EM guidemap - Hemophilia

Introduction

Clinical presentation

Medical decision-making Appendix
Introduction
- with the advent of home therapy of hemophilia, ED physicians are seeing fewer hemophiliac patients in the ED => consequently, they may not easily remember all the details relating to the acute management of bleeding emergencies in a hemophiliac patient
- this guidemap will provide an ED physician with some basic information about hemophilia, and will also allow an ED physician to rapidly navigate to the relevant section of the guidemap for a 'quick-look' at reference guidetables/dosage calculators

- there are two types of hemophilia - type A (factor VIII deficiency) and type B (Chistmas disease - factor IX deficiency) - and type A hemophilia is 4 - 8x more common than type B

- these two inherited factor deficiencies account for > 90% of all inherited coagulation factor deficiencies (excluding von Willebrand's disease)

- both conditions present with the same pattern of bleeding complications and they cannot be clinically differentiated

- petechiae and minor mucosal bleeding are uncommon, while easy bruisability and bleeding into joints and muscles and fascial spaces are much more common, and bleeding from deeper wounds may be continuous, recurrent or delayed

- both conditions cause an abnormally elevated PTT, and they can only be differentiated by serum factor VIII and IX activity level assays

- both diseases are most commonly inherited as sex-linked (X chromosome) genetic diseases and they therefore manifest clinically in males, although 20 - 30% of cases of hemophilia A cases are due to sporadic genetic mutations (non-familial type), which can occur in any family at any time

- the severity of hemophilia varies considerably, and the severity tends to run 'true-to-form' within a particular family showing remarkable consistency from generation-to-generation

- classification of severity of hemophilia based on factor VIII levels:-
 

Clinical severity of hemophilia
Disease severity Factor VII levels Clinical manifestations
Severe < 1% Spontaneous bleeding common, bleeding common with even minor trauma or minor surgery
Moderate 1 - 5% Spontaneous bleeding uncommon, bleeding common with minor or major trauma/surgery
Mild 5 - 30% Bleeding with major trauma or surgery only

- approximately 60% of cases are severe, 15 % are mild and 15% moderate

Clinical presentation

- severe hemophilia presents within the first year of life with unusual bleeding following minor trauma (eg. circumcision) or as joint hemarthrosis or muscle hematoma/sc bleeding when the toddler starts to walk-and-fall

- mild hemophilia may only present later in life with unusual or continuous bleeding following surgery or major trauma, and an abnormal PTT alerts the treating physician to a possible underlying coagulopathy

(* the PTT may lack sensitivity in this sub-group of mild hemophilia patients, because the PTT is only significantly prolonged when the factor VIII levels are < 30 - 40%)

Hemarthrosis

- bleeding occurs spontaneously into joints during the acute stage causing distension of the synovial space and synovial ischemia

- the commonest joints involved are (in order of frequency) the knees, elbows, ankles, shoulders and wrists

- patients can often tell when spontaneous intra-articular joint bleeding is occurring and they may become aware of a warm tingling sensation ("aura") in the joint before any clinical manifestations become apparent

(* the treating physician should always believe patients who state that they are bleeding into their joints, even if there are no clinical signs of a hemarthrosis - empirical factor VIII replacement therapy should always be administered early - when the patient experiences the "bubbling-feeling aura")

- often a single dose of replacement factor therapy (to achieve serum factor VIII activity levels of > 30 - 50%)  is sufficient, although repeat doses may be necessary prn if the joint is still painful and swollen the next day => the patient should be seen at the HTC if the bleeding episode does not resolve in 3 days => refractory hemorrhages may require 3 - 5 days of therapy

(* weight-bearing should be avoided and ice packs/splinting used prn; avoid joint aspiration => consult the HTC if the joint is grossly distended requiring aspiration; X-rays are only required for possible fractures following significant trauma)

