THROMBOEMBOLIC DISORDERS

THROMBOEMBOLIC DISORDERS Meena Kalyanaraman, MD Pediatric Critical Care Medicine Rafael Barilari, MD Pediatric Hematology-Oncology Children’s Hospital of New Jersey Newark Beth Israel Medical Center TO CLOT ANTICOAGULANTS PROCOAGULANTS OR NOT TO CLOT PROCOAGULANTS ANTICOAGULANTS HEMOSTATIC SYSTEM INTRINSIC PATHWAY COMMON PATHWAY EXTRINSIC PATHWAY Thrombin Fibrinogen Fibrin PLATELETS CLOT COLLAGEN TISSUE FACTOR VESSEL WALL COAGULATION PATHWAY INTRINSIC PATHWAY Factor XII Factor XI Factor IX Factor XIIa Factor XIa Factor IXa Platelets EXTRINSIC PATHWAY Vascular injury Ca++ Factor VIIa Tissue Factor Factor VII VIIIc Ca++ Factor Xa Platelets Factor X Prothrombin Factor XIII Va Ca++ Thrombin Factor XIIIa Fibrinogen Fibrin COMMON PATHWAY CLOT FIBRINOLYSIS FIBRIN POLYMER D D E D E D E D D D D E E D D D E D D-DIMER FIBRIN SPLIT PRODUCTS D D THROMBOEMBOLIC DISORDERS Epidemiology  Incidence  0.7 – 1.9 per 100000 children  0.51 per 10000 newborns THROMBOEMBOLIC DISORDERS  Venous thromboembolism  Arterial thromboembolism VENOUS THROMBOEMBOLISM Clinical presentation         catheter related thrombosis renal vein thrombosis portal vein thrombosis cerebral infarction purpura fulminans sinovenous thrombosis atrial thrombosis pulmonary embolism VENOUS THROMBOEMBOLISM Clinical presentation Catheter related loss of patency sepsis thrombocytopenia from consumption of platelets lower extremity abdominal, inguinal or leg pain swelling of abdomen or leg reddish/blue-purple discoloration of lower extremity VENOUS THROMBOEMBOLISM Clinical presentation Catheter related upper venous system swelling pain discoloration of upper extremity swelling of face and neck, distended veins superior vena cava syndrome chylothorax chylopericardium VENOUS THROMBOEMBOLISM Clinical presentation Renal vein thrombosis  hematuria  proteinuria  thrombocytopenia  nonfunction of involved kidney  abdominal mass VENOUS THROMBOEMBOLISM Clinical presentation Cerebral sinovenous thrombosis  Most common in neonates  0.67 per 100000 patients  Presentation  58% seizures  76% diffuse neurologic signs  42% focal Seizures at presentation and venous infarcts predict adverse outcome     acute systemic illnesses 54% prothrombotic states 41% chronic systemic diseases 36% head and neck disorders 29%  Risk factors deVeber G NEJM 2001; 345: 417-23 THROMBOEMBOLISM Atrial thromboembolism  Right atrial thrombus  risk factors  central venous catheter  atrial flutter/fibrillation  Fontan procedure  Left atrial thrombus  risk factors  risk for pulmonary embolism  atrial flutter/fibrillation  rheumatic mitral valve disease PULMONARY EMBOLISM “The detachment of larger or smaller fragments from the end of the softening thrombus which are carried along by the current of blood and driven into remote vessels. This gives rise to the very frequent process on which I have bestowed the name of Embolia”. Rudolf Virchow, Cellular pathology, 1859 special ed. PULMONARY EMBOLISM  THROMBOTIC PE  embolic in origin  thrombotic occlusion in patients with pulmonary hypertension  NON-THROMBOTIC PE  pathologic process  tumor, infection  body‟s organ systems  foreign material  fat, bone marrow, bile, brain  catheters, talc, bullet, valve parts PULMONARY EMBOLISM Pathophysiology  Increase in pulmonary vascular resistance  Ventilation-perfusion mismatch  Abnormalities of gas exchange   airway resistance  compliance  Pulmonary infarction PULMONARY EMBOLISM Pathophysiology  Increase in pulmonary vascular resistance  vascular obstruction   pulmonary artery pressure when > 25-30% of arterial tree is obstructed  mean PAP of 30-40mm Hg represents severe pulmonary hypertension  vasoconstriction by vasoactive amines  serotonin, thromboxane A2  vasoconstriction by baroreflex PULMONARY EMBOLISM Pathophysiology  Ventilation-perfusion mismatch  increased dead space  intrapulmonary shunt  intracardiac shunt PULMONARY EMBOLISM Pathophysiology  Abnormalities of gas exchange  increased alveolar dead space (Vd)  