Anemia and The Bleeding Patient November 1, 2005 Eli Denney D.O.

Anemia and The Bleeding Patient

November 1, 2005

Eli Denney D.O.

Definition of Anemia

Anemia – a reduced concentration of red blood cells. Measured by Hct, Hgb and RBC count.

Anything that reduces production or increases destruction will result in anemia if the processes are not corrected.

Anemia - Causes

Most common causes in U.S. Iron deficiency Thalassemia Anemia of Chronic Disease

Physiologic Reactions to Blood Loss

Acute – Peripheral vasoconstriction and central vasodilatation If blood loss continues – small vessel

dilatation with compensatory decreased PVR, resulting in increased CO.

Chronic - Increased plasma volume keeps intravascular volume normal Erythropoietin released by kidneys –

reticulocytes in 3-7 days.

Signs and Symptoms

Depend upon Rate of blood loss Amount of blood lost Age Overall Health Comorbid disease states

Signs and Symptoms

Weakness Fatigue Dyspnea

Palpitations Orthostatic

symptoms Lethargy

Physical Exam Findings

+ Orthostatic BP’s Tachycardia Pallor Systolic ejc. murmur

Widened pulse pressure GI bleeding/Uterine

bleeding Altered Mental Status

Diagnosis

Confirmed by lab values – RBC count, Hgb and Hct.

CBC may not determine specific cause – need to obtain other labs to begin appropriate workup CBC-provides RBC indices (MCV) Reticulocyte count Peripheral smear Iron studies Folate, B12 levels

Treatment

In ED, anemia from hemorrhage is the most common need for treatment Symptomatic Hemodynamically unstable Asymptomatic - can do outpatient work up -

depends upon clinical situation. Based on clinical situation, patients should be

typed and cross-matched for transfusion Admit Patients with ongoing blood loss for

definitive care

Increased Likelihood of Bleeding Disorder

Spontaneous bleeding-multiple sites Bleeding from untraumatized sites Bleeding several hours after trauma Bleeding into deep tissues or joints Family history of bleeding disorder Excessive bleeding after dental extractions or

surgical procedures Liver disease

Increased Likelihood of Bleeding Disorder

Drugs – Ethanol Coumadin ASA NSAIDS Antibiotics Plavix

Bleeding Site May Indicate Specific Abnormalities Indicative of Platelet Disorder

Mucocutaneous Bleeding Petechiae Ecchymosis Epistaxis GI/GU bleeding Heavy menstrual bleeding

Purpura are associated with thrombocytopenia and commonly indicates a systemic disease

Coagulation Factor Deficiencies

Bleeding into joints, potential spaces, retroperitoneum and delayed bleeding

Mucocutaneous bleeding and bleeding into deep spaces may be signs of DIC – both pathways of homeostasis are involved.

Normal Coagulation

Platelet Plug (Primary Homeostasis)

Cross-linked Fibrin (Secondary Homeostasis)

Fibrinolytic system – counter regulatory system that prevents excessive clot formation.

Primary Homeostasis

Depends upon platelet interaction with endothelium Requires normal vascular endothelium,

functional platelets, von Willebrand factor, and normal fibrinogen

von Willebrand factor connects platelets to the endothelium by glycoprotein Ia

Fibrinogen connects platelets by glycoproteins IIB-IIIA.

Secondary Homeostasis

See Fig 218-3 - Coagulation Cascade

Fibrinolytic System

Purpose is to limit the size of fibrin clots Endothelial cells release tPA which converts

plasminogen to plasmin which is already a part of the fibrin clot

Plasmin degrades fibrinogen and fibrin monomer into fibrin degredation products and cross linked fibrin into D-Dimers

Other Inhibitory Proteins

Antithrombin III – inhibits clotting cascade. Inhibits function of XIIa, XIa, IXa and

Thrombin. Heparin potentiates this interaction.

Proteins C and S

Activated Protein C – binds with cell surface bound Protein S – the bound proteins inhibit factors Va and VIIa.

Inhibitory Proteins

Deficiencies or dysfunction of proteins C,S or antithrombin III can cause a hypercoagulable state.

Initial Testing for Bleeding Disorders

CBC PT/INR PTT Further testing as indicated (Table 218-4)

Acquired Bleeding Disorders

Acquired Platelet Defects

Quantitative Defects Decreased production Increased destruction Splenic sequestration

Platelet levels less than 10-20,000 / microL increases the likelihood of spontaneous bleeding – especially intracranial

Levels less than 10,000 – transfusion of platelets will be necessary

Decreased Production

Bone marrow infiltration Aplastic anemia Viral infections – CMV, Rubella Drugs (Thiazides, Ethanol, Chemo-agents) Vitamin B12, Folate deficiency Radiation

Increased Destruction

ITP TTP HUS DIC

Viral infections – HIV, Varicella, EBV

Drugs – Heparin/Protamine

Idiopathic Thrombocytopenic Purpura

Autoimmune disease involving thrombocytopenia, purpura or petechiae, normal bone marrow function and no other known cause for decreased platelets.

