07 Heme 2
Anaphylaxis
Anaphylaxis is a severe Type I hypersensitivity reaction mediated by the cross-linking of multiple membrane-bound IgE antibodies by a specific antigen. Read more about hypersensitivity reactions.
IgE-Fc receptor aggregation on the surface of mast cells results in the release of histamine, prostaglandins, tryptase and leukotrienes. Histamine is considered to be the primary mediator of anaphylactic shock.
Anaphylactoid reaction (pseudoanaphylaxis) is different from anaphylaxis as it is caused by direct mast cell degranulation and is not IgE mediated. However, anaphylactoid reaction presents like anaphylaxis and is treated similarly.
Anaphylaxis can be caused by:
Food (most common) – peanuts, shellfish
Medications – penicillin, sulfa drugs
Insect bites
Latex
Diagnosing an anaphylactic reaction is clinical, based on a thorough physical exam and patient presentation. Anaphylaxis generally presents shortly (from several minutes to a few hours) after exposure to the causative antigen. Symptom severity escalates rapidly.
Rash, hypotension, respiratory distress and GI disturbances coupled with recent exposure to a known allergen should raise clinical suspicion of anaphylaxis.
Complications of anaphylaxis include:
Anaphylactic shock
Respiratory failure
Myocardial ischemia
Brain injury from hypoxia
Death
The first priority when treating an anaphylactic patient is to assess Airway, Breathing and Circulation (ABCs). Maintaining the patient’s airway via intubation or cricothyrotomy may be necessary to ensure adequate oxygen supply. IV fluid may be required to maintain adequate blood pressure.
Epinephrine (IV or IM) is the drug of choice in the treatment of anaphylaxis. It is crucial for restoring airflow obstruction and preventing cardiovascular collapse.
The preferred route of administration of epinephrine in cases of anaphylaxis WITHOUT shock is intramuscular. In cases of anaphylaxis WITH shock, IV administration is preferred.
Several drugs including antihistamines, glucocorticoids and nebulized albuterol can be used as adjunctive agents to optimize treatment but DO NOT replace epinephrine in the acute management of anaphylaxis. Antihistamines including H1 blockers (diphenhydramine, cetirizine) and H2 blockers (ranitidine) are used to relieve itching and hives. Glucocorticoids prevent the late-phase response and albuterol can be used to promote bronchodilation.
Eosinophilia
Eosinophilia is defined as abnormally high levels of eosinophils with an absolute eosinophil count in the peripheral blood of ≥500 eosinophils/microL.
Eosinophils are white bloods cells of granulocytic origin and found predominantly within tissues.
Blood eosinophil counts can be increased by a clonal expansion of an abnormal hematopoietic cell, or by cytokine stimulation of eosinophil production and/or egress from the bone marrow.
Eosinophilia is commonly seen in:
Addison disease
Neoplasm (e.g. primary hypereosinophillic syndrome, eosinophilic leukemia)
Asthma
Allergic reactions
Collagen vascular diseases
Transplant rejection
Parasitic infection
Blood eosinophils can be decreased by:
Fever
Bacterial/viral infections
Glucocorticoids
Eosinophilia can cause tissue and end organ damage at levels exceeding 1500 eosinophils/microL.
Symptoms
A patient presenting with eosinophilia will commonly be asymptomatic. A careful history may reveal a predisposing condition.
A patient with end organ damage due to eosinophilia may present with:
Rash/pruritus
Nasal involvement
Wheezing/cough/chest congestion
Gastrointestinal involvement/diarrhea
Myalgia
Nervous system symptoms
Diagnosis of eosinophilia is made via peripheral blood smear revealing elevated eosinophil counts. Further workup is indicated to determine the underlying cause of the eosinophilia.
Treatment
An acutely ill patient with end organ damage due to eosinophilia should be admitted to the hospital and treated with high dose glucocorticoids. Further work up will be needed determine the cause of eosinophilia.
Eosinophilia discovered as an incidental finding in an otherwise healthy individual can be evaluated on an outpatient basis. The evaluation should include a complete history, physical examination, and baseline laboratory testing.
In some cases eosinophilia has been found to resolve on its own with no intervention. Potential explanations for resolution of eosinophilia include:
Removal of an offending agent
Clearance of an infection
Downregulation of host responses (reported in the setting of chronic helminth infections)
Hypersensitivity Reactions
Type 1
Type 1 hypersensitivity reactions involve an antigen cross-linking preformed IgE on the surface of mast cells and basophils, which release vasoactive amines(e.g. histamine, leukotrienes). A prior, sensitizing exposure is required to make those preformed IgE.
