Bleeding disorder resident survival guide

Bleeding disorder Resident Survival Guide
Overview
Causes
Diagnosis
Management
Dos
Don'ts

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Javaria Anwer M.D.[2]
Synonyms and keywords: Approach to bleeding diathesis, Bleeding diathesis workup, Bleeding diathesis management

Overview

A bleeding disorder can be due to coagulopathy, platelet dysfunction, or vessel pathology. They can be genetic or acquired. History of the site, duration, associated symptoms, and a thorough physical exam to evaluate the type of bleeding (subcutaneous vs deep tissue) are essential to diagnosis. Screening tests include CBC with peripheral blood smear, platelet count, PT, aPTT, PFA-100. Management depends upon the type of disorder, severity, and active bleeding. Plasma exchange, fresh frozen plasma, and factor replacement are the main treatment options available. The initial clinical impression based on the baseline screening tests should direct specialized laboratory tests to save time, effort, and money.

Causes

Common causes of bleeding (bleeding disorders) are enlisted below.

Causes of bleeding disorders

Platelet disorders

Coagulopathy

Vessel/ Supporting tissue defect

Acquired

Genetic

❑Aging ❑Corticosteroid use

❑ Myeloproliferative disorders ❑ Uremia ❑ Drugs (NSAIDs, asprin, clopidogrel, etc.) ❑ Neoplasia ❑ Monoclonal gammopathies ❑ DIC ❑ Ehrlichiosis ❑ Retroviral infection ❑ Snake venom ❑ Cirrhosis

❑ Glanzmann's thrombasthenia ❑ Bernard-Soulier syndrome ❑ Von Willebrand's disease

Genetic

Acquired

Prothrombotic

❑ Prohemorrhagic liver diseases ❑ Vitamin K deficiency ❑ Drug-induced such as warfarin and heparin ❑ Hemodilution and massive transfusion ❑ Disseminated Intravascular Coagulation (DIC) ❑ Immunoglobulin mediated Factor Deficiency (VIII, V, XIII, X) ❑ Hyperfibrinolysis ❑ Venom induced

❑ Heparin Induced Thrombocytopenia ❑ Antiphospholipid Antibody Syndrome ❑ Microvascular Thrombosis (warfarin induced skin necrosis)

Hemorrhagic disorders

Hypercoaguable disease

❑ Factor VIII deficiency (Hemophilia A) ❑ Factor IX Deficiency (Hemophilia B) ❑ Von Willebrand factor deficiency ❑ Factor XI deficiency (Hemophilia C) ❑ Factor II, V, VII, X deficiency (Common Pathway Proteins) ❑ Factor XIII deficiency and fibrinogen deficiency

❑ Antithrombin III deficiency ❑ Protein C deficiency and protein S deficiency

Diagnosis

The algorithm illustrates the approach to the diagnosis of bleeding disorder.
Abbreviations: HEENT: Head, Eyes, Ears. Nose, and Throat exam; CBC: Complete blood count; APTT Partial thromboplastin time; CMP: Comprehensive metabolic panel; LFTs:Liver function tests
Boxes in red signify that an urgent management is needed.

History ❑ Demographics: Patient age, gender,and race to screen for inherited disorders. ❑ Bleeding history: ❑ Onset of bleed: Differentiate between spontaneous vs post-trauma or post-surgery bleed. Post-trauma may suggest an inherited bleeding disorder. ❑ Duration of bleed: Lifelong vs recent. coagulation factor defect. ❑ Type and site of bleed (skin or muscle): Petechiae, purpura, epistaxis, gingival bleeding, and bruises may suggest a vascular or platelet abnormality. Joint or muscle bleed may suggest coagulation factor abnormality. ❑ Past medical history: For the underlying disease. History of blood or blood components transfusion. Childhood history of epistaxis, bleeding post-circumcision, and umbilical stump bleeding may suggest an inherited bleeding disorder. ❑ Past surgical history: May reveal post-surgical bleed such as after a tooth extraction. History of poor wound healing. ❑ Drug history: For the drugs causing bleeding. Distinguish between drug induced thrombocytopenia and idiopathic thrombocytopenic purpura, or other forms of thrombocytopenia. ❑ Family history: Certain bleeding disorders. Consanguineous marriage history. ❑ Gynaecological history: Menorrhagia or hematuria may suggest vascular or platelet abnormality.

Physical exam Appearance of the patient Petechie, bruises, or hemorrhages ❑ Vital signs: Temperature; heart rate (tachycardia with regular pulse may demonstrate hypovolemia); respiratory rate, blood pressure (hypotension); and oxygen saturation may be low due to anemia. ❑ Assess the sites and severity of the bleeding. ❑ Assess if the bleeding is due to systemic disorder, local defect, or hemostatic disorder; inherited or acquired; platelet abnormality, coagulation disorder, or vascular defect. ❑ HEENT ❑ Cardiovascular examination ❑ Respiratory examination ❑ Gastrointestinal system exam includes oral examination, abdominal examination, and digital rectal exam. ❑ Extremities exam ❑ Skin exam: Evaluate for petechie, bruises, hemorrhages. Location, symmetry, and pattern are important.

