI PM. Molecular basis of fibrinogen Naples associated with defective thrombin binding and thrombophilia. Homozygous substitution of B beta 68 Ala----Thr. J Clin Invest [online] 1992 Jul, 90(1):238-244 [viewed 12 November 2014] Available from: doi:10.1172/JCI115841
  8. TANG W, SCHWIENBACHER C, LOPEZ LM, BEN-SHLOMO Y, OUDOT-MELLAKH T, JOHNSON AD, SAMANI NJ, BASU S, GöGELE M, DAVIES G, LOWE GD, TREGOUET DA, TAN A, PANKOW JS, TENESA A, LEVY D, VOLPATO CB, RUMLEY A, GOW AJ, MINELLI C, YARNELL JW, PORTEOUS DJ, STARR JM, GALLACHER J, BOERWINKLE E, VISSCHER PM, PRAMSTALLER PP, CUSHMAN M, EMILSSON V, PLUMP AS, MATIJEVIC N, MORANGE PE, DEARY IJ, HICKS AA, FOLSOM AR. Genetic Associations for Activated Partial Thromboplastin Time and Prothrombin Time, their Gene Expression Profiles, and Risk of Coronary Artery Disease Am J Hum Genet [online] 2012 Jul 13, 91(1):152-162 [viewed 12 November 2014] Available from: doi:10.1016/j.ajhg.2012.05.009
  9. SEDANO-BALBáS S, LYONS M, CLEARY B, MURRAY M, GAFFNEY G, MAHER M. Acquired Activated Protein C Resistance, Thrombophilia and Adverse Pregnancy Outcomes: A Study Performed in an Irish Cohort of Pregnant Women J Pregnancy [online] 2011:232840 [viewed 12 November 2014] Available from: doi:10.1155/2011/232840
  10. MADJUNKOVA S, VOLK M, PETERLIN B, PLASESKA-KARANFILSKA D. Detection of Thrombophilic Mutations Related to Spontaneous Abortions by a Multiplex SNaPshot Method Genet Test Mol Biomarkers [online] 2012 Apr, 16(4):259-264 [viewed 12 November 2014] Available from: doi:10.1089/gtmb.2011.0173
  11. Guidelines on the investigation and management of thrombophilia. The British Committee for Standards in Haematology. J Clin Pathol [online] 1990 Sep, 43(9):703-709 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC502744
  12. KHAN S, DICKERMAN JD. Hereditary thrombophilia Thromb J [online] :15 [viewed 12 November 2014] Available from: doi:10.1186/1477-9560-4-15
  13. GIOVANNINI L, DONADIO C. Fingertips Ischemia, Nephroangiosclerosis, and Focal Segmental Glomerulosclerosis: Is Genetic Thrombophilia the Unique Explanation? Case Rep Med [online] 2014:832592 [viewed 12 November 2014] Available from: doi:10.1155/2014/832592
  14. ARROYAVE JA, QUIñONES J. Mutation in the Prothrombin Gene G20210A as a Cause of Cerebral Venous Thrombosis Case Rep Med [online] 2012:828050 [viewed 12 November 2014] Available from: doi:10.1155/2012/828050
  15. LAWSON S, BUTLER D, ENAYAT M, WILLIAMS M. Congenital thrombophilia and thrombosis: a study in a single centre Arch Dis Child [online] 1999 Aug, 81(2):176-178 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1718022
  16. BOGDANOVA N, MARKOFF A. Hereditary thrombophilic risk factors for recurrent pregnancy loss J Community Genet [online] 2010 Jun, 1(2):47-53 [viewed 12 November 2014] Available from: doi:10.1007/s12687-010-0011-3
  17. PARKER C, OMINE M, RICHARDS S, NISHIMURA JI, BESSLER M, WARE R, HILLMEN P, LUZZATTO L, YOUNG N, KINOSHITA T, ROSSE W, SOCIé G, FOR THE INTERNATIONAL PNH INTEREST GROUP. Diagnosis and management of paroxysmal nocturnal hemoglobinuria Blood [online] 2005 Dec 1, 106(12):3699-3709 [viewed 12 November 2014] Available from: doi:10.1182/blood-2005-04-1717