- early treatment may cause resolution of the bleeding and re-absorption of the blood, although incomplete blood resorption is common and persistent blood products often cause a chronic synovitis => swollen, tender and painful joints for months/years

(* the patient's joints may become chronically swollen and it may not be possible to differentiate an acute bleed from a chronic hemophiliac arthropathy - because the joint often does not appear red or warm with an acute bleed)

- recurrent bleeds cause synovial proliferation (villonodular synovitis) and the proliferated synovium is friable and predisposed to recurrent bleeding => cycle of progressive joint bleeding and progressive damage => subchondral ischemia and hyaline cartilage loss, subchondral cysts and ankylosis  => chronic hemophiliac arthropathy (which is very disabling)

Muscle bleeds

- may occur spontaneously or following minor injuries

- often a group of muscles, rather than a single muscle, is involved and the condition may be occult and not readily apparent => minor intra-muscular bleeds are often misdiagnosed as a minor muscle strain

- a hemophiliac patient should not simply be treated symptomatically for a presumed "pulled" muscle, and sufficient factor VIII replacement therapy should be administered to achieve serum factor VIII activity levels of  > 40% for 1 - 2 days if the diagnosis is uncertain

- always consider the possibility of compartment syndrome in extremely painful intramuscular bleeds,especially if the degree of muscle swelling/discomfort is progressive or unrelenting, or if the patient develops symptoms suggestive of a compressive neuropathy eg. femoral nerve palsy secondary to a bleed in the ilio-psoas muscle => numbness and tingling in the antero-lateral thigh is an early symptom => consult an orthopedist and admit the patient to hospital for observation

- serum factor VIII activity levels should be raised to 70 - 100% for 3 - 5 days in limb-threatening muscle bleeds

- hemorrhage into the retroperitoneal muscle compartment may present with non-specific back pain (and shock if a retroperitoneal bleed is not promptly diagnosed)

- bleeding into the right iliopsoas muscle may mimic appendicitis, and a CT scan should be liberally performed to exclude bleeding in any hemophiliac patient presenting with signs suggestive of appendicitis

- bleeding into the psoas muscle may also mimic a bleed into the hip joint => CT scan or MRI may be required to differentiate the two entities

(* a mass may be palpable in the groin due to an iliopsoas bleed; a patient with a large hip hemarthrosis may have a positive "leg-roll" test)

- a patient with an iliopsoas bleed needs to be admitted to hospital => loading dose of factor VIII/IX to achieve 100% correction => 50% of that dose q12 hourly for 2 - 3 days => then daily

- bleeding into the retropharngeal space may cause dysphagia and a potential airway emergency if not rapidly diagnosed and treated

- all patients with a retropharyngeal or retroperitoneal bleed should be admitted and have sufficient factor VIII replacement therapy to achieve serum factor VIII activity levels of 100% as soon as possible and the levels should be kept high for 3 - 5 days after bleeding ceases

Skin wounds

- minor abrasions and skin tears may be treated symptomatically +/- local hemostatic agents eg. surgicel and pressure dressings without factor VIII replacement therapy

- replacement therapy is required for all lacerations requiring suturing (and repeated when the sutures are to be removed) and steristrips/skin adhesives should preferably be used to avoid any tissue damage

- larger lacerations may require daily factor VIII replacement therapy to maintain serum levels > 20% while the wound is healing

Oral bleeding

- minor gingival oozing can be treated with topical hemostatic agents (Avitene) and anti-fibrinolytic therapy

- factor replacement therapy is indicated if bleeding persists for > 30 minutes or "stop-and-start" bleeding occurs => administer a one-time dose of factor replacement therapy + amicar

- dental anesthetic infiltration into firm tissue or intrapulpal tissue can be given without factor VIII replacement therapy, but regional blocks require factor VII replacement therapy - to achieve serum factor VIII activity levels > 40%

- large lacerations and excessive mucosal bleeding usually require a single dose of factor VIII replacement therapy to achieve serum factor VIII activity levels > 40%

