Bleeding Disorders

Rebolledo, Isobelle Victoria B., RN

HEMOSTASIS
Cessation of bleeding Vascular Phase Platelet Phase Coagulation Phase

Vascular Phase
30 mins to a few hours after injury Local: damage to endothelial cells release ADP, tissue factor (III), thromboxane A2, serotonin Systemic: epinephrine released by adrenal glands stimulates general vasoconstriction

Platelet Phase
15 seconds after injury Platelets( thrombocytes) contain actin and myosin - have no nuclei therefore cannot reproduce -produce thromboxane A2 A special glycoprotein membrane prevents them from adhering to normal epithelium. About 1/3 of platelets are stored in the spleen or other vascular organs waiting to be mobilized.

Platelets
normal range: 150,000 450,000/mcL - decreased platelet count (thrombocytopenia) may be due to increased platelet destruction; decreased platelet production -increased platelet count (thrombocytosis) increased platelet formation may be due to infection, inflammation, cancer

after injury
platelets swell, become large and irregular; contractile proteins release:
ADP Thromboxane A2 Calcium ions feedback = formation of

platelet plug

Coagulation Phase
30 seconds after injury Clotting cascade a series of events resulting in the formation of a clot (thrombus) a. intrinsic b. extrinsic

Clotting Factors
I fibrinogen II prothrombin III - tissue thromboplastin (tissue factor) IV - ionized calcium ( Ca++ ) V - labile factor or proaccelerin VI unassigned VII - stable factor or proconvertin VIII - antihemophilic factor IX - plasma thromboplastin component, Christmas factor X - Stuart-Prower factor XI - plasma thromboplastin antecedent XII - Hageman factor XIII - fibrin-stabilizing factor Prekallikrein Fletcher factor Kininogen Fitzgerald factor

Fibrinolysis
damaged endothelial cells release tissue plasminogen activator (tPA) urokinase, Kallikrein and neutrophil elastase activators convert plasminogen to plasmin to breakdown fibrin tPa is inhibited by PAI plasminogen activator inhibitor plasminogen deposits on fibrin strands breaking down fibrinogen, factors II (thrombin) and VIII

Controlling Clotting
1. Antithrombin III inhibits formation of thrombin
- inactivates prothrombin, factor IX, X

- Heparin binds to antithrombin III greatly enhancing its inhibition of thrombin synthesis.

Controlling Clotting
2. Tissue Factor Pathway Inhibitor (TFPI) inhibits factor Xa 3. Activated fibrin inhibits thrombin via a negative feedback mechanism

Controlling Clotting
4. Protein C produced by the bond of excess thrombin to cell-surface receptor call thrombomodulin - with its cofactor protein S, further inhibits thrombin formation by directly inhibiting factor V and indirectly inhibiting factor VIII

Controlling Clotting
*Vitamin K cofactor needed for the synthesis of factors II, VII, IX, X, and proteins C and S *Warfarin Vit. K antagonist

Monitoring
Warfarin Extrinsic pathway EP produces a bit of fibrin quickly PT-INR Normal Value: 10-12 seconds Heparin Intrinsic pathway IP produces large amounts of fibrin but takes a while to get going. PTT, aPTT Normal Value PTT: 60-70s Normal Value aPTT: 20-35s

Disorders
Vitamin K 3 main types:
K-1 (also known as phylloquinone or phytonadione) derived from plants; K-2 (menaquinone) - produced by the intestinal flora; K-3 (menadione)- synthetic, water-soluble form used for treatment

adult's daily requirement - estimated at 100200 mcg/day

 Infants with VK deficiency are at risk for hemorrhagic disease of newborn Causes:
lack of VK reaching the fetus across the placenta low level of VK in breast milk low colonic bacterial synthesis liver prematurity with prothrombin synthesis

Vit. K Deficiency in Adults

Causes
Malabsorption syndrome Biliary Diseases Parenchymal liver diseases Dietary Deficiencies Various drugs (cholestyramine, coumadin, Cefamandole, cefoperazone, salicylates, hydantoins, rifampin, isoniazid, and barbiturates)

 Signs and symptoms: mucosal and subcutaneous bleeding, such as epistaxis, hematoma, gastrointestinal bleeding, menorrhagia, hematuria, gum bleeding, and oozing from venipuncture sites, easy bruisability

diagnostics
Measurements of serum PT and PTT: Patients with VK deficiency tends to have an elevated PT and a normal aPTT. Both PT and aPTT can be elevated in more severe deficiency states. Measurements of des-gamma-carboxy prothrombin [DCP]: This is a most sensitive marker, which is elevated in VK deficiency states.