  18. RISITANO AM, ROTOLI B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents Biologics [online] 2008 Jun, 2(2):205-222 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721357
  19. LOCKSHIN MD, KIM M, LASKIN CA, GUERRA M, BRANCH DW, MERRILL J, PETRI M, PORTER F, SAMMARITANO L, STEPHENSON MD, BUYON J, SALMON JE. LUPUS ANTICOAGULANT, BUT NOT ANTICARDIOLIPIN ANTIBODY, PREDICTS ADVERSE PREGNANCY OUTCOME IN PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES Arthritis Rheum [online] 2012 Jul, 64(7):2311-2318 [viewed 12 November 2014] Available from: doi:10.1002/art.34402
  20. MERONI PL, CHIGHIZOLA CB, ROVELLI F, GEROSA M. Antiphospholipid syndrome in 2014: more clinical manifestations, novel pathogenic players and emerging biomarkers Arthritis Res Ther [online] 2014, 16(2):209 [viewed 12 November 2014] Available from: doi:10.1186/ar4549
  21. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 12 November 2014] Available from: doi:10.2450/2010.0066-10
  22. NAGY V, TAKACS L, STEIBER Z, PFLIEGLER G, BERTA A. Thrombophilic screening in retinal artery occlusion patients Clin Ophthalmol [online] 2008 Sep, 2(3):557-561 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694013

Investigations - Fitness for Management

Fact Explanation
Fasting blood sugar level This is to assess the blood sugar levels of the patient as it can further progress the thrombotic complications[1][2]
Lipid profile test As hperlipidaemia can cause secondary thrombophilia, this test alsom useful in assessing the fitness of the patient[3][4].
Renal function tests including UFR, serum creatinine, blood urea and serum elcetrolytes Nephrotic syndrome can predispose to hypercoagulability these tests are useful. Aslo important in assessing the thrombotic complications causing renal vein thrombosis. These are useful in assessing the renal function prior to contrast medicated investigations as well[5][6].
ECG/ echocardiogram Heart failure is another secondary cause for thrombophilia. So these tests will assess the cardiac function of the patients[7][8].
References
  1. SILVER RM, VARNER MW, REDDY U, GOLDENBERG R, PINAR H, CONWAY D, BUKOWSKI R, CARPENTER M, HOGUE C, WILLINGER M, DUDLEY D, SAADE G, STOLL B. WORK-UP OF STILLBIRTH: A REVIEW OF THE EVIDENCE Am J Obstet Gynecol [online] 2007 May, 196(5):433-444 [viewed 12 November 2014] Available from: doi:10.1016/j.ajog.2006.11.041
  2. JANSSEN AW, DE LEEUW FE, JANSSEN MC. Risk factors for ischemic stroke and transient ischemic attack in patients under age 50 J Thromb Thrombolysis [online] 2011 Jan, 31(1):85-91 [viewed 12 November 2014] Available from: doi:10.1007/s11239-010-0491-3
  3. MANDALA E, LAFARAS C, TSIONI C, SPELETAS M, PAPAGEORGIOU A, KLETA D, DARDAVESSIS T, ILONIDIS G. Prevalence of thrombophilic mutations in patients with unprovoked thromboembolic disease. A comparative analysis regarding arterial and venous disease Hippokratia [online] 2012, 16(3):250-255 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738733
  4. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 12 November 2014] Available from: doi:10.2450/2010.0066-10