- patients with tongue lacerations and large bleeds should be hospitalised for observation and repeat factor VIII replacement therapy prn

- gingival oozing after dental work can be treated with anti-fibrinolytics for 3 - 5 days, while EACA (Amicar) or tranexamic acid (Cyklokapron) should be given for 7 - 10 days following dental  extractions (EACA - 200 mg/kg po initially and then 100mg/kg po q 6h to a maximum of 24g in 24 hours; tranexamic acid - 25 mg/kg po tid)

(* EACA should be given regularly every 6 hours around-the-clock to ensure clot stability; EACA may not be stocked in local pharmacies and it may be necessary to obtain EACA from the hospital pharmacy; a tranexemic mouth wash can be prepared by pharmacy by diluting the 10% IV solution with an equal volume of saline solution)

- anti-fibrinolytics are contra-indicated in the presence of hematuria or when using prothrombin concentrates (may cause thrombosis)

- a soft diet and the avoidance of drinking through a straw is advisable

Gastro-intestinal bleeding

- minor GIT bleeding is uncommon in the absence of local pathology => hospitalisation and routine diagnostic endoscopy is highly recommended

- serum factor VIII activity levels should be raised to 100% initially and then > 30% until healing occurs

Genito-urinary bleeding

- very common and microscopic hematuria does not imply local identifiable pathology

- factor VIII replacement therapy is indicated to achieve serum factor VIII levels of 100% initially and then > 30% until healing occurs

- empiric steroids (prednisone - 2 mg/kg) are often used concurrently for 2 days in patients with idiopathic hematuria

- anti-fibrinolytics are contraindicated because they may cause blood clotting within the ureter => ureteral obstruction

- consult an urologist to exclude other causes of hematuria

Epistaxis

- minor nosebleeds will often stop spontaneously if local pressure is applied => use topical phenylephrine or oxymetazolone spray prn if minor bleeding persists and re-apply pressure

- topical surgicel or Avitene can be applied for continued oozing, and packing with epinephrine-soaked vaseline gauze may occasionally be necessary

(* avoid nasal packing if at all possible; cautery is contra-indicated)

- replacement factor VIII therapy is used for continued bleeding, and when any necessary nasal packing is removed

- replacement therapy should achieve a serum factor VIII activity level > 40% and repeat therapy given prn

- only a single dose of replacement therapy is required for mild bleeds  => anti-fibrinolytics may also be used for 5 days

Intracranial hemorrhage

- ICH is the leading cause of death and the risk is 2 - 3%/year

- the most common sites of bleeding are subarachnoid (33%), intracerebral (33%) and subdural (23%)

- 50% of adult patients have no history of a head injury and prophylactic factor VIII replacement therapy is indicated when a hemophiliac patient has a severe unexplained headache lasting > 4 hours, any focal neuro signs, or empirically following any minor head injury

- treat presumptively first => perform a complete clinical evaluation and further diagnostic studies after the initiation of factor replacement therapy

- a CT scan should be liberally ordered in all hemophiliac patients with minor head trauma, any new or persistent headache, or any abnormal CNS signs - after the administration of factor VIII/IX replacement therapy

- factor VIII replacement therapy should be given immediately to achieve a serum factor VIII activity level of 100% and maintained at high activity levels (50 - 100%) for 10 - 14 days by 12 hourly IV boluses or a continuous IV infusion

- appropriate laboratory monitoring is essential to document that hemostatic levels of coagulation factor have been achieved => a post-infusion aPTT and factor assay should be performed to document that an adequate factor level has been attained

- if the patient has evidence of an ICH on CT scan or abnormal neurological symptoms => admit the patient to hospital for continued replacement therapy

(* head injury infants may only present with irritability or nausea/vomiting; factor replacement therapy should be given for 3 - 5 days if the patient has post-concussion symptoms and a negative CT scan => head injury instructions should be followed for two weeks after the head injury)

