Rare Bleeding Disorder

Hemophilia: 

Hemophilia is a genetic disorder characterized by a deficiency or absence of one of the clotting proteins in plasma, resulting in delayed clotting.  

Deficiencies of factor VIII (8) [Hemophilia A or Classic Hemophilia] and factor IX (9) [Hemophilia B or Christmas Disease] are the most common and referred to as hemophilia.  

Persons with hemophilia do not bleed faster than others; rather the bleeding is continuous. Significant blood loss can occur if treatment is delayed. 

Hemophilia mostly affects males due to the X-linked inheritance pattern. The incidence worldwide is estimated to occur in 1:7,500 live male births; all races and ethnic groups are affected. Factor VIII (8) deficiency is four times more common than factor IX (9) deficiency but the clinical presentations and inheritance patterns are the same.  

Basics 

Serious bleeding sites 

The six major sites of serious bleeding which threaten life, limb, or function are: 

  • Intracranial 
  • Spinal cord 
  • Throat 
  • Intra-abdominal 
  • Limb compartments 
  • Ocular 

Acquired Hemophilia A: 

  • Acquired hemophilia is an auto-immune disease caused by autoantibodies to FVIII, which result in FVIII deficiency and a bleeding tendency1 
  • 1-1.5 per million persons are affected yearly1 
  • Acquired hemophilia must be treated quickly and effectively because: 
  • Fatal bleeds may occur at any time until the inhibitor has been eliminated2, with up to 21% mortality rate3 
  • 70% of AH patients will experience a life-threatening bleed4 
  • Increased frequency in young women of childbearing age who are between 20 and 40 years old2, increase associated with postpartum bleeding2 
  • General increase in acquired hemophilia with age among males and females, especially in individuals aged 60 years and older2 
  • ED physicians are in a unique position to affect outcomes of acquired hemophilia patients who present to the ED 
  • Higher awareness of AHA may lead to earlier diagnosis and improved outcomes 

 For additional information on Acquired Hemophilia (AH) click here 

Von Willebrand Disease: 

  • VWD is the most common congenital bleeding disorder with a prevalence of 1:100 to 1:1000 
  • Bleeding symptoms can vary depending on severity and type of VWD 
  • Bleeding symptoms are commonly mucocutaneous (e.g. epistaxis, gingival, gastrointestinal, genitourinary, uterine/menorrhagia) and can occur with invasive procedures (dental extractions, surgery) and childbirth. 

References 

1 Guidelines for Emergency Department Management of Individuals with Hemophilia and Other Bleeding Disorders. National Hemophilia Foundation. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/Guidelines-for-Emergency-Department-Management-of-Individuals-with-Hemophilia. Published March 28, 2014. Accessed February 9, 2018. 

2 https://caep.ca/resources/ctas/implementation-guidelines 

3 Canadian Hemophilia Society http://www.hemophilia.ca/en/care-and-treatment/emergency-care/ 

4 Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al; Treatment Guidelines Working Group on Behalf of the World Federation of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-e47.

 

Authors

Eddy Lang, MDCM- CCFP(EM)-CSPQ
Michel Le May, BSc, MD
Mark Mensour, MD CCFP EM ANAES FCFP

 

Acquire Hemophilia A #1

  • 77 y/o female presents with a painful buttock bruise. 
  • Lost her footing after getting out of the shower and tripped over the bathroom counter, immediately painful. 
  • Wasn’t sure about coming into hospital but bruise seemed large. 
  • May have taken ASA 2 days earlier for headache. 
  • No history of bleeding tendencies. 
  • Examination
  • Actions

Initial Visit: 

NIDDM  

  • HTN 
  • Dyslipidemia 
  • Medications: metformin, Ramipril 
  • Allergies: NKA 
  • Tried ASA for primary prevention years earlier – didn’t like skin effects 
  • O/E 
  • VS Normal 
  • Large 15 X 20cm buttock hematoma, superficial, no collection. No other bleeding stigmata. 

