Adv Pathophysiology Module 4 Page 1 of 13

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1 Adv Pathophysiology Module 4 Page 1 of 13 Learning Objectives for this file: 1. Basic lab evaluation of coagulation 2. Problems with coagulation vascular, platelet, coagulopathies (clotting disorders) 3. Coagulopathies hemophilias, DIC, hypercoagulable states

2 Adv Pathophysiology Module 4 Page 2 of 13 HEMOSTATIC DISORDERS (DISORDERS OF COAGULATION & HEMOSTASIS): Balance between clotting & bleeding Normal hemostasis requires correct interaction and function of vessel, platelets, plasma factors; with inhibitory effects to limit clot formation. Abnormalities in this system lead to excessive bleeding or excessive thrombosis. OVERVIEW LAB TESTS TO MEASURE COAGULATION FUNCTION: Balance between clotting (coagulation & hemostasis) & bleeding Normal hemostasis requires correct interaction and function of vessel, platelets, plasma factors; with inhibitory effects to limit clot formation. Abnormalities in this system lead to excessive bleeding or excessive thrombosis. A. SELECTED LABORATORY DIAGNOSTICS: Bleeding time: o BP cuff on upper arm inflated to 40 mm Hg (makes hemostatic plugs hold against a back pressure) & incision made on forearm measure time to clot (< 6 min) o Elevated in: thrombocytopenia, TTP or ITP, ASA o Elevated in aspirin therapy: inhibits platelet enzyme cyclooxygenase (needed for oxidation of arachidonic acid to endoperoxides & thromboxane A2). Partial thromboplastin time (PTT) and the activated PTT (aptt): o screens for abnormalities of contact activation reactions (usual range sec -- measured daily by lab on normal specimens). o Often used to monitor heparin therapy at typical dosing o testing for fibrinogen, prothrombin, factors V, VIII, IX, X, XI, XII, prekallikrein, and HMWK (intrinsic pathway clotting factors and other proteins) o This is ALWAYS measured against a normal control, so value is usually sec (against control). o Increased: with heparin therapy, Hemophilia A & B, prolonged tourniquet use on blood sampling, & polycythemia. o Decreased: (rare) thrombotic coagulopathies.

3 Adv Pathophysiology Module 4 Page 3 of 13 Activated coagulation time (activated clotting time) or ACT: o This is done as a bedside test to measure time to clot in seconds whole blood placed in a tube with a clotting activator and then proprietary technology measures clotting time USED when heparin is dosed at very high dosing levels (at these high levels, the PTT is not useful since it depends on an in vitro clotting reaction that doesn t occur at high heparin levels) o CLINICAL: use in cardiopulmonary bypass, extracorporeal membrane oxygenation (ECMO), hemodialysis, cardiac catheterization, vascular surgery; ECMO initiates clotting due to blood coming in contact with machinery o the higher the ACT value the greater the heparinization so usually the ACT value is kept above a minimum target value (e.g. in cardiac surgery, above 480sec reflecting heparin levels of 4-5units/mL o affected by blood temperature, platelet count & function, comorbidities (e.g. lupus) Prothrombin time (PT): o screens for coagulation due to high concentration of tissue factor o measures extrinsic pathway clotting factors and other proteins (fibrinogen, prothrombin, factors V, VII, X). o PREVIOUSLY used to monitor warfarin (Coumadin) therapy INSTEAD now mainly us the INR) o is also measured against a normal control, usually it is sec (against control). o Increased: coumadin, vitamin K deficiency (neonate), liver disease, prolonged use of tourniquet on blood sampling, DIC (disseminated intravascular coagulation), heparin little effect on PT at usual doses International Normalized Ratio (INR): (<1) International normalized ratio. o monitor warfarin therapy o normal level is < 1, therapeutic level is 2-3 for most indications (higher with mechanical prosthetic heart valves), o used now in place of PT to monitor coumadin (warfarin) therapy. o Usually done Q 2-4 weeks once dose is stabilized. Nanosphere Verigene Warfarin Metabolism Nucleic Acid test: o Checks on genetic variants in warfarin metabolism o Can help determine initial dosage of warfarin, to avoid bleeding complications Thrombin time (T or TT): o screens for last step of coagulation (thrombin-fibrinogen reaction) o prolonged when plasma antithrombin activity is increased (as when heparin is present).