  5. CAINE GJ, STONELAKE PS, LIP GY, KEHOE ST. The Hypercoagulable State of Malignancy: Pathogenesis and Current Debate Neoplasia [online] 2002 Nov, 4(6):465-473 [viewed 12 November 2014] Available from: doi:10.1038/sj.neo.7900263
  6. GIOVANNINI L, DONADIO C. Fingertips Ischemia, Nephroangiosclerosis, and Focal Segmental Glomerulosclerosis: Is Genetic Thrombophilia the Unique Explanation? Case Rep Med [online] 2014:832592 [viewed 12 November 2014] Available from: doi:10.1155/2014/832592
  7. SZARSZOI O, MALY J, TUREK D, URBAN M, SKALSKY I, RIHA H, MALUSKOVA J, PIRK J, NETUKA I. Implantation of Left Ventricular Assist Device Complicated by Undiagnosed Thrombophilia Tex Heart Inst J [online] 2012, 39(5):615-617 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461681
  8. JANSSEN AW, DE LEEUW FE, JANSSEN MC. Risk factors for ischemic stroke and transient ischemic attack in patients under age 50 J Thromb Thrombolysis [online] 2011 Jan, 31(1):85-91 [viewed 12 November 2014] Available from: doi:10.1007/s11239-010-0491-3

Investigations - Followup

Fact Explanation
Plasma D dimer concentration This is useful in diagnosis of the Deep vein thrombosis and assess the risk of developing pulmonary embolism[1][2].
PT/ INR This is useful in patients on anticoagulants. According to target levels recommended by the British Society for Haematology (2000), Target INR is 2.0-3.0 : treatment of DVT, Pulmonary embolism, atrial fibrilation, recurrent DVT off warfarin; symptomatic inherited thrombophilia, cardiomyopathy, mural thrombus, cardioversion Target INR is 3.0-4.0 : recurrent DVT while on warfarin, mechanical prosthetic heart valve, APLs. [3][4][5]
Serial compression ultrasound combine with colour doppler/ duplex scan This is useful in investigating a patient with DVT. This will assess the exact site and size of the thrombus[6][7].
Contrast venography This is useful in patients who are clinically suspicious as having DVT but ultrasound examination is normal. This is the most sensitive investigation in diagnosis of DVT. In here X ray views are taken after injecting a contrast medum[8][9].
Chest X ray In a suspecting case of pulmonary embolism chest X ray will be useful. There may be evidence of pulmonary infarctions[10][11].
MRI This is useful in assessing both venous and arterial thrombosis ( eg; cerebral venous thrombosis/ strokes, renal vein occlusion, hepatic vein occlusion)[12][13].
Ventilation perfusion (VQ) scintigraphy Useful in pulmonary embolism and with this look for the perfusion defects with no corresponding ventilation defects[14][15].
Computer tomography pulmonary angiography This is the 1st line investigation in diagnosing pulmonary embolism. It shows the anatomy of pulmonary arteries[16][17].
pulmonary angiography/ MRI pulmonary angiography These tests also use in diagnosing pulmonary embolism[18][19].
ECG/ Echocardiogram In severe cases of pulmonary embolism, there will be right heart strain. This can be diagnose with Echocardiogram. Also useful in assessing the thrombotic complications affecting the cardiac vessels (eg; myocardial innfarction)[20][21].