This reaction occurs rapidly after antigen stimulation.
Examples include:
Anaphylaxis
Atopic skin reactions (e.g. eczema, hives)
Insect venom allergy
Asthma
Hay fever
Food allergies
Skin testing can be used to test for type 1 hypersensitivity reactions.
The treatment for non-anaphylactic type 1 hypersensitivity reaction includes symptomatic relief with antihistamines, and leukotriene receptor blockers (e.g. montelukast). Anaphylaxis is treated with epinephrine. It is discussed more here.
Type 2
All type 2 hypersensitivity reactions are mediated by IgG or IgM binding to their antigen, which is fixed on the exterior of a cell.
Type 2 hypersensitivity reactions can be classified as cytotoxic or non-cytotoxic.
In the non-cytotoxic pathway, the physical presence of the antibody causes a reaction. For example, it can block or stimulate a receptor. No significant inflammation occurs.
In the cytotoxic pathway, antibodies attach to cell surfaces and induce local inflammation. The cell is killed by neutrophils, macrophages, NK cells or complement.
The direct Coomb’s test can detect type 2 hypersensitivity reactions. This test looks for the presence of antibodies attached to cells.
Examples of cytotoxic type 2 hypersensitivity include:
Autoimmune hemolytic anemia
Erythroblastosis fetalis
Hyperacute transplant rejection
Goodpasture's disease
Rheumatic Fever
Pernicious Anemia
Examples of non-cytotoxic type 2 hypersensitivity include:
Grave’s disease
Myasthenia gravis
Lambert-Eaton syndrome
Type 3
Type 3 hypersensitivity reactions are characterized by deposition of immune complexes.
First, circulating immune complexes of antigen-antibody are deposited in tissue. Then, the immune complexes activate complement, which attract neutrophils, which release lysosomal enzymes that cause tissue damage.
The reaction can take several days.
Examples include:
Arthus reaction (after vaccine boosters)
Glomerulonephritis
Lupus
Hypersensitivity pneumonitis
Polyarteritis nodosa
Serum sickness
Often, the white count is elevated, and complement is reduced, indicating that complement is being consumed.
In serum sickness, a type 3 hypersensitivity reaction, the antigen is most commonly a drug, not serum. TMP-SMX, penicillin-class antibiotics, and therapeutic antibodies such as infliximab or rituximab often cause serum sickness.
Serum sickness presents with a fever, rash, malaise and polyarthralgias, 1-2 weeks after first exposure to the offending agent.
The best therapy for serum sickness is removal of the causal agent. Symptomatic relief, such as antihistamines, NSAIDs or oral prednisone may be required.
Type 4
Type 4 hypersensitivity reactions are known as delayed-type or T-Cell mediated.
When exposed to antigen, presensitized Th1 cells release cytokines, which activate macrophages. No antibody is used.
Examples include:
Contact dermatitis
PPD skin test for TB
Type 1 diabetes mellitus
Multiple sclerosis
Guillain-Barre
Hashimoto’s thyroiditis
Granuloma formation (e.g. tuberculosis, sarcoidosis)
Normal Coagulation
Primary Hemostasis
Primary hemostasis involves forming a platelet plug at the site of endothelial injury. It occurs in 4 steps:
Endothelial injury
Platelet adhesion
Platelet activation
Platelet aggregation
1. To begin primary hemostasis, platelets are activated by exposure to subendothelial collagen. Thrombin, ADP and epinephrine can also activate platelets. Activated platelets adhere to subendothelial collagen via vWF (von Willebrand Factor). vWF binds to both collagen and the GpIb receptor on platelets. Bernard-Soulier syndrome is a defect of GpIb on platelets.
2. Fibrinogen binds to the GpIIb/IIIa receptors on two adjacent platelets, linking the platelets together and causing them to aggregate. Glanzmann Thrombasthenia is a disease resulting from the deficiency of the GpIIb/IIIa receptor.
3. Platelets secrete the contents of their:
Alpha-granules, which promote further platelet adhesion (vWF, fibrinogen, fibronectin, PDGF, platelet-factor-4)
Dense granules which activate other platelets (ADP, ATP, serotonin, calcium, histamine)
4. Finally, platelets express Thromboxane A2 and phospholipids which serve to activate many components of the coagulation cascade.
