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Hematology Pathophysiology: Platelets, Blood Coagulation and Hemostasis (Gabali) PLATELETS: Production of Platelets: Basics: derived from cytoplasmic fragmentation of BM megakaryocytes (small, NON-NUCLEATED discs) o Immature megakaryocytes (small, basophilic cytoplasm, less granules, less nuclear lobulation) must transform into mature megakaryocytes (larger, less basophilic cytoplasm, more granules, more nuclear lobulation) Megakaryocytes undergo endomitotic synchronous nuclear replication (without separating) to form a hyperlobulated nucleus Granules appear in cytoplasm of megakaryocyte o Cytoplasm fragments to form platelets (each megakaryocyte forms 1000-4000 platelets) o This differentiation process takes ~10 days Regulation: entire process is regulated by THROMBOPOIETIN o Glycoprotein hormone produced by the liver and kidneys Therefore, decreased in liver and kidney disease (may present with mild thrombocytopenia) o Results in proliferation and maturation of MEGAKARYOCYTES (not platelets themselves), which then fragment into platelets Normal Values: o Life span of platelet is 7-10 days o Normal platelet count is 150,000-450,000/uL(mm3) Platelet Granules: Dense Granules: o Number: 2-7 per platelet o Content: ADP and ATP Serotonin Ca++ Mg++ Cyclooxygenase Alpha Granules: o Number: 50-70 per platelet o Content: PDGF PF4 HMWK Fibronectin Thrombospondin Factor V vWF Fibrinogen Lysosomal Granules: o Content: phagocytosed debris Role of Platelets in Hemostasis: Hemostasis (In General): function is to keep blood within a damaged blood vessel o Vasoconstriction o Platelet plug formation o Clot formation o Dissolution of the clot Main Function of Platelets: formation of PLATELET PLUG o Occurs in response to vascular injury o Occurs via 3 steps- adhesion, activation (secretion) and aggregation PRIMARY HEMOSTASIS- FORMATION OF THE PLATELET PLUG: Transient Vasoconstriction: Mediated by: o Reflex neural stimulation o Endothelin release from endothelial cells Platelet Adhesion: Basics: occurs due to the exposure of the subendothelial collagen due to vascular damage o von Willebrand Factor (vWF): monomer composed of 2813 amino acids Monomers bind head-to-head and tail-to-tail Produced in megakaryocytes (stored in alpha granules) and endothelium (stored in WeibelPalade bodies) Has receptors for: Collagen* (important for platelet adhesion) Factor VIII (involved in transport of FVIII) GPIb (on platelet) GPIIb/IIIa (on platelet; also binds fibrinogen) Process: o Platelet adheres to exposed subendothelial collagen by one of 2 mechanisms: Indirectly using vWF, which the platelet binds using the GPIb/V/IX receptor vWF binds exposed subendothelial collagen and then platelet binds vWF Directly via platelet receptor GPIa/IIa (in LOW SHEER STRESS conditions) Platelet binds directly to subendothelial collagen Result: o Single layer of platelets attached to subendothelium and covering the site of injury Platelet Activation: Basics: once adhesion occurs, platelets become activated, changing their shape and releasing their granules o Changes shape from disk to a sphere with extended pseudopodia o Release of granules results in release of various mediators Release of Granule Contents: o ADP: promotes the exposure of GPIIb/IIIa receptor on platelets (required for platelet aggregation) Pathoma concept* o Arachadonic Acid + COX: leads to the formation of TXA2 (potent platelet aggregator) o Other Substances Released: Serotonin Fibrinogen (required for aggregation; also found in the plasma)* PF4 Lysosomal enzymes Platelet Aggregation: Basics: platelets aggregate to the site of injury via expression of GPIIb/IIIa o Aggregation promoted by ADP and TXA2 Process: o Fibrinogen is used as a linking molecule (binds GPIIb/IIIa on 2 separate platelets, linking them together) Pg. 179 of the notes also shows vWF being