DISORDERS OF HEMOSTASIS

PATHOPHYSIOLOGY Platelets (Boxx 116-1) Coagulation Cascade (Figure 116-1) Notes on Coagulation Cascade Exposure to tissue factor at the site of the injured vessel initiates the pathway The extrinsic pathway initiates the processs The intrinsic pathway sustains the process Thrombin sensitive factors: I, V, VIII, XIII Vit K sensitive: II, VII, IX, X Heparin active sites: Iia, Ixa, Xa (major), Xi LABORATORY INVESTIGATIONS CBC and peripheral blood smear Drop of Hb and Hct actually lags behind the loss or rbcs in acute hemorrhabge because of slow equilibration times PBS: schistocytes or fragmenteed RBCs can be seen in DIC Nucleated RBCs: myelopthisic disease Platelet counts Thrombocytopenia = < 100,000/mm# Bleeding risk generally doesnt greatly increase until < 20,000 Platelet counts have NO info about platelet FUNCTION Bleeding Times Test of vascular integrity and platelet function Two 1 mm deep and 1 cm long incisions made on the arm while a bp cuff is inflated at 40 mmHg and time to when the blood stops oozing Normal is < 8 min, Borderline 8-10 min, Abnormal > 10 min Bleeding time > 10 min + platelet count > 100 = platelet dysfunction Drugs, renal failure, Von Willebrand dz Prothrombin Times Prolonged with deficiencies in fibrinogen, prothrombin, factor V/VII/X Used to test the extrinsic factor Partial Thromboplastin Time Tests all components of the intrinsic and common pathways (essentially all factors EXCEPT VII and XIII) Factor levels generally must fall by 40% before the PTT is prolonged Can be prolonged by external or internal factors CLUE: prolonged PTT in pt with DVT/PE/CVA etc: think lupus anticoagulant Other Low fibrinogen: DIC, liver failure (will lead to prolonged PT, PTT, TT) High fibrinogen: acute phase reactant Thrombin Time: measures conversion of fibrinogen to fibrin; good screen for abnormal fibrinogen, low fibrinogen levels(DIC), fibrinogen inhibitors (heparin, FDPs) Factor Level Assays: specific bioassays for each level

APPROACH TO BLEEDING DISORDERS

INTRODUCTION Commonly present with purpuric rashes: see box 116-3 for Hx/Px important points Purpura = blood in the skin or mucous membrane; divided into petechiae and echymosis Petechia = small, <0.3mm reddish-purple macular lesions (non-raised), do not blanch Ecchymosis = larger lesions that are often tender and may be raised, do not blanch PURPURIC LESIONS DO NOT BLANCH Vascular dilation or vascular anomalies will blanch (spider angiomas for example) Characteristic resolution: purple > golden-brown -> yellow Three groups of problems Vascular problem Platelet problem Coagulation system problem

PLATELET DISORDER ONSET AFTER TRAUMA LOCATION OF BLEEDING Immediate onset Superficial - skin petechiae - mucosal petechiae - GI, GU bleeding - menorrhagi, epistaxis, melena are all common

COAGULATION FACTOR PROBLEM Delayed onset (hours/days) Deep - intrasmuscular - intraarticular - retroperitoneal - hemarthrosis and hematuria common - menorrhagia, epistaxis, GI bleeding are uncommon Hemarthrosis Hematomas Platelets and BT normal PT or PTT abnormal

PHYSICAL FINDINGS OTHER

Petechiae Echymosis Platelet count or BT abnormal PT and PTT normal

DIFFERENTIAL DIAGNOSIS OF BLEEDING PROBLEMS/PURPURIC RASH VASCULAR INTEGRITY PROBLEM

Trauma: normal, abuse (NAT in kids!!), snake bites, etc Infection: meningococcus, viral NOS, mono, endocarditis, ricketssia, strep Drugs: purpura from steroids Vit C deficient Congenital connective tissue disorders: Ehlers-danlos, osteogenesis imperfecta VASCULITIS (small or medium vessel) Medium vessel: PAN, Wegeners, Kawasakis, Behcets Small vessel:Goodpastures syndrome, Erythema nodosum, Panniculitis, Churg-Strauss syndrome, Buergers disease