Secondary Hemostasis
Secondary hemostasis involves the clotting cascade, which is a series of zymogens (proenzymes) which are sequentially cleaved into enzymes. Eventually, fibrin is activated and polymerizes to stabilize the platelet plug formed in primary hemostasis. The clotting cascade is divided into the intrinsic, extrinsic, and common pathways.
The intrinsic pathway begins with Factor XII (Hageman factor), which is activated by subendothelial collagen.
The extrinsic pathway begins with Factor VII, which is activated by tissue factor (aka Factor III or thromboplastin).
The intrinsic and extrinsic pathway converge with the activation of Factor X. The common pathways begins with Factor X, and ends with the formation of fibrin polymers.
Fibrinolysis is the dissolution of a clot. The clot releases the enzyme plasminogen activator, which activates plasminogen to plasmin. Plasmin lyses fibrinogen and fibrin, dissolving the clot slowly.
PT/INR
The prothrombin time (PT) measures the extrinsic and the common coagulation pathways. This includes factors VII, X, V, II (prothrombin), and I (fibrinogen).
The INR (international normalized ratio) is another measure of of the prothrombin time (PT), calculated slightly differently.
Notably, the PT / INR is elevated in:
Warfarin use
Vitamin K deficiency
DIC
Liver dysfunction (all the procoagulants except Factor VIII and vWF are made in the liver)
Antiphospholipid antibody syndrome
Polycythemia
PTT
The partial thromboplastin time (PTT) measures the intrinsic and the common coagulation pathways. This includes factors XII, XI, IX, VIII, X, V, II (prothrombin), I (fibrinogen).
Notably, the PTT is elevated in:
von Willebrand Disease (vWF stabilizes Factor VIII)
DIC (disseminated intravascular coagulation)
Vitamin K deficiency
Hemophilia A or B
Antiphospholipid antibody syndrome
Liver disease (all the clotting factors except vWF and Factor VIII are made in the liver)
Bleeding Time
Bleeding time measures platelet function, both qualitative and quantitative deficiencies.
Clinically, platelet dysfunction manifests as petechiae.
The bleeding time is elevated in any platelet disease. For example:
Bernard-Soulier disease
Glanzmann’s thrombasthenia
ITP (Immune Thrombocytopenia)
TTP (Thrombotic thrombocytopenic purpura)
von Willebrand Disease (because vWF initiates the platelet plug formation, von Willebrand Disease acts as a qualitative deficiency in platelets)
DIC (Disseminated Intravascular Congestion).
Uremia-induced platelet dysfunction
Opportunistic Infections
Opportunistic infections occur more frequently in immunosuppressed patients. AIDS-defining illnesses can be used to diagnose AIDS (acquired immunodeficiency syndrome) in a person infected with HIV (human immunodeficiency virus). Alternatively, a CD4 T-Cell count less than 200 cells/microliter in an HIV-positive person defines AIDS.
Some high-yield AIDS-defining illnesses are:
Recurrent bacterial infections
Esophageal candidiasis
Disseminated mycosis (e.g., coccidioidomycosis, histoplasmosis)
Disseminated tuberculosis
HIV-related encephalopathyor wasting syndrome
Kaposi Sarcoma
Pneumocystis jirovecii
Toxoplasmosis of brain
Prophylaxis against infections is recommended based on CD4 counts. Details are discussed in this topic.
Diseases that present in AIDS patients with CD4 counts less than 500 include:
Disease
Presentation
Treatment
Herpes Zoster / Simplex
Shingles; oral or genital lesions
Acyclovir, valacyclovir, foscarnet
HHV-8
Kaposi Sarcoma (red/purple macules or plaques)
Topical alitretinoin / chemotherapy
Parasitic diarrhea (Isospora, Strongyloides or Cryptosporidium)
Prolonged diarrhea, weight loss
Metronidazole, TMP/SMX
Coccidioidomycosis occurs with a CD4 count less than 250. It presents with chronic cough, fever and bilateral reticulonodular infiltrates on chest x-ray.
Opportunistic infections of AIDS patients with CD4 counts less than 200 include:
Disease
Presentation
Treatment
Bacterial pneumonia (S. Pneumoniae, H. Influenzae, Nocardia)
Rapid onset dyspnea, fever
Antibiotics
Candida esophagitis
Odynophagia, white patches that can be scraped off.
