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Stroke Education Series - 2010 Hypercoaguable states & Stroke Phaniraj Iyengar MD Director Disclosure • I am on the speaker panel for Bristol Myers and Sanofi Aventis Discussion Points 1. 2. 3. 4. 5. 6. 7. 8. Introduction Hemostasis Thrombosis Neurologist workup philosophy Inherited hypercoaguable states Acquired hypercoaguable states Case presentations (Two) Final summary Hypercoaguable states & Stroke • Coagulation disorders that predispose to strokes remain POORLY DEFINED. • They may have been implicated in venous strokes (Cerebral venous thrombosis) rather than arterial strokes. • Known hematological abnormalities are estimated to account for about 4% of all strokes. This proportion may be higher for younger people. Hypercoaguability and Stroke Hemostasis Introduction • The ability of blood to coagulate is ESSENTIAL to the survival of the species. • In humans, when coagulation is TOO EFFICIENT, thrombosis becomes one of THE MOST COMMON CAUSES of morbidity and mortality in developed countries – specifically CAD & STROKE. Hemostatic Process The Three main Steps 1. Primary hemostasis Local vasoconstriction & platelet plug formation. 2. Coagulation cascade. 3. Fibrinolysis Hemostasis A very complex process!!! Rube Goldberg Machine Pencil Sharpener Open window (A) and fly kite (B). String (C) lifts small door (D) allowing moths (E) to escape and eat red flannel shirt (F). As weight of shirt becomes less, shoe (G) steps on switch (H) which heats electric iron (I) and burns hole in pants (J). Smoke (K) enters hole in tree (L), smoking out opossum (M) which jumps into basket (N), pulling rope (O) and lifting cage (P), allowing woodpecker (Q) to chew wood from pencil (R), exposing lead. Emergency knife (S) is always handy in case opossum or the woodpecker gets sick and can't work. Platelet Activation & Aggregation First Step Exposed endothelial surface Platelets exposed to collagen Platelets are activated Release contents of cytoplasmic granules Adenosine Diphosphate (ADP) Accelerates Platelet activation Platelet aggregation Thromboxane (TxA2) Vasoconstriction Increases ADP release from Platelets Hemostatic Process Coagulation Cascade To stabilize and reinforce the weak platelet plug Fibrinogen → fibrin Three main steps: 1. Formation of prothrombin activator 2. Conversion of prothrombin into thrombin 3. Conversion of fibrinogen to fibrin Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30. Coagulation Pathways Intrinsic Pathway “Contact Activation” IX “TF Pathway” XI XIIa Prekallikrein HMW Kininogen Extrinsic Pathway TF-VIIa Ca2+ Tissue Factor + VII X Common Pathway PL Prothrombin XIa PL, Ca2+ (Tenase) IXa PL, Ca2+ VIIIa Xa Anticoagulation proteins: Protein C, Protein S, (Prothrombinase) Va Antithrombin III, TFPI XIII Thrombin Fibrinogen XLXIII a Fibrin Fibrin Monomer Polymer Coagulation Some facts to consider… Coagulation is a MULTIFACTORIAL PATHWAY of "accelerators". Coagulation is TIGHTLY REGULATED and only a SMALL quantity of each coagulation enzyme is converted to its active form. Regulation is important - there is enough clotting potential in 1 mL of blood to CLOT ALL THE FIBRINOGEN IN THE BODY in 10 to 15 seconds! Hypercoaguability and Stroke Thrombosis Thrombosis An Eye Opener Thrombosis Is Clotting In the Wrong Place Introduction • Thrombosis can be divided anatomically into VENOUS and ARTERIAL thrombosis. • Pathophysiology of these two types of clotting is quite different. • Clotting in the low flow venous system is generally associated with DEPOSITION OF FIBRIN, whereas in the arterial system, thrombosis is associated with PLATELET REACTIVITY AND VASCULAR WALL DAMAGE. Arterial Thrombosis Pathophysiology Arterial thrombosis is the result of an Atheromatous plaque rupture that causes platelet activation and aggregation resulting in an obstructive lesion that subsequently leads to tissue damage. Hypercoaguability Factors that ACCELERATE the hemostatic mechanism or INHIBIT mechanisms that counteract hemostasis CONTRIBUTE to an INCREASED state of THROMBOGENICITY or HYPERCOAGUABILITY, and thereby play an etiological role in strokes. Hypercoaguable Workup in Stroke Is Challenging because of The relative LOW PREVALENCE of these disorders in stroke patients Their UNCERTAIN SIGNIFICANCE Their POTENTIAL INTERACTION with traditional stroke risk factors The HIGH COST of testing The LACK OF diagnostic gold standards The DIFFICULTY WITH INTERPRETATION of some tests in the setting of acute thrombosis.