Return Visit (Day 2) 

  • Hematoma has grown, extensive bruising involving entire buttock and tracking down thigh to lower leg, increasingly painful. 
  • Exam now shows large fluctuant hematoma. Rest of exam normal. 
  • Labs: PT/INR, CBC normal, Hgb: 120 

Initial Management: 

Traumatic hematoma => expectant management. F/u as needed  

Return Visit Management 

  • Hematoma evaluation performed with 150 cc removed through 5cm incision, loose packing and dressing applied. 
  • Rushed back to hospital 6 hours later due to presyncopal symptoms and worsening buttock pain. Dressing soaked through completely. 
  • Pale, slightly diaphoretic, anxious. 
  • O/E Wound continues to ooze with impressive flow. 
  • Surgical packing and pressure dressing applied. 
  • Tranexamic acid IV given. 
  • Blood loss diminished now but still ongoing. 
  • Severe pain with hip flexion and contraction of gluteus muscle (unable to stand up from chair). 
  • Hgb 90 
  • PT/ INR normal 
  • PTT 78sec 

Practice Considerations 

Acquired hemophilia is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors, most frequently factor VIII (FVIII). 

AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with new bleeding tendency or prolonged activated partial thromboplastin time who have no prior personal or family history of bleeding.  

In approximately 50% of AHA patients, especially elderly patients, autoantibody development against factor VIII is idiopathic [2, 26, 27], indicating that the acquired inhibitors develop via an autoimmune mechanism.  

Treatment  

During acute bleeding episodes, effective control of bleeding manifestations is the primary objective. However, the ultimate therapeutic goal is to eliminate the inhibitor and cure the disease. Hemostatic therapy with bypassing agents should be provided. Immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed. 

Hemophilia with Care Plan #2

23 y/o male presents with right sided abdominal and groin pain 

Pain started several hours after jumping on a trampoline with his friends 

He tells you he has hemophilia B 

  • Examination
  • Actions

Temperature 37.7oC 

Pulse 115 

BP 110/65 

Appears very uncomfortable. Unable to stand up straight or lie completely flat on exam bed due to pain 

Keeps both hips and knees in flexed position 

Reports “pins and needles” with altered sensation to anterolateral right thigh 

Guarding on palpation, no mass 

No swelling, warmth or bruising to abdomen or over groin 

Initially bloodwork: Hgb 117, plts 400, WBC 14.3, INR 1.2, aPTT 76sec 

Initial Management: 

Possible bleed must be on the differential given underlying hemophilia 

Confirm the type and severity of hemophilia and if bleeding is suspected, always treat first before initiating investigations/imaging 

This patient has a Factor First card stating he has severe hemophilia B (FIX level < 1%) and should receive recombinant factor IX (rFIX) concentrate for bleeding 

Per the patient treatment protocol, he is given rFIX concentrate 110U/kg IV push for suspected major bleeding 

Differential diagnoses at this point could include: 

Pulled groin muscle 

Hip joint bleed 

Iliopsoas muscle bleed 

Appendicitis 

Renal colic 

He is sent for CT abdo/pelvis that reveals a large right iliopsoas bleed 

Practice Considerations 

Hemophilia A and B are X-linked congenital bleeding disorders that occur due to deficiency in FVIII or FIX clotting factors respectively 

Hemophilia is classified based on severity of the clotting factor deficiency. Factor levels < 1% (<0.01U/ml) is considered severe disease, factor levels 1-5% (0.01 – 0.05U/mL) is moderate, and factor levels > 5% to 40% (>0.04 – 0.40U/mL) is mild 

Bleeding tendency correlates with degree of clotting factor deficiency and those with severe hemophilia can present with spontaneous as well as trauma-associated bleeding 

Severe hemophilia patients may be on prophylaxis treatment with regular clotting factor infusions to prevent/protect against spontaneous bleeding 

Timely evaluation and treatment of suspected bleeding is critical in hemophilia and patients should always be given clotting factor concentrate as soon as possible to prevent complications of uncontrolled bleeding (i.e. “treat first” or “factor first”).  