Fluconazole / ketoconazole
Cervical cancer
History of HPV; confirmation with Pap smear
Resection, topical 5-fluorouracil, ketoconazole
Pneumocystis Jirovecii pneumonia (PCP)
Gradual onset, nonproductive cough
TMP/SMX; steroids
Tuberculosis
Cough, night sweats, weight loss, fever
Rifampin, Isoniazid, Pyrazinamide, Ethambutol
Epstein-Barr virus can cause oral hairy leukoplakia in HIV-positive patients. It presents as white plaques usually on the lateral tongue. Unlike candida, the plaques of oral hairy leukoplakia cannot be scraped off.
Histoplasmosis can occur in AIDS patients when their CD4 count reaches 150 or below.
Disease
Presentation
Treatment
Cerebral toxoplasmosis
Headache, focal neurologic symptoms, positive IgG
Pyrimethamine, sulfadiazine, clindamycin
Progressive multifocal leukoencephalopathy (due to JC Virus).
Ataxia, motor deficits, mental status change
Antiretroviral therapy
Bartonella
Bacillary angiomatosis, constitutional symptoms
Erythromycin, doxycycline
Aspergillus Fumigatus
Pulmonary or CNS abscesses.
Amphotericin B, Caspofungin
Opportunistic infections in AIDS patients with CD4 counts below 50 include:
Disease
Presentation
Treatment
Cryptococcal meningitis
Headache, neck stiffness, mental status changes
Amphotericin B, Fluconazole
CMV (Cytomegalovirus)
Vision loss, esophagitis, diarrhea
Ganciclovir, foscarnet, valganciclovir
Mycobacterium avium complex (MAC)
Weight loss, fatigue, fever, abdominal pain, lymphadenopathy, hepatosplenomegaly
Clarithromycin, azithromycin, ethambutol, rifampin, rifabutin
AIDS Complications
Wasting syndrome is an AIDS complication consisting of greater than 10% baseline weight loss associated with chronic diarrhea, chronic weakness and fever.
Both lean body mass and fat are lost, with muscle loss contributing to the chronic weight loss.
Electromyography (EMG) on patients with wasting syndrome will reveal peripheral nerve dysfunction.
Management of wasting syndrome involves:
Antiretroviral therapy (increases lean body mass in naive patients)
Exercise
Steroid hormones (e.g, testosterone, megestrol acetate, nandrolone and dehydroepiandrosterone (DHEA))
AIDS dementia is an AIDS complication associated with confusion, mental status changes, and generalized neurologic symptoms (such as tremors).
AIDS dementia commonly occurs when the CD4 count isless than 200 cells/microL.
Risks factors for AIDS dementia include:
High serum or cerebrospinal fluid (CSF) HIV viral load
Low educational level
Advanced age
Anemia
Illicit drug use
Female sex
AIDS dementia is a clinical diagnosis made upon:
History of declining mental status
Generalized neurologic symptoms
Elevated ß2 microglobulin in CSF
Cerebral atrophy on CT or MRI
Treatment with antiretrovirals can improve symptoms.
Lymphoma (CNS or non-hodgkin) is a complication of AIDS that presents with headache, confusion, and focal neurologic symptoms.
Lymphoma in AIDS patients commonly develops when the CD4 count isless than 100 cells/microL.
CT or MRI will reveal a lesion and biopsy will confirm the diagnosis.
The best therapy for lymphomas in the setting of AIDS has not yet been determined. Antiretroviral therapy is started or modified to control the infection. Once the infection is controlled, the administration of chemotherapy and/or radiation therapy can begin. As in the HIV-seronegative population, the choice of therapy is determined by the subtype and stage of lymphoma.
Cervical cancer is a potential complication of HIV/AIDS with incidence being4 to 5 times higher in HIV positive women than HIV negative women.
Guidelines from the American College of Obstetricians and Gynecologists and the United States Preventive Services Task Force recommend that women who are infected with HIV should undergo cervical cytology for cancer screening twice in the first year after diagnosis of HIV infection and then annually, provided the test results are normal.
See cervical cancer for more information.
Pediatric Langerhans
Hand-Schüller-Christian disease and Letterer-Siwe disease while once considered to be separate conditions are now recognized as different manifestations of the same disease known as **Langerhans cell histiocytosis.
*In this topic, Hand-Schüller-Christian disease and Letterer-Siwe disease will be presented as distinct entities for testing purposes.
Most children with Langerhans cell histiocytosis will present with lytic bone lesions and skin lesions that can present as a rash or flaking of the scalp that resembles "cradle cap".