used as a linking molecule, but is not mentioned in the notes (could use either GPIb or GPIIb/IIIa receptor)* o ADP causes platelets to swell and helps them stick together Presumably due to increased GPIIb/IIIa expression? (Pathoma) As they stick together, more ADP is released (+) feedback system o Overall end result is the formation of a platelet plug Weak and needs to be stabilized through the coagulation cascade Defects in Platelet Aggregation: to be discussed later* o Glanzmann’s Thrombasthemia (GPIIb/IIIa deficiency) o Von Willebrand’s Disease (vWF deficiency) o Bernard-Soulier Syndrome (GPIb deficiency) SECONDARY HEMOSTASIS- STABILIZATION OF THE PLATELET PLUG (COAGULATION CASCADE): Coagulation Cascade: Overall Result: leads to the generation of thrombin, which converts fibrinogen to fibrin o Fibrin incorporates into platelet aggregates at site of injury o Stabilizes platelet plug and converts it into a firm clot Intrinsic Pathway: o Factors: HMWK, prekallikrein, XII, XI, IX, VIII FVIII is a cofactor for IXa in converting XXa o Test: PTT - Note: while deficiencies in factor XII, HMWK and prekalikrein will lead to abnormally increased PTT, they do NOT result in bleeding Extrinsic Pathway: o Factors: Tissue Factor (FIII), VII TF called tissue thromboplastin in Pathoma TF exposed via endothelial damage and binds FVII, activating it (VIIa) TF/VIIa is also known as ninase and tenase VIIa converts XXa (tenase) VIIa also crosses over to intrinsic pathway to convert XI XIa (ninase- misnomer since it is actually converting FXI) o Test: PT Common Pathway: o Factors: X, V, II (prothrombin), I (fibrinogen) FV is a cofactor for Xa in converting prothrombin thrombin o Test: PT, PTT Role of Thrombin: Thrombin has 5 activities in the coagulation cascade: o Converts fibrinogen fibrin + fibrinopeptides A and B Fibrin assembles into NON-crosslinked lattice initially (requires XIIIa for cross-linking) o Activates factor V Va o Activates factor VIII VIIIa o Activates factor XI XIa (POSITIVE FEEDBACK LOOP) o Activates factor XIII XIIIa (fibrin stabilizing factor- allows for cross-linking of fibrin lattice) Production of Clotting Factors: General: coagulation cascade factors are produced in the liver (in general) in an INACTIVE state o Activation: requires 3 things Exposure to an activating substance (ie. TF activates FVII in extrinsic pathway) Phospholipid surface of the platelet Calcium (released from dense granules of the platelet) Factors Produced in the Liver: o All factors (including fibrinogen, factor VIII and vWF) Factors Produced in the Endothelium: o vWF (stored in Weibel Palade bodies) o Factor VIII Factors Produced in the Megakaryocyte: o vWF (stored in alpha granules) o Fibrinogen (stored in alpha granules) o Factors V? (content of alpha granule- posted on BB) Role of Vitamin K: Function: responsible for carboxylation of gamma carbon in vitamin K dependent factors Vitamin K Dependent Factors: II, VII, IX, X, C, S Natural Anticoagulants: Tissue Factor Pathway Inhibitor (TFPI): o Inhibits: VIIa/TF complex (ninase and tenase) o Release: released from damaged tissue o Function: only able to block coagulation cascade in the absence of thrombin When thrombin is still present, positive feedback on FXI is stronger than the inhibition from the VIIa/TF complex Once thrombin is no longer present, TFPI can block the pathway all together Antithrombin III: o Inhibits: IIa, IXa and Xa o Function: normally binds heparin-like products secreted by the endothelial cells (or heparin itself, if being administered) to inhibit the above factors ATIII can inhibit without the help of these heparin-like products, but it is much faster with them (Pathoma) Proteins C and S: o Inhibits: Va, VIIIa, TPAI (inhibition promotes fibrinolysis) o Activation of Protein C: thrombomodulin released from the endothelium redirects thrombin to activate protein C (Pathoma) Normal