Ultrasound scan This will be useful in assessing thrombotic complications like in gynaecological and obstetric complications (recurrent miscarriages, placenta previa, intra uterine death, pre eclampsis) to assess the foetal weii being and in hepatic vein thrombosis, to assess ascites.[22][23]
References
  1. DI MICCO P, D'UVA M, STRINA I, MOLLO A, AMATO V, NIGLIO A, DE PLACIDO G. The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility J Transl Med [online] :38 [viewed 12 November 2014] Available from: doi:10.1186/1479-5876-2-38
  2. KABRHEL C, COURTNEY DM, CAMARGO CA JR, PLEWA MC, NORDENHOLZ KE, MOORE CL, RICHMAN PB, SMITHLINE HA, BEAM DM, KLINE JA. Factors Associated With Positive D-dimer Results in Patients Evaluated for Pulmonary Embolism Acad Emerg Med [online] 2010 Jun, 17(6):589-597 [viewed 12 November 2014] Available from: doi:10.1111/j.1553-2712.2010.00765.x
  3. KURUVILLA M, GURK-TURNER C. A review of warfarin dosing and monitoring Proc (Bayl Univ Med Cent) [online] 2001 Jul, 14(3):305-306 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1305837
  4. AMIWERO C, CAMPBELL I, PRESCOTT R. A re-appraisal of Warfarin control in the treatment of Deep Vein Thrombosis and / or Pulmonary Embolism Afr Health Sci [online] 2009 Sep, 9(3):179-185 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887034
  5. FITZMAURICE DA, MACHIN SJ. Recommendations for patients undertaking self management of oral anticoagulation BMJ [online] 2001 Oct 27, 323(7319):985-989 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1121512
  6. TOVEY C, WYATT S. Diagnosis, investigation, and management of deep vein thrombosis BMJ [online] 2003 May 31, 326(7400):1180-1184 [viewed 12 November 2014] Available from: doi:10.1136/bmj.326.7400.1180
  7. KASSAï B, BOISSEL JP, CUCHERAT M, SONIE S, SHAH NR, LEIZOROVICZ A. A systematic review of the accuracy of ultrasound in the diagnosis of deep venous thrombosis in asymptomatic patients Thromb Haemost [online] 2004 Apr, 91(4):655-666 [viewed 12 November 2014] Available from: doi:10.1267/THRO04040655
  8. TSE HF, YIU KH. Deep vein thrombosis demonstrated by contrast enhanced helical computed tomographic venography Heart [online] 2004 Mar, 90(3):251 [viewed 12 November 2014] Available from: doi:10.1136/hrt.2003.021097
  9. DOUKETIS JD, GINSBERG JS. Diagnosis of deep vein thrombosis. Can Fam Physician [online] 1996 Mar:497-503 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2146310
  10. HOGG K, DAWSON D, MACKWAY‐JONES K. Outpatient diagnosis of pulmonary embolism: the MIOPED (Manchester Investigation Of Pulmonary Embolism Diagnosis) study Emerg Med J [online] 2006 Feb, 23(2):123-127 [viewed 12 November 2014] Available from: doi:10.1136/emj.2005.027110
  11. MOUA T, WOOD K. COPD and PE: A clinical dilemma Int J Chron Obstruct Pulmon Dis [online] 2008 Jun, 3(2):277-284 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629964
  12. SAFAVI-ABBASI S, DI ROCCO F, NAKAJI P, FEIGL GC, GHARABAGHI A, SAMII M, VALAVANIS A, SAMII A. Thrombophilia Due to Factor V and Factor II Mutations and Formation of a Dural Arteriovenous Fistula: Case Report and Review of a Rare Entity Skull Base [online] 2008 Mar, 18(2):135-143 [viewed 12 November 2014] Available from: doi:10.1055/s-2007-1003926
  13. MCAREE BJ, O'DONNELL ME, BOYD C, SPENCE RA, LEE B, SOONG CV. Inferior Vena Cava Thrombosis in Young Adults - a review of two cases Ulster Med J [online] 2009 May, 78(2):129-133 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699201
  14. SKARLOVNIK A, HRASTNIK D, FETTICH J, GRMEK M. Lung scintigraphy in the diagnosis of pulmonary embolism: current methods and interpretation criteria in clinical practice Radiol Oncol [online] , 48(2):113-119 [viewed 12 November 2014] Available from: doi:10.2478/raon-2013-0060
  15. PILECKI S, GIERACH M, LASEK W, DROBIK P, JUNIK R. Single photon emission computed tomography in pulmonary embolism - estimation of selected, scintigraphic regions of interests Pol J Radiol [online] 2010, 75(1):43-47 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389847