Screening Labs ❑ CBC with differential ❑ Platelet count ❑ Prothrombin time (PT) ❑ APTT ❑ Peripheral smear ❑ Thrombin time ❑ Bleeding time/ PFA-100

Soft tissue hematoma, deep internal hemorrhage, hemarthrosis

Superficial cutaneous or mucous membrane bleeding

PT normal, aPTT prolonged

PT prolonged, aPTT normal

PT prolonged, aPTT prolonged

Low platelet count

Normal platelet count

❑ Factor VIII, factor IX, factor XI, factor XII, and prekallikrien deficiency ❑ Von Willebrand Disease ❑ Heparin contamination ❑ Lupus anticoagulant

❑ Factor VII deficiency ❑ Vitamin K deficiency ❑ Early anticoagulation therapy

❑ Check thrombin time

❑ Idiopathic Thrombocytopenic Purpura (ITP) ❑ Hereditary platelet disorder ❑ Bone marrow failure

Check PFA-100

Prolonged

Normal

Prolonged closure time

Normal

❑ Fibrinogen deficiency ❑ Liver disease ❑ Heparin

❑ Factor II, factor V, factor X deficiency ❑ Vitamin K deficiency ❑ Liver disease

❑ Full blood count ❑ vWF screen ❑ Platelet function testing

High clinical suspician

❑ vWF screen ❑ Platelet function testing (required to exclude abnormal platelet function)

Management

The following tables illustrate the treatment to common bleeding disorders.

Disorder	Labs	Treatment
Factor VII deficiency	Measure factor VII coagulant activity for isolated prolonged PT Diagnosis is confirmed with a repeat factor VII assay	Consider the type (such as type I: quantitative defects, type II: qualitative defects, for the management. Replacement therapy: Recombinant FVIIa (rFVIIa) is most used. Median dosage of 60 μg/kg is safe for bleeding such as hematomas, hemarthrosis, and epistaxis.
Hemophilia A and Hemophilia B	Factor VIII and factor IX assay	Factor VIII concentrate (20-50 IU/ml) BPAs (bypass agents) help get around factor VIIa and Factor IX to generate thrombin. Immune tolerance induction (ITI) is the standard of care for inhibitor eradication predominantly among patients with severe hemophilia A.
Factor X deficiency	Prolonged PT and APTT Factor X levels	No specific factor X replacement product is yet readily available. Bleeding or surgery preparation: Administer fresh frozen plasma and prothrombin complex concentrates.
Hemophilia C	Factor XI assay	Fresh frozen plasma Factor XI is rarely required
Von Willebrand disease	Factor VIII, Protein C, VWF Ag, VWiCof	Bleeding prevention: 0.3 mcg/kg desmopressin acetate (DDAVP), 90 min before surgery helps prevent bleeding (increases the level of VWFAg and factor VIII to normal). Minor bleed: desmopressin acetate is the first-line agent. Tranexamic acid can be used. Major bleed: Replacing VWF and utilizing plasma-derived products. Antifibrinolytic drugs may be utilized as a hemostatic adjunct. Transfuse platelets only if other treatments fail. Factor VIII concentrates and plasma products also help overcome bleeding.
Microangiopathic hemolytic anemia	Platelet count] (also look for the clinical signs such as neurological deficits among TTP and renal dysfunction among HUS patients.	Total plasma exchange, cryoprecipitate lacking HMV VW multimers. 0.4 mg/kg IVIG for five days with a target platelet count to be 80,000. Among pregnant females with TTP/ HUS administer FFP and avoid RPR.
Glanzmann's thrombasthenia	Platelet aggregation assays. Confirmed through flow cytometry. To read more about diagnosis click here	Desmopressin (DDAVP): Increases the levels of tissue plasminogen activator (tPA), FVIII, and von Willebrand factor (VWF) in plasma. Rituximab Hematopoietic stem cell transplantation Gene therapy Platelet transfusion To read more about the treatment, click here.
Bernard-Soulier syndrome	PFA-100 is used for screening. Prolonged bleeding time.	Supportive care. Pharmacotherapy for bleeding episodes such as tranexamic acid or ε-aminocaproic acid, platelet transfusion, and Desmopressin (DDAVP). To read more about the management click here.
Thrombocytopenia of pregnancy	Platelet count	Mild: Corticosteroids Severe: Intervenous methyl prednisolone.
SLE	Platelet count	RPR
Liver disease	LFTs, APTT, platelet count	Vitamin K if the patient has vitamin K deficiency. Treat per deficiency.
Antithrombin III deficiency	Antithrombin III levels	Anticoagulants Antithrombin concentrate
Protein C deficiency	Functional assays such as aPTT based assay, factor Xa based anzymatic assay to determine the function of protein C. Antigenic determination of protein C levels.	Pharmacotherapy is recommended among patients with Warfarin-induced skin necrosis, neonatal purpura fulminans and pulmonary embolism. To read more about the treatment click here.
Protein S deficiency	Free protein S antigen (most reliable of the three tests). ELISA technique Total protein S antigen Protein S activity assay (not very reliable due to the inability to differentiate from factor V Leiden mutation; resistance to activated protein C). To read more about the diagnosis click here.	Asymptomatic patients with no history of venous thromboembolic events do not require medical therapy. An acute event of venous thrombosis requires the same initial medical therapy regardless of the cause being hereditary or not. To read about the management of patients of pulmonary embolism, click here. To read about the management of patients of deep venous thrombosis, click here. Patients with protein S deficiency suffering from a venous thromboembolic event are advised to continue anticoagulation indefinitely especially for unprovoked events (occurred without a preceding major risk event like surgery, trauma, oral contraceptives, and immobility). To read more about the treatment click here.

Dos

• A study by Wahlberg et al. demonstrated that the patient's perception of his/her own bleeding may be understated or exaggerated, so labs are vital in the assessment of bleeding disorders.
• The initial clinical impression based on the baseline screening tests should direct specialized laboratory tests to save time, effort and money.

Don'ts

• It is important to not miss the genetic workup for a diagnosed bleeding disorder.
• A bleeding disorder may present as anemia so common signs/ complaints should not be missed.

References