(thombophlebitis obliterans), Hypersensitivity vasculitis (HSP, serum sickness, cryoglobulinemia, Vasculitis associated with SLE/PBC/IVDA/Sjogrens/lymedz)

PLATELET PROBLEM
Thrombocytopenia Decreased production Sepsis: esp meningococcus Drug, toxin suppression Aplastic anemia BM infiltration Increased destruction Sepsis/DIC Drug: quinine, quinidine, heparin, sulpha, dilantin, digoxin, GIIbIIIais HUS, TTP, ITP Vasculitits: SLE, lymphomas, etc Hereditary spherocytosis Autoimuune hemolytic anemia Increased sequestration Splenomegaly: liver dz, hematologic malignancies Dilutional (massive transfusion) Platelet Dysfunction Acquire platelet disorders: uremia, aspirin, other drugs/herbs, multiple myeloma, myelodysplastic syndromes Congenital platelet disorders: Bernard-Soulier, Glanzmans thrombathenia, Hermansk-Pudnak syndrome VonWillebrands disease Increased INR (normal PTT) Warfarin Vit K deficiency: biliary obstruction (fat sol vit ADEK), hemolytic dz of newborn, dietary (rare) Factor VII deficiency (rare) Increased PTT (normal INR) Factor VIII def (Hemophilia A) Factor IX def (Hemophilia B) Factor XI def von Willebrands disease can have normal or prolonged PTT No bleeding: XII, prekallikrein, fletcher factor deff, Lupus anticoagulant Heparin Increased INR, increased PTT, increased TT DIC Fibrinogen deficiency: congenital (rare), acquired (usu DIC)

COAGULATION FACTOR PROBLEM

APPROACH TO THE PURPURIC RASH MUST consider non-accidental trauma Other causes of sepsis actually more common than meningococcus for the sick purpuric rash The well looking person/child with a petechial rash? Is it meningococcemia???? Many infections can cause petechiae or ecchymosis in absence of platelet or coagulation disorder Capillary damage from the infection Rubeola, mono, ricketsia, streptococcal, RMSF, endocarditis can all present Keep in mind the above ddx: vascular integrity problem, thrombocytopenia, coagulation factor problem Approach

Toxic appearing: monitored bed, iv access, draw labs, fluid bolus, draw cultures, start antibiotics, resuscitate as needed History and Physical: drugs, infectious symptoms, bleeding history, easy bleeding or brusing, lumps or bumps, weight loss or systemic symptoms, full review of symptoms Order: CBC, diff, platelet count, retic count, PTT, INR, bleeding time Thrombocytopenia Prolonged INR/PTT: sepsis and DIC Normal INR/PTT: ITP, TTP, HUS, bone marrow suppression, bone marrow infiltration, platelet sequestration Platetlets normal, INR/PTT prolonged Hemophilia Liver dz Warfarin Platelets normal, INR/PTT normal, Bleeding Time prolonged Von-Willebrand disease Aspirin or other platelet inhibitors Platelets normal, INR/PTT normal, Bleeding Time normal Vasculitis: HSP, serum sickness, cryoglobuinemia, IVDA, kawasakis Trauma Infections Drugs Connective tissue disease

SEVERITY OF THROMBOCYTOPENIA Mild 50 - 100 X 10^9 /L Moderate 20 - 50 Severe < 20 Significant spontaneous bleeding does not occur generally until plt < 10

IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) Also called Werlhofs disease, or purpura hemorrhagica Acquired hemorrhagic disorder with immunological destruction of platelets char. by..... Thrombocytopenia (acute, recurrent, or chronic) Purpura (typically petechial in nature; severity correlates w/ platelet count) Absence of other thrombocytopenic disorders: must r/o other causes of thrombocytopenia or associated diseases (SLE, lymphomas, etc)