hypoxemia        absolute dead space (complete obstruction) and  physiologic dead space (incomplete obstruction)  normal Vd/Vt is < 0.35 preexisting cardiopulmonary disease degree of vascular obstruction V/Q mismatch reflex bronchoconstriction, atelectasis, infarction decreased cardiac output PULMONARY EMBOLISM Pathophysiology   airway resistance   compliance  ? Serotonin mediated bronchoconstriction  pulmonary edema, fibrosis, atelectasis  loss of surfactant  pulmonary infarction  occlusion of small PA PULMONARY EMBOLISM Risk Factors  deep vein thrombosis  prolonged immobilization  postoperative state  obesity  heart disease  neoplasia  systemic disease-collagen vascular, venous anomalies  primary hypercoagulable state PULMONARY EMBOLISM Clinical Features  ACUTE COR PULMONALE  dyspnea, cyanosis, right ventricular failure, hypotension  PULMONARY INFARCTION  pleuritic pain, hemoptysis  NON SPECIFIC  cough, fever, apprehension Dyspnea is the most frequent symptom and tachypnea is the most frequent sign PULMONARY EMBOLISM Radiologic Signs  Enlargement of Distal PA  Right heart enlargement  Westermark sign  Hampton hump  areas of decreased pulmonary vascularity  infarct-cardiac margin is „hump‟ shaped  Elevated hemidiaphragm  Pleural effusion PULMONARY EMBOLISM ECG  Tachycardia, ST depression  ST and T wave inversion  S1 Q3 T3 pattern  S wave in lead 1, Q wave with T wave inversion in lead 3 PULMONARY EMBOLISM Echocardiogram  Thromboemboli within right heart or PA  Dilatation of right PA  RV dilatation, increased RV/LV diameter ratio  RV hypokinesis  Abnormal septal position and paradoxical systolic motion  TR/PR PULMONARY EMBOLISM ABG   PaO2   PaCO2  PaCO2   P (A-a) O2 „Normal PaO2 does not rule out pulmonary embolism‟ PULMONARY EMBOLISM Investigations  D-Dimer  ELISA more sensitive than rapid latex agglutination  sensitivities variable in studies (65% 95%  Vd/Vt  > 0.4  sensitivity 100%, specificity 94% PULMONARY EMBOLISM Pulmonary Angiography  “gold standard”  indications  indeterminate scan  low probability scans with high clinical suspicion  high probability scan in whom confirmation is necessary because of high risk of bleeding from anticoagulation  massive embolism in whom embolectomy is planned  significant clinical evidence for an alternative diagnosis PULMONARY EMBOLISM  High probability V/Q scans V/Q scan  Intermediate probability V/Q  Low probability V/Q  specificity 30%  > 2 large or > 2 moderate segmental perfusion defects + 1 large segmental defect - without corresponding ventilation or roentgenographic abnormalities  > 4 moderate segmental perfusion defects without corresponding ventilation or roentgenographic abnormalities  specificity is 88%  specificity 14% PIOPED STUDY JAMA 1990; 263: 2753-2759 V/Q SCAN Ventilation scan of patient ‘A’ with suspected pulmonary emboli V/Q SCAN Ventilation scan of patient ‘A’ with suspected pulmonary emboli V/Q SCAN Perfusion scan of patient ‘A’ with suspected pulmonary emboli showing multiple segmental defects PULMONARY EMBOLISM Spiral CT  sensitivity 87%; specificity 91% (Rathbun SW et al Ann Intern Med 2000; 132: 227-232 Mullins MD et al Arch Intern Med 2000; 160: 293-298)  can be performed quickly in hemodynamically unstable patients  lacks sensitivity for emboli in subsegmental arteries SPIRAL CT Right pulmonary artery thromboembolism NEONATAL THROMBOSIS  Catheter related ( majority)  Spontaneous  renal/caval/portal/hepatic  Secondary to risk factors  peripartum asphyxia, sepsis, dehydration, maternal diabetes NEONATAL THROMBOSIS Risk Factors Deficiency in thrombin inhibition Relatively deficient fibrinolysis Most anticoagulants are decreased 3-6 months: hemostatic factors reach adult levels Protein C reach adult level at puberty AT, Protein C, S low plasminogen and t-PA normal Alpha 2 antiplasmin  low Vit K dependent factors DVT Upper venous system in 80% neonates and 60% of children CATHETER RELATED THROMBOSIS Incidence  3.5 per 10000 admissions in retrospective studies; 8-35% in prospective