Langerhans cell histiocytosis can also present as a child with recurrent otitis media with a mass involving the mastoid bone.
The classic triad of Hand-Schüller-Christian disease is:
Lytic bone lesions
Exophthalmos
Central diabetes insipidus
Hand-Schüller-Christian is a milder disease than Letterer-Siwe Disease, which is rapidly fatal. In addition to skin rash and lytic bone lesions, Letterer-Siwe disease also has extensive organ involvement including:
Lymphadenopathy
Hepatosplenomegaly
Anemia
Thrombocytopenia
Diagnosis is made with biopsy of suspicious lesions and staining for CD1a or finding Bierbeck granules on electron microscopy.
Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells that have characteristic Birbeck granules shaped like a tennis racket.
There is no specific treatment protocol for children with solitary lesions of Langerhans cell histiocytosis but most treatment involves different combinations of surgery, steroids, radiation and chemotherapy.
Children with lesions involving the orbit, mastoid, or temporal bones (so called "CNS risk" lesions) require treatment with vinblastine plus prednisone for 6 months.
DIC
Disseminated Intravascular Coagulation (DIC) is a systemic process of both thrombosis and hemorrhage that occurs as a result of underlying illness. DIC occurs in several steps:
The most common etiologies of DIC include:
Sepsis - bacterial lipopolysaccharides activate coagulation
Trauma, especially to the central nervous system
Malignancy - "cancer procoagulant" is produced by some mucinous tumors & can activate factor X
Obstetrical complications such as preeclampsia, retained dead fetus, or acute fatty liver of pregnancy
Severe intravascular hemolysis, for example, an acute hemolytic transfusion reaction or severe malaria
DIC can manifest as either an acute or chronic process, depending on the etiologyandrate at which the precipitating factors appear.
Acute (Decompensated) DIC arises when the bloodstream is flooded with a large amount of tissue factor in a brief period of time, resulting in an aggressive consumptive coagulopathy and severe bleeding diathesis. Specific manifestations include:
Bleeding, including petechiae and ecchymoses; classically, blood may ooze from any IV or catheter sites
Acute renal failure, secondary to microthrombi and/or hypotension
Hepatic dysfunction
Pulmonary disease, including pulmonary hemorrhage
Neurologic disease, including both delirium and focal neurologic findings that may result from microthrombi
Chronic (Compensated) DIC develops when the bloodstream is continuously exposed to a small amount of tissue factor, and patients can be asymptomatic or have a predilection for thrombosis.
Purpura fulminans is a rare but potentially fatal complication of DIC. Extensive tissue thrombosis & skin necrosis are present. It is often associated with an inherited Protein C deficiency, and can therefore be treated empirically withintravenous protein C administration.
The diagnostic criteria for DIC differs for acute and chronic presentation, and involves excluding TTP/HUS which is clinically similar, but involves distinct management.
The diagnosis of acute DIC is based on:
History/Clinical presentation
Thrombocytopenia(typically < 100,000/uL)
Schistocyteson the peripheral blood smear
Low plasma fibrinogen
Lab studies suggesting increased thrombin production
Decreased fibrinogen, elevated aPTT and PT
Lab studies suggesting increased fibrinolysis
Elevated fibrin degradation products (FDPs) and D-dimer
Similar to acute DIC, the diagnosis of chronic DIC is based primarily on elevated FDPs and D-dimerand evidence of schistocytes on peripheral blood smear. However, it is distinguished by the lack of coagulopathy as the chronic nature of clotting factors is balanced by compensatory production of these proteins. Therefore, labs will show:
No thrombocytopenia
Normal PT and aPTT
Normal fibrinogen levels
Note: Mild thrombocytopenia, mildly prolonged PT and aPTT, and/or slightly elevated plasma fibrinogen may be present.
Management of DIC is primarily focused on addressing the underlying condition.
Some supportive measures may be indicated:
For patients withplatelets < 50,000/uL and serious bleeding platelets should be transfused.
For patients with active bleeding, marked INR elevation and/or decrease in fibrinogen, FFPor cryoprecipitate should be administered.
Anticoagulation
Heparin is commonly used for DVT treatment & prophylaxis. Heparin binds antithrombin-III; this complex inactivates:
Thrombin
Factors IXa, Xa, XIIa
Fibrin
Use aPTT (activate partial thromboplastin time) to monitor heparin, but not LMWH (Low Molecular Weight Heparin). Use platelet counts to monitor for HIT (Heparin Induced Thrombocytopenia).