  16. HOGG K, BROWN G, DUNNING J, WRIGHT J, CARLEY S, FOEX B, MACKWAY‐JONES K. Diagnosis of pulmonary embolism with CT pulmonary angiography: a systematic review Emerg Med J [online] 2006 Mar, 23(3):172-178 [viewed 12 November 2014] Available from: doi:10.1136/emj.2005.029397
  17. LU GM, WU SY, YEH BM, ZHANG LJ. Dual-energy computed tomography in pulmonary embolism Br J Radiol [online] 2010 Aug, 83(992):707-718 [viewed 12 November 2014] Available from: doi:10.1259/bjr/16337436
  18. STEIN PD, CHENEVERT TL, FOWLER SE, GOODMAN LR, GOTTSCHALK A, HALES CA, HULL RD, JABLONSKI KA, LEEPER KV JR, NAIDICH DP, SAK DJ, SOSTMAN HD, TAPSON VF, WEG JG, WOODARD PK. Gadolinium-Enhanced Magnetic Resonance Angiography for Pulmonary Embolism: A Multicenter Prospective Study (PIOPED III) Ann Intern Med [online] 2010 Apr 6, 152(7):434-W143 [viewed 12 November 2014] Available from: doi:10.1059/0003-4819-152-7-201004060-00008
  19. HOCHHEGGER B, LEY-ZAPOROZHAN J, MARCHIORI E, IRION K, SOARES SOUZA A JR, MOREIRA J, KAUCZOR HU, LEY S. Magnetic resonance imaging findings in acute pulmonary embolism Br J Radiol [online] 2011 Mar, 84(999):282-287 [viewed 12 November 2014] Available from: doi:10.1259/bjr/26121475
  20. TOVAR EA, BORSARI A, KUNELIS CT, SONG M. Diagnosis of fulminant pulmonary embolism by transthoracic echocardiography. Tex Heart Inst J [online] 1997, 24(1):68-70 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC325400
  21. JANSSEN AW, DE LEEUW FE, JANSSEN MC. Risk factors for ischemic stroke and transient ischemic attack in patients under age 50 J Thromb Thrombolysis [online] 2011 Jan, 31(1):85-91 [viewed 12 November 2014] Available from: doi:10.1007/s11239-010-0491-3
  22. MIRZAEI F, FARZAD-MAHAJERI Z. Association of hereditary thrombophilia with intrauterine growth restriction Iran J Reprod Med [online] 2013 Apr, 11(4):275-278 [viewed 12 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941427
  23. RODRíGUEZ-LEAL GA, MORáN S, CORONA-CEDILLO R, BROM-VALLADARES R. Portal vein thrombosis with protein C-S deficiency in a non-cirrhotic patient World J Hepatol [online] 2014 Jul 27, 6(7):532-537 [viewed 12 November 2014] Available from: doi:10.4254/wjh.v6.i7.532

Investigations - Screening/Staging

Fact Explanation
Indications for screening a patient for thrombophilia Screening for thromboplilia with special tests is indicated in patients with, 1) Arterial thrombosis in patients less than 50 years of age (screen for APLS) 2) Venous thrombosis in patients less than 40 years of age with no risk factors 3) Unexplained recurrent venous thrombo embolism 4) Thrombi formation in unusual sites like mesenteric vein thrombosis, portal vein thrombosis 5) Familial venous thrombo embolism 6) Venous thrombo embolism with oral contraceptives/ pregnancy 7) Recurrent miscarriages (3 or more) 8) Neonatal thrombosis [1][2]
Staging the various hereditary (familial or primary) thrombophilia types according to the supportive data available. Conditions with strongly supportive data: -Antithrombin, Protein C, Protein S deficiency -Activated protein C resistance -Factor V Leiden -Prothrombin G20210A -Homocystinuria Conditions with supportive Data: -Increased plasma factors I (fibrinogen), II (prothrombin), VIII, IX, XI -Factor XIII polymorphisms -Hyperhomocysteinemia -Dysfibrinogenemia -Reduced tissue factor pathway inhibitor Conditions with weakly supportive Data: -Reduced protein Z and Z-dependent protease inhibitor -Tissue plasminogen activator deficiency -Increased plasminogen activator inhibitor (PAI)-1 -Increased thrombin-activatable fibrinolysis inhibitor -Hypoplasminogenemia and dysplasminogenemia -Hypofibrinolysis [3][4]
Genetic screening Patients and family members of the patients who are having recurrent spontaneous thrombotic complications can under go genetic screening for various causes of primary thrombophilia. The way of inheritence and the risk of genetic transmission should be discussed with patients[5][6].