* Brigden ML. The hypercoagulable state: who, how, and when to test and treat. Postgrad Med.1997; 101: 249–267. Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies in patients with ischemic stroke. Stroke. 2000; 31: 3067–3078. Bushnell CD, Siddiqi Z, Morgenlander JC, Goldstein LB. Use of specialized coagulation testing in the evaluation of patients with acute ischemic stroke. Neurology. 2001; 56: 624–627. Before ordering please……… Attempt to connect the dots by asking the right questions especially in the context of History Presentation Imaging Because these tests are expensive!!! Cost of Hypercoaguabilty workup Test Natural anticoagulants (antithrombin, protein C, protein S): Genetic tests (factor V Leiden, prothrombin G20210A): Antiphospholipid antibodies: Other (factor VIII, homocysteine): TOTAL PANEL COST Approximate Cost* $450-750 $600 $1000-1500 $200 $2250-3050 * Duke Coagulation Laboratory Hypercoaguability and Stroke Neurologists Hypercoaguability Workup philosophy Workup of a suspected Hypercoaguable state causing Stroke Fifty-nine (75%) surveys were completed. Specialized coagulation tests were reported to INFREQUENTLY influence stroke patient management (<25% of the time or NEVER for 95% of respondents). Factors reported to INCREASE test-ordering included young patient age (76%), history of thrombosis (46%), history of miscarriages (36%), and HAVING FEW traditional stroke risk factors (35%). Workup of a suspected Hypercoaguable state causing Stroke MOST (88%) indicated they would order specialized coagulation tests for a hypothetical young patient with NO known stroke risk factors. In contrast, ONLY A FEW (14%) would obtain the tests for a patient having traditional stroke risk factors, and NONE would order the tests for a stroke patient with Atrial fibrillation. Laboratory Evaluation RISK FACTOR LABORATORY ASSAY Antithrombin Deficiency AT activity Protein C Deficiency Protein C Deficiency PC activity (clotting or chromogenic) Protein S Deficiency Protein S Free Antigen (ELISA, LIA) APC Resistance / Factor V Leiden Mutation APC Resistance (aPTT); FV Leiden genetic test if abnormal Prothrombin Mutation G20210A Genetic Test Hypherhomocysteinemia EIA, HPLC Lupus Anticoagulant DRVVT Clotting Assay Anticardiolipin Antibody, IgG / IgM aCL IgG / IgM Antigen ELISA Hypercoaguability and Stroke Evaluation for Causes of a Hypercoaguable State is Complicated What the Mind Does Not Know, The Eye Does Not See Factors leading to Thrombosis Inherited Risk Factors APC resistance-Factor V Leiden Anti-Thrombin deficiency Protein C deficiency Protein S deficiency Prothrombin Mutation Fibrinogen Mutations Platelet protein polymorphisms Sickle cell disease Acquired Risk Factors Age Malignancy Immobilization Trauma, Post-op Pregnancy Estrogen use Antiphospholipid Antibodies Long distance flights Hematologic Diseases TTP Inherited or Acquired Risk Factors Hyperhomocystenemia Elevated levels of Factor VIII, IX,XI Hypercoaguability and Stroke Inherited Hypercoaguable States Inherited Hypercoaguable States MUTATIONS RARE Antithrombin III deficiency. Protein C deficiency. Protein S deficiency POLYMORPHISMS COMMON Factor V Leiden. Prothrombin gene polymorphism. Thermolabile MTHFR variant. Inherited Hypercoaguable States Defect Incidence % of Hypercoaguable States Factor V Leiden Prothtombin Gene Mutation Protein C deficiency Protein S deficiency 2–8% 40-60% 1-2 % ?10% 1: 200 5-10% 1: 5,000 5-10% Antithrombin III deficiency Dysfibrinogenemia 1: 2- 5000 1-3% rare 1% Inherited Hypercoaguable States Polymorphisms of coagulation proteins • The MOST common cause of venous thrombosis is Activated Protein C resistance (APC Resistance) which is MOST OFTEN associated with a single mutation causing substitution of arginine by glutamine at residue 506 of Factor V gene (Factor V Leiden). Inherited Hypercoaguable States Factor V Leiden 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 Hypercoaguable States Factor V Leiden Occurs in 5-7% of the population Occurs in 20% of patients with DVT. Occurs in 60% of patients with recurrent DVT’s. Incidence of Factor V Leiden with stroke is UNKNOWN. Inherited Hypercoaguable States Factor V Leiden Factor V Leiden is suspected to be associated with paradoxical emboli or with venous