complications
Infants hemorrhagic disease of the newborn Adults - osteoporosis

Medical Management
VK-1 : SC or IM Oral VK (5-20 mg): requires normal absorption VK-3: used in malabsorption cases; not given to newborns to avoid risk of hemolysis VK-1 incorporated in 5%Dextrose or 0.9%NaCl: urgent situations (WOF: anaphylaxis)

Diet
Oils, such as olive, canola, cottonseed, and soybean oils, as well as green, leafy vegetables, green peas and beans, watercress, asparagus, spinach, and broccoli, as well as oats and whole wheat

Idiopathic Thrombocytopenic Purpura (ITP)

AKA primary immune thrombocytopenic purpura and autoimmune thrombocytopenic purpura isolated thrombocytopenia with normal bone marrow and the absence of other causes of thrombocytopenia

 a decrease in the number of circulating platelets in the absence of toxic exposure or a disease associated with a low platelet count The 2 distinct clinical syndromes: acute (children);chronic (adults)

Pathophysiology
Acute ITP - often follows an acute infection and has a spontaneous resolution within 2 months. Chronic ITP persists longer than 6 months without a specific cause.

 ITP is primarily a disease of increased peripheral platelet destruction, with most patients having antibodies to specific platelet membrane glycoproteins. Relative marrow failure may contribute to this condition, since studies show that most patients have either normal or diminished platelet production.

Precipitating factors
Abrupt onset (childhood ITP) Gradual onset (adult ITP) Recent live virus immunization (childhood ITP) Recent viral illness (childhood ITP)

Signs and Symptoms

Epistaxis Nonpalpable petechiae, which mostly occur in dependent regions Hemorrhagic bullae on mucous membranes Purpura Gingival bleeding Signs of GI bleeding Menometrorrhagia, menorrhagia Retinal hemorrhage

 Evidence of intracranial hemorrhage, with possible neurologic symptoms Spontaneous bleeding when platelet count is less than 20,000/mm3

Diagnostics
CBC
Isolated thrombocytopenia Truly giant platelets on peripheral smear suggest congenital thrombocytopenia. The WBC count and hemoglobin typically are normal, unless severe hemorrhage has occurred.

Diagnostics
Coagulation studies are normal, and a bleeding time is not useful.

Imaging Studies - A CT scan of the head is warranted if concern exists regarding intracranial hemorrhage.

Medications
Glucocorticoids prednisone, prednisolone Blood products intravenous immuneglobulin (IVIg) Thrombopoietic agents eltrombopag (Promacta); romiplostim (Nplate)

*Platelet transfusion is indicated for controlling severe hemorrhage. **Splenectomy is reserved for patients in whom medical therapy fails. Emergent splenectomy is indicated in patients with life-threatening bleeding in whom medical therapy fails.

In the UK an indium labelled platelet spleen scan can be performed in the nuclear medicine department of certain hospitals to investigate whether the platelets are being destroyed in the spleen. If this test shows that platelets are mainly being destroyed elsewhere in the immune system a splenectomy is unlikely to raise the platelet count.

Complications
Intracranial or other major hemorrhage Adverse reactions from corticosteroids Pneumococcal infection from splenectomy

Patient Education
Instruct patients to return for follow-up in order to assess for a potentially reduced platelet count. Emphasize close outpatient follow-up care. Because of the increased risk of bleeding, instruct patients to avoid aspirin products.

Essential Thrombocytosis
AKA primary thrombocythemia, is associated with sustained megakaryocyte proliferation that increases the number of circulating platelets characterized by a platelet count greater than 600,000/L, megakaryocytic hyperplasia, splenomegaly, and a clinical course complicated by thrombotic and/or hemorrhagic episodes

Causes
Genetic transmission of this disorder is rare reports show several families with multiple members affected by essential thrombocytosis Research suggests that a thrombopoietin production or receptor abnormality can cause familial essential thrombocytosis

 Neurologic symptoms
Headache is the most common neurologic symptom. Microvascular occlusion of the toes and fingers causes digital pain, gangrene, or erythromelalgia The pain increases with exposure to heat and improves with cold; a single dose of aspirin may provide relief for several days.