Autoantibodies attach to circulating platelets and are destroyed by the reticulendothelial system.

Platelets function normally despite low numbers and bound with antibodies

ITP – Acute and Chronic Course

Acute – typically occurs in children, males = females, duration 1-2 months.

Chronic – typically occurs in adults, lasts greater than 3 months, female > male, resolution unlikely even with treatment.

Patients with chronic ITP more commonly have another disease or autoimmune disorder.

ITP – PE and Lab

Commonly PE will show petechiae, epistaxis, gingival bleeding, bruising, and possible menorrhagia. Remaining PE may be normal.

Lab – CBC - low platelets, otherwise normal. Peripheral smear-normal platelets, few in number

If history, PE, and above lab support the diagnosis of ITP, no further ED testing is necessary.

Treatment - ITP

Minimize bleeding risks – Meds, falls, comorbid disease states and procedures.

Asymptomatic and healthy, with platelet counts > 50,000 – no treatment is needed

< 50,000 and symptoms require treatment <20,000-30,000 require treatment

Treatment - ITP

Prednisone 60-100 mg/d – tapered after platelet count returns to normal ranges.

If steroid therapy fails – splenectomy – produces remission in 65 percent of patients.

If bleeding is life threatening – local hemorrhage control should instituted and high dose methylprednisolone 1-2 g/d for 2-3 days used.

Intravenous immunoglobulin as needed. Platelets transfused after steroids or immunoglobins.

Drug Induced Thrombocytopenia – Table 219-2 Common drugs

Heparin Sulfas ASA Ethanol Thiazides Indomethacin Valproic Acid Lasix

Platelet Sequestration

Splenomegaly and thrombocytopenia without significant bleeding is not uncommon. Another bleeding disorder is usually involved if significant hemorrhage is present.

Splenectomy is the definitive therapy for patients with low counts and evidence of significant hemorrhage.

Qualitative Platelet Abnormalities

Liver disease Uremia DIC SLE ITP Cardiopulmonary

Bypass

Myeloprolifertive disorders

Dysproteinemias Von Willebrands

disease Leukemias

Drug Induced Platelet Dysfunction

ASA NSAIDS Clopidogrel Ticlopidine

Liver Disease

Any disease that affects the hepatocytes can affect the production of the clotting factors

Malabsorption of Vit. K by primary biliary cirrhosis and intra and extrahepatic cholestasis will affect factor II, VII, IV, and X

In more severe liver disease, decreased synthesis of plasmin inhibitor will cause a general state of fibrinolysis and increase D-Dimers and fibrin degradation products

Lab

To evaluate coagulation in liver disease the following labs will need to be ordered Hematocrit PT aPTT Platelet count FDP and D-Dimer

Treatment

Lab abnormalities without bleeding – patients can be observed

Bleeding or invasive procedure needed – treatment is necessary

Vitamin K for liver disease FFP if prolongation of PT and aPTT Cryopercipatate if fibrinogen levels < 100

mg/dL Platelet transfusion if indicated - <10,000

Renal Disease

Dialysis related thrombocytopenia Toxin inhibition of platelet aggregation –

uremic toxins. For life threatening bleeding, treatment is

usually dialysis and transfusion for anemia, DDAVP and conjugated estrogens.

Platelet transfusion and cryoprecipitate transfusions as needed.

Disseminated Intravascular Coagulation DIC – an acquired syndrome characterized by

activation of the coagulation system resulting in fibrin formation. The fibrinolytic system is also activated which breaks down clots, uses all coagulation proteins and results in bleeding - Tintinalli

DIC is associated with many conditions – Table 219-5

Pathophysiology

Disease process begins by the activation of tissue factor – extrinsic pathway.

Thrombin converts fibrinogen to fibrin leading to formation of small clots that are deposited in capillaries causing tissue ischemia – organ dysfunction.

Excessive activation of the coagulation system leads to depletion of coagulation proteins and platelets.

tPA is activated indirectly by thrombin and fibrin and the fibrinolytic system is activated – in DIC the system works in excess and can result in uncontrolled bleeding

DIC Manifestations

Hemorrhage and thrombosis both take place, one form usually is dominate.