All hemophilia patients should be managed and followed by a comprehensive care hemophilia treatment centre (HTC). In Canada, hemophilia patients should be included in the national registry and all HTC-associated hemophilia patients should carry with them a “Factor First” card which states their diagnosis and treatment protocol for emergency bleeding. 

Treatment 

Iliopsoas bleeds: 

Do not miss this bleed! 

High morbidity and potentially life-threatening 

Requires aggressive treatment 

Physiotherapy is very important because inflammation from bleeding can cause fibrosis and muscle contracture 

Muscle dysfunction – high risk of re-bleeding 

May be misdiagnosed because pain can mimic 

Appendicitis 

Renal colic 

Hip bleed 

Hip or lower back arthritis 

Often no bruising or swelling superficially (deep muscle bleed) 

There may not be a drop in Hgb initially 

Exam findings 

Patient walks with limp, on toe, knee bent 

Pain in along iliopsoas bursitis distribution  

Groin 

Back 

Front of the leg 

Hip flexion contracture – unable to extend on affected side without arching the lower back 

Maneuvers that stretch the iliopsoas causes pain 

Red flags! 

If the patient complains of numbness, tingling, or pins and needles sensation 

If there is weakness on knee extension 

Suggests vessel or femoral nerve compromise 

Femoral nerve or vessels have been compressed or damaged 

Requires immediate attention 

replay 

Von Willebrand Disease (VWD) #3

31-year-old female G1P1 presents with heavy vaginal bleeding 6 days post-partum following an uncomplicated spontaneous vaginal delivery. 

Her flow has increased significantly over the past 24 hours. She has soaked through several heavy absorbency pads and is now using a towel. 

Past medical history: 

She tells you she has von Willebrand’s disease. 

In the past she has had problems with: 

Epistaxis requiring cautery 

Excessive bleeding for 4 days after wisdom teeth extraction 

Heavy menstrual bleeding 

Received DDAVP prior to lumpectomy for a benign breast lesion 

She did not require DDAVP or VWF concentrate with her delivery as third trimester VWF levels were above 75% (i.e. normalized)  

Her only medications are pregnancy multivitamins and tranexamic acid that were prescribed by her hematologist to take for 14 days post-partum 

Her Factor First card states she should receive DDAVP for bleeding

  • Examination
  • Actions
  • Temperature 37.1oC 
  • Pulse 115 bpm 
  • BP 100/65 
  • She appears pale 
  • Gyne exam – firm uterus with fundus below umbilicus, bright red blood and 5cm clots in the vagina 

Initial Management: 

  • Supportive management 
  • Investigations: 
  • CBC, type & screen, lytes, creatinine, INR, PTT, fibrinogen 
  • VWF levels (VWF:Ag, VWF:RiCoF activity, and FVIII activity) sent but will not return for a few days 
  • Old chart and hematologist notes reports type 1 VWD with baseline VWF:Ag 0.28 U/mL (28%), VWF:RiCof activity 0.26 U/mL (26%), FVIII activity 0.41 U/mL (41%) 

Results and Supportive Management 

  • Her bloodwork returns showing normal platelet and WBC count. Hemoglobin is 87. 
  • Creatinine, electrolytes, and INR are normal. 
  • aPTT is elevated at 38 seconds (can be seen when VWF and FVIII levels are low)

 Treatment 

  • The patient was given a dose of DDAVP 0.3mcg/kg subcutaneously followed by a second dose 24 hours later. VWF levels were re-sent after the second DDAVP dose and she was sent home on tranexamic acid 
  • 2 days later she returns to ED with recurrent heavy vaginal bleeding. 
  • A third dose of DDAVP is given. 
  • The post-second DDAVP dose VWF levels returned showing normal levels [VWF:Ag 1.13 U/mL (113%), VWF:RiCof 1.08 U/mL (108%), FVIII activity 1.50 U/mL (150%)] 
  • Continued bleeding with normal VWF levels should prompt investigations for other causes of bleeding (e.g. anatomic 
  • Gynecology is consulted and retained products/placenta evacuated from the uterus 