studies Lowest in Internal jugular and higher in femoral/subclavian vein catheters Classification Occlusion  Fibrin sheath Jacobs BR. Critical Care Clinics 2003; 19: 489-514  partial or complete  thrombotic or non-thrombotic CATHETER RELATED THROMBOSIS Classification  Occlusion  partial or complete  partial: coating or precipitate acts as a ball valve permitting infusions but not withdrawal of fluid ; complete: inability to withdraw or infuse  thrombotic: blood elements within, surrounding or at tip of catheter; non-thrombotic: medication/mineral/lipid deposits; mechanical obstruction  thrombotic or non-thrombotic  Fibrin sheath  fibrin adheres and accumulates on external surface and encases the device to form a sheath  generally forms in 5-7 days  filling defects or reflux of contrast material seen during contrast venography CATHETER RELATED THROMBOSIS Pathophysiology  vessel wall injury  from catheter placement resulting in exposure of basement membrane Von Willebrand‟s factor (vWf)  sluggish and turbulent flow from catheter in situ  alterations in blood flow  hypercoagulability  platelets bind to vWf activating the coagulation system CATHETER RELATED THROMBOSIS Risk factors  Patient factors  Catheter factors CATHETER RELATED THROMBOSIS Risk factors – Patient related        cancer chemotherapy agents TPN infections hemodialysis prothrombotic factors venous stasis from conditions like dehydration, polycythemia, DKA CATHETER RELATED THROMBOSIS Risk factors – catheter related  catheter composition  polyvinyl chloride and polyethylene are stiffer with irregular surface (higher incidence of thrombosis) while silicone is pliable and smoother (lower incidence of thrombosis)  catheter diameter to vessel diameter ratio  infusate  high ratio  increased risk of thrombosis  fat emulsion and TPN noted to induce monocyte and endothelial cell procoagulant activity VENOUS THROMBOEMBOLISM Clinical presentation Portal vein thrombosis  occurrence  umbilical vein catheterization  liver transplantation  intra-abdominal sepsis  splenectomy  presentation  acute abdomen  chronic obstruction: splenomegaly, GI bleeding VENOUS THROMBOEMBOLISM Complications  Mortality 14-23% Determined by underlying disease  Recurrence first VTE recurrence is 9%  Postphlebitic syndrome POSTPHLEBITIC SYNDROME  complication of DVT  pain, swelling, hyperpigmentation, induration, ulceration  from venous hypertension and valvular incompetence  may occur 5-10 years after a TE PURPURA FULMINANS  Procoagulant pathways are activated and anticoagulant/fibrinolytic pathways are impaired  Congenital and acquired deficiencies of Protein C and S  Sepsis-esp. meningococcal  consumption of Protein C,S and AT along with disruption of activated endothelial protein C complex RISK FACTORS  Inherited  Acquired  most common mutations in Factor V gene (Factor V Leiden) Prothrombin gene mutation (prothrombin 20210 A)‟  other  deficiency of AT,Protein C,S  hyperhomocysteinemia  dysfibrinogenemia  Indwelling catheter device  Hyperviscosity (dehydration, polycythemia)  Surgery or trauma  Infection (HIV, varicella, suppurative thrombophlebitis)  Autoimmune disorders (LA, APLS, IBD, BD, DM)  Renal disease (nephrotic syndrome, chronic renal disease)  Congenital heart disease  Malignancy  Chemotherapy (Lasparaginase, prednisone)  Liver disease  Thallesemia (postsplenectomy PVT)  Sickle cell disease  APCC or PCC administration INHERITED RISK FACTOR Factor V Leiden  mutation in Factor V causing resistance to activated protein C  single G-A mutation at nucleotide 1765 within factor V gene: arginine is replaced by glutamine at position 506  most common inherited cause of thrombosis in Caucasians  3-8% Caucasians carry the mutation and 0.1% are homozygotes  homozygotes have 80 fold increased risk of thrombosis INHERITED RISK FACTOR Prothrombin 20210A  Genetic defect at nucleotide position 20210A in prothrombin gene  results in high prothrombin levels which causes increased thrombin generation  2-3% in