Fibrinolysis: Fibrinolysis: NORMAL response to vascular injury Process: o Fibrin fibrin split products via PLASMIN Fibrin split products include D-dimers and Fragment E Note that the presence of D-dimers indicates that the entire coagulation cascade has been activated (and that it has come to completion) o Plasmin is formed from plasminogen in the presence of tPA (tissue plasminogen activator, a serine protease) LABORATORY TESTS OF COAGULATION: Tests to Assess Platelets: Platelet Count: o Thrombocytopenia: <150,000 o Thrombocytosis: >450,000 Mean Platelet Volume (MPV): o Varies inversely with platelet count (ie. decreased counts result in increased MPV) o Due to the fact that megakaryocytes have less time to fragment when trying to make up for low counts Tests of Platelet Function: these are NOT routine tests (need to specifically request them)* o Agonist-Induced Platelet Aggregation: Method: addition of aggregating agent to platelet-rich plasma with subsequent measurement of optical density of the tube If the platelets are aggregating normally, more light will pass through the tube resulting in a low optical density Suspected defect detected depends on the agonist that is used to promote aggregation Different Agonists: ADP/EPI/Collagen/TXA2: aggregate platelets through GPIIb/IIIa and fibrinogen o Therefore, if one of these agonists is added and the platelets do not respond with aggregation, there is an issue with GPIIb/IIIa or fibrinogen Ristocetin: aggregates platelets through GPIb and vWF o Therefore, if ristocetin is added and the platelets do not respond with aggregation, there is a problem with GPIb or vWF o Note that ristocetin is an Abx that is no longer used because it causes platelet aggregation Phases of Platelet Aggregation in Response to ADP (Figure on pg.187): as measured by changes in optical density Initial increase in OD: due to increase/change in platelet size First decrease in OD: first phase of aggregation due to ADP release from granules Plateau in OD: because platelet has consumed all the granules that were preformed (needs to synthesize more) Second decrease in OD: second phase of aggregation due to release of newly synthesized ADP o Bleeding Time: not really used anymore* Test for Platelet Adhesion (Mainly): based on making a standard incision and recording time to bleeding cessation with blot and filter paper every 30s Bleeding normally stops in 3-8 minutes Cons to Use: Needs to be performed by trained personnel (liability issues) Poor predictor of bleeding during surgery o Platelet Function Analyzer (PFA-100): replaced bleeding time* Basics: tests adhesion and aggregation in response to agonists Cartridges contain either collagen + EPI or collagen + ADP o Collagen tests adhesion o EPI/ADP tests aggregation PFA-100 machine measures the time needed for occlusion of the cartridge Use: Determine if a patient is taking ASA or another platelet inhibitor Determine if a patient is responding to therapy with ASA or another platelet inhibitor Tests to Assess Clotting Factors: Prothrombin Time (PT)- Extrinsic and Common Pathways: o Factors Tested: I, II, V, X (common), VII (extrinsic) o Method: TF + thromboplastin (XI) + Ca + citrated plasma Normal time is 10-14s Critically dependent on the characteristics of the thromboplastin used in the assay PTs vary between laboratories, and therefore the INR has been established to standardize PT results between different labs o Use: Standard test for monitoring warfarin therapy (sensitive to vitamin K dependent factors II, VII and X- not IX) o Causes of Prolonged PT: Liver disease (decreased clotting factor production) Vitamin K antagonists (ie. Warfarin) Heparin (in high concentrations) Better tested by PTT Fibrin and fibrinogen degradation products Lupus anticoagulant (if in increased concentration) Better tested by PTT Partial Thromboplastin Time (PTT)- Intrinsic