sinus thrombosis. At this time, the data available DO NOT suggest any role between factor V Leiden and arterial thrombosis (stroke, heart attack). Inherited Hypercoaguable States Factor V Leiden Treatment Warfarin x 6 months or until thrombosis free for 2 months LMWH x 2 wks after Warfarin then retested Long term anticoagulation if persist or recurrent thrombotic event Inherited Hypercoaguable States Antithrombin deficiency 1965 - First inherited trait associated with thrombophilia. Although called anti-thrombin, it actually serves to inhibit virtually ALL of the coagulation enzymes to at least some extent. Inherited Hypercoaguable States Antithrombin deficiency • Although isolated reports exist of arterial disease in patients with heterozygous antithrombin deficiency, there is NO clear evidence of increased arterial disease in antithrombin deficiency. Inherited Hypercoaguable States Prothrombin Gene Mutation 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 Hypercoaguable States Prothrombin Gene Mutation At this time, there is CONTRADICTING evidence regarding the role of the Prothrombin Gene mutation and arterial thrombosis (stroke, heart attack). Inherited Hypercoaguable States Prothrombin Gene Mutation and Stroke Based on these data, for persons with the prothrombin gene mutation, the MOST IMPORTANT preventive steps for the purposes of arterial disease are controlling other risk factors including: Smoking, Hypertension, Hyperlipidemia, Obesity and a sedentary lifestyle (limited activity). Inherited Hypercoaguable States Protein C Vitamin K dependent plasma glycoprotein Functions by inactivating factors Va and VIIIa Protein C activity is enhanced by Protein S Autosomal dominant inheritance Inherited Hypercoaguable States Protein C deficiency Prevalence in normal population ~0.2-0.4% Present in ~3-4% of patients with venous thromboembolism. Homozygosity is associated with neonatal purpura fulminans. 50% of patients with protein C deficiency WILL have a thrombosis by age 36 years. Inherited Hypercoaguable States Protein C deficiency • At this time, the data available DO NOT suggest any role between protein C deficiency and arterial thrombosis (stroke, heart attack). Inherited Hypercoaguable States Protein S Vitamin K dependent anticoagulant Cofactor to protein C and enhances its activity against factors Va and VIIIa. Inherited Hypercoaguable States Protein S Deficiency Prevalence in the normal population ~0.003% Present in ~2-3% of patients with venous thromboembolism. Homozygosity is associated with neonatal purpura fulminans. 50% of patients with protein S deficiency WILL have a thrombosis by age 36 years. Inherited Hypercoaguable States Protein S Deficiency and Stroke A prospective study did find free Protein S deficiency in 23% of young patients with Stroke of Uncertain Cause, but this finding could be associated with higher levels of C4b (an acute phase reactant that decreases free Protein S Levels). Inherited Hypercoaguable States Protein S Deficiency and Stroke At this time, the data available DO NOT suggest any role between protein S deficiency and arterial thrombosis (stroke, heart attack). Inherited Hypercoaguable States Fibrinogen Elevated Fibrinogen levels are a common and consistent finding in patients with Stroke Serum fibrinogen levels are variable and can increase in response to infectious or inflammatory conditions as part of the acute phase response. Polymorphisms within the Fibrinogen gene have been associated with Stroke. Inherited Hypercoaguable States Fibrinogen Polymorphisms and Stroke Results from the Austrian Stroke Study showed an association between a polymorphism in the beta chain of fibrinogen at position 148 and Carotid atherosclerosis. Results from a Japanese study showed an association between a polymorphism at position 455 with cerebrovascular disease. Inherited Hypercoaguable States Fibrinogen Polymorphisms and Stroke Over time, more polymorphisms are likely to be discovered in the Fibrinogen gene that are related to stroke. Inherited Hypercoaguable States Polymorphisms of Platelet Proteins & CAD A common point mutation in glycoprotein IIIa, termed PLA2, leads to a substitution of proline for leucine at position 33. PLA2 has been suggested as a risk factor for CAD1. Although potentially associated with CAD, several studies have suggested that this polymorphism is UNLIKELY to be associated with Stroke2. 