Practice Considerations 

  • VWD is the most common congenital bleeding disorder with a prevalence of 1:100 to 1:1000 
  • Bleeding symptoms can vary depending on severity and type of VWD 
  • Bleeding symptoms are commonly mucocutaneous (e.g. epistaxis, gingival, gastrointestinal, genitourinary, uterine/menorrhagia) and can occur with invasive procedures (dental extractions, surgery) and childbirth. 
  • Bleeding assessment tools (BATs) are helpful for objective evaluation of bleeding symptoms and should be used in the work up of possible VWD or bleeding disorders. (E.g. ISTH BAT, condensed MCMDM-1 VWD score – these scoring tools can be found on the WFH website). 
  • DDAVP increases endogenous release of VWF multimers from endothelial cells and is effective treatment in type 1 and some type 2 VWD. However, DDAVP testing for response prior to treatment is recommended as not all VWD patients have an adequate response to DDAVP. 
  • DDAVP can cause symptomatic hyponatremia especially in young children and elderly. Electrolytes should be monitored with repeated dosing (especially if given more frequently than q 24 hours) and patients should restrict fluids to ≤ 1500mL for 24 hours after DDAVP 
  • In those where DDAVP response is inadequate or unknown, VWF concentrate (e.g. Humate P, Wilate) is recommended 
  • Tachyphylaxis can occur with repeated DDAVP dosing given within a short interval (e.g. < 24 hours). Hematology should be consulted if initial doses are ineffective or more than 2 consecutive doses of DDAVP have been given. 
  • Use of antifibrinolytics (e.g. tranexamic acid) either alone in mild mucosal bleeding or as an adjunct to DDAVP or VWF concentrate for more severe mucosal bleeding is recommended.
  • DDAVP may be given subcutaneously or IV (in 50cc saline infused over 30mins) at a dose of 0.3mcg/kg 
  • It can also be administered intranasally as 150mcg/metered dose nasal spray, 2 sprays for adults, 1 spray if <40kg. Intranasal DDAVP dose for VWD should not be confused with the dose used for nocturnal enuresis (10mcg/spray). 
  • VWF and FVIII levels increase during pregnancy and can also increase during a stress response 
  • If levels normalize in the third trimester (VWF:RiCof activity >0.50U/mL, 50%), usually no primary hemostatic prophylaxis is given for labor and delivery.
  • Delayed post-partum bleeding can occur when VWF levels fall back to normal usually within the first week post-partum. 
  • Post-partum bleeding is reported in 20-25% of VWD women (vs. 1.3% in the normal population). 
  • Tranexamic acid prescribed for 14 days post-partum is usually effective at preventing this however more significant bleeding may still occur.
  • DDAVP or VWF concentrate maybe required to control bleeding.
  • If there is continued bleeding despite adequate VWD treatment (I.e. normal VWF levels), then other causes of bleeding (anatomical, retained products of conception) must be considered. 

VWD Case – Meningitis needing LP #4

  • 21-year-old female presents with severe headache, neck stiffness, photophobia and fever 
  • You are concerned about meningitis and would like to do a lumbar puncture for diagnosis 
  • Past medical history: 
  • She tells you she has von Willebrand’s disease. 
  • In the past she has had problems with: 
  • Epistaxis requiring cautery 
  • Excessive bleeding for 4 days after wisdom teeth extraction 
  • Heavy menstrual bleeding 
  • She does not have a medical alert bracelet or a Factor First Card on her. 
  • She does not recall what type of von Willebrand’s disease she has and has never been treated with DDAVP before. 
  • Examination
  • Actions
  • Temperature 38.9oC 
  • Pulse 105 
  • Respiratory rate: 24 
  • She lies on her side, curled in the fetal position and demonstrates signs of nuchal rigidity 
  • Several quarter sized bruises on her lower extremities, no petechiae 
  • Chest is clear, abdominal exam is benign 