Major Findings (1) NO Significant Hepatosplenomegaly (2) Abundant Megakaryocytes in BM aspirate

ACUTE ITP Definition

Complete, sustained remission within 6 months of onset - single episode, variable severity - recurrent, largely biphasic Children (peak incidence 2-6yo) Male = Females of all cases in children < 15yo MCC of acquired bleeding in childhood Post viral IgG attaches to platelet Ag Sudden onset of thrombocytopenia following one week a/f a trivial viral illness. Sudden fall in platelet (<20 10^9) leads to nose bleed, gum bleeds, purpura, raccoon eyes, subscleral hemorrhages. Duration usu a few weeks. Diagnosis of exclusion (for both)............. (1) CBC and PBS (2) BM asp to r/o Ca, aplastic anemia (3) R/O other disorders (autoAb screen, anticardiolipin Ab, LAC, HIV) Supportive care + wathcful waiting is the mainstay - replace sign acute blood loss w/ rbcs - ferrous sulfate for anemia of chronic blood loss - restriction of activity until resolution - should remain in school but avoid contact sports Corticosteroids - prenisone 2mg/Kg/d X 4wks - 80% show inc platelet count - 90% show clearance of purpura - stop at one months regardless of pl # IVIG - 0.5g/Kg X 9 days

CHRONIC ITP
Sustained remission not achieved w/i 6 months from onset - continous episode, variable severity - recurrent multiphasic Older children and adults (10 - 30yo) 3 Females: 1 Male Acute or chronic May appear at any age

Epidemiology

Etiology Clinical Course

Autoantibody to platelet membrane Ag in 80% (most target GPIIa/IIIb protein) Insidious onset of bleeding problems or may be asymptomatic. Serious bleeding problems are rare and only occur when platelet count is < 10 - 20 X 10^9/L. Usually in young female. Splenomegaly suggests another diagonsis. No specific test for both but look for ..... PBS: rbc morphology normal, decrease platelet count but increase pl size BM: increase # of megakaryocytes (Classical finding) Supportive care + watchful waiting is the mainstay of management - should try to avoid long term steroids - pl > 50 X 10^9/L and free of purpura should have supportive care - consider treatment if pl < 30 or purpura Corticosteroids st - Prednisone 1 line tx if tx required IVIG - Try this if there is no response to steroids Splenectomy - Consider when platelet count cannot be maintained on nontoxic steroid levels - May delay hoping for resolution;

Investigations

Management

ACUTE ITP
- 80% show inc pl count in 7days - w/i one month (i) complete remission (ii) recurs when Rx stopped(iii)partial or NO response

CHRONIC ITP
shouldbe done w/i one year of onset -Menorrhagia in teenage girls is an indication for splenectomy

Prognosis

Spontaneous resolution in > 90% if less than 10yo; about 70% if under 16yo. Rarely associated w/ serious complications and occurs w/i 6 months by definition. If no remission by 6 months, it is now chronic ITP and consider new approach.

Spontaneous resolution rare but response to splenectomy is good. Post splenectomy thrombocytopenia tx is difficult.