Caucasians, 4-5% in Mediterranean  Less severe clinical manifestation INHERITED RISK FACTOR Antithrombin deficiency AT forms a complex with activated clotting factors thrombin, Xa, IXa, XIa and this is accelerated by heparin or cell surface heparan sulfate Type 1 AT deficiency  decreased synthesis and functional activity of AT Type 11 AT deficiency  decreased AT activity and normal antigenic levels INHERITED RISK FACTOR Protein C deficiency  vitamin K dependent plasma glycoprotein functions by inactivating factors Va and VIIIa  protein C activity is enhanced by another vitamin K dependent inhibitory cofactor protein S  autosomal dominant inheritance  Type 1  Type 2  decreased plasma concentration and functional activity  decrease in functional activity  could present as neonatal purpura fulminans, DIC, recurrent TE in later life INHERITED RISK FACTOR Protein S deficiency  Vitamin K dependent anticoagulant  Cofactor to protein C and enhances its activity against factors Va and VIIIa  Type 1  Type 2  quantitative defect  qualitative defect INHERITED RISK FACTOR Hyperhomocysteinemia  deficiency of cystathionine b-synthase  MTHFR gene polymorphism: reduces amount of 5methyltetrahydrofolate available for conversion of homocysteine to methionine INHERITED RISK FACTOR- Others  Lipoprotein - Lp(a) levels  F VIII levels high levels inhibit fibrinolysis by competing with plasminogen for binding to fibrin or cell surfaces increased levels increased risk for TE >1500 IU/L has 6 fold increased risk when compared to levels <1000 IU/L INHERITED RISK FACTOR Dysfibrinogenemia  Autosomal recessive  Impaired binding of thrombin to abnormal fibrin and defective fibrinolysis due to impaired assembly of tissue plasminogen activator and plasminogen activation on the abnormal fibrin  Can lead to thrombosis and bleeding INHERITED DISORDERS Laboratory tests            Antithrombin Protein C,S Factor V Leiden Prothrombin gene (G20210A) Homocysteine level(5,10 methylenetetrahydrofolate reductase) Lipoprotein (a) Lupus anticoagulant Anticardiolipin antibodies Factor VIII Fibrinogen Studies for rare causes:         Activated protein C resistance Factor XI, XII Heparin cofactor 2 Thrombomodulin Tissue factor pathway inhibitor Plasminogen Plasminogen activator inhibitor-1 Tissue plasminogen activator THERAPY  In general, 3 months is indicated after resolution of an initial TE with resolved risk factors  for residual vascular obstruction or if risk factors persist then 6 months of therapy is recommended  Prolonged treatment considered for continued presence of risk factors such as lupus anticoagulants, multiple thrombophilic traits or recurrent TE  Pulmonary embolism: “time window” of treatment: most effective when treated early but may extend upto 14 days after symptom onset  FFP infusions to raise AT or plasminogen levels may improve the therapeutic effectiveness of treatment VENOUS THROMBOEMBOLISM Treatment  Heparin-unfractionated  Heparin-Low molecular weight  Thrombolytic-tissue plasminogen activator  Catheter directed thrombolysis  Oral anticoagulants-warfarin  Direct thrombin inhibitors  Direct Factor Xa inhibitors  Indirect Factor Xa inhibitors ACTION AND MONITORING HEPARIN-ANTITHROMBIN FACTOR XIIa FACTOR XIa WARFARIN ANTICOAGULANTS LMWH FACTOR Xa FACTOR VII FACTOR IX FACTOR X PROTHROMBIN (II) FACTOR IXa FACTOR Xa THROMBIN (IIa) PTT Anti Xa levels PT/INR FIBRINOLYTICS tPA UROKINASE PLASMINOGEN PLASMIN FIBRINOGENFIBRIN FIBRIN DEGRADATION PRODUCTS CATHETER DIRECTED THROMBOLYSIS  Recombinant tissue plasminogen activator  Bolus of 4-5mg followed by infusion of 0.02mg/kg/hour-0.04mg/kg/hour  Technical problems, local and distant bleeding, vessel rupture HEPARIN Acidic glycosaminoglycan that acts by catalyzing AT to inhibit serine proteinases particularly factor IIa (thrombin), IX, X In newborns and children, increases in heparin clearance, plasma protein binding of heparin as well as lower plasma AT concentrations necessitate higher dosing Adverse effects: bleeding