and Common Pathways: o Factors Tested: I, II, V, X (common), XII, XI, IX, VII (intrinsic) o Method: phospholipid + surface activator + Ca + citrated plasma Normal time is 30-40s o Use: Monitoring heparin therapy Monitoring factor replacement therapy in patients with hemophilia Screening test for detection of coagulation inhibitors (ie. lupus anticoagulant) o Causes of Prolonged PTT: Heparin (inhibits Xa and IIa) Vitamin K antagonists (in high doses) Better tested by PT Fibrin and fibrinogen degradation products Lupus anticoagulant Mixing Study: done if prolonged PTT* o Method: mixture of normal and patients plasma (50:50 mix) and check for correction of PTT If PTT corrects by >50% of the difference between PTT of normal and patient plasma, it indicates a deficiency in a clotting factor If PTT does NOT correct, it suggests a factor inhibitor Inhibitor of a specific factor, OR Non-specific inhibitor (ie. lupus anticoagulant) o Use: distinction between factor deficiency and factor inhibitor Thrombin Time (TT): done if prolonged PTT* o Method: Diluted bovine thrombin + citrated plasma Normal time is 10-15s o Use: functional test of FIBRIN generation o Causes of Prolonged TT: Congenital: Afibrinogenemia Hypofibrinogenemia Dysfibrinogenemia (dysfunctional fibrinogen) Acquired: Hypofibrinogenemia (liver disease, DIC, thrombolytic therapy) Dysfibrinogenemia (liver disease, hepatic malignancy) Others: Fibrin degradation products Heparin Anti-thrombin antibodies HEMOSTATIC DISORDERS: General: Abnormal bleeding may result from: o Vascular disorders o Quantitative or qualitative defective platelet function o Defective coagulation Vascular Disorders: Basics: o Characteristics: Easy bruising Spontaneous bleeding from small vessels o Underlying Abnormality Occurs in: Vessels, OR Perivascular connective tissue Inherited Causes: o Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome): Inheritance: autosomal dominant Description: development of telangiectasias (dilated microvascular swellings) Appear during childhood and increase in number in adulthood Develop in: o Skin o Mucous membranes o Internal organs (risk of recurrent GI hemorrhage with IDA- common presentation) Treatment: Laser Embolization Estrogen therapy? (seems counter intuitive since estrogen causes telangiectasiaasked on BB) o Ehlers-Danlos Syndrome: Inheritance: most forms are autosomal dominant Description: results in collagen abnormalities Clinical Presentation: Purpura Hyperextensibility of the joints Dissecting aneurysms Acquired Causes: o Scurvy: vitamin C deficiency defective collagen Present with: Ecchymoses Mucocutaneous bleeding o Senile Purpura: caused by atrophy of supporting tissue of cutaneous blood vessels o Purpura associated with Infection: vascular damage due to immune complex formation Bacterial or viral (measles, dengue fever, meningococcal septicemia) o Henoch-Schonlein Purpura: IgA mediated vasculitis in children (self-limiting) Occurs after an acute infection (usually URI) Characterized by purpuric rash Need to watch for renal failure (can get IgA nephropathy) Platelet Disorders: Thrombocytopenias (QUANTITATIVE): o Definition: platelet count <150,000/uL In general, bleeding is not a problem until platelet count <50,000/uL + surgery/trauma Spontaneous bleeding may occur with platelet counts of 5000-20,000/uL o Causes: Bone Marrow Failure: Aplastic anemia Chemotherapy Irradiation Neoplasms: Leukemia Infections: Many of the thrombocytopenias caused by infections are immune mediated, via a molecular mimicry process Post Transfusion Purpura: Thrombocytopenia 10 days after transfusion Due to Abs in the recipient against HPA-1a on transfused (donor) platelets Drug Induced Thrombocytopenia: Quinine Quinidine Heparin (HIT) Immune Thrombocytopenic Purpura (ITP): most common cause of thrombocytopenia in children AND adults* Cause: increased destruction of platelets