Unsteadiness Dysarthria Dysphoria Vertigo Dizziness

Migraine Syncope Scotoma Seizures

 Thrombosis large veins & arteries = occlusion of leg, coronary, or renal arteries
Venous thrombosis = splenic, hepatic, or leg and pelvic veins Priapism is a rare complication Pulmonary HPN

 Bleeding GIT, skin, eyes, urinary tract, joints

Usually not severe, rarely requires a transfusion Platelet count of >1 million/L
Weight loss, sweating, low-grade fever, pruritus

Pregnancy complications
Increase in spontaneous abortions. Placental infarctions may occur, resulting in intrauterine growth retardation and fetal death. In most cases, fetal loss occurs during the first trimester.

 A patient history of spontaneous abortion is the greatest risk factor for subsequent spontaneous abortions. Excessive bleeding during delivery is rare. Patients with successful pregnancies show a decrease in platelet count

Diagnostics
Complete blood cell (CBC) count
sustained, unexplained thrombocytosis. Leukocytosis, erythrocytosis, and mild anemia The peripheral blood may show occasional immature precursor cells Large platelets are typically identifiable on routine peripheral blood smear. Mild basophilia and eosinophilia

Diagnostics
Bone marrow
increased bone marrow cellularity in approx 90% patients Megakaryocytic hyperplasia. Giant megakaryocytes. Hyperplasia of granulocyte and reticulocyte precursors Bone marrow reticulin is usually increased, but collagen fibrosis is uncommon.

Diagnostics
Platelet aggregation studies
PT and aPTT studies usually within reference ranges. Platelet aggregation study findings are abnormal and show impaired platelet aggregation to epinephrine, adenosine diphosphate, and collagen but not to ristocetin and arachidonic acid.

Some patients may present with spontaneous platelet aggregation.

Diagnostics
Chemistries
elevated uric acid (UA) levels in 25% of patients at diagnosis. Pseudohyperkalemia, and falsely elevated phosphorus (P) and acid phosphatase levels Pseudohypoxemia may develop from extreme thrombocytosis. Vitamin B-12 levels are increased in 25% of patients with essential thrombocytosis.

Management
Medications 1.Antimetabolites hydroxyurea (HYDRA) 2.Imidazoquinazoline agents anagrelide (AGRYLIN) 3.Biologic response modifiers interferon alpha (ROFERON-A, INRON-A) 4.Radionuclides Phosphorus-32

Risk factors for complications

Age 60 years or older History of thrombosis Platelet count greater than 1.5 million x 109/L, Obesity Cardiovascular risk factors such as smoking, hypertension, and hypercholesterolemia Markers of hypercoagulability such as factor V Leiden and antiphospholipid antibodies

*Recommend lifestyle modifications to all patients with essential thrombocytosis. **Low-risk patients may be managed with low-dose aspirin alone or with observation.

 ***Patients with essential thrombocytosis undergoing surgery are at increased risk for bleeding and thrombosis. Administer cytoreductive therapy to decrease the platelet count to the reference range before surgery. Avoid splenectomy because it can markedly increase the platelet count and the risk of both hemorrhagic and thrombotic events.

complications
Transformation to AML occurs in 0.6-5% of patients Transformation to polycythemia vera and agnogenic myeloid metaplasia may occur. Spontaneous abortion, intrauterine death, or intrauterine growth retardation may complicate pregnancy

Secondary Thrombocytosis
Platelets are acute-phase reactants = they increase in response to various stimuli (systemic infections, inflammatory conditions, bleeding, and tumors) Also called reactive or secondary thrombocytosis

causes
Infection and inflammatory disorders Postsplenectomy or hyposplenism Malignancy Trauma Chronic inflammatory conditions Hemorrhage, blood loss, or both Iron-deficiency anemia Rebound thrombocytosis Asplenia (anatomic or functional) Idiopathic

Signs and symptoms

referable to the primary condition that may have precipitated the secondary thrombocytosis Physical findings reflect the underlying condition

diagnostics
Erythrocyte sedimentation rate (ESR), CRP Cytogenetic analysis Leukocyte alkaline phosphatase, vitamin B-12 Antinuclear antibody (ANA), rheumatoid factor (RF)

 Iron studies (serum iron, total iron-binding capacity [TIBC], serum ferritin) Peripheral blood smear review