heparin induced thrombocytopenia osteopenia HEPARIN-INDUCED THROMBOCYTOPENIA Pathophysiology  HIT and HIT/Thrombosis is an immune reaction  triggered by generation of antibodies (IgG)that bind to a complex of heparin with various proteins on the surface of platelets and endothelial cell surface  the antibody causes platelet activation, aggregation and platelet/endothelial cell destruction HEPARIN-INDUCED THROMBOCYTOPENIA Pathophysiology IgG Antibody Heparin Platelet factor 4 Platelet activation/aggregation Platelet and endothelial destruction Heparin-induced thrombocytopenia Heparin-induced thrombocytopenia/thrombosis HEPARIN - INDUCED THROMBOCYTOPENIA Diagnosis  usual onset at day 3-14 of heparin therapy  50% or more decrease in platelet number from baseline value  absence of other causes of thrombocytopenia  return of platelet numbers to baseline when heparin is stopped HEPARIN - INDUCED THROMBOCYTOPENIA Diagnosis  confirmation  platelet aggregation assay  ELISA test to quantitate antibodies to the heparin-PF4 complex HEPARIN - INDUCED THROMBOCYTOPENIA Treatment  stop heparin immediately  if original condition persists  direct thrombin inhibitor  lepirudin  argatroban  monitor with Aptt  assess for HIT-Thrombosis  if prophylaxis is needed-argatroban may be used SYSTEMIC HEPARIN ADMINISTRATION FOR CHILDREN Protocol Loading Dose: Heparin 75 units/kg IV over 10 minutes Initial maintenance dose: 28 units/kg/h for infants, 1 year, 20 units/kg/h for children older than 1 year Adjust heparin to maintain aPTT 60-85 seconds aPTT < 50 50-59 60-85 86-95 >120 Bolus, units/kg 50 0 0 0 0 0 0 0 0 30 60 Hold, minutes Rate Change % +10 +10 0 -10 -10 -15 Repeat aPTT 4 hours 4 hours Next day 4 hours 4 hours 4 hours 96-120 0 Adapted from Michelson AD, Bovill E, Andrew M: Antithrombotic therapy in children. Chest 1995; 108:506s-522S REVERSAL OF HEPARIN THERAPY Time Since Last Heparin Dose, Minutes <30 30-60 60-120 >120 Protamine Dose, mg/100 units Heparin 1 0.5-0.75 0.375-0.5 0.25-0.375 Maximum dose=50 mg. Infusion rate 10 mg/mL solution should not exceed 5 mg/minute Adapted from Monagle P, Michelson AD, Bovill E and Andrew M: Antithrombotic therapy in children. Chest 2001; 119:344-370S LMWH  Chemically or enzymatically cleaved polymer of standard heparin that average 4kd to 6kd compared to average polymer of standard heparin 12-15kd  Binds to AT, causing a conformational change that binds and inactivates factor Xa Therapeutic range – drawn 4 hours post administration 0.6-1.0 anti-Xa U/ml  1mg/kg SQ Q12, 1.5mg/kg SQ Q12 in <2months of age NOMOGRAM FOR MONITORING LMWH Anti-Factor Xa u/ml Hold next dose? Dose change? Repeat Anti-Factor Xa <0.35 0.35-0.49 0.5-1.0 No No No Increase by 25% Increase by 10% No 4h after next dose 4h after next dose Next day, then 1 wk later and monthly thereafter (4h after dose) Before next dose Before next dose then 4h after next dose Before next dose, if not < 0.5u/ml, repeat q12h 1.1-1.5 1.6-2.0 >2.0 No 3h Until anti-factor Xa 0.5U/ml Decrease by 20% Decrease by 30% Decrease by 40% Monagle P, Michelson AD, Bovill E, Andrew M. Chest 2001; 119:344S-370S LMWH  advantages  pharmacokinetics more predictable  minimize frequency of monitoring  subcutaneous administration  risk of heparin-induced thrombocytopenia decreased  risk for osteoporosis is decreased  does not interfere with diet or drugs WARNING: DO NOT USE HEPARIN AND LMWH CONCURRENTLY WARFARIN  inhibition of gamma carboxylation of the vitamin K-dependent coagulation proteins made in liver and factors II, VII, IX, X  INR 2-3 for TE adverse effects bleeding warfarin induced skin necrosis teratogenic I. Day 1: if baseline INR is 1.0-1.3: dose = 0.2mg/kg orally WARFARIN - PROTOCOL Max: 10mg/dose II. Loading days 2-4: If INR is : INR 1.1-1.3 1.4-1.9 2.0-3.0 3.1-3.5 ACTION Repeat loading dose 50% of initial loading dose 50% of initial loading dose 25% of loading dose > 3.5 Hold until INR is < 3.5, then restart at 50% less than previous dose WARFARIN - PROTOCOL III: Maintenance