due to autoimmune production of IgG against platelet antigens (destruction of Ab coated platelets occurs in the spleen) o Note that Pathoma states that the Abs are produced by the splenic macrophages; therefore, source of Ab AND site of destruction is the spleen Two Forms: o Chronic Form: seen mostly in ADULTS Commonly women of child-bearing age (15-50) Usually idiopathic May also be seen with: Autoimmune disease (SLE, AIHA) Infection (HIV) Malignancy (CLL) AutoAbs to platelets result in early removal (shortened life span of platelet) o Acute Form: seen mostly in CHILDREN ~75% follow an infection or a vaccination Result of NON-SPECIFIC immune complex attachments Self-limited (usually results in spontaneous remission) Lab Values (Pathoma): o Decreased platelet count o Normal PT/PTT (coagulation cascade not affected) o Increased megakaryocytes on BM biopsy Thrombotic Thrombocytopenic Purpura (TTP): Cause: deficiency of a metalloproteinase (ADAMTS13) that normally breaks down high molecular weight vWF o Can be an inherited deficiency in the enzyme, OR o An acquired autoAb to ADAMTS13 (Pathoma- this is the most common) Result: large, uncleaved monomers lead to abnormal platelet adhesion and aggregation microthrombi Characteristics: o Fever o Thrombocytopenia o Microangiopathic hemolytic anemia (due to microthrombi) o Uremia (due to renal problems as a result of thrombi- Pathoma states this is more common in HUS) o Neurological symptoms (thrombi in vessels of the CNS- Pathoma states this is more common in TTP) - Lab Values (Pathoma): o Decreased platelet count o Increased bleeding time o Normal PT/PTT (coagulation cascade not affected) o Anemia with schistocyytes o Increased megakaryocytes on BM biopsy Treatment: o Plasmapheresis with FFP (removes large vWF multimers) Note that Pathoma says plasmapheresis removes autoAbs from circulation (if that is the cause of deficiency); corticosteroids could also be used in this case to decreased autoAb production Hemolytic Uremic Syndrome (HUS): Presentation: similar to TTP, with damage limited to the kidneys o Usually seen in CHILDREN* Cause: associated with E. coli O157-Hy7 o Verotoxin damages endothelial cells resulting in platelet microthrombi Characteristics: same as TTP, but neurological symptoms usually not seen o Also have increased splenic pooling (90% of platelets sequestered in the spleen) splenomegaly o Lifespan of the platelet is normal, and therefore the patients usually don’t have bleeding issues Lab Findings: same as TTP Treatment: o Platelet transfusion is CONTRAINDICATED (more platelets would be consumed) o May require dialysis Decreased Platelet Function (QUALITATIVE): o Hereditary: Glanzmann’s Thrombasthenia: Inheritance: autosomal recessive Deficiency: GPIIb/IIIa Result: impaired platelet aggregation (platelet cannot bind to fibrinogen) Diagnosis: platelet aggregation study o Abnormal aggregation with ADP, EPI, collagen, TXA2 o Normal aggregation with ristocetin Bernard-Soulier Syndrome: Inheritance: autosomal recessive Deficiency: GPIb Result: impaired platelet adhesion (platelet cannot bind vWF defective adherence to subendothelial collagen) Characteristics: o Thrombocytopenia (decreased life span of platelet) o Anemia o ENLARGED PLATELETS (more immature platelets being released to compensate for thrombocytopenia) Diagnosis: platelet aggregation study o Normal aggregation with ADP, EPI, collage, TXA2 o Abnormal aggregation with ristocetin Storage Pool Disorder (SPD): Grey Platelet Syndrome: o Rare autosomal recessive disorder resulting in the absence of ALPHA granules in the platelet o Platelets are large o Patient may or may not have thrombocytopenia o Platelet aggregation studies abnormal with ADP/EPI/collagen/TXA2, but normal with ristocetin Delta Storage Pool Disorders: disorders characterized by the absence/decrease in the amount of DENSE granules in the platelet