THROMBOTIC THROMBOCYTOPENIC PURPURA Result of platelet deposition/aggregation in capillaries and arteriaoles HUS: less CNS involvement, more renal involvement TTP: more CNS involvement, less renal involvment Initiating event unclear: porstacyclin and abnormal platelet aggregation Presentation: fever, purpuric rash, fluctuating neurologic sympomts Labs: thrombocytopenia, microangiopathic hemolytic anemia, renal failure Platelet counts usually 10,000/mm3 to 50,000/mm3 All are anemic: Hcts often < 20% Hemolytic anemia: increased indirect bili, pallor and jaundice, peripheral blood smear with schistocytes and fragmented rbcs., increased reticulocyte counts, increased LDH, dark urine (increased urobilinogen) Neurological symptoms: storke, seizures, paresthesias, altered LOC, coma Renal: hematuria, proteinuria, +/- acute renal failure Fever: 90% Nhx: 80% mortality within months if untreated Tx: steroids, splenectomy, anticoagulation, exchange transfusion, dextran Treatment of choice: plasmapheresis with FFP (mortality 90%>17%) Antiplatelet agents may be used: aspirin, persantine Splenectomy or gammaglobulin in resistant cases KEY ED ISSUE: No platelet transfusions unless life threatening hemorrhage (increases thrombosis in microcirculation) THROMBOCYTOSIS Primary (Essential) Thrombocytosis: chronic myeloproliferative disorder Secondary (Reactive) Acute infection Acute hemorrhage Hemolysis Iron deficient anemia Post splenectomy Hodgkins, non-Hodgkins lymphoma Trauma Rebound from EtOH, chemotherapy, folate/B12 deficiencies

Chronic inflammation: RA, IOBD, TB, sarcoid, Wegeners

PLATELET TRANSFUSIONS Most platelet function disorders are not treated well with platelet transfusions Commonly indicated for primary bone marrow disorders: aplastic anemia, acute leukemias Hemorrhage cause by platelets is unlikely with counts > 50,000 /mm3 Risk is moderate b/q 10-50,000/mm3 Risk significantly increases with counts < 10-20,000 / mm3

WHY DO CHRONIC LIVER DISEASE PATIENTS BLEED? Thrombocytopenia from hypersplenism (portal HTN) Platelet dysfunction Reduction of synthesis of vit K dependant factors: II, VII, IX, X Dysfibrinogenemia: synthesis of abnormal fibrinogen DIC Enhanced fibrinolysis

COMPARE HUS, TTP, HSP

HUS PATHOPHYS Microvascular damage: platelet deposition and aggregation and microangiopathic hemolytsis KIDS > ADULTS SETTING OF BLOODY DIARRHEA/ABDO PAIN (GASTROENTERITIS) Ecoli 0157 - H7 Shigella, coxsac,GAS Hemolytic anemai Thrombocytopenia Renal failure Hypertension GI bleeding Stool for Ecoli increased indirect bili, schistocytes and nucleated rbcs on smear, coombs -ve Thrombocytopenia (10-50 is usual range) Urine with blood, protein, TTP Microvascular damage: platelet deposition and aggregation and microangiopathic hemolytsis ADULTS FEVER PURPURIC RASH NEUROLOGICAL SYMPTOMS RENAL INVOLVEMENT (More neuro and less renal) Hemolytic anemia Thrombocytopenia Nepritis or Renal failure Neurologic: sz, coma, stroke Hemolysis: anemia, increased retics, increased indirect bili, schistocytes and nucleated rbcs on smear, coombs -ve Thrombocytopenia (10-50 is usual range) Urine with blood, protein, HSP Small vessel vasculitis

PRESENTATION

SCHOOL AGE PURPURIC RASH IN WELL LOOKING CHILD ARTHRALGIAS, ARTHRITIS

COMPLICATIONS

Intussuception Testicular torsion Nephritic syndrome, HTN, renal failure GI bleeding Normal platelets, INR, PTT NO hemolytic anemia Hematuria =/- proteinuria (can be nephritic or nephrotic syndrome) May have increased Scr, BUN Increased IgA

DIAGNOSIS

HUS urobilinogen Increased BUN/Cr TREATMENT Fluids, lytes, give blood and platelets Dialysis prn Control HTN No abx for Ecoli enteritis No plasmapharesis in kids

TTP urobilinogen Increased BUN/Cr Plasmapheresis with FFP is tx of choice Steroids, aspirin, splenectomy NO platelet transfusion unless lifethreatening hemorrhage