- the same approach should be adopted in patients with a possible/suspected intra-spinal hemorrhage

- if a lumbar puncture needs to be performed, serum factor VIII activity levels should be raised to > 40% of normal ~ 45 - 60 minutes prior to the procedure

Trauma

- major tauma requires aggressive coagulation factor replacement therapy - give a stat dose of factor VIII (50mg/kg) or factor IX (80mg/kg) => measure the aPTT 10 minutes after replacement => give factor VIII (25mg/kg) every 4 hours and then every 6 hours for the first 24 hours, or factor IX (40mg/kg) every 8 hours initially and then every 12 hours + consult a HTC (or transfer to a HTC capable of performing coagulation factor assays around-the-clock)

- maintain a baseline coagulation factor level of 50% until the bleeding cases and wound healing is complete (10 - 14 days minimum)

Fractures

- give a stat dose of 50mg/kg of factor VIII and then 25mg/kg q 12 hourly until the swelling has gone down in 2 - 3 days, then daily for 7 days or until the fracture is stable

(* give a stat loading dose of 80mg/kg of factor IX and then 40mg/kg of factor IX daily for 7 days)

- give factor replacament at the time of any fracture manipulation or cast removal

- do not use use a circumferential cylindrical cast for the first 2 - 3 days => use a bi-valve splint

Medical decision-making and factor VIII/IX replacement therapy

- if a bleeding patient has no previous history of hemophilia and a prolonged aPTT is corrected by normal serum => perform an assay for factor XIII activity => if negative => perform an assay for factor IX activity

(* an acquired inhibitor to factor VIII or IX can be ruled out by mixing patient plasma with normal plasma (mixed aPTT) and demonstrating a correction of the aPTT; the bleeding time and PT are normal in hemophilia)

- information cards should be kept in the ED on all hemophiliac patients in the local area and the cards should contain information about:-

- IM injections are contra-indicated and parenteral agents should be given sc or IV

- peripheral venipuncture is safe, but the smallest IV needles should be used for vascular access

- factor VIII replacement therapy is required prior to any central venous catheterisation or arterial puncture

- tight arm tourniquets should not be applied

- aspirin, or any agents that inhibit platelet aggregation, should not be administered

Hemophiliacs should never wait to be seen - evaluation and treatment must begin immediately

If there is any clinical suspicion of a bleed, the appropriate factor replacement product should be administered immediately - before clinical evaluation is completed and diagnostic procedures initiated

(* if factor replacement is not available => immediately transfer the patient to a hemophilia center and do not delay transfer to perform diagnostic studies)

- contact the patient's hematologist (or HTC) immediately if a life-threatening bleed occurs; and prior to discharge for minor bleeds in order to coordinate follow-up factor doses and further management

Factor VIII replacement therapy

- it is appropriate to allow families to use their own factor VIII replacement agents

- DDAVP (desmopressin) is often used in mild hemophiliacs, who are known to increase their serum factor VIII activity levels > 3x in response to DDAVP treatment (as previously documented by elective testing)

- the dose = 0.3 mcg/kg in 30 - 60 ml of normal saline over 15 - 20 minutes IV with an expected peak effect in 30 - 60 minutes

- concentrated nasal spray has similar efficacy to IV desmopressin, but the peak effect is delayed (60 - 90 minutes)

(* one nasal spray for patients < 50 kg and two nasal sprays for patients > 50 kg)

- the half-life of DDAVP is 6 hours and the dose has to be repeated q 12 hourly prn

- several doses of desmopressin can be given before tachyphylaxis occurs, and responsiveness to DDAVP usually recovers within a few days

- mild/moderate total fluid restriction and close monitoring of the urine output is required during desmopressin therapy, because it may cause water intoxication and hyponatremia (especially in infants)

- desmopressin may cause arterial thrombosis and AMI/CVA in elderly patients and caution should be exercised