1. Platelet count greater than 600,000/mm3 on 2 occasions, separated by a 1month interval 2. Absence of an identifiable cause of secondary thrombocytosis (reactive thrombocytosis) 3. Normal red blood cell mass 4. Absence of significant bone marrow fibrosis (ie, less than one third of the bone marrow) 5. Absence of the Philadelphia chromosome (Ph) by karyotyping or absence of thebcr-abl fusion product 6. Splenomegaly by physical examination or ultrasonography 7. Bone marrow hypercellularity with megakaryocyte hyperplasia 8. Presence of abnormal bone marrow hematopoietic progenitor cells as determined by the growth of endogenous erythroid cells and/or megakaryocyte colonies with increased sensitivity to IL-3 9. Normal levels of CRP and IL-6 10. Absence of iron deficiency anemia as documented by either a normal bone marrowstainable iron or normal serum ferritin level 11. In females, demonstration of clonal hematopoiesis by restriction fragment length polymorphism (RFLP) analysis of genes present on the X chromosome

Management
The primary treatment of secondary thrombocytosis should address the underlying cause of the thrombocytosis. In general, no treatment is indicated to directly reduce the platelet count. For patients with platelet counts in excess of 1,000,000/L, aspirin (antiplatelet aggregate) 65 mg daily may be considered to minimize the rare development of stroke or thrombosis.

Protein C Deficiency
Autosomal dominant Type I Quantitative
protein C antigen and activity levels that are approximately one half that of normal patient plasma

Type II Functional
associated with decreased functional activity and normal immunologic levels of protein C

Acquired Protein C Deficiency

Causes Acute thrombosis Warfarin therapy Liver disease Vitamin K deficiency Sepsis Disseminated intravascular coagulation (DIC) Certain chemotherapeutic agents (eg, Lasparaginase)

 development of a protein C autoantibody and hematopoietic stem cell transplantation A severe form, associated with purpura fulminans may be observed in patients with meningococcemia and other causes of severe sepsis

Venous Thromboembolism (VTE)

Cardinal sign of protein C deficiency Presents 7x more than those unaffected Risk factors: pregnancy, the postpartum state, hormonal therapy, surgery, or immobilization Common sites: lower extremities, elevated risk for mesenteric vein and cerebral sinus thrombosis 40% - evidence of pulmonary embolism

Warfarin-induced Skin Necrosis (WISN)

catastrophic complication of warfarin therapy that arises from the different halflives of the vitamin K-dependent proteins. The reduced level of protein C activity relative to these other procoagulant molecules creates a transient hypercoagulable state.

Warfarin-induced skin necrosis. Breast appearance 7 days, 4 weeks, and 2 and 6 months after start of warfarin for a PE. As soon as the diagnosis was made, wafarin was stopped, the INR reversed, and a different anticoagulant given (heparin at first, later LMWH)

 The skin lesions of WISN arise on the extremities, torso, breasts, and penis, which begin as erythematous macules and, if appropriate therapy is not initiated promptly, evolve to become purpuric and necrotic. Dermal biopsy demonstrates ischemic necrosis of the cutaneous tissue with cutaneous vessel thrombosis and surrounding interstitial hemorrhage

Neonatal Purpura Fulminans (NPF)

a life-threatening condition that occurs in newborns, usually during the first several days of life. Affected neonates present with diffuse ecchymoses. Skin biopsy demonstrates extensive thrombosis of cutaneous venous and arterial channels, much as is observed in WISN Laboratory testing reveals severe deficiency (< 1% of normal) of immunologic protein C levels.

Personal History
Is there a previous history of VTE? At what anatomic site? At what age did VTE occur? Were there any antecedent provoking factors, or did VTE occur spontaneously? Have there been previous thrombotic challenges that the patient has undergone without developing VTE? If so, at what age did these occur? Was thromboprophylaxis used? Has the patient been treated with anticoagulation in the past? Is there a history of WISN? Was there bleeding or other complications of anticoagulation therapy? Is there a history of pregnancy loss or other obstetric complications? At what gestational age did pregnancy loss occur? Was a cause of pregnancy loss ever identified?

Family History
Is there a family history of VTE? In which family member? At what anatomic site? At what age? Were there any antecedent provoking factors, or did VTE occur spontaneously? Have family members been treated with anticoagulation? Is there a family history of WISN? Is there a family history of pregnancy loss or other obstetric complications (eg, prematurity, preeclampsia, eclampsia)? At what gestational age did pregnancy loss occur? Was a cause of pregnancy loss ever identified? Is there a family history of NPF?