HSP

Observation for HTN, RF, intuss Occasionally steroids used for severe abdo pain

DISORDERS OF COAGULATION PATHWAY

PROLONGED INR, NORMAL PTT, NORMAL BT Warfarin Vit K deficiency Liver dz Factor VII deficiency (rare) PROLONGED PTT, NORMAL INR, NORMAL BT NO BLEEDING Factor XII deficiency (Hageman factor) Prekallikrein (Fletcher factor) High molecular wieght kininogen BLEEDING Factor VIII deficiency (Hemophilia A) Factor IX deficiency (Hemophilia B) Factor XI deficiency Factor VIII assay Most important initial test in patient with prolonged PTT and normal INR Measures ability of patients serum to coagulate factor VIII deficient blood Presented as a % of normal Abnormal test does not distinguish from an abnormal FVIII (Hemophilia A) or low levels of normal FVIII (Von Willebrands)

FACTOR VIII DEFICIENCY = HEMOPHILIA A Background FVIII levels normal but the protein is abnormal Sex-linked recessive nature (female carriers and males affected commonly) 30% occur spontaneously, 70% have familial trend PTT may be NORMAL if mild hemophilia (PTT only prolonged if factor VIII activity is < 30%) Bleeding first noticed in the first years as the child starts to walk Limbing child with bruising, swollen knees, ++bleeding after venipunture Deep bleeding: hematomas, hemarthrosis, intracranial, urinary Recurrent hemarthrosis and joint destruction are major problems Intracranial bleeding is major cause of death Epistaxis, oral bleeding, menorrhagia rare unless associated with von Willes Late bleeding is characteristic: bleed hours to days after trauma (consider with minor head trauma, admission for observation!!) Preparation: hemophiliac file with FVIII activity level, blood type, presence of antibodies, time of last hospitalization etc should be kept in ED

Factor VIII:C activity assay determines severity <1% severe: spontaneous bleeding common

1-5% moderate: spontaneous bleeding rare but bleeding after surgery or trauma is common\ 5-10% mild: generally no spontaneous bleeding but still can bleed after surgery or trauma >10% very mild: occassionally problems with significant stress

Replacement Therapy Main ED replacement options are cryoprecipitate or FVIII:C concentrates Recombinant FVIII is commonly used but may not be available in ED Concentrates are heated to decrease risk of hepatitis HIV etc Cryoprecipitate: cold precipitable protein fraction derived from FFP If a patient says they are bleeding, they are bleeding!!!! See Tables 116-1, 2 for indications and dosing: summary Mild bleeding: goal is 12.5% factor activity Moderate bleeding: goal is 25% factor activity Severe bleeding: goal is 50% factor activity Plasma volume (50ml/kg X wt) X [desired - current] = units One unit/kg increases FVIII by 2% Monitor response: clinically, decreasing PTT, increasing factor VIII levels No response: circulating autoantibodies: results in severe deficiency, complex treatment with exchange transfusion, immunosuppresion, etc. Acquired anti factor VIII autoantibodies can occur in non-hemophiliacs too Post partum Pcn Phenytoin IBD, RA DDAVP Increases levels of FVIII and VIII:Ag in hemophilia A and VWD Dose: 0.3 ug/kg/dose Works in mild to moderate disease Effect lasts 4-6hrs Antifibrinolytics (Amicar) Occasionally used for bleeding from nose or oral cavity Must r/o hematuria (risk of hydro from clotted ureteral blood) General Management Admit for observation after trauma Deep lacerations can be a big problem Minor head trauma can be life-threatening Head trauma: administer FVIII to a goal of 50% activity and admit Give FVIII before CT or other investigations

FACTOR IX DEFICIENCY = HEMOPHILIA B Sex-linked recessive Incidence is 1/5th of hemophilia A Dx by factor IX assay (factor VIII activity normal)

Tx: purified factor IX or recombinant factor IX FFP and plasma prothrombin complex (II, VII, IX, X) are useful if factor IX not available