- desmopressin is only of value in the mild hemophiliac patient and factor VII replacement therapy will be required in the moderate-severe hemophiliac patient

The mainstay of successful hemophilia treatment is the prompt IV administration of sufficient amounts of factor VIII/IX to obtain and maintain hemostatic levels

- state-of-the-art replacement therapy consists of plasma-derived or recombinant proteins

(* cryoprecipitate should only be used in the HIV negative patient if factor VIII concentrates are not available - each bag of cryoprecipitate contains ~ 100 units of factor VIII)

- there is a wide variability among replacement products with respect to final product purity - defined as units of specific activity (SA) /mg protein

(* see the appendix for a list of  factor VII/IX replacement products available in the USA)

- one unit of factor VIII replacement/kg raises the plasma level by ~ 2%, and one unit of factor IX replacement/kg raises the plasma level by 1%

- the dosage does not need to be exact, but it should be closely approximated - it is also not harmful to administer a reasonable excess of the replacement factor
 

(* see the appendix for a table of pre-calculated dosages of factor replacement; use the complete vial and never discard any vial contents)

- factor VIII's disappearance from the blood stream is biphasic and the serum half-life is ~ 12 hours, while the serum half-life of factor IX is ~ 24 hours => factor VIII is usually administered every 6 - 12 hours, and factor IX every 12 - 24 hours, depending on the severity of the bleed

- because there is considerable variation in plasma factor VIII/IX recovery, extensive laboratory evaluation will be required in situations of ongoing major bleeding when more precise serum levels are required to ensure hemostasis

- the desired serum factor VIII/IX activity level depends on the type and extent of bleeding

- in general, a 30 - 50% serum factor VIII activity level is required for most bleeding episodes of lesser severity and 1 - 3 doses of factor VIII replacement are usually sufficient to stop the bleeding

- however, 50 - 100% of normal levels are required to treat limb-threatening or life-threatening hemorrhages, and hospitalisation is usually required for prolonged in-hospital therapy (3 - 14 days) - either by intermittent IV bolus therapy every 6 - 12 hours, or by continuous IV infusion

Guidelines for factor replacement therapy in hemophilia A and B
Site of bleed Desired hemostatic factor level Dose of factor A Dose of factor B
Joint 30 - 50% minimum 20 - 40 U/kg qd prn 30 - 40 U/kg qd prn
Muscle 40 - 50% minimum 20 - 40 U/kg prn 40 - 60 U/kg prn
Oral mucosa Initially 50%, then give antifibrinolytics 25 U/kg 50 U/kg
Epistaxis Initially 80 - 100% then 30% until healing occurs 40 - 50 U/kg then 30 - 40 U/kg qd prn 80 - 100 U/kg then 70 - 80 U/kg qd prn
Gastro-intestinal Initially 100% then 30% until healing occurs 40 - 50 U/kg then 30 - 40 U/kg qd prn 80 - 100 U/kg then 70 - 80 U/kg qd prn
Genito-urinary Initially 100% then 30% until healing occurs 40 - 50 U/kg then 30 - 40 U/kg qd prn 80 - 100 U/kg then 70 - 80 U/kg qd prn
CNS Initially 100% then 50 - 100% for 10 - 14 days 50 U/kg then 25 U/kg q 12h 100 U/kg,then 50 U/kg q 24h
Trauma or surgery Initially 100% then 50% until wound healing begins,then 30% until wound healing complete 50 U/kg then 25 - 50 U/kg q 12h prn 100 U/kg then 100 U/kg q 24h

- hemophilic patients may have antibodies to factor VIII (occurs in 20 - 33% of hemophilia A and 1 - 4% of hemophilia B patients)

- antibody levels are expressed in "bethesda units" - BU

- patients with low BU titres  (<  10 BU) are usually treated with high doses of factor VIII (200 - 300 units/kg) by initial bolus and more frequent doses prn; or high-dose continuous IV infusion at ~ 1,000 units/hour)