Management
VTE same management as DVT, compression stockings, ambulation, anticoagulant therapy, etc.. WISN - immediate discontinuation of warfarin,
administration of vitamin K, and initiation of therapeutic doses of heparin. administration of exogenous protein C, either in the form of fresh frozen plasma (FFP) or, preferably, as purified protein C concentrate (Ceprotin)

 NPF - Highly purified protein C concentrate (Ceprotin) represents an attractive alternative that does not subject patients to the high volume and protein load of fresh frozen plasma -After treatment of the acute phase of NPF, patients are transitioned to anticoagulation therapy, on which they must remain indefinitely. Warfarin may be used in this setting, provided that exogenous protein C is administered during its initiation in order to avoid the development of WISN.

Diet
patients on warfarin should consume a steady diet and avoid large day-to-day fluctuations in the amount of vitamin K they ingest.

Activity
There are no specific restrictions with respect to physical activity that are recommended for individuals with protein C deficiency. All individuals should ambulate regularly during prolonged travel to reduce the risk of VTE. Patients on anticoagulation therapy should avoid contact sports to reduce the risk of trauma and major bleeding.

Medications
1. Anticoagulants heparin, enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep), fondaparinux (Arixtra), warfarin (Coumadin) 2. Exogenous protein C used in the management of WISN and NPF Ex. Protein C Contentrate (Ceprotin) 3. Fresh Frozen Plasma (FFP) contains plasma components of whole blood

Prevention
Thromboprophylaxis should be considered for surgery, pregnancy and the puerperium, trauma, and prolonged air travel in individuals with heterozygous protein C deficiency, particularly if there is a strong family history of thrombosis.

Prevention of WISN
Large loading doses of warfarin (>5 mg/d) should be avoided. When warfarin is initiated, it should be overlapped with a parenteral anticoagulant such as unfractionated or low molecular weight heparin. The parenteral anticoagulant should be continued for at least 5 days and until the international normalized ratio (INR) measurement has been 2.0 or greater for at least 2 days

Protein S Deficiency
may be hereditary or acquired, the latter is usually due to hepatic diseases or a vitamin K deficiency. Protein S deficiency usually manifests clinically as venous thromboembolism (VTE).

 Acquired deficiencies of protein S occur with liver disease, vitamin K deficiency, or as a result of antagonism with oral warfarin anticoagulants. Protein S levels decrease in pregnancy and can fall into the abnormal-low laboratory range.

Deep Vein Thrombosis (DVT)

The most common manifestation is venous thrombosis of the lower extremities (90%) Superficial veins that are obviously thrombosed usually appear distended, firm, and noncompressible (cords), with or without associated redness or pain. Superficial thrombophlebitis can be observed in some cases, with or without DVT.

 Suspect DVT if identifying signs of venous obstruction and local inflammation are present on examination. The classic presentation of DVT is a triad of calf pain, edema, and pain on dorsiflexion of the foot (ie, Homans sign).

 In postphlebitic syndrome, chronic swelling and pain are present in the limb, and the occurrence of a new venous thrombosis is often impossible to assess without Doppler or venography.

Pulmonary Embolism
experience dyspnea, chest pain, syncope, or cardiac palpitations; tachypnea is the most frequent sign Some patients with massive pulmonary embolism can present with syncope or cyanosis. Classic pleuritic chest pain, cough, or hemoptysis suggests an embolism with pleural involvement. Acute right-sided heart failure occurs rarely and is associated with massive embolus.

Unusual sites of thrombosis (eg, mesenteric vein, cerebral sinuses) are rare (< 5%) but, when observed, characteristically suggest one of the inherited thrombophilias (eg, protein S deficiency).

Patient Education: anticoagulant tx

Take the prescribed amount of medication. Do not miss or add doses. Follow the health care practitioner's instructions closely about when to get lab tests for blood coagulation.

 Ask the health care pratitioner before starting or stopping any medication, including over-the-counter medications. Many medicines increase or otherwise interfere with the effect of anticoagulants. Ask what foods should be avoided, because some foods may change the effectiveness of blood-thinning drugs.

 Wear a Medic-alert bracelet with information about any anticoagulants you are taking. Inform any other medical professionals including dentists or podiatrists that you are taking an anticoagulant before undergoing any procedure.

Thank you!!
Good Day!