LMWHs (Low Molecular Weight Heparins) include enoxaparin, dalteparin, ardeparin. They have a stronger effect on Factor Xa than antithrombin-III.
Protaminequickly reverses both heparin & reduces clinical bleeding in LMWH.
Fondaparinux, like heparin, binds antithrombin-III. It mainly inactivates factor Xa. It can be used in DVT treatment or prophylaxis, like heparin. Additionally, it can be used for anticoagulation in Heparin Induced Thrombocytopenia (HIT).
Warfarin inhibits the synthesis of vitamin-K-dependent clotting factors (factors II, VII, IX, X as well as Proteins C & S). Specifically, it inhibits epoxide reductase, which prevents vitamin K from being reduced into its active form. Therefore, less vitamin K is available as a cofactor for the synthesis of factors II, VII, IX, and X.
Monitor warfarin via PT or INR (prothrombin time or international normalized ratio).
Foratrial fibrillation or DVT prophylaxis/treatment, the target INR is 2-3.
If the patient has certain mechanical heart valves, the target INR is increased to 2.5-3.5.
To lower a patient’s INR, for example in a warfarin overdose:
First, consider holding the warfarin briefly and letting the INR normalize on its own.
Vitamin K can also be supplemented to help slowly decrease the INR.
If there is already a bleed, or if the INR is severely elevated,the following medications (alone or together) can quickly correct the INR:
Vitamin K
Fresh frozen plasma (FFP)
Prothrombin complex concentrate (PCC)
It takes 2-5 days to achieve target INR when starting warfarin therapy. Therefore, you must ALWAYS bridge these patients with heparin until the INR is therapeutic. Warfarin blocks Protein C & Protein S first, making the patient transiently hypercoagulable when starting warfarin. Heparin effectively anti-coagulates them during this transitional period.
Direct thrombin inhibitors such as lepirudin, dabigatran, or argatroban bind directly to thrombin to inactivate thrombin, bypassing antithrombin-III.
Direct thrombin inhibitors are used for:
Non-valvular atrial fibrillation
Deep Venous Thrombosis prophylaxis and management
HIT (Heparin Induced Thrombocytopenia)
Urokinase, streptokinase, alteplase and tissue plasminogen activator (t-PA) are all pharmaceutical plasminogen activators. t-PA is produced endogenously, but can also be administered during an acute MI, stroke or pulmonary embolism.
Desmopressin (aka DDAVP, antidiuretic hormone) treats Hemophilia A & vWD (von Willebrand Disease) by releasing vWF from storage sites.
Aspirin irreversibly inhibits both COX-1 and COX-2 (cyclooxygenase). This prevents platelets from producing thromboxane A2 or prostaglandins, and further platelet activation is blocked.
Aspirin is used as:
Antipyretic
Analgesic
Antiinflammatory
Prevention & treatment of acute coronary syndromes(including an MI)
Ischemic stroke
Transient ischemic attack (TIA)
Revascularization procedures (CABG- coronary artery bypass graft, carotid endarterectomy)
ADP receptor inhibitors include:
Clopidogrel
Prasugrel
Ticagrelor (reversible)
Ticlopidine
ADP receptor inhibitors block ADP receptors on the surface of platelets, thereby preventing ADP-induced expression of glycoproteins IIb/IIIa on the surface of platelets. Decreased GPIIb/IIIa expression, in turn, reduces platelet aggregation.
Unlike other ADP receptor inhibitors that irreversibly inhibit ADP receptors, ticagrelor reversibly inhibits ADP receptors.
Indications for ADP receptor inhibitors include:
Acute coronary syndrome
Coronary stents: placement & long-term prophylaxis
Post-thrombotic stroke
Post-TIA
Ticlopidine can cause neutropenia, which can manifest as fevers and mouth ulcers.
GpIIb/IIIa inhibitors include abciximab, eptifibatide, and tirofiban. They work on activated platelets to prevent aggregation.
Cilostazol and dipyridamole are phosphodiesterase inhibitors.
Inhibition of phosphodiesterases increases cAMP levels within platelets, which inhibits platelet aggregation and induces vasodilation .
Clinical uses for cilostazol and dipyridamole include:
Intermittent claudication
Coronary vasodilation
Stroke and TIA prophylaxis (with aspirin)
Angina prophylaxis
Toxicities of cilostazol and dipyridamole include:
Abdominal pain
Facial flushing
Headache
Hypotension
Nausea
Warfarin and unfractionated heparin are preferred for anticoagulation in patients with severe renal failure (creatinine clearance ≤30 mL/min) since they are not extensively metabolized by the kidneys.