References
  1. MERRIMAN L, GREAVES M. Testing for thrombophilia: an evidence-based approach Postgrad Med J [online] 2006 Nov, 82(973):699-704 [viewed 12 November 2014] Available from: doi:10.1136/pgmj.2006.048090
  2. MIDDELDORP S. Evidence-based approach to thrombophilia testing J Thromb Thrombolysis [online] 2011 Apr, 31(3):275-281 [viewed 12 November 2014] Available from: doi:10.1007/s11239-011-0572-y
  3. KHAN S, DICKERMAN JD. Hereditary thrombophilia Thromb J [online] :15 [viewed 12 November 2014] Available from: doi:10.1186/1477-9560-4-15
  4. BERNARD TJ, MANCO-JOHNSON MJ, GOLDENBERG NA. The roles of anatomic factors, thrombophilia, and antithrombotic therapies in childhood-onset arterial ischemic stroke Thromb Res [online] 2011 Jan, 127(1):6-12 [viewed 12 November 2014] Available from: doi:10.1016/j.thromres.2010.09.014
  5. GAGALA J, BURACZYNSKA M, MAZURKIEWICZ T, KSIAZEK A. Prevalence of genetic risk factors related with thrombophilia and hypofibrinolysis in patients with osteonecrosis of the femoral head in Poland BMC Musculoskelet Disord [online] :264 [viewed 12 November 2014] Available from: doi:10.1186/1471-2474-14-264
  6. SAUKKO PM, ELLARD S, RICHARDS SH, SHEPHERD MH, CAMPBELL JL. Patients' understanding of genetic susceptibility testing in mainstream medicine: qualitative study on thrombophilia BMC Health Serv Res [online] :82 [viewed 12 November 2014] Available from: doi:10.1186/1472-6963-7-82

Management - General Measures

Fact Explanation
Health education The patient should be thoroughly educated regarding the disease, aetiology, complications associated with, early identification of complications, investigation and treatment options available[6][7].
Prevention/ minimize of thrombi formation Patient education and close monitoring of the thrombotic complications is very important. Prophylactic measures are very important here. eg: Prevent DVT: DVT prophylaxis can be non pharmacological and pharmacology modalities. Non pharmacological moralities are good hydration, adequate mobilization of the patient, limb physiotherapy and thrombo embolic detergenic stocking. The main pharmacological propylaxis is low molecular weight heparin in high risk patients if no contraindication (eg: Sub cutaneous enoxaparin 0.5mg/kg/day). [8][9]
Modification of co-existing acquired risk factors Patient should be advised regarding the secondary causes of thrombipilia as there are some well known modifiable/ acquired risk factors for development of arterial and venous thrombosis. Risk factors for the development of arterial thrombi are smoking, hypertension, hyperlipidaemia, diabetes mellitus, polycythemia and connective tissue disorders like SLE, APLS.Risk factors for the development of venous thrombi are surgery, trauma, immobilization, pregnancy, use of oral contraceptive pills, hormone replacement therapy, obesity, varicose veins and presence of systemic conditions (heart failure, malignancy, nephrotic syndrome). these risk factors nees to be identify and removal/ control need to be done [1][2][3][4][5]. Eg: Changing to an other contraceptive method from oral contraceptive pills. Control hypertension, hyperlipidaemia and diabetes Early mobilization after syrgery, prophylaxia LMW heparin, compression stockings to prevent DVT. Maintain average body weight.