Initial Management: 

  • Fluids and Tylenol as needed to treat fever 
  • Investigations: 
  • CBC, lytes, Creatinine, PTT, INR, blood cultures 
  • VWD studies: VWF:Ag, VWF:RCoF activity, FVIII level 
  • If there is no documentation of her baseline VWF levels or diagnosis, VWF levels should ideally be sent before initiating any treatment. 
  • However, the turn-around-time for VWD studies is generally between 1-2 days up to a couple of weeks depending on your local hemostasis laboratory and availability of testing. 
  • Decision for treatment in an urgent setting (bleeding, procedural intervention) must be made without these results. 

Results and Supportive Management 

  • Her bloodwork returns showing normal hemoglobin and platelet levels. WBC is slightly elevated at 14.1. 
  • Creatinine, electrolytes, and INR are normal. 
  • aPTT is elevated at 40 seconds. 

Treatment 

  • Treat as per usual the suspected meningitis with antibiotics before the lumbar puncture. 
  • In this case where the baseline VWF levels and response to DDAVP is unknown, VWF concentrate should be given prior to an invasive procedure such as a lumbar puncture. 
  • The aPTT is elevated on the baseline bloodwork which suggests VWF and FVIII levels <0.30 U/mL (30%). 
  • For lumbar punctures where there is a concern for epidural bleeding, targeting VWF and FVIII levels of >0.50U/mL (50%) is recommended. 
  • The recommended dose for VWF concentrate for severe bleeding or prior to invasive procedure is 60 RiCof units/kg IV. 

Practice Considerations 

  • VWD is the most common congenital bleeding disorder with a prevalence of 1:100 to 1:1000 
  • Bleeding symptoms can vary depending on severity and type of VWD 
  • Bleeding symptoms are commonly mucocutaneous (e.g. epistaxis, gingival, gastrointestinal, genitourinary, uterine/menorrhagia) and can occur with invasive procedures (dental extractions, surgery) and childbirth. 
  • Bleeding assessment tools (BATs) are helpful for objective evaluation of bleeding symptoms and should be used in the work up of possible VWD or bleeding disorders. (E.g. ISTH BAT, condensed MCMDM-1 VWD score – these scoring tools can be found on the WFH website).
  • DDAVP increases endogenous release of VWF multimers from endothelial cells and is effective treatment in type 1 and some type 2 VWD. However, DDAVP testing for response prior to treatment is recommended as not all VWD patients have an adequate response to DDAVP.
  • DDAVP can cause symptomatic hyponatremia especially in young children and elderly. Electrolytes should be monitored with repeated dosing (especially if given more frequently than q 24 hours) and patients should restrict fluids to ≤ 1500mL for 24 hours after DDAVP.
  • In those where DDAVP response is inadequate or unknown, VWF concentrate (e.g. Humate P, Wilate) is recommended. 
  • Tachyphylaxis can occur with repeated DDAVP dosing. Hematology should be consulted if initial doses are ineffective or more than 2 consecutive doses of DDAVP have been given.
  • Use of antifibrinolytics (e.g. tranexamic acid) either alone in mild mucosal bleeding or as an adjunct to DDAVP or VWF concentrate for more severe mucosal bleeding is recommended. 
  • DDAVP may be given subcutaneously or IV (in 50cc saline infused over 30mins) at a dose of 0.3mcg/kg. 
  • It can also be administered intranasally as 150mcg/metered dose nasal spray, 2 sprays for adults, 1 spray if <40kg. Intranasal DDAVP dose for VWD should not be confused with the dose used for nocturnal enuresis (10mcg/spray). 

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