4 Adv Pathophysiology Module 4 Page 4 of 13 Fibrinogen & Fibrin split products: o these tests may be ordered when it is suspected that disseminated intravascular coagulation (DIC) is occurring, to see if there is a reduction in these elements indicating they have been "used up" due to this pathology. serious bleeding due to thrombocytopenia and depletion of plasma clotting factors that is worsened by secondary fibrinolysis). o Seen in complications of GYN surgery, TOP, prostatectomy -- basically surgery of raw surfaces). D-Dimer: o elevation indicates high probability of a thrombosis (clot) o clinically -- a clinical deep venous thrombosis (DVT) or presence of emboli (venous thrombo-embolism, VTE) o also used in the emergency department to help diagnose acute aortic dissection (AAD) because as the aorta dissects into the aneurismal defect a clot is formed Verify-Now Platelet test for Aspirin & Clopidogrel (Plavix) response: o Patients taking aspirin or clopidogrel want to inhibit platelet aggregation to prevent stroke or MI o This in-office (CLIA waived) test measures measures platelet induced aggregation as an increase in light transmittance (a turbimetric analysis light shines thorugh the sample and checks for platelet aggregation in the presence of fibrinogen activation reagent) o Similar to how the Coulter Counter works shining a light through the sample to determine the values for the CBC Genetic testing for metabolization of clopidogrel (Plavix) and warfarin (Coumadin): o CYP2C9 or VKORC1 genetic variations affect warfarin levels o CYP2C19 enzyme variation can create poor metabolizers of clopidogrel these patients won t get the anti-thrombotic preventive benefit o various genetic tests now available to evaluate metabolization of various drugs

5 Adv Pathophysiology Module 4 Page 5 of 13 B. VASCULAR DISORDERS OF COAGULATION: something wrong with blood vessel Clinical: petechiae, purpura, bruising due to extravascular extravasation of blood into skin; sometimes telangiectasias are seen due to vascular anatomical abnormalities. Remember: o petechiae, ecchymoses & intradermal hemorrhage do not blanch since it is due to extravasation of blood into the skin o starts out red, then blue, then green/yellow, then fades or leaves hemosiderin deposit (brown). Telangiectasia, hemangiomas, arterial spiders are purely vascular and do blanch, fade, or pulsate with pressure. Use microscope slide to do blanching test. lab tests usually normal rarely leads to serious hemorrhage (but can, depending on situation) Conditions: Purpura simplex: vascular fragility. Usually older women. Vitamin K injections help (but serious adverse reactions possible) & usually improve with HRT. Senile purpura: deep purple ecchymoses due to excessive sunlight exposure, seen in older patients. May leave brown discoloration of hemosiderin. No treatment. Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber): autosomal dominant, both male/female. Telangiectasia on mucosal surfaces. Become Fe deficient due to chronic GI bleeding, nosebleeds. Sometimes associated AV fistulas. Ehlers-Danlos Syndrome & other Connective Tissue disorders: deficiences of vascular and perivascular collagen causes bleeding due to vascular anatomical abnormalities. (other: Marfan's, osteogenesis imperfecta, etc.) Allergic purpura (Henoch-Schonlein, anaphylactic purpura): vasculitis of small vessels. Preceded by acute URI and/or drug therapy. Serum complexes of IgA often present that deposit in joints, kidney & can lead to renal damage. Treatment is supportive and immunosuppressive (steroids and/or chemotherapeutic). Vascular purpura due to dysproteinemias: Multiple types: Hypergammaglobulinemia of IgG causing purpura; Macroglobulinemia (Waldenstroms, multiple myeloma) causing IgG gelling when plasma is cooled; Hyperviscosity syndromes; Amyloidosis (increased vascular fragility & purpura). Auto-erythrocyte sensitization (Gardner-Diamond): uncommon, in women, painful burning ecchymoses on extremities. Etiology unknown, can reproduce by RBC injection. Scurvy: o vitamin C deficiency o perifollicular petechiae over thighs & buttocks, can involve large intramuscular hemorrhage and periosteal hemorrhage in children. o Due to improper formation of collagen due to ascorbic acid (vitamin C) deficiency. o Longstanding disease leads to more severe manifestations (gum disease & tooth loss, gangrene, arthritis, etc).