Management in an emergency situation The possible emergencies in patients with thrombophilia are pulmonary embolism, stoke, myocardial infarction, cerebral venous thrombosis, mesenteric infarction. In these circumstances ABC management is essentially life saving. Airway has to be secured, breathing has to be assessed and respiratory support should be given. Circulation has to be assessed and fluid resuscitation with inotrope support has to started as indicated[10][11].
References
  1. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 08 November 2014] Available from: doi:10.2450/2010.0066-10
  2. SYKES TC, FEGAN C, MOSQUERA D. Thrombophilia, polymorphisms, and vascular disease Mol Pathol [online] 2000 Dec, 53(6):300-306 [viewed 08 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1186984
  3. GIOVANNINI L, DONADIO C. Fingertips Ischemia, Nephroangiosclerosis, and Focal Segmental Glomerulosclerosis: Is Genetic Thrombophilia the Unique Explanation? Case Rep Med [online] 2014:832592 [viewed 08 November 2014] Available from: doi:10.1155/2014/832592
  4. KHALAFALLAH AA, IBRAHEEM AR, TEO QY, ALBARZAN AM, PARAMESWARAN R, HOOPER E, PAVLOV T, DENNIS AE, HANNAN T. Review of Management and Outcomes in Women with Thrombophilia Risk during Pregnancy at a Single Institution ISRN Obstet Gynecol [online] :381826 [viewed 08 November 2014] Available from: doi:10.1155/2014/381826
  5. CAINE GJ, STONELAKE PS, LIP GY, KEHOE ST. The Hypercoagulable State of Malignancy: Pathogenesis and Current Debate Neoplasia [online] 2002 Nov, 4(6):465-473 [viewed 08 November 2014] Available from: doi:10.1038/sj.neo.7900263
  6. KHAN S, DICKERMAN JD. Hereditary thrombophilia Thromb J [online] :15 [viewed 12 November 2014] Available from: doi:10.1186/1477-9560-4-15
  7. SAUKKO PM, ELLARD S, RICHARDS SH, SHEPHERD MH, CAMPBELL JL. Patients' understanding of genetic susceptibility testing in mainstream medicine: qualitative study on thrombophilia BMC Health Serv Res [online] :82 [viewed 12 November 2014] Available from: doi:10.1186/1472-6963-7-82
  8. CAYLEY WE JR. Preventing deep vein thrombosis in hospital inpatients BMJ [online] 2007 Jul 21, 335(7611):147-151 [viewed 13 November 2014] Available from: doi:10.1136/bmj.39247.542477.AE
  9. HUANG A, BARBER N, NORTHEAST A. Deep vein thrombosis prophylaxis protocol--needs active enforcement. Ann R Coll Surg Engl [online] 2000 Jan, 82(1):69-70 [viewed 13 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2503451
  10. BĕLOHLáVEK J, DYTRYCH V, LINHART A. Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism Exp Clin Cardiol [online] 2013, 18(2):129-138 [viewed 13 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718593
  11. BĕLOHLáVEK J, DYTRYCH V, LINHART A. Pulmonary embolism, part II: Management Exp Clin Cardiol [online] 2013, 18(2):139-147 [viewed 13 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718594

Management - Specific Treatments

Fact Explanation
Deep vein thrombosis management LMWH (eg; enoxaparin 20mg/24 hours, sub cutaneously) can be given but in severe ileofemoral thrombi will need unfrationated heparin. Stary warfarin with the heparin and continue while heparin can be stopped with INR 2-3. Warfarin need to continue for 6 months as in Primary Thrombophilia no cause can be found.[1][2]