o Hermansky-Pudlak Sydrome: severe oculocutaneous albinism Patients have NO dense granules Autosomal recessive o Chediak-Higashi Syndrome: partial albinism Large cytoplasmic granules cause defective WBC function Due to defective microtubule polymerization Autosomal recessive o Thrombocytopenia with Absent Radii o Wiskott-Aldrich Syndrome: X-linked recessive Patients present with: Eczema Thrombocytopenia Immune deficiency Other Platelet Disorders: May-Hegglin Anomaly: o Autosomal dominant o Giant platelets and thrombocytopenia o WBCs containing Dohle bodies o Acquired: Antiplatelet Drugs: ASA: most common cause of defective platelet function o Single dose defect lasts 7-10 days (entire life of the platelet due to irreversible inhibition of COX) Hyperglobulinemia: Plasma cell myeloma Waldenstrom’s macroglobulinemia Myeproliferative Disorders Myelodysplastic Disorders Uremia: build up of nitrogenous waste due to impaired renal function Affects both platelet aggregation and adhesion Defective Coagulation: Hereditary Coagulation Disorders: o Hemophilia A (FVIII): Inheritance: X-linked recessive Deficiency: absent or low levels of plasma factor VIII Presentation: Infants develop profuse hemorrhage, joint/soft tissue bleeds and excessive bruising when they start to become active o Recurrent, painful hemarthroses (joint bleeds) joint deformity Operative/traumatic hemorrhage may be life threatening Lab Findings: Abnormal (increased) PTT Abnormal factor VIII clotting assay Normal PT and bleeding time Prenatal Diagnosis: DNA analysis from CVS at 8-10 weeks gestation Demonstration of low factor VIII in fetal blood (from umbilical vein) at 16-20 weeks gestation Treatment: Bleeding episodes treated with factor VIII replacement therapy o Plasma derived (virally inactivated for patients with HIV/HepC) o Recombinant (for all children and previously untreated patients) Spontaneous bleeding is controlled if patient’s factor VIII level is raised > 5% of normal o Maintaining FVIII levels often requires daily treatment (COSTLY) o - Factor levels should be raised to 100% of normal for major surgery (and maintained at 50% of normal when acute bleeding has stopped) Antifibinolytic agents may be added to control mucosal bleeding Complications of Treatment: Serious complication of hemophilia is the development of Abs to INFUSED factor VIII (occurs in 5-10% of patients) o Patient refractory to further replacement therapy (VERY HIGH doses have to be given to achieve significant rise in plasma factor VIII activity) o Immunosuppression has been used in an attempt to reduced formation of the Ab o Hemophilia B (FIX)- Christmas Disease: Inheritance: X-linked recessive Deficiency: absent or low levels of plasma factor IX Presentation: same as hemophilia A Can only be distinguished by specific coagulation factor assays Incidence: less common than hemophilia A (1/5 incidence of A) Treatment: recombinant factor IX is available Note: the half life of factor IX is longer and therefore treatments do not have to be given as often o Von Willebrand Disease: most commonly inherited bleeding disorder* Inheritance: various subtypes (3 important ones have been described), usually with autosomal dominant inheritance Exceptions: types 2N and 3 are autosomal recessive Deficiency: reduced OR abnormal function of vWF due to point mutation or major deletion Quantitative and/or qualitative defects based on subtype of disease Normal vWF: Synthesis: in large multimers Function: o Promotes platelet adhesion to damaged endothelium o Carries factor VIII Presentation: Mucous membrane bleeding Excessive blood loss from superficial cuts and abrasions Hemarthrosis and hematomas (joint and subcutaneous bleeds) are RARE* Laboratory Findings: Prolonged bleeding time Prolonged PTT (low factor VIII levels due to decreased half-life; vWF normally stabilizes it) Normal PT Low vWF quantification