In contrast, low-molecular-weight heparins (e.g. enoxaparin, dalteparin), the indirect inhibitor of factor Xa fondaparinux, and direct factor Xa inhibitors (e.g. rivaroxaban) undergo more extensive renal metabolism and are therefore generally avoided in patients with severe renal failure.
HIV
The human immunodeficiency virus (HIV) is spread from person to person through the sharing of bodily fluids such as by sexual contact (oral, anal, and vaginal), needle stick (in intravenous drug use (IVDU) or accidentally in health care workers), and blood transfusion.
The two cells infected by HIV are CD4+ T-cellsandmacrophages.
Blood levels of the HIV virus seem to predict levels of the virus in other bodily fluids; thus patients with acute HIV infection are most contagiousafter seroconversion, when they have the highest levels of the HIV virus in their blood.
Acute HIV infection is usually symptomatic after seroconversion; however, most patients with acute HIV infection do not receive medical attention as their symptoms are similar to a non-specific viral illness such as mononucleosis. A common presentation of HIV infection is chronic fatigue and anorexia with low-grade fever.
Another common presentation of HIV infection is chronic diarrhea, although again the lack of specificity of this symptomatology makes HIV difficult to diagnose in a patient without a high index of clinical suspicion.
The usual time from initial HIV infection to development of symptoms is an average of 2 to 4 weeks, although there are reports of incubation periods as long as 10 months.
In early HIV infection after seroconversion, the viral load (i.e. HIV RNA level) is often > 100,000. Enzyme-linked immunoassay (ELISA) is used as the screening test for HIV infection.
The Western blot is the confirmatory test for HIV infection if the ELISA is positive. This is done to decrease the rate of false positives.
If a patient is thought to be at high risk of exposure to HIV, postexposure prophylaxis may be started before rapid HIV testing and serology results are available with a 3-drug regimen of tenofovir, emtricitabine, and raltegravir. The first two drugs are available as a combination pill. Rapid HIV testing of the source is acceptable if results will be available within 2 hours and the source is considered low-risk for HIV.
RBC Physiology
Red blood cells (RBC) serve to transport oxygen from the alveoli of the lungs to the tissues and to transport carbon dioxide from the tissues back to the alveoli.
Hemoglobin (Hgb) acts as a binding site for oxygen and carbon dioxide. The affinity of Hgb for oxygen varies depending on physiologic conditions and can be represented on a Hbg-O2 dissociation curve.
A left shift indicates an increase in affinity for oxygen and occurs due to:
Metabolic alkalosis
Decreased body temperature
Increased fetal hemoglobin
A right shift indicates a decrease in affinity for oxygen and occurs due to:
Metabolic acidosis
Increased body temperature
High altitude
Exercise
Red blood cells (RBC) originate from the same pluripotent stem cells in the bone marrowas myeloid cells and lymphoid cells.
RBC become enucleate during development and rely on glycolysis for survival.
The majority of blood CO2 is transported as bicarbonate (HCO3-) in the plasma. The RBC contains a carbonic anhydrase enzymewhich allows the cell to convert CO2 and water into bicarbonate for transport. The bicarbonate is expelled into the plasma by a Cl-HCO3- antiport within the RBC membrane. CO2 can also be transported bound to hemoglobin.
In the lungs, oxygenation of hemoglobin promotes dissociation of H+ from hemoglobin pushing equilibrium towards CO2 formation from bicarbonate, thus releasing CO2 to the lungs to be exhaled.
Normal hemoglobin and hematocrit are:
14 to 18 g/dL and 42% to 52% in men
12 to 16 g/dL and 37% to 47% in women
Low hemoglobin and hematocrit can result in insufficient oxygen supply to the tissues resulting in hypoxic tissue damage.
Sideroblastic anemias result from defective heme synthesis. Since iron cannot combine with heme, unused iron accumulates in mitochondria around the nucleus.
The basophilic inclusions are seen on Prussian Bluestaining of bone marrow. These inclusions are the unused iron.
When so much unused iron accumulates in the mitochondria around the nucleus, the iron can encircle the nucleus. These cells are known as ringed sideroblasts.