- however, a high titre of anti-factor VIII antibody (> 10 BU) precludes high-dose therapy, and either temporary removal of factor VIII antibody by plasmapheresis or the use of porcine factor VIII (Hyate:C) is required

- other approaches to patients with high titres of anti-factor VIII antibody include using aPCCs (activated prothrombin concentrates) in doses of 75 - 100 units/kg repeated q 12 - 24 hourly

- using aPCC is known as "bypass therapy" because these concentrates bypass the requirement for factor VIII/IX for clot formation

- recombinant factor VIIa is presently undergoing clinical trials as an alternative to aPCC in bypass therapy; and it has no risk of viral transmission with less thrombogenic potential

- the treatment of patients with inhibitors is complex and should only occur at HTCs under the guidance of a specialist in bleeding disorders

Appendix

Factor VIII replacement products available in the USA

Low purity (SA < 5 U/mg protein)

Intermediate purity (SA 1 - 10 U/mg protein) High purity SA 50 - 1,000 U/mg protein) Very high (ultra) purity (SA - 3,000 U/mg)

    Plasma-derived , monoclonal antibody-purified

    Recombinant Factor IX replacement products available in the USA

Low purity

High purity Factor replacement dosage chart calculator:

- to calculate the number of units of factor VIII replacement needed  (double the dose for factor IX)
 

% increase of circulating factor desired
Weight 10% 15% 20% 25% 30% 40% 50% 60% 70% 80% 90% 100%
20 lbs 45 68 91 114 136 182 227 273 318 364 409 455
30 lbs 68 102 136 170 205 273 341 409 477 545 614 682
40 lbs 91 136 182 227 273 364 455 545 636 727 818 909
50 lbs 114 170 227 284 341 455 568 682 795 909 1023 1136
60 lbs 136 205 273 341 409 545 682 818 955 1091 1227 1363
70 lbs 159 239 318 398 477 636 795 955 1114 1273 1432 1590
80 lbs 182 273 364 455 545 727 909 1091 1273 1455 1636 1818
90 lbs 205 307 409 511 614 818 1023 1227 1432 1636 1841 2045
100 lbs 227 341 455 568 682 909 1136 1364 1591 1818 2045 2273
110 lbs 250 375 500 625 750 1000 1250 1500 1750 2000 2250 2500
120 lbs 273 409 545 682 818 1091 1364 1636 1909 2182 2455 2727
130 lbs 295 443 591 739 886 1182 1477 1773 2068 2364 2659 2955
140 lbs 318 477 636 795 955 1273 1591 1909 2227 2545 2864 3182
150 lbs 341 511 682 852 1023 1364 1705 2045 2386 2727 3068 3409
160 lbs 364 545 727 909 1091 1455 1818 2182 2545 2909 3273 3636
170 lbs 386 580 773 966 1159 1545 1932 2318 2705 3091 3477 3864
180 lbs 409 613 818 1023 1227 1636 2045 2455 2864 3273 3682 4091
190 lbs 432 648 864 1080 1295 1727 2159 2591 3023 3455 3886 4318
200 lbs 455 682 909 1136 1364 1818 2273 2727 3182 3636 4091 4545

(* presume that the serum factor VIII activity level is zero - if the actual level
is not known in a particular patient)

Disclaimer: My EM guidemaps reflect my personal approach to problem-solving/managing clinical cases in an ED setting and they should not be regarded as the standard of care. They merely represent the personal opinions of the author and they should only be used in clinical practice if the reader-user has substantial reason to believe that the clinical advice contained in the guidemaps is valid and accurate. The guidemaps are not meant to be "authoritative" and the reader-user should consult standard medical textbooks and expert opinion articles/guidelines for more authoritative advice. The reader-user should particularly confirm all drug doses, their indications and contra-indications, prior to their use.