test Defective platelet aggregation with ristocetin (normal with ADP/EPI/collagen) Diagnosis: May be masked by elevated levels of vWF in acute phase reactions (vWF is an acute phase reactant) o Examples: pregnancy, strenuous exercise, stress Determination of Type: Measurement of vWF with multimer analysis o Type 1: reduction in all types of monomers o Type 2A: absent large and intermediate multimers o Type 2B: absent large monomers o Type 3: absence of all types of monomers Treatment: DDAVP (Desmopressin): for type 1 VWD (reduction in monomers) o Increases release of vWF from Weibel-Palade bodies Factor VIII Concentrates w/vWF: may be given for low levels Acquired Coagulation Disorders: o Vitamin K Deficiency: Source: fat soluble vitamin obtained from green vegetables and bacteria in the gut o o o o Deficiency: Newborns (sterile gut) Later in life (inadequate diet, malabsorption, long-term Abx use, inhibition of vitamin K with warfarin) Liver Disease: Biliary Obstruction: impaired absorption of vitK decreased FII, VII, IX, X synthesis Severe Hepatocellular Disease: decreased II, VII, IX, X, V and fibrinogen levels Decreased Thrombopoietin Production: contributes to thrombocytopenia Hypersplenism: due to portal HTN thrombocytopenia Disseminated Intravascular Coagulation: Pathologic activation of the coagulation cascade: Widespread intravascular deposition of fibrin (microthrombi) Consumption of coagulation factors and platelets Mechanism: consequence of many diseases in which there is a release of procoagulant material into the circulation Causes widespread endothelial damage or platelet aggregation Examples of Causes (Pathoma): Obstetric complications (tissue thromboplastin in amniotic fluid activates coagulation) Sepsis (endotoxins and cytokines cause endothelial cells to make tissue factor) Adenocarcinoma (mucin activates coagulation) APL (primary granules activate coagulation) Rattlesnake bite (venom activates coagulation) Clinical Manifestations: bleeding AND/OR thrombosis Bleeding from venipuncture sites or recent wounds Generalized bleeding (GI tract, oropharynx, lungs, UG tract) Microthrombi skin lesions, renal failure, or gangrene of extremities (less common) Lab Findings: Increased PT, PTT and TT Decreased fibrinogen Decreased platelet count Increased fibrinogen split products and D-dimers o D-dimers best screening test (Pathoma) Microangiopathic hemolytic anemia (due to microthombi) o Schistoscytes on peripheral blood smear Treatment: TREAT UNDERLYING CAUSE** (most important) Supportive care includes: o FFP and platelet concentrates (for severe bleeding) o Cryoprecipitate (concentrated source of fibrinogen) o Red cell transfusion (may be required) o ATIII and protein C concentrates (inhibit DIC) Do NOT give: o Heparin or anti-platelet drugs (may aggravate bleeding) o Fibrinolytic inhibitors (failure to lyse thombi adverse effects) Coagulation Factor Inhibitor (Pathoma)*: Basics: acquired Ab against a coagulation factor that results in impaired factor function Most Common: anti-FVIII (would be clinically similar to hemophilia A) Diagnosis: Mixing Study: PTT will not correct upon mixing normal plasma with patient’s plasma (would correct in simply a factor deficiency) Disorders of Fibrinolysis (Pathoma)*: Basics: due to plasmin overactivity leading to excessive cleavage of serum fibrinogen Examples of Causes: Radical prostatectomy releases urokinase, which activates plasmin Liver cirrhosis reduces production of alpha2-antiplasmin,which normally inactivates plasmin Presentation: clinically similar to DIC (increased bleeding; no microthrombi*) Differences from DIC: o Normal platelet count o No D-dimers Laboratory Findings: Increased PT and PTT (plasmin destroys coagulation factors) Increase bleeding time (plasmin blocks platelet aggregation) Normal platelet count Increased fibrinogen split products (serum fibrinogen is