VON WILLEBRANDS DISEASE Three activities of factor VIII FVIII:C: Anithemophiliac (coagulant) activitiy: VIII:C FVIII:vWF: Platelet aggregation activity: von Willebrand factor activity FVIII: Ag: Factor VIII antigen VWD has a decrease in factorVIII:Ag and VIII:C due to under production thus the platelets cant aggregate properly VWD: decreased FVIII:C, FVIII:vWF, FVIII:Ag Hemophilia A: decreased FVIII:C + normal FVIII:vWF and FVIII:Ag MC hereditary bleeding disorder (1%): autosomal dominant FVIII:C levels are usually 5-50% Bleeding sites are usually superficial: epistaxis, mucosal, GI, menorrhagea Dx: abnormal Bleeding time, decreased factor VIII:Ag Tx: cryoprecipitate is preferred initial tx (I bag/10kg) FFP can be used but doesnt contain as much fVIII Factor VIII can be used if there are no alternatives DDAVP can be useful but only with certain types and should discuss with hematology; iv or intranasal administration q 12-24hrs (works for type I) DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Coagulation system has the foot on the gas (coagulation) and the break (anticoagulation) at the same time -----------> the result is microvascular clotting early and bleeding late Pathophysiology Thrombin is formed and overwhelmes the inhibitor system leading to acceleration of the coagulation process Fibrin is deposited in microvasculature of all organs The fibrinolytic system trys to lyse fibrin and impair thrombin formation Coagulation inhibitors (AIII, ProtC, tissue factor pathway inhibitor) are all decreased leading to more microvascular coagulation Fibrin degredation products are released which inhibits platelet function Coagulation factors (esp V, VIII, XIII, and fibrinogen) and platelets are CONSUMED thus the patient starts to BLEED Clinical Results Microvascular coagulation and mulit-organ dysfunction from ischemia and/or Bleeding Most common findings: extensive skin and mucous membrane bleeding and hemorrhage from many sites (incisions, venipuntures, catheters) Less commonly: periperal acrocyanosis, thrombosis, gangrenous digits/genitalia/nose May only have laboratory abnormalities Etiology of DIC Release of tissue factors (procoagulants) Hemolysis

Cancer cells Fat embolism Tissue destruction (trauma, ischemia, hypoxia) Infections, sepsis Amniotic fluid embolism Allergic reactions Transplant rejections Toxins: snake bites, drugs, stimulants Hemolytic transfusion reactions Endothelial damage HUS Acute GN RMSF Aortic rupture Vascular malformations Kasabach-Merrit syndrome: giant hemangiomas

Laboratory Dx Decreased: fibrinogen (best predictor of bleeding), platelets Increased: INR, PTT, Thrombin time, FDPs, d-dimer Peripheral blood smear: low platelets, shistocytes, fragmented rbcs Other: renal failure, hepatic failure Differential Dx Severe liver disease: also will have increased INR, PTT, TT with decreased platelet counts and fibrinogen levels The only was to distinguish liver dz vs DIC is a factor VIII level because factor VIII is not made in the liver but will be consumed with DIC PEARL: normal (or increased) factor VIII level occurs with liver disease and DIC will have a decreased factor VIII level Primary fibrinolysis: rare disorder that affects fibrinogen and fibrin but usually leaves the coagulation components in the low normal range; the paracoagulation test is negative and the euglobulin lysis time is rapid Management of DIC The most important step is to reverse the precipitating cause: sepsis, trauma, overdose, hypothermia, amniotic fluid embolism, abruption, etc CLINICAL BLEEDING PREDOMINANCE Prbcs: 2-4 units Platelets: 5-10 units FFP: 4-6 units + Vit K 10 mg iv Cryoprecipitate: 10 units CLINICAL THROMBOSIS PREDOMINANCE Heparin: low dose infusions (300-500 units/hr) Certain disease states are more associated with fibrin deposition in which case heparin has more of a role: purpura fulminans, dead fetus retention, giant hemangiomas, acute promyelocytic leukemias Heparin is of little benefit: meningococcemia, abruption, severe liver dz, trauma