Iron studies will show an iron-overloaded state, which would include the following:
Increased serum iron
Reduced TIBC(total iron binding capacity)
Increased serum transferrin saturation
Increased serum ferritin
Vitamin K Deficiency
Vitamin K deficiency in otherwise healthy adults is rare, because it is produced by gut flora, it is easily recycled in cells, and is fairly ubiquitous in plants. However, several conditions can predispose patients to a deficiency.
Since vitamin K is a fat-soluble vitamin,fat malabsorption can limit vitamin K absorption.
Intestinal gut bacteria produce Vitamin K. Long-term oral antibiotic therapy can kill this normal gut flora, leading to decreased production of vitamin K. Trimethoprim/sulfamethoxazoleand ciprofloxacin are common causes.
Vitamins A & E compete for absorption with vitamin K. Excess of these vitamins can decrease vitamin K absorption.
Vitamin K is found in many foods, especially inleafy greens. Starvation, fasting or anorexia after chemotherapy may limit vitamin K intake.
The liver produces the vitamin-K dependent clotting factors (II, VII, IX, X). Therefore, liver disease can mimic vitamin K malabsorption. Factors V & VII measurements can distinguish between the liver dysfunction & vitamin K deficiency.
Symptoms of vitamin K deficiency are related to impaired coagulation:
Bleeding from the GI tract,GU tract or any mucosal surface
Easy bruising
Splinter hemorrhages
Hematuria
Newborns commonly are vitamin K deficient due to a lack of intestinal flora, poor placental transmission, low levels in breast milk, and maternal medications (e.g., anticonvulsants). This leads to Vitamin K Deficient Bleeding (VKDB, previously known as Hemorrhagic Disease of the Newborn - HDN).
VKDB presents as bleeding from mucosal or incision sites (e.g., circumcisions), or intracranial hemorrhage.
To prophylax against Vitamin K Deficient Bleeding, all infants receive parenteral vitamin K at birth, followed by supplementation of infant formulas.
Warfarin (aka coumadin) inhibits the production of vitamin-K dependent clotting factors, II, VII, IX, X. Vitamin-K deficiency will enhance the effects of warfarin, raising the PT or INR (prothrombin time or international normalized ratio).
Clinically, vitamin K levels are typically not measured directly.PIVKA-II (Proteins Induced in Vitamin K Absence) can be ordered on patients with conditions that predispose them to vitamin K deficiency. PT or INR as well as Factors II, VII, IX, X can also be measured, but PIVKA-II is more sensitive. Direct measurement of Vitamin K levels is not done.
Vitamin K deficiency is treated with oral supplementation. Parenteral dosing is usually not needed.
Bridging therapy
Starting anticoagulation in a hemodynamically stable patient 48-72 hours after surgery is generally safe and does not significantly increase the risk of bleeding. Inferior vena cava filters can be used in patients in whom anticoagulation is contraindicated (eg, massive gastrointestinal bleed, hemorrhagic stroke).
Unfractionated heparin would generally not be started alone as it is an intravenous medication and needs to be continued until the INR is therapeutic, which can take several days. The goal is to discharge the patient on oral warfarin quickly.
This patient therefore will need to be started on intravenous unfractionated heparin for immediate treatment of the DVT (as it acts quickly) and then on warfarin (typically in the evening of the same day). Heparin is continued for 4-5 days until the INR is at therapeutic levels (goal 2–3).
Both low molecular weight heparin (eg, enoxaparin) and rivaroxaban are not recommended in end-stage renal disease (ESRD); they are metabolized by the kidney, so their use in patients with ESRD is associated with increased bleeding risk. Intravenous unfractionated heparin is not contraindicated in ESRD.
Chemo types
The radiation therapy is considered salvage therapy, defined as a form of treatment for a disease when a standard treatment fails.
Adjuvant therapy is defined as treatment given in addition to standard therapy. This would be the case in this patient if the radiation therapy was given at the same time as the radical prostatectomy.
Consolidation therapy is typically given after induction therapy with multidrug regimens to further reduce tumor burden. An example is multidrug therapy after induction therapy for acute leukemia.
Induction therapy is an initial dose of treatment to rapidly kill tumor cells and send the patient into remission (<5% tumor burden). A typical example is induction chemotherapy for acute leukemia.
Maintenance therapy is usually given after induction and consolidation therapies (or initial standard therapy) to kill any residual tumor cells and keep the patient in remission. An example is daily antiandrogen therapy for prostate cancer.
Neoadjuvant therapy is defined as treatment given before the standard therapy for a particular disease. This would be the case in this patient if the radiation therapy was given before the radical prostatectomy was done.
Transfusion reactions
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