lysed) o NO D-dimers due to absence of fibrin thrombi (ie. the coagulation cascade has not reached completion) Treatment: aminocaproic acid (blocks activation of plasminogen) THROMBOSIS: Basics: Hereditary Disorders with Increased Risk of Thrombosis: o Prevalence of these disorders is as high as bleeding disorders o Should be suspected in young adults who suffer from: Spontaneous thrombosis Recurrent DVT Thrombosis at an unusual site Risk Factors for Thrombosis (Acquired): o Venous stasis and immobility o Malignancy o Blood disorders (hyperviscosity, thrombocytosis, PV, ET) o Estrogen therapy (have increased levels of FII, VII, VIII, IX, X; have decreased ATIII levels) o Heparin Induced Thrombocytopenia (HIT) Ab to PF4/heparin complex results in platelet activation/consumption microthrombi Hereditary Disorders: Factor V Leiden Gene Mutation: most common inherited cause of increased risk of thrombosis* o Basics: activated protein C resistance (normally breaks down activated FV) o Defect: genetic polymorphism (NOT A MUTATION) in the factor V gene (argglu at 506) Makes factor V less susceptible to cleavage by protein C Heterozygotes ~5x increased risk of venous thrombosis Homozygotes ~50x increased risk of venous thrombosis Anti-Thrombin III Deficiency: o Inheritance: autosomal dominant May also be seen in patients with nephritis, due to excessive proteinuria (acquired form) o Defect: Decreased synthesis of ATIII (type 1) Dysfunctional activity of ATIII (type 2) o Presentation: Recurrent venous thrombosis starting early in life Arterial thrombosis occasionally seen Heparin ineffective (PTT does not rise with standard heparin dosing) Protein C Deficiency: o Inheritance: autosomal dominant (with variable penentrance) Acquired forms are also possible: Liver disease (made in the liver) DIC Sepsis Vitamin K deficiency (I added this- assumption since it is vit K dependent) o Warfarin CONTRAINDICATED: due to development of skin necrosis (vessel occlusion due to formation of microthrombi) Protein C has a shorter half life than other coagulation factors (depleted first, resulting in initially hypercoaguable state during treatment; pre-existing deficiency makes this really bad) Protein S Deficiency: o Inheritance: autosomal dominant o Presentation: similar to protein C deficiency (cofactor for protein C) Prothrombin G20210: o Defect: base pair substitution at prothrombin allele G20210A on cs 11 that leads to INCREASED plasma prothrombin levels (synthesized in the liver) Prothrombin gets converted to thrombin increased thrombotic risk (~2x) o Diagnosis: mutation detected by PCR Hyperhomocystinemia (may also be acquired): o Defect: mutation in MTHFR gene (product responsible for generating 5-methylTHF) 5-methylTHF is a cosubstrate for homocysteine conversion to methionine Results in increased levels of homocysteine (cannot convert to methionine) increased risk of both venous and arterial thrombosis o Another Defect (Pathoma): Cystathionine beta synthase (CBS) deficiency (normally converts homocysteine to cystathionine) Acquired Conditions: Hyperhomocystinemia (may also be hereditary): o Vitamin B12 or folate deficiency Acquired forms of ATIII deficiency: already discussed Acquire forms of Protein C deficiency: already discussed Antiphospholipid Syndrome (APS): o Definition: occurrence of thrombosis OR recurrent miscarriage in association with laboratory evidence of PERSISTENT antiphospholipid Ab Example: lupus anticoagulant antibody o Mixing Study: prolonged PTT that does not correct (coagulation factor inhibitor) o Antiphospholipid Antibodies: associated with arterial and venous thrombosis Childhood Conditions Associated with Anti-Phospholipid Antibodies: Autoimmune diseases (APS, SLE, juvenile arthritis) Pediatric stroke Hematological diseases (AIHA) Various infections (adenovirus, varicella) May also see in NORMAL Children: ~5-10% of cases -