Hemorrhage – most dominate Petechiae Ecchymoses GI/GU bleeding Wounds/IV sites

DIC Manifestation

Thrombosis Purpura fulminans Mental Status Changes MOF Oliguria ARDS Tissue necrosis

In chronic DIC the liver produces enough coagulation proteins to compensate

DIC - Lab

Increased PT Thrombocytopenia – most common Low fibrinogen levels

Fibrinogen levels less than 100 mg/dL, - more likely to see bleeding complications

D-Dimers are more specific than FDPs in diagnosing DIC

Increased LDH, decreased haptoglobin, schistocytes on peripheral smear

DIC Treatment

Treatment of underlying disease triggering DIC Hemodynamic support as needed –PRBCs, IVFs,

vasopressors as needed. Supplementation of coagulation proteins, platelets

and fibrinogen Cryoprecipitate in 10-unit doses to keep fibrinogen to

100-150 mg/dL Platelet transfusion if < 20,000 or < 50,000 with

bleeding FFP transfused at 10-15 mL/kg to replace clotting

proteins Vitamin K, Folate

DIC Treatment

Heparin for thrombotic dominant DIC or chronic DIC and known clots –purpura fulminans

Antifibrinolytic agents are withheld for proven hypofibrinogenemia and fibrinolysis. Heparin should be infused before to decrease chance of thrombosis

HIV Bleeding Disorders

Thrombocytopenia is one of the earliest signs of HIV infection

Bleeding problems are uncommon, the most common problems being bruising, mucosal bleeding and petechiae

Thrombocytopenia caused by Increased destruction – immune complex

related and HIV medications Decreased synthesis – immune complex

related and HIV medications

HIV Bleeding Disorders

HIV patients commonly have Lupus anticoagulant – increased aPTT, which

may appear and disappear with infection Anticardiolipin antibody – rarely causes a

disorder in itself

Circulating Anticoagulants

Antibodies that affect coagulation factors Known inhibitors for each coagulation protein

exist but the two most common are Factor VII inhibitors Antiphospholipid antibodies – lupus

anticoagulant and anticardiolipin antibodies.

Factor VIII Inhibitors

Can develop at any time but usually affect patients with hemophilia A

Patients at risk of developing factor VIII inhibitors Elderly Postpartum patients Autoimmune disorders – SLE, RA, UC, Mult.

Myeloma Have drug reactions – PCNs, Sulfas,

Phenytoin

Factor VIII Inhibitors

Signs and Symptoms Large bruising without trauma Ecchymoses Hematomas

Lab Normal PT Normal Thrombin clotting time Prolonged aPTT – does not correct after

mixing Factor VIII assay will be low

Factor VIII Inhibitors

Treatment of Bleeding Episodes Pressure to bleeding site Factor VIII concentrates Factor IX complex concentrates Prothrombin complex concentrates Recombinant factor VIIIa concentrates Plasmaphersis Ultimately a hematologist should direct care

for life or limb threatening bleeding episodes

Antiphospholipid Antibody Syndrome

Presence of lupus anticoagulant or anticardiolipin antibodies, plus one or both of the following: thrombosis and/or complications with pregnancy (recurring fatal loss <34 weeks)

Antiphospholipid Antibody Syndrome

In reality SLE patients rarely have the antibody (5-15 percent) in vivo patients develop clots rather than bleed.

Lupus anticoagulant more common in HIV patients, cancer, drug reactions and other autoimmune disorders

Anticardiolipin antibodies commonly occur with lupus anticoagulant but both can occur separately

Antiphospholipid Antibody Syndrome

Lupus anticoagulant lab abnormalities Normal or prolonged PT Prolonged aPTT – does not correct when mixed Normal Thrombin clotting time Patients may develop antibodies to prothrombin

causing a deficiency – suggested by markedly prolonged PT

Factor assays – all factors will be mildly low Russell viper venom time – detects presence of lupus

anticoagulant Anticardiolipin antibodies detected by ELISA assay

Antiphospholipid Antibody Syndrome

Signs and Symptoms Thromboembolism – venous > arterial Pregnancy complications Thrombocytopenia

Patients who develop thrombosis and remain positive for lupus anticoagulant have a 50 percent chance of another clot forming within 2 years

Recurrent fetal loss most likely due to thrombosis of placental vessels

Antiphospholipid Antibody Syndrome

Treatment Asymptomatic – observation, reduce risks for

Virchows triad. Treat underlying disorder if known Corticosteroids for both AAS and autoimmune

disease together Patients with episodes of thrombosis need

lifelong anticoagulation ASA alone is inadequate LMWHs – good role for these medicines

Bibliography

Tintinalli Judith E., Emergency Medicine A Comprehensive Study Guide 6th Edition. Chapters 218-219

Questions

T/F Lupus Anticoagulant is always present in patients with SLE?

T/F von Willebrand disease is a disorder of the extrinsic clotting pathway?

T/F Definitive treatment of DIC is heparin followed by coumadin therapy?

T/F Defiencies of proteins C and S cause thrombotic disorders?

T/F This was a fun and interesting chapter? F, F, F, T, F