warfarin dose guidelines: INR 1.1-1.4 1.5-1.9 2.0-3.0 ACTION Increase by 20% of dose Increase by 10% of dose No change 3.1-3.5 > 3.5 Decrease by 10% of dose Hold until INR < 3.5, then restart at 20% less than previous dose Michelson AD, Bovill E, Andrew M. Chest 1995;108:506S-522S IVC INTERRUPTION  Indications  contraindications for anticoagulation  recurrent PE despite appropriate anticoagulation malpositioning migration venous thrombosis proximal or distal to filter sepsis hemorrhage at puncture site Complications Types permanent eg: Kimray-Greenfield filter retrievable filters if risk is transient THROMBOLYTIC THERAPY t-PA  For massive PE, extensive DVT, arterial thrombosis 0.5mg/kg/hour for 6 hours  concurrent Heparin infusion – 20units/kg/hour  if no response after 6 hours, check plasminogen levels – may need FFP  For MI 0.2 mg/kg (MAX 15mg) followed by infusion of 0.75mg/kg over a 30min period (max 50mg) and then an infusion of 0,5mg/kg over 60 min period (max 35mg) heparin - simultaneously bolus 75mg/kg followed by 20units/kg/hour SYSTEMIC THROMBOLYTIC THERAPY Precautions No IM injections Minimal manipulation of patient Avoid concurrent use of warfarin or antiplatelet agents No urinary cath, rectal temp, arterial punctures SYSTEMIC THROMBOLYTIC THERAPY Complications  Bleeding occurs in 30-50% of patients  Oozing from wound or puncture sites-local pressure  Severe bleeding stop infusion of thrombolytic agent infuse cryoprecipitate (1unit/5kg) Amicar – to reverse thrombolytic process protamine sulfate-to reverse heparin  Fever, urticaria, anaphylactic reactions CATHETER RELATED THROMBOSIS Treatment  Replacement or removal  Anticoagulant therapy  determined individually for each patient  heparin  low molecular weight heparin  low dose t-PA to restore catheter patency  fibrin selective agents (alteplase and tenecteplase) and non fibrin selective agents (streptokinase, reteplase)  warfarin  catheter directed thrombolysis CATHETER RELATED THROMBOSIS Treatment  Vena cava filter  indications  contraindication to anticoagulation  thromboembolic problems despite anticoagulation  Surgical thrombectomy  indications  right atrial thrombus causing hemodynamic instability DIRECT THROMBIN INHIBITORS  bind specifically to thrombin  inhibit both free and bound thrombin  FDA approved drugs  lepirudin  bivalirudin  Argatroban  Administration/monitoring  Iv administration(most drugs), APTT monitoring  Oral drug: Melagatran-no monitoring required FACTOR XA INHIBITORS  Direct Factor Xa inhibitor exclusive Factor Xa inhibition inhibits circulating and clot bound Xa under development YM-60828 DX-9065a FACTOR XA INHIBITORS  Indirect  enhances AT-mediated inhibitory activity against Factor Xa  total chemical synthesis  fondaparinux 100% bioavailability predictable dose response effect risk of heparin induced thrombocytopenia unlikely ARTERIAL STROKE  STROKE  „rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death with no apparent cause other than of vascular origin‟ WHO MONICA Project definition ARTERIAL STROKE 8 per 100,000 per year ISCHEMIC 55% HEMORRHAGIC 45% Traumatic Nontraumatic Cardiac emboli Prothrombotic states Nonatherosclerotic vasculopathy Ruptured vascular malformation Bleeding diathesis Sympathomimetic drug abuse Intracranial tumoral bleeding  Imaging  MRI/MRA ARTERIAL STROKE Investigations  W/U for hypercoagulable state  Infectious  CSF/serum studies for bacteria/virus/mycoplasma/rickettsia  Collagen vascular disease  SLE/APLA  Metabolic  for MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke like episodes): serum/CSF lactate/pyruvate, DNA analysis  for urea cycle enzyme defects-serum ammonia  for hyperlipidemia (serum TGL, cholesterol, HDL, LDL)  for homocystinuria (serum amino acids, homocysteine levels)  for Fabry disease (urine ceramide trihexoside, leukocyte agalactosidase) ARTERIAL STROKE Treatment  Heparin or LMWH for minimum of 5 days  Subsequent anticoagulation with warfarin or ASA – duration dependent on etiology