Pulmonary embolism management In an massive pulmonary embolism, 1) 100% oxygen need to be given after ensuring the patent air way 2) For pain management IV morphine 10 mg can be given with antiemetics 3) Cannulate with a wide bore needle and send blood for investigations (eg; PT/INR) and give IV heparin bolus followed by 18u/kg/hour with the guidence of APTT. 4) If the systolic blood pressure more than 90mmHg, start warfarin 10mh/24 hours orally. 5) if the systolic blood pressure less than 90mmHg, give colloid infusion, then dobutamine (after 500 ml of colloid) and finally noradrenaline to pick up the blood pressure and continue warfarin as above. 6) Finally confirm the diagnosis with investigations. Placement of vana caval filtration will be useful in patients with emboli development despit of anticoagulation [3][4]
Management of complications of the treatment Eg: warfarin over dose According to British Commitee for standards Haematology, INR 3.0-6.0 ; warfarin dose need to be reduce/ stopped (target INR 2.5) INR 4.0-6.0 ; warfarin can re start with INR less than 5.0 ( target INR 3.5) INR 6.0-8.0 with no/ minor bleeding; stop warfarin and re start with INR less than 5.0 INR more than 8.0 with no/ minor bleeding; stop warfarin and re start with INR less than 5.0. If other risk factors for bleeding is present give 0.5-2.5 Vitamin K orally Major bleeding; stop warfarin, give prothrombin complex concentrates 50U/Kg in preference, Give FFP 15ml/Kg when available and give IV/ oral Vitamin K 5mg.[5][6]
Fibrinolytic agents Fibrinolytic agents like Streptokinase, tissue plasminogen activator, single chain urokinase type plasminogen activator and acylated plasminogen streptokinase activator complex can be given in acute myocardial infarction, major pulmonary embolism and acute peripheral arterial occlusion[7].
Antiplatelet drugs These drugs ( aspirin, clopodogrel, abcximab) are proven to be useful in secondary prevention of vascular thrombotic events[8][9].
References
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  2. TOVEY C, WYATT S. Diagnosis, investigation, and management of deep vein thrombosis BMJ [online] 2003 May 31, 326(7400):1180-1184 [viewed 13 November 2014] Available from: doi:10.1136/bmj.326.7400.1180
  3. CHITWOOD WR JR, LYERLY HK, SABISTON DC JR. Surgical management of chronic pulmonary embolism. Ann Surg [online] 1985 Jan, 201(1):11-26 [viewed 13 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1250614
  4. SEKHRI V, MEHTA N, RAWAT N, LEHRMAN SG, ARONOW WS. Management of massive and nonmassive pulmonary embolism Arch Med Sci [online] 2012 Dec 20, 8(6):957-969 [viewed 13 November 2014] Available from: doi:10.5114/aoms.2012.32402
  5. HANLEY JP. Warfarin reversal J Clin Pathol [online] 2004 Nov, 57(11):1132-1139 [viewed 13 November 2014] Available from: doi:10.1136/jcp.2003.008904
  6. COSTA-LIMA C, FIUSA MM, ANNICHINO-BIZZACCHI JM, DE PAULA EV. Prothrombin complex concentrates in warfarin anticoagulation reversal Rev Bras Hematol Hemoter [online] 2012, 34(4):302-304 [viewed 13 November 2014] Available from: doi:10.5581/1516-8484.20120076
  7. KYRIAZI V. Breast Cancer as an Acquired Thrombophilic State J Breast Cancer [online] 2012 Jun, 15(2):148-156 [viewed 13 November 2014] Available from: doi:10.4048/jbc.2012.15.2.148
  8. JILMA B, KAMATH S, LIP GY. Antithrombotic therapy in special circumstances. II--In children, thrombophilia, and miscellaneous conditions BMJ [online] 2003 Jan 11, 326(7380):93-96 [viewed 13 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1125035
  9. PREVITALI E, BUCCIARELLI P, PASSAMONTI SM, MARTINELLI I. Risk factors for venous and arterial thrombosis Blood Transfus [online] 2011 Apr, 9(2):120-138 [viewed 13 November 2014] Available from: doi:10.2450/2010.0066-10