1Wciss EJ et al. N Engl J Med 1996;334:1090-1094 2Carlsson LE at al. Stroke 1997;28:1392-1395 Inherited Hypercoaguable States Platelet Protein Polymorphisms & Stroke The Glycoprotein Ib/IX/V complex is a platelet protein responsible for platelet adhesion using vWF as the ligand. A polymorphism in the region of the glycoprotein Lb gene responsible for keeping the ligand binding region distal to the platelet surface leads to a variable number (1,2,3,4) of tandem repeats. There appears to be an association of repeat number genotype with Cerebrovascular disease1. Gonzalez-ConejeroR et al. Blood 1998;92:2771-2776 Inherited Hypercoaguable States Hyperhomocysteinemia Hyperhomocystenemia is associated with a Vasculopathy. Unlike most other hypercoaguable states, it causes more arterial strokes than venous strokes. Elevated levels of Homocysteine and related disulfitide compounds are clear risk factors for Stroke Inherited Hypercoaguable States Hyperhomocysteinemia Mutations, Polymorphisms heterozygotic 30-40% 1-2% Mutations, homozygotic <<1% Nutrition 30-40% Renal insufficiency Homocysteine Oxidative stress Endothelial Venous dysfunction thrombosis PVD CVD CAD Inherited Hypercoaguable States Homocysteinemia Caused by two primary enzyme defects 1. Cystathionine Beta-Synthase (CBS) 2. Methylene-Tetra-Hydro-Folate Reductase (MTHFR), Inherited Homocysteinemia Clinical Manifestations 1. Ocular manifestations – ectopia lentis Inherited Homocysteinemia Clinical Manifestations 2. Marfanoid appearance combined with CNS manifestations, like mental retardation Inherited Homocysteinemia Clinical Manifestations 3. Musculo-skeletal manifestations osteoporosis Inherited Homocysteinemia Clinical Manifestations 4. Vascular manifestations – vascular occlusions, thromboembolism Inherited Hypercoaguable States Homocysteinemia from CBS Polymorphisms Most common genetic cause of severe homocysteinemia. Classic homocystinuria is homozygous deficiency of CBS. Inherited as autosomal recessive trait. Occurs in 1 in 100,000 live births. Inherited Hypercoaguable States Homocysteinemia from CBS Polymorphisms - Homozygotes Fasting tHcy levels up to 40 fold seen A vascular event occurs before the age of 30 in over 50% of untreated homozygotes. Inherited Hypercoaguable States Homocysteinemia from CBS Polymorphisms - Heterozygotes Risk of vascular events is unclear as it is often associated with normal tHcy levels and may present with a mild clinical picture. Over 60 mutations of CBS gene have been described with the most common being I278T and G307S. Inherited Hypercoaguable States Homocysteinemia from MTHFR Polymorphisms Homozygous deficiency is extremely rare and results in early death. 10-30% of white population is homozygous for this mutation. This defect in the presence of suboptimal folate intake will result in moderately elevated tHcy plasma levels. Inherited Hypercoaguable States MTHR Polymorphisms & Stroke MTHFR C677T, Homozygous TT or A1298C are NOT risk factors for cerebral arterial or venous thrombosis. Inherited Hypercoaguable States Homocysteinemia and Stroke The incidence of stroke increases with increasing Homocysteine levels. Experimental studies suggest Homocysteine promotes ATHEROGENESIS and THROMBOEMBOLISM. All young patients with unexplained stroke, especially those with atherosclerosis, SHOULD have Homcysteine levels checked. Inherited Hypercoaguable States Homocysteinemia Treatment Treated directly with vitamin supplementation. Primary vitamin used is folate. Taking folate and vitamin B12 can lead to an additional decrease in Homocysteine levels above that seen with folate alone. Inherited Hypercoaguable States Homocysteinemia Treatment Anticoagulation following vascular thrombosis Generally used for 3-6 months. Further continuation is generally not indicated in hyperhomocysteinemia after a single thromboembolic episode given the risk of bleeding associated with anticoagulation. Patients with multiple thromboembolic episodes may need to be on long-term anticoagulation. INHERITED RISK FACTOR Sickle Cell Disease Autosomal recessive genetic disease: β-globin gene (chromosome 11q) mutation GAGGTG at 6th codon Glutamic Acid Valine at the 6th amino acid along the β-globin chain α2β2 = normal hemoglobin α2βS = heterozygote = Sickle trait α2S2 = homozygous recessive = Sickle cell disease INHERITED RISK FACTOR Sickle Cell Disease Sickle cell disease causes a vasculopathy that, along with stasis in small arteries, is a principal mechanism by which it causes strokes. The mechanism is a progressive, segmental narrowing of the distal internal carotid artery and portions of the circle of willis and proximal branches of the major intracranial arteries. INHERITED RISK FACTOR Sickle Cell Disease The incidence of brain infarction peaks around age 10 years. The incidence of stroke in patients with Hb SS is 10% and those with Hb SC is 2-5%. Hypercoaguability and Stroke Acquired Hypercoaguable States Hypercoaguability and Stroke Antiphospholipid Syndrome Antiphospholipid Syndrome Most common acquired thrombophilia Described by Dr. Graham Hughes (1983) now at the Lupus Center, London, UK. A syndrome characterized by the association of: thrombosis, obstetric complications and/or thrombocytopenia antibodies against phospholipids or against proteins bound to phospholipids. Antiphospholipid Syndrome Etiology • Combination of genetic background and environmental factors: infection, trauma, drugs - infections – molecular mimicry with B2GPI APS Pathophysiology aCL platelets Coagulation cascade Activate platelet aggregation Inhibit Protein C, Protein S, thrombomodulin, antithrombin III fibrinolysis Placental tissue Complement system Endothelial cells Trophoblastic cell growth, TF, adhesion molecules and proinflammatory cytokines apoptosis IL-3 Antiphospholipid Syndrome Clinical manifestations • Venous thrombosis: Most common: deep or superficial veins of the legs Less common: IVC, iliofemoral, axillary, renal, portal, hepatic, or retinal veins • Arterial thrombosis: Most common: Cerebral infarct, cardiogenic emboli. Less common: Coronary, retinal, and visceral artery • Cutaneous: Livedo reticularis (up to 80%), splinter hemorrhages, leg ulcer, skin insarcts, blue toe syndrome • Neuro: Multi-infarct dementia, chorea, transverse myelopathy, Pseudotumor cerebri, cerebral venous thrombosis APLA are found in as many as 50% of patients who get migraines • Cardiac: CAD, valve vegetations or thickening 30%, intracardiac thrombus • Hematologic: Thrmobocytopenia (40% of patients), hemolytic anemia • Obstetric: Fetal loss (15-75%), IUGR Antiphospholipid Antibodies Three primary classes of Antibodies 1. Lupus Anticoagulant (LA) antibodies are directed against plasma proteins bound to anionic phospholipids 2. Anti-Cardiolipin (aCL) antibodies are directed against phospholipids bound to proteins Can be IgA, M, or G (subclasses 1-4) IgG (esp G2) associated with a greater risk of APS 3. Anti Beta 2 Glycoprotein (b2GPI) antibodies are directed against a plasma protein that binds phospholipid with high affinity Antiphospholipid Syndrome Epidemiology Many patients have laboratory evidence of APS antibodies WITHOUT clinical disease. APS antibodies found in 10% of healthy donors, 30-50% of SLE patients APS may develop in 50 to 70 % of patients with both SLE and APS antibodies after 20 years of follow-up. Nonetheless, up to 30 percent of patients with SLE and anticardiolipin antibodies lacked any clinical evidence of APS over an average follow-up of seven years. Antiphospholipid Syndrome Frequency of APS antibodies in different populations Population aCL LA Normal individuals: 2-5% 0-1% Normal pregnancy: 1-10% - Elderly (>70 years of age): >50% - Patients with SLE: 17-86% 7-65% Family members of patients with APS: 8-31% - Antiphospholipid Syndrome Risk of thrombosis in patients with APS antibodies Odds Ratios for VTE SLE with lupus anticoagulant 6.32 (3.80-8.27)* Non-SLE with lupus anticoagulant 11.1 (3.81-32.3)** Incidence of thrombosis: ~2-2.5%†. Coincident risk factors for thrombosis: up to 50%‡. Lupus (1997) 6: 467. ** Lupus (1998) 7: 15. † Am J Med (1996) 100: 530. ‡ J Rheumatol (2004) 31: 1560. Antiphospholipid Antibodies Detection & Clinical Relevance Despite the frequent concordance between lupus anticoagulant antibodies and either anticardiolipin or anti– B 2 Glycoprotein I antibodies, these antibodies are NOT identical. In general, lupus anticoagulant antibodies are MORE SPECIFIC for the antiphospholipid syndrome, whereas anticardiolipin antibodies are MORE SENSITIVE. Antiphospholipid Antibodies Detection & Clinical Relevance The SPECIFICITY of anti-cardiolipin antibodies for APS INCREASES WITH TITER and is HIGHER for IgG than for the IgM isotope. MULTIPLE TESTS for antiphospholipid antibodies SHOULD BE USED, since patients may be negative according to one test yet positive according to another. Antiphospholipid Syndrome Classification Primary APS If the patient HAS NO known underlying autoimmune disorder. Secondary APS If the patient HAS an underlying autoimmune disorder, such as SLE. Antiphospholipid Syndrome Classification Studies have NOT SHOWN any clear differences between patients with Primary APS versus Secondary APS. A risk of recurrent thrombi, both arterial and venous, is associated with both types of APS. Most studies suggest that patients who have a recurrent episode will have it in a similar blood vessel type. Antiphospholipid Syndrome Diagnosis - Clinical Criteria Vascular thrombosis: One episode of arterial, venous, or small vessel, in any tissue or organ, confirmed by objective validated criteria Pregnancy morbidity: Unexplained fetal death at or beyond 10 weeks gestation Premature birth before 34 weeks gestation because of eclampsia, severe pre-eclampsia, or placental insufficiency Three or more consecutive spontaneous abortions before 10 weeks gestation International Consensus Statement on Classification Criteria for APS (2006). Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295-306 Antiphospholipid Syndrome Diagnosis - Laboratory Criteria • Lupus anticoagulant (LA), present on at least 2 occasions, at least 12 weeks apart • Anticardiolipin antibodies (aCL), IgG or IgM >30 units for both, present on at least 2 occasions, at least 12 weeks apart • Anti-beta-2-glycoprotein I antibodies (antiB2GPI), IgG or IgM >20 units for both, present on at least 2 occasions, at least 12 wks apart International Consensus Statement on Classification Criteria for APS (2006). Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295-306 Antiphospholipid Syndrome Diagnosis A diagnosis of Antiphospholipid Syndrome should NOT be made if a period of greater than five years separates the clinical event and positive laboratory test. Although antiphospholipid antibodies ALSO OCCUR in association with other conditions (including infections, cancer, and the use of drugs or hemodialysis), they are usually IgM antibodies that are present at low levels and ARE NOT associated with thrombotic events. Hypercoaguability and Stroke Antiphospholipid Syndrome and Stroke Antiphospholipid Syndrome & Stroke Incidence • Published figures range from 7% of all strokes1 to 41% of all strokes2 (study relied on one single aPL assessment) • In the younger population (under 45), it may be as high as one in 5 of all strokes associated with aPL. 1Montalban J et al. Stroke 1991;22:750-753 2Levine SR et al. JAMA 2004;291:576-584 Antiphospholipid Syndrome & Stroke APASS Study 2004 Only RCT Study (prospective cohort study). Conducted within the WARSS study. 720 of the 1770 patients in WARSS tested positive for aPL (41%) Compared warfarin (target INR 1.4 to 2.8) vs. ASA. Analyzed antiphospholipid status after stroke. Composite outcome measure including death, ischemic stroke, or other thromboembolic events. APASS Study Outcomes Proportion with Event at 2 Years 30 20 10 aPL + aPL - 0 Warfarin Aspirin Treatment Group APASS Investigators, JAMA, 2004; 291: 576. Antiphospholipid Syndrome & Stroke APASS Study 2004 - Caveats Patients from the general population who have sustained an initial non-cardioembolic stroke and are POSITIVE for LA and aCL (ELISA – low, medium or high titers included) within 30 days of the Stroke (patients tested once) DO NOT have a different prognosis than those who test NEGATIVE. This result was consistent the Aspirin and Warfarin arms of the trial. Hypercoaguability and Stroke Treatment Antiphospholipid Syndrome ACCP Guidelines • Prevention of noncardioembolic cerebral ischemic events. – For most patients, we recommend antiplatelet agents over oral anticoagulation (Grade 1A). – For patients with ‘well-documented’ prothrombotic disorders, we suggest oral anticoagulation over antiplatelet agents (Grade 2C). Albers, et al., Chest, 2004; 126 (Supplement): 483S. Antiphospholipid Syndrome Evidence for Treatment Recommendations • Retrospective studies suggest target INR > 3.0. – Rosove & Brewer (1992). – Khamashta, et al. (1995). • Prospective randomized trials suggest target INR of 2 to 3. – Crowther, et al. (2003). – Finazzi, et al. (2005). Antiphospholipid Syndrome Treatment of aPL positive patients We conclude that the presence of a persistent aPL has NOT been demonstrated as such an important risk factor for recurrent thrombosis that it warrants more intensive (and more risk-bearing) treatment1. Patients with positive aPL tests would really be helped with data from studies that enable evidence based recommendations for treatment1. 1RHWM Derkson et al. Lupus 2010 19. 470-474 Hypercoaguability and Stroke Thrombotic Thrombocytopenic Purpura (TTP) TTP History • In 1924, Dr.Eli Moschcowitz described a 16year old girl with abrupt onset of petechiae, pallor, followed by paralysis, coma, and death. • Autopsy showed ‘hyaline’ thrombi occluding terminal arterioles and capillaries. TTP Presentation Clinical findings Classic Pentad 1. Fever 2. Neurologic changes All 5 criteria present 3. Renal impairment Laboratory findings 4. Microangiopathic hemolytic anemia (Hb < 10g/dl) 5. Thrombocytopenia (Platelets < 20,000/µl) TTP Clinical Presentation • • • • • • Approx. 1000 new cases occur each year Common in middle age; median age = 40 Female : male (2:1) Acute onset and fulminant course Mortality rate >90% in pre-pheresis era. Relapse rates, 10-40% ranging from months to years have been reported. TTP Pathogenesis Deficiency of VWF- cleaving protease Termed ADAMTS13 Corresponding gene : chromosome 9q34. TTP Pathogenesis – ADAMTS13 Metalloprotease SP M D 1 Thrombospondin 1 Cys Spacer 2 3 4 5 6 7 8 CUB CUB Disintegrin A Disintegrin-like And Metalloprotease with ThromboSpondin-1 repeats (ADAMTS13) Discovered in 1996 by Tsai and by Furlan Requires Ca2+ and Zn2+ ions Cleaves VWF between Tyr1605 - Met1606 Activated by shear stress, mild denaturants TTP Pathogenesis – ADAMTS13 Proteolysis by ADAMTS13 Cleaves VWF Tyr1605-Met1606 INCREASE causes VWD (type 2A) DECREASE causes TTP TTP Primary TTP 1. Familial recurrent TTP: Constitutional deficiency of VWF TTP Secondary TTP • Drug-induced – Acute immune mediated: • Ticlopidine - frequency is 1/2000-1/5000 in pts receiving ticlid post-coronary stent1. • Plavix – frequency is <1/20,000. Usually occurs in first 2 weeks, responds to stopping medication2. – Dose-related: mitomycin, tacrolimus, pencillin, cyclosporine, cisplatin, bleomycin, OCP – Quinine: HUS like illness. 1Bennett et al Ann Inter Med 1998 2Bennett et al N Engl J Med 2000 TTP Secondary TTP • • • • Pregnancy and post-partum. Allogenic bone marrow transplant. Autoimmune disorders (SLE,scleroderma) HIV infection. TTP Diagnosis – There is no Gold Standard Primary diagnostic criteria Thrombocytopenia ( often below <20,000) Microangiopathic hemolytic anemia Negative Coomb’s test. Fragmented red cells (schistocytes) on peripheral smear LDH elevation is the hallmark of RBC destruction and tissue injury related to ischemia. Presence of above criteria is sufficient to establish presumptive diagnosis & begin PE TTP Diagnosis • At present there are no confirmatory tests available. • Other features in pentad support the diagnosis. • Tests for ADAMTS13 deficiency or inhibitors are not readily available and lack standardization. TTP Differential Diagnosis • Disseminated intravascular coagulation. • Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia. • Preeclampsia/eclampsia, HELLP. • Disseminated malignancy. • Hemolytic-uremic syndrome • Evans syndrome • Malignant hypertension. TTP Treatment Plasma exchange: Untreated TTP has 80-90% mortality. Removes ULvWF multimers, autoantibody and replaces metalloproteinase. Randomized controlled trial (Rock et al, 1991) FFP as the replacement fluid is most widely used and cost effective. TTP Response To Treatment Mental Status changes improve dramatically. Thrombocytopenia require several days. Parameters of hemolysis improve promptly, yet anemia may continue to worsen. Recovery from renal failure is unpredictable and often slow. Prolonged courses of Plasma Exchange, with frequent exacerbations is characteristic of idiopathic TTP TTP Duration of treatment. No studies precisely determine optimal schedule AABB extracorporeal therapy committee: daily PE until plt ct > 150k for 2-3 days. American Society for Apheresis: daily PE until Plt > 100k, complete normalization of LDH. Tapering schedule to 3 times per week after sustained response is highly recommended. TTP Treatment AVOID prophylactic platelet transfusion UNLESS life-threatening bleeding is present1,2 because Platelet transfusion provides additional substrate for thrombus formation. MI and strokes have reportedly occurred after transfusion. 1Gordon et al , 1987; 2Harkness et al 1981 TTP Treatment Plasma exchange DOES NOT address the underlying autoimmune disorder Refractory disease MAY benefit from immunosuppression ADAMTS13 and inhibitor assays MAY become useful to guide therapy TTP Other Treatment Options Antiplatelet Therapy Steroids Splenectomy (Crowther et al, 1996) Chemotherapy: Cytoxan, Vincristine, Rituxan, CHOP. High- dose IV IgG Protein A immunoadsorption columns. TTP Follow-up and outcome Follow up Duration of initial treatment is undefined Monitor CBC and LDH Outcome Relapse rates 29-82% Chronic renal insufficiency (~25%) Long term neurological effects (incidence ?) Hypercoaguability and Stroke Case Presentations Case #1 Case #1 Mrs FC 44y R handed White female, non-smoker with h/o Migraines on Maxalt who presented with new right handed numbness and weakness after a week following an uncomplicated tubal ligation done as an outpatient. Past medical history significant for DVT during pregnancy (2nd and 4th) and had been on anticoagulation with Coumadin for 6 months after the last pregnancy. Extensively worked up for a hypercoaguable state on multiple occasions including 6 months prior – all unremarkable / inconclusive. Her evaluation during this hospitalization revealed a cortical infarct in the left hemisphere. Case #1 Repeat hypercoaguable work up – Protein C / S, Homocysteine, aCL, LA, Factor V Leiden, Prothrombin gene mutation, ANA, RA all negative. TEE – Normal, No PFO. Hematology consultation Started on Zocor, ASA and discharged with 21 day event monitor set up. Will this be her last admission for a Stroke? GOK Hypercoaguability and Stroke Case Presentations Case #2 Case #2 Mrs WW 55 yr old AA, h/o HTN. Non smoker. Dad had CVA at 50. In February 2003, she presented with her first stroke at age 48. After an inconclusive Stroke in the Young, started on Plavix along with BP meds. In July 2005, she presented with her second stroke and was started on Aggrenox. Had a repeat inconclusive Stroke in the Young work up. In February 2006 presented with TIA like symptoms along with thrombocytopenia. Aggrenox suspected as cause of Thrombocytopenia. Seen by Hematology. Started on Coumadin. In May 2007, presented with non-specific complaints, Platelets down to 13,000. Peripheral smear showed some hemolysis. Seen by hematologist and diagnosed with TTP. Started on Plasmapheresis and Steroids. Coumadin stopped. Case #2 Mrs WW In July 2007 she presented with sepsis / septic shock, treated and discharged. In October 2008, she presented with her third stroke. I saw her then. Repeated stroke n the young work up again along with a cardiac MRI – negative. Continued on ASA 81mgs. In December 2008, presented with worsening thrombocytopenia and admitted and started on plasmapheresis and steroids. In April 2009, she presented with her fourth stroke. Started on Plasmapheresis and steroids and continued on ASA 81mgs. Then refused chemotherapy and splenectomy. Case #2 Mrs WW In April 2010 she presented with her fifth stroke. Again started on Plasmapheresis and steroids and continued on ASA 81mgs. Again refused chemotherapy and splenectomy. In May 2010 she presented with her sixth stroke. Again started on Plasmapheresis and steroids and continued on ASA 81mgs. Her ADAMTS 13 inhibitor levels were 6.8 (normal < 0.4) suggestive of a possible recurrence. This time she agreed to be started on the Rituximab and an elective splenectomy. She was discharged on May 17, 2010. Will this be her last admission for a Stroke? GOK Case # 2 – MRI DWI Imaging Feb 2003 Jul 2005 Apr 2010 Oct 2008 Feb 2009 May 2010 Hypercoaguability and Stroke Final Summary Connect the dots…. 1. ASK the right questions in History. 2. LOOK for embolic strokes or venous strokes on MRI Imaging. 3. CONFIRM presence or absence of PFO. 4. ORDER patient specific Hypercoaguable workup. 5. OBTAIN hematologist consultation BEFORE initiating anticoagulation. 6. NEVER forget to address the usual stroke causes. 7. PRAY for and with your patient. Remember…. Site of Thrombosis Vs. Coagulation Defect Abnormality Arterial Factor V Leiden Prothrombin G20210A Antithrombin deficiency Protein C deficiency Protein S deficiency Hyperhomocysteinemia LA/ aCL / aPL + + Venous + + + + + + + Hypercoaguability and Stroke The End Thank You Questions / Comments