6 Adv Pathophysiology Module 4 Page 6 of 13 C. PLATELET DISORDERS: Think of it as three categories either too few (thrombocytopenia), too many (thrombocytosis), or platelet dysfunction Note that clinical presentations may overlap FIRST TOO FEW PLATELETS Thrombocytopenia: (platelet number < 150,000/mm 3 ) workup with CBC & peripheral smear, bone marrow aspiration (for megakaryocytes) Etiology: marrow failure, platelet sequestration, platelet destruction and/or consumption, hemodilution. Immune Thrombosytopenic Purpura (ITP): o May be idiopathic, usually seen after infections (e.g., viral infections especially in children) o Systemic symptoms (weight loss, fever) and evidence of bleeding (e.g., petechiae) o There is an auto-ab that causes platelet destruction in the spleen o Use immunosuppressive therapy and/or splenectomy as indicated o Other immunologic types in HIV patients, autoimmune disease like SLE, 7-10 days post-transfusion, drug related (quinidine, gold); may be chronic in adults Heparin Induced Thrombocytopenia (HIT): o antibodies form & bind to heparin; binding of heparin-ab complexes to platelet membrane receptors causes thrombosis ("white thrombus" due to mostly platelets). o Therapy would be an oral anticoagulant & stop heparin. o This is why it is important to monitor the CBC as well as the PTT!! (look for RBC and platelet numbers) Drug Induced Thrombocytopenia (DIT): o similar to above, antibody complexes form due to reaction to other drugs. Other: o Hypersplenism o gram-negative sepsis o adult respiratory distress syndrome (ARDS) Thrombocytopenia associated with RBC abnormalities & hemolysis: TTP (thrombotic thrombocytopenic purpura): o potentially fatal, acute & difficult to treat, with unknown cause o presentation of overaggregation of platelets in small vessels causing organ ischemia o also includes platelet overconsumption thus bleeding may also occur Neoplasm: o ectopic production of mucin causes microangiopathic hemolytic anemia o acts like TTP clinically HUS (hemolytic uremic syndrome): o uncertain etiology o seen in children & pregnant/post-partum patients. o Acute anuric renal failure occurs, requiring dialysis. o May be due to E. coli strain 0157:H7 in undercooked chopped meat and now even found in steak! COOK IT ALL WELL!!!!!!

7 Adv Pathophysiology Module 4 Page 7 of 13 Transient neonatal thrombocytopenia: One of the most common hematological problems in the newborn (1-5%) and very common in the NICU (over 20%) Presentation includes petechiae, purpura, intra-cranial hemorrhage More common causes: o Inadequate production may be due to fetal hypoxia (placental insufficiency), prematurity o Consumption and/or sequestration destruction by antibodies, or part of disseminated intravascular coagulation (DIC) due to neonatal sepsis or hypoxia Less common causes: o Genetic abnormalities (e.g., trisomy-13, -21, -18) o Autoimmune disorders (ITP, SLE) o Congenital infection (e.g., the TORCH syndromes) o In later neonatal period, may be due to sepsis or necrotizing enterocolitis More on Neonatal Alloimmune Thrombocytopenia (NAIT): o Probably incorrectly caused alloimmune since it is really isoimmunity due to maternal sensitization to antigens on platelets derived from paternal allele o This should sound familiar! o Same mechanism as in hemolytic disease of the newborn (HDN) resulting from Rh incompatibility, except here it affects the platelets and not the RBCs Good overview (sometimes website is down): Now the OPPOSITE TOO MANY PLATELETS Thrombocytosis also called thrombocythemia: Too many platelets (>400,000 / microliter) Secondary: o Post-splenectomy (spleen is absent and thus can t destroy old platelets) o Reactive due to inflammatory conditions OR post-exercise Essential: o excess production therefore, a myeloproliferative disorder o may results from excess thrombopoietin stimulating factor o may include excess RBC as well Presentation: o Thrombotic occlusion of small vessels and organ/tissue ischemia o Headache, paresthesias, and erythromyalgia result (congested, red hands and feet) o Increases risk for thrombotic stroke if it affects arteries (e.g., carotids) o If overconsumption of platelets occurs, primary presentation may be bleeding (hemorrhage) rather than thrombosis o Thus treatment is aimed at controlling presenting symptoms

8 Adv Pathophysiology Module 4 Page 8 of 13 NOW THE LAST CATEGORY PLATELET DYSFUNCTION Platelet Dysfunction: normal numbers of platelets, but hemostatic plugs do not form Hereditary: o von Willebrand's disease (VWD) with abnormality of VW factor three variants affects a normal plasma protein secreted by endothelial cells to help platelets to adhere to subendothelium at sites of vessel wall injury, and also affects factor VIII (normal VWF maintains VIII levels)(hemophilia A also affects factor VIII). Precipitation of symptoms: stress, RX with cryoprecipitate. Treatment: One variant treatable with desmopressin (DDAVP, vasopressin) Good overview article (2016): o Other hereditary: insufficient ADP inside platelets ASA, NSAID use can mimic this disorder Acquired: common o Seen in multiple clinical states such as multiple myeloma, myeloproliferative disease, uremia, cirrhosis, SLE o Also seen with some drugs such as penicillin/cephalosporin coating, aspirin/nsaid, therapeutic (cardiac bypass surgery).

9 Adv Pathophysiology Module 4 Page 9 of 13 D. COAGULOPATHIES: either can t clot or clot too much Don t mix this up with platelet thrombosis (too many), thrombocytopenia (too few) Here we are talking about actual clotting factors (proteins of the coagulation cascade) and NOT dysfunction of cells!! Both hereditary and acquired First, clotting too little (these folks are bleeding too much ) Hereditary Coagulation Disorders: hemophilias Deficiencies of coagulation factors: o Hemophilia A (mutation in the gene for factor VIII) o Hemophilia B (mutation in the gene for factor IX, also called FIX ) also called Christmas disease (named in 1952 after the patient s last name); notable royal families famous for the illness (Queen Victoria was a carrier, Russian Romanov family) sex-linked recessive inheritance pattern specific factor assays are the lab tests needed to differentiate them. Since there are different abnormal alleles, expression of the hemophilia syndrome varies among affected individuals, depending on the percentage of normal factor VIII or IX present in the blood. Usually, there is a prolonged PTT, normal bleeding time, normal PT. Management: o avoidance of ASA, may be able to use limited NSAID o good dental care (to avoid need for extractions/surgery) o don't give IM drug injectaions (hematomas develop) o aggressive vaccinations against Hepatitis B, influenza, pneumonia, etc. against all vaccine-preventable disease. o Hemophilia-A is factor VIII, may be mild or severe (depending on amt. of factor); see prolonged activated PTT (aptt) due to intrinsic surface active factor absence; treat with factor VIII transfusion, DDAVP (raises factor VIII), cyroprecipitate; may develop "inhibitors" or Ab to factor VIII after transfusions that complicate case. o Hemophilia-B same as for "A", except DDAVP doesn't work, you use factor IX transfusions (FIX concentrate therapy) o Transfusion therapy: Sometimes, transfusion therapy can cause Ab to factor VIII that further reduce factor VIII activity & worsen the bleeding. This can be tested for prior to elective transfusion. Genetic therapy? Hemophilia B (Christmas disease) has been treated by using an adenovirus injection The virus manufactures FIX (factor IX) and the injection gave a response rate for one year This doesn t change the patient s genome, we use the virus to manufacture the clotting factor See Merry Christmas for Patients with Hemophilia B (2011):

10 Adv Pathophysiology Module 4 Page 10 of 13 Acquired Coagulation Disorders: Vitamin K deficiency: o causes hypo-prothrombinemia since this vitamin controls the formation in the liver of factors II (prothrombin), VII (proconvertin), IX (Christmas factor), and X. o Need 2 mg daily, usually formed by intestinal bacterial synthesis. o Neonate gets 1 mg injection in nursery, no enteric bacteria to produce this vitamin. o Oral antibiotics, esp. sulfa drugs, cause reduced vit. K synthesis. o With obstructive jaundice and lack of bile salts or other GI malabsorption problems, lack of Vit. K absorption may be the problem. Liver disease: clotting factors aren't made Circulating anticoagulants: endogenous substances inhibiting coagulation. o May be Ab that neutralize clotting factors, or substances mimicking heparin. o Examples are factor VIII anticoagulant (formed after multiple transfusions) and lupus anticoagulants.

11 Adv Pathophysiology Module 4 Page 11 of 13 Disseminated intravascular coagulation (DIC): First there is overwhelming coagulation and THEN followed by overwhelming bleeding That is why the CLINICAL PRESENTATION is that of bleeding Entrance into the blood of tissue factor activity (TFA) initiates coagulation. Widespread coagulation activation, but then the clotting factors are all used up and uncontrolled bleeding takes place. Subacute form: o thromboembolic phenomena Acute form: o medical emergency o leads to overconsumption of clotting factors and thrombocytopenia with serious bleeding (fibrin split products seen & low fibrinogen) Etiologies: o when raw surfaces are operated on (GYN) o malignancies (produce proteins with tissue factor activity) o infection (endotoxins cause monocyte production of TFA) o external toxins (e.g. venoms) o sepsis Treatment: o uncover & treat underlying cause (evacuate uterus in abruptio placenta, hysterectomy after TOP, antibiotics in infection) o Sometimes heparin is given in the subacute form, and fresh frozen plasma in the acute form with platelets DIC development: Response to bacterial infection causes inflammatory response, upregulating tissue factor and causing microvascular thrombus formation with platelet consumption. (With permission from: Hunt, B.J. (2014) Bleeding and Coagulopathies in Critical Care, New England Journal of Medicine, 370, 9, 847)

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13 Adv Pathophysiology Module 4 Page 13 of 13 And now, for clotting too much Hypercoagulability (Hypercoagulable state)(increased thrombosis): Etiology: o Genetic deficiencies of anticoagulant proteins protein C, protein S, antithrombin III o and/or hypercoagulable state Cancer, SLE, pregnancy, DM, polycythemia Presentation: o spontaneous clotting & infarct (bone, viscera) Diagnosis: o Look at blood flow with extremity Doppler ultrasound scans, nuclear scans (perfusion scans), angiography; laboratory studies like D-Dimer and coagulation profiles. Complications: o deep venous thrombosis (DVT) o venous thrombo-embolism (VTE)(emboli) o gangrene of infarcted tissues. Management: o fibrinolytic agents during acute phase (urokinase, streptokinase, tpa), FFP (fresh frozen plasma) o proteins C/S/AT-III transfusion o chronic A/C therapy. o Usually needs hematologist management. Selected examples of pharmacologic anticoagulants: treatment of hypercoagulable states preventive care to prevent stroke and myocardial infarction Heparin: acts by inhibiting factor X; both unfractionated and fractionated types o heparin activates antithrombin III to inhibit factor X, action is immediate since it affects the action of the clotting factors. o This prevents the initiation of clot, but is ineffective once factor X is activated o Protamine is antidote, a protein that complexes with heparin to inactivate it. Warfarin: normally start heparin concomitantly with warfarin (coumadin). o inhibits vitamin K dependent factors by inhibiting their synthesis in the liver (II, VII, IX, X, & proteins C & S, not by inhibiting their action. o Since you must wait for synthesis it takes a few days to work. o Vitamin K is the antidote, but also takes a few days to work. o To rapidly reverse warfarin, must give actual clotting factors (fresh frozen plasma, concentrated IX). Direct Thrombin Inhibitors (DTIs): (examples: rivaroxaban, apixaban) o Used for primary management o DVT prophylaxis, stroke prophylaxis o originally found in the saliva of leeches o antidote is idarucizumab (Praxbind) Direct Factor Xa Inhibitors: (example: dabigatran) o Used